Handbook Of Clinical And Experimental Neuropsychology 9780863775420

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HANDBOOK OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY

Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

Handbook of Clinical and Experimental Neuropsychology Gianfranco Denes Neurology Division, Ospedale Civile, Venice

Luigi Pizzamiglio University of Rome “La Sapienza,” Italy

First published 1999 by Psychology Press Published 2020 by Routledge 2 Park Square, Milton Park, Abingdon, Oxon OX14 4RN 52 Vanderbilt Avenue, New York, NY 10017 Routledge is an imprint of the Taylor & Francis Group, an informa business Copyright© 1999 by Taylor & Francis All rights reserved. No part of this book may be reprinted or reproduced or utilised in any form or by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying and recording, or in any information storage or retrieval system, without permission in writing from the publishers. Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. British Library Cataloguing in Publication Data

A catalogue for this book is available from the British Library Typeset by Facing Pages, Southwick, W. Sussex ISBN 13: 978-0-86377-542-0 (hbk)

Contents List of contributors

xi

Evaluation of the effects of treatments Advances in data analysis Acknowledgements

PART I: METHODOLOGICAL PROBLEMS IN NEUROPSYCHOLOGY 1. Neuropsychology: Introductory Concepts

3

2. Behavioural Methods in Neuropsychology

15

Giacomo Rizzolatti and Luigi Pizzamiglio

Maria Pia Viggiano Introduction Stimuli and presentation techniques Measures of performance Experimental paradigms

3. Electrophysiological Methods in Neuropsychology

15 15 27 30

33 35 37 39

4. The Evaluation of Experimental Data in Neuropsychology

57

69

Daniela Perani and Stefano F Cappa Introduction Anatomical imaging Functional imaging Conclusions

69 71 79 93

6. The Methodological Foundations of Neuropsychology

95

Giuseppe Vallar The neural basis of mental activity A simulation approach: Connectionist modelling The neuropsychological method Cognitive neuropsychology Some specific methodological problems Acknowledgements Notes

33

Luciano Mecacci and Donatella Spinelli Introduction The autonomic nervous system Retinal activity and eye movements Brain activity

Erminio Capitani and Marcella Laiacona Introduction Measurement Sampling: Group vs. single case studies Neuropsychological tests and diagnostic practice

5. Neuroimaging Methods in Neuropsychology

65 66 68

96 101 105 107 113 130 130

PART II: LANGUAGE DISORDERS 7. Development of the Concept of Aphasia

57 57

Guido Gainotti The principle of localisation and the associationistic model The noetic school and the unitary interpretation of aphasia

60 63 v

135 136 144

vi CONTENTS

Empirical classifications and Geschwind’s neo-associationist model 148 Luria and the concept of functional systems 150 Linguistic interpretations of aphasia 152

8. The Neurological Foundations of Language

Stefano F Cappa and Luigi A. Vignolo Introduction Neurological correlates of the aphasie syndromes Neurological correlates of aphasie symptoms Aphasia in special populations Functional mapping of the cerebral organisation of language in normal subjects Conclusions

9. Clinical Aspects of Aphasia

Anna Basso and Roberto Cubelli Definition of aphasia Why a diagnosis? Diagnostic criteria Conclusions

10. Phonological Disorders in Aphasia

Gianfranco Denes, Carlo Semenza and Emanuela Magno Caldognetto Introduction Production disorders Comprehension disorders The relationship between production disorders and comprehension

11. Lexical-Semantic Disorders in Aphasia

Carlo Semenza Introduction Semantics The lexicon: A general model The representation of complex words Comprehension and production in aphasia

155 155 155 164 166 169 177

181 181 183 185 193

195 195 200 210 214

215 215 216 217 223 225

Factors influencing retrieval and understanding of words Modality-specific aphasias Category-specific aphasias The question of multiple semantic systems Access (refractory) vs. storage deficits The central (semantic and conceptual) levels of representation

12. Grammatical Deficits in Aphasia

Gabriele Miceli Introduction Agrammatism as a production deficit Agrammatism as a deficit of central mechanisms Dissociations between production and comprehension deficits Analyses of grammatical production deficits Paragrammatic production Problems with research on clinically defined grammatical disorders Grammatical production deficits Grammatical comprehension deficits Anatomo-clinical correlates of grammatical disorders Conclusions Acknowledgements Notes

13. Disorders of Conceptual Thinking in Aphasia Luigi A. Vignolo Introduction History Revival of research in the 1960s Tentative hypotheses and recent research Conclusions Appendix: Practical implications

14. Acquired Dyslexias and Dysgraphias Gianfranco Denes, Lisa Cipolotti and Marco Zorzi Orthographic systems

228 231 233 236 237 239

245 245 247 248 251 251 254 255 258 264 268 269 270 270

273 273 274 277 281 286 287

289 289

CONTENTS

Acquired dyslexias Computational models The diagnosis of dyslexia Cognitive classification of the acquired disorders of reading Central dyslexias Peripheral dyslexias Models of writing Central agraphias Peripheral agraphias

290 298 300 300 301 307 310 315 317

Giuseppe Vallar The architecture of human memory Disorders of LTM: Amnesia Deficits of short-term memory Notes

321 321 327 358 368

PART IV: RECOGNITION DISORDERS 16. Agnosia

Ennio De Renzi Anatomo-functional organisation of the visual cortex Perceptual deficits Visual agnosia Tactile agnosia

17. The Neuropsychology of Music Anna Basso Normal subjects Brain-damaged subjects Single cases Music production Conclusion

371 371 372 374 403

409 410 412 412 413 413

PART V: MOVEMENT DISORDERS 18. Apraxia

Ennio De Renzi and Pietro Eaglioni Ideomotor apraxia

19. Constructional Apraxia

Dario Grossi and Luigi Trojano Definition Assessment ofconstructional abilities

434 435 437 438

441 441 442

PART VI: SPATIAL DISORDERS

PART III: MEMORY DISORDERS 15. Neuropsychological Disorders of Memory

Melokinetic apraxia Ideational apraxia Trunk apraxia Oral apraxia

vii

421 421

20. Visuospatial and Imagery Disorders

453

21. Unilateral Neglect and Related Disorders

479

Paolo Nichelli Spatial perception and its disorders 454 Optic (visuomotor) ataxia 461 Bâlint-Holmes syndrome 464 Right hemisphere developmental learning disability 467 Spatial memory and its disorders 467 Disorders of topographical orientation 471 Reduplicative paramnesia for places 472 Visuospatial imagery 474

Edoardo Bisiach Clinical manifestations Allied disorders Clinico-anatomical correlations The course of unilateral neglect Interpretation of the syndrome Spatial features Influence of stimulation Anosognosia Somatoparaphrenia Dyschiria and its interpretation Implications for cognitive sciences

479 481 481 482 482 487 489 490 492 492 493

22. Disorders of Body Awareness and Body Knowledge 497 Gianfranco Denes Introduction Clinical aspects Mechanisms underlying bilateral disturbances of body knowledge

497 498 502

viìi CONTENTS

Hemisomatoagnosia Somatoagnosic illusions and hallucinations Concluding remarks

504 504 505

PART VII: ATTENTIONAL DISORDERS 23. Neuropsychology of Attention

Carlo A. Marzi Introduction Level of selection Automatic and controlled processes One or many attentional systems? Acknowledgements

24. The Frontal Lobe

509 509 510 514 516 524

525

Pietro Faglioni Structure and connectivity of the frontal cortex 525 Functions of the frontal eye field and premotor cortex: Attending to the present 534 Functions of the prefrontal cortex: Planning for the future 547 Acknowledgements 569

25. Acute Confusional State

Carlo Caltagirone and Giovanni A. Carlesimo Introduction Clinical manifestations of the acute confusional state Etiological factors Neuropsychology Conclusions

571 571 572 574 576 578

PART VIII: SPECIAL SYNDROMES 26. Calculations and Number Processing

Gabriele Miceli and Rita Capasso Introduction The number processing system Calculation Other components

583 583 584 594 606

Calculation, number processing, and other cognitive systems Anatomo-clinical correlates Conclusions Acknowledgements Notes

27. Neuropsychology of Emotions

Guido Gainotti What are emotions? Theoretical and applicative aspects Characteristics of the emotional and cognitive systems The role of subcortical and cortical structures in the spontaneous expression and control of emotions Cortical regulation of the basic mechanisms of emotion Emotional disorders in brain-damaged patients Conclusions

28. Interhemispheric Disconnection Syndromes

Giovanni Berlucchi and Salvatore Aglioti Introduction Historical development Symptomatology Temporary unrelated symptoms Mind and consciousness in the split brain

29. The Neuropsychological Approach to Consciousness Edoardo Bisiach Preliminary definitions Explanatory practicability The mapping of consciousness in the brain The diachronic articulation of consciousness The causal role of consciousness Neural mechanisms of consciousness Conclusions Acknowledgements Notes

607 608 610 611 611

613 613 614 614 618 621 629 633

635 635 638 642 665 667

671 671 673 675 677 679 680 682 685 685

CONTENTS ix

PART IX: DEMENTIA 30. Dementia: Definition and Diagnostic Approach Hans Spinnler and Sergio Della Sala The meaning of the term “dementia” Neuropsychological taxonomy of the dementias Descriptive definition of dementia Operational definition of CPCD Diagnostic approach Conclusions

31. Alzheimer’s Disease

Hans Spinnler Introduction Memory disorders Deficits of the “instrumental” functions Deficits of the “control” functions Tentative general understanding of AD Diagnosis, contact with relatives, and ethical issues Acknowledgements

32. Non-Alzheimer Dementias

François Boiler and Silvia Muggia Introduction Degenerative dementias Dementias associated with “extrapyramidal” pathology Vascular dementia Dementias and cognitive disorders associated with infectious pathology Dementia of normal pressure hydrocephalus (NPH) Cognitive disorders associated with multiple sclerosis (MS) Dementia associated with metabolic and deficiency states Dementia and psychiatry Miscellaneous

689 689 690 691 693 694 696

699 699 713 724 732 741 744 746

747 747 748 756 761 764

34. Language Disorders in Dementia

Claudio Luzzatti Introduction Language modifications in the elderly Language disorders in Alzheimer’s dementia The cognitive neuropsychological approach to AD Language disorders and dementia of various aetiologies Primary progressive aphasia and dementia General conclusions Notes

769

PART X: RECOVERY OF FUNCTIONS

770

35. Recovery of Cerebral Functions

770 771 773

33. Slowly Progressive Isolated Cognitive Deficits 775 Sergio Della Sala and Hans Spinnler Overview

Introduction 775 Definition 776 Slowly progressive aphasia 778 Semantic dementia 781 Slowly progressive aphemia 784 Slowly progressive Gerstmann syndrome 788 Slowly progressive apraxia 788 Slowly progressive amusia 794 Slowly progressive prosopagnosia 795 Slowly progressive unilateral visuospatial neglect 796 Slowly progressive simultanagnosia 797 Slowly progressive isolated anterograde amnesia 799 Conclusions 805 Acknowledgements 807 Note 807

775

Anna Basso and Luigi Pizzamiglio Cerebral plasticity Neuropsychological disorders The prognosis Conclusions

36. Aphasia Rehabilitation Anna Basso A brief history

809 809 810 813 824 838 840 845 845

849 850 856 862 867

869 869

x CONTENTS

Effectiveness of rehabilitation A theory of rehabilitation Conclusions

37. Visual, Visuospatial, and Attentional Disorders

Pierluigi Zoccolotti Introduction Disorders involving reductions of the visual field Heminattentive disorder Constructive apraxia Basic attention disorders

870 872 873

875 875 876 877 882 883

General conclusions Note

38. The Rehabilitation of Memory

Giovanni A. Carlesimo Introduction A brief theoretical framework Methods of memory rehabilitation Effectiveness of rehabilitative methods Conclusions

References Subject index

885 885

887 887 887 888 889 896

899 1095

List of Contributors Salvatore Aglioti, Department of Neural and Visual

Ennio De Renzi, Neurological Clinic, University of

Sciences, Human Physiology Section, University of Verona, Strada le Grazie, 37134 Verona, Italy. Anna Basso, Neurological Clinic, University of Milan, Via Sforza 35, 20122 Milano, Italy a n d IRCCS S Lucia, Via Ardeatina 306, 00179 Roma, Italy. Giovanni Berlucchi, Department of Neural and Visual Sciences, Human Physiology Section, University of Verona, Strada le Grazie, 37134 Verona, Italy. Edoardo Bisiach, Lurago Marinone, 22070 (CO), Italy. François Boiler, INSERM Unit 324, 2 ter rue d’Alésia, 75014 Paris, France. Carlo Caltagirone, Neurological Clinic, University of Rome, Viale dell’Umanesimo 10,00144 Roma, Italy a n d IRCCS S Lucia, Via Ardeatina 306,00179 Roma, Italy. Rita Capasso, Neurological Clinic, Catholic University, Largo Gemelli 8, 00168 Roma, Italy a n d IRCCS S Lucia, Via Ardeatina 306, 00179, Roma, Italy. Erminio Capitani, Neurological Clinic, University of Milan, Via di Rudini’ 8, 20142 Milano, Italy. Stefano Cappa, Neurological Clinic, University of Brescia, Spedali Civili, 25125 Brescia, Italy. Giovanni A. Carlesimo, IRCCS S Lucia, Via Ardeatina 306, 00179 Roma, Italy. Lisa Cipolotti, Neuropsychology Department, National Hospital for Neurology and Neurosurgery, Queen Square, London WC13, UK. Roberto Cubelli, Department of Psychology, University of Padua, Via Venezia 8, 35100 Padova, Italy. Sergio Della Sala, Department of Psychology, University of Aberdeen, King’s College, Aberdeen AB9 2UB, UK. Gianfranco Denes, Neurology Division, Ospedale Civile, Camp San Giovanni e Paolo, 30122 Venezia, Italy.

Modena, Via del Pozzo 71, 41100 Modena, Italy.

Pietro Faglioni, Neurological Clinic, University of

Modena, Via del Pozzo 71, 41100 Modena, Italy. Gainotti, Neurological Clinic, Catholic University, Largo Gemelli 8, 00168 Roma, Italy. Dario Grossi, Department of Neurological Sciences, Frederico II University, Via S. Pansini 5, 80131 Napoli, Italy. Marcella Laiacona, Medical Centre of Veruno, Neuropsychology Unit, Neurology, S. Maugeri Foundation, IRCCS, 28010 Veruno (Novara), Italy. Claudio Luzzatti, Institute of Psychology, School of Medicine, University of Milan, Via Tommaso Pini 1, 20134 Milano, Italy. Emanuela Magno Caldognetto, Centro di Fonetic CNR, Largo Salvemini 5, 35100 Padova, Italy. Carlo A. Marzi, Department of Neural and Visual Sciences, Human Physiology Section, University of Verona, Strada le Grazie, 37134 Verona, Italy. Luciano Mecacci, Department of Psychology, University of Florence, Via san Niccolo’ 93, 50125 Firenze, Italy. Gabriele Miceli, Neurological Clinic, Catholic University, Largo Gemelli 8, 00168 Roma, Italy. Silvia Muggia, Neurological Clinic, University of Milan, Via di Rudini’ 8, 20142 Milano, Italy. Paolo Nichelli, Neurological Clinic, University of Modena, Via del Pozzo 71, 41100 Modena, Italy. Daniela Perani, Consiglio Nazionale delle Ricerche, Istituto di Neuroscienze, Via Olgettina 60, 20132 Milano, Italy. Luigi Pizzamiglio, Department of Psychology, University of Rome “La Sapienza,” Via dei Marsi 78, 00185 Rome, Italy a n d IRCCS S Lucia, Via Ardeatina 306, 00179 Roma, Italy.

Guido

XI

xii HANDBOOK OF CLINICAL AND EXPERIMENTAL PSYCHOLOGY

Giacomo Rizzolatti, Institute of Human Physiology,

University of Parma, Via Gramsci 15,43100 Parma, Italy. Carlo Semenza, Department of Psychology, University of Trieste, Via Università 7, 34123 Trieste, Italy Donatella Spinelli, Department of Psychology, University of Rome “La Sapienza”, Via dei Marsi 78, 00185 Roma, Italy a n d IRCCS S. Lucia, Via Ardeatina 306, 00179 Roma, Italy. Hans Spinnler, Neurological Clinic, University of Milan, Via di Rudini’ 8, 20142 Milano, Italy. Luigi Trojano, S. Maugeri foundation, IRCCS, Rehabilitation Center of Telese, Loc. S. Stefano in Lanterna, 82037 Telese (BN), Italy. Giuseppe Vallar, Department of Psychology, University of Rome “La Sapienza”, Via dei Marsi 78, 00185

Roma, Italy a n d IRCCS S Lucia, Via Ardeatina 306, 00179 Roma, Italy. Maria Pia Viggiano, Department of Psychology, University of Florence, Via san Niccolo’ 93, 50125 Firenze, Italy. Luigi A. Vignolo, S. Maugeri foundation, IRCCS, Neurological Clinic, University of Brescia, Spedali Civili, 25125 Brescia, Italy. Pierluigi Zoccolotti, Department of Psychology, University of Rome “La Sapienza”, Via dei Marsi 78, 00185 Roma, Italy a n d IRCCS S. Lucia, Via Ardeatina 306, 00179 Roma, Italy. Marco Zorzi, Department of Psychology, University of Trieste, Via Università 7, 34123 Trieste, Italy a n d Department of Psychology, University College London, Gower Street, London WC1E 6BT, UK.

Part I

Methodological Problems in Neuropsychology

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1 Neuropsychology: Introductory Concepts Giacomo Rizzolatti and Luigi Pizzamiglio

Therefore, it deals with one of the oldest and most basic scientific and philosophical problems: the relationship between mind and brain. The means used by neuropsychology to tackle the problem are not, however, the deductive ones of philosophy but those of the experimental sciences. Neuropsychology is an eminently interdisciplinary science, converging with neurology, neuroanatomy, neurophysiology, neurochemistry, psychology, linguistics, and artificial intelligence. It is difficult to say exactly when neuropsychology began. However, the Cartesian model posed the following problem for the first time with the clarity necessary for its verification and “falsification”. The brain is the site of the mind. However, it is also the point of arrival for sensory information and the point of departure for voluntary motor commands. Is it possible to conceive of the brain as a homogeneous structure, or does the dichotomy between neurological and psychic functions imply an anatomo-functional inhomogeneity? Given that there are receptive cortical areas and other efferent ones, is the remaining part of the brain homogeneous or can it be separated into areas with different functions? A scientifically

Although the historical priority of an idea or of a theory is always debatable, it is generally accepted that the first coherent conception of human and animal behaviour expressed in neurological terms was the Cartesian one. Figure 1.1 shows a graphic representation of the Cartesian conception. The nervous system is subdivided into two basic levels: a lower level, which can be assimilated in anatomical terms in the spinal cord and the brain stem, and an upper level, corresponding to the brain. Sensory information arrives at both levels. At the lower level it activates circuits, so that the organism responds to sensory stimuli with motor responses. This lower level is the level of reflexes. The sensory information that arrives in the brain is also transformed into motor commands. However, the sensorimotor transformation is not mechanical, as it is in the lower level, but occurs through the action of the mind. The latter creates a representation of the external world, stores sensations in the form of memories and decides how to act in the external world. Neuropsychology is the discipline that studies the processes belonging to the mental level in the Cartesian schemata through experimental means. 3

4 RIZZOLATTI AND PIZZAMIGLIO

FIGURE 1.1 The Cartesian model of the central nervous system

satisfactory answer to this question was given in the second half of the nineteenth century. The period extending from 1860 to 1900 is the period of the great neurological and neurophysiological discoveries. The empirical and conceptual bases of neuropsychology were laid down during these 40 years. Broca’s studies (1861a, 1863, 1865) showed that a correlation exists between language motor disorders and lesions of the left frontal regions. Wernicke (1874) localised sensory aphasia in the posterior part of the superior left temporal gyrus and provided a systematic picture of the aphasias. Development of Wernicke’s concepts brought Lichtheim (1885) to propose the anatomo-functional schema of language centres, which has constituted the base of classification of the aphasias up to the present time. In 1870 Fritsch and Hitzig demonstrated that electrical stimulation of an area in the frontal lobe produces isolated movements of contralateral limbs in the dog. This zone—the motor area—was soon defined in other mammals, including humans. The discovery of the motor area and the facility with which the experiment was replicated definitively defeated the antilocalisationist positions (Flourens, 1823) and opened the era of the electrophysiological study of the cerebral cortex in animals and in humans. Ferrier (1876) demonstrated the existence

of motor areas in the monkey and suggested that the parietal lobe has visual functions. Munk (1878) established that the visual functions are primarily localised in the occipital lobe. Wernicke (1895) demonstrated that the somatosensory and somatoperceptual functions are localised in the parietal lobe. Bianchi (1895) described the spatial hemineglect syndrome in monkeys and suggested that the frontal lobe is involved in processes of memory and learning. The century closed with Liepmann’s (1900a) description of various types of apraxia and the possible neuronal circuits underlying voluntary movements. The years stretching from the beginning of the 1900s to the end of the Second World War were less fruitful in terms of results than the preceding era. New discoveries were made, better descriptions and better localisation of syndromes were obtained, and the limits of the concept of localisation were debated, but the questions posed by researchers did not seem radically different from those posed at the end of the 1800s. Various factors concurred during this period of conceptual stagnation in neuropsychological research. The first was the success of the preceding era. Results of experiments on animals and clinical observation had shown that the brain was basically organised in a way rather similar to the nervous

1. INTRODUCTORY CONCEPTS 5

centres forming the lower level of the Cartesian model (spinal cord, brain stem). Also, in the cerebral cortex there were sensory areas, motor areas, and intermediate areas (associative) linking the sensory and motor areas. Why should the function of these circuits be described with concepts such as mind, attention, consciousness? A neurophysiological explanation could and should be sufficient. This point of view was reinforced by Pavlov’s (1927) experiments in Russia and Thorndike’s (1932) and Watson’s (1914) in the United States. If a slightly acid solution is placed in the mouth of a dog, it salivates. The response to the stimulus is a pure physical fact, so no mental explanation seems necessary. Now, if a sound is associated with the administration of the slightly acid solution, the animal will salivate when it hears the sound before, or also in the absence of, the administration of the solution. The response to the sound (conditioned response) follows precise laws as does the natural (unconditioned) reflex. Therefore, it is not logical to postulate two independent explanation systems for such similar phenomena. The turning point reached by psychology through the learning experiments freed it (and neuropsychology as well) from many of its problems. If attention does not exist, but is simply a verbal description of certain behaviours, there is

no sense in studying it, at least in neuropsychological terms. If there is no mental process during learning, and a certain nervous pathway is simply “reinforced”, the only real problem is that of localising the pathway or pathways involved in learning. Pavlov did not deny the dichotomy between the brain and the lower centres. According to his conception, learning is a specific function of the cerebral cortex. Therefore, the dichotomy between the brain and lower levels was accepted but was then resolved in terms of innate connections and learned connections. The Cartesian schema in Fig. 1.1 was substituted by that in Fig. 1.2. Once this schema is accepted, the task of the neuropsychologist is no longer that of explaining mental functions, which do not exist, but of localising the areas in which the associations responsible for the various behaviours occur. The strongly antimentalistic intellectual climate that characterised the first 40 years of this century changed progressively and radically after the war. The works of Hebb (1949) and Broadbent (1958) reinstated and gave scientific dignity to terms such as attention and “set” (predisposition to respond in a certain way). Moruzzi and Magoun’s (1949) experiments demonstrated that a precise neuronal substrate exists for attention, at least in its intensive dimension. Sperry’s (1976) experimental results

FIGURE 1.2

The Behaviouristic model of the central nervous system.

6 RIZZOLATTI AND PIZZAMIGLIO

and theories brought the concept of consciousness to the fore. The brain-mind problem reappeared, and solutions that implied a brain-mind interaction were proposed both in a materialistic (Sperry, 1976) and spiritualistic (Eccles, 1986) vein. In a decade, more or less coinciding with the 1970s, psychology was transformed from behaviourism to cognitivism. The development of machines that showed intelligent behaviour changed the way of tackling the study of brain functioning, passing from a passive attitude of observation to an active one of builders of robots with “mental” faculties. Modem neuropsychology was bom from the contribution of these new ideological tendencies and new scientific knowledge. Besides the ideological factors, which created a favourable situation for the development of neuropsychology, a series of factors linked to the progress of neighbouring disciplines favoured its growth. Progress in neurosurgery and new radiological and brain imaging methods permitted anatomo-clinical correlations that were inconceivable only 10 years before. New neurophysiological techniques made it possible to study neurone activity in nonanaesthetised animals with freedom of movement during the execution of complex tasks. Psychology offered methods and models of a complexity incomparable to the simple models borrowed from nineteenth-century psychology. Making use of these advances, neuropsychology assumed its individuality and independence, which increasingly separated it from clinical neurology. The term neuropsychology (Bruce, 1985), introduced in the 1950s, substituted the term brain pathology (Kleist, 1934a) or study of the higher nervous functions (Pavlov, 1927) and marked the birth of a new discipline, which was autonomous with regard to techniques and problems. A chronological description of recent neuropsychological discoveries is beyond the scope of this chapter. A brief history of neuropsychology, subdivided into its basic sections—cerebral localisation, hemispheric dominance, memory, aphasia, agnostic disorders—has been published by Benton (1988). The reader can find essential information there. However, there are two interesting examples of how the various disciplines

forming modem neuropsychology concur in the study of a neuropsychological problem. An example of the multidisciplinarity of the neuropsychological approach, which has relevance for the brain-mind problem, is that of neglect. A second example is the problem of hemispheric dominance. Neglect is a disorder characterised by the inability to perceive and respond to stimuli presented in a particular area of space. The presence of neglect, at least in its most serious forms, can be determined by observing the patient’s behaviour in carrying out normal activities. The patient appears to ignore the space contralateral to the lesion. If the physician speaks to the patient from this side he or she does not respond or look towards where the voice of the physician is coming from, turning around to the opposite side. Often, when eating, patients, take food from only half of the plate. If they have to make a drawing, they execute only the part ipsilateral to the lesion. Neglect can affect not only extrapersonal but also personal space. For example, patients can forget to wash the part of their body contralateral to the lesion, or forget to shave half of their face. They can forget to dress the half of their body contralateral to the lesion. Finally, even when they have no motor deficits, patients do not explore the space opposite to the lesion either with their eyes or by turning their head. More rarely there can be partial or total absence of contralesional limb movements in the absence of paralysis. For a complete description of the neglect syndrome see Bisiach’s chapter in this volume. What problems are posed by neglect? The first, common to all neurological syndromes, is the site of the lesion. This problem can be divided into two parts, one anatomical and one functional. Is the syndrome due to hypofunctioning or to nonfunctioning of the anatomically lesioned nervous tissue or to an alteration of other centres connected with it? In lower-level neurological syndromes, the anatomical explanation coincides with the functional one. For example, a lesion that causes flaccid paralysis affects (with very rare exceptions) the spinal motoneurones or their extensions. The lesioned mechanism is the conduction of the nervous impulses from spinal centres to the muscle. The situation is different when the lesion involves

1. INTRODUCTORY CONCEPTS

the higher nervous centres. In the case of neglect in humans, even if various cortical areas can be affected, the most frequent lesion is that of the right parietal lobe. How can this observation be explained? There are various possibilities. The first is that the neuronal substrate whose destruction produces the syndrome is in the right parietal lobe. This explanation seems to be the simplest and the most immediate. However, it is not necessarily true. In fact, it is possible that the information that is indispensable for awareness of contralateral space (lesioned in neglect) passes through the parietal lobe, but is used by other structures in the frontal lobe, in the cingulate gyrus, or even in the subcortical centres. In this case, the syndrome is due to a disconnection of the centres really responsible for the functioning of those that provide lower-order information necessary for obtaining this awareness. A third possible explanation is that the lost function in neglect does not result from the activity of a centre, but of an entire circuit, of which the parietal lobe is part. It is obvious that postmortem techniques and traditional radiological methods cannot answer these questions. They can only localise the site of the anatomical damage. The problem of functional localisation of the deficit will be clarified in the future when new methods of functional investigation of cerebral activity, based on measures of cerebral blood flow or on measures of cerebral metabolism, become more diffused and more precise. Naturally, attentive clinical observation should be added to this, with particular emphasis on atypical cases of neglect, which can provide hints about other areas involved besides the right parietal lobe. Once the centres whose lesion causes the deficit are identified, it becomes possible to investigate their functioning, with less indirect (and vague) observations than those made through their destruction, whether experimental or due to illness. The nervous system is a machine with the primary task of processing information. The most direct approach for discovering what is processed is to record the electrical activity of single neurones. Each neurone can be imagined as a microcircuit with various entrances and one exit. The recording of single neurones in certain conditions (for

7

example, in animals with freedom of movement) permits one to establish which are the entrances (that is, the type of information arriving at the neurone) and, correlating the discharge with the animal’s behaviour, which is the exit. The technique of microelectrode recording has been little used in patients, as the morbid situation rarely justifies its application. On the contrary, it has been largely used in animals, giving a very rich picture of how sensory information is processed by the nervous system. Neglect represents a typical case in which the microelectrode technique can be usefully employed to clarify a neuropsychological syndrome. In fact, neglect can be obtained in animals and the areas involved in the syndrome can be studied with the microelectrode technique. In the monkey, experimental neglect similar to that most commonly observed in humans (neglect of extrapersonal space) is obtained with frontal lobe lesions (area 8). Recording in this area, various types of neurones can be found, schematically divisible into three functional classes: neurones that respond to visual stimuli (visual units), neurones that are activated during ocular movements (motor units), neurones that respond to visual stimuli and are activated during ocular movements (visuomotor units). Recording from areas of the lower parietal lobe, anatomically connected to area 8, has revealed neurones with essentially similar characteristics, while in other parts of the same lobe the neurones respond to somatosensory stimuli and are activated during skeletal movements. Leaving aside the details of the neuronal properties of the areas whose lesion produces neglect (for a thorough treatment see Rizzolatti & Berti, 1990; Rizzolatti et al., 1994), what seems to be the main characteristic of these areas is the transformation of sensory information into movements directed towards a goal. Neurophysiological data are consistent with the clinical aspects of the syndrome. The clinical disorder is neither purely sensory nor purely motor. The neurones of the areas involved are not purely sensory and cannot be defined as motor. However, the problem still remains of why a lesion, which may even be very small experimentally, brings about global neglect of an area of space and not a

8 RIZZOLATTI AND PIZZAMIGLIO

sensorimotor deficit. Why is a monkey with a lesioned area 8 not only not able to move its eyes towards an interesting object presented in the contralateral space, but also does not react to emotional stimuli appearing in this space? Why does the destruction of a visuomotor centre accompany a deficit in awareness of the existence of the contralateral space? Obviously there is something in the syndrome that cannot be reduced to the function of neurones of the lesioned area, but requires a higher-order integration. The concept that the brain is an instrument that processes information is at the base not only of neurophysiology but also, and more explicitly, of cognitive psychology. Unlike neurophysiology, psychology makes no reference to cerebral areas or centres. The mind, which in some way coincides with the brain, is conceived as a set of structures, some in series, others in parallel, where information is represented in different forms. Rules exist for passing from one stage of representation to another. Although some cognitive psychologists consider the correlation between stages of psychological processing and nervous structures of little or no importance, the concept that the way in which psychological processes unfold depends strictly on the nervous structures at their base is being increasingly accepted (McClelland & Rumelhart, 1986). Two of the psychological concepts used in recent years to explain the deficits observed in neglect have been particularly successful. The first is that the basic deficit of neglect is attentional. The information that comes from the space contralateral to the lesion is processed normally along the various centres (or stages) that lead to conscious perception. However, the neurological lesion impairs an “attentional circuit”, localised in the parietal lobe and also including the frontal lobe and the cingulate gyrus. Without this circuit, spatial information does not become conscious, or at any rate is not usable in a conscious way. However, even in the absence of a lesion of the primary sense or motor pathways, the patient is not able to utilise this information appropriately, denies having perceived it, and does not react to it. A second interpretation is that the deficit is representational. The lesioned circuit (or stage) is

not responsible for focalising the images coming from the contralateral space, but is the place where spatial images are formed. The parietal lobe or the fronto-cingulate-parietal circuit represents the stage where the images of space, coming from the external world or from long-term memory, are organised to give rise to an analogous (pictorial) representation of the external world. It is beyond the scope of this introductory chapter to discuss whether these interpretations are correct. What is important to underline here is how the problem of spatial awareness, and thus of neglect, has developed from a problem of neurological localisation to become a problem concerning attention, mental representation, and the relationships of these “mentalistic” terms with cerebral neurophysiological organisation. The interaction among disciplines belonging to the neurosciences and cognitive disciplines has allowed for a new view of the problem without taking anything away from the richness of the phenomenon. A second example that shows the peculiarity and originality of the neuropsychological approach is hemispheric dominance. The concept of hemispheric dominance was bom in the last century from the need to schematise some important clinical-neurological observations made by Dax (1865) and by Broca (1863). The clear anatomical documentation that focal lesions of the left hemisphere provoke aphasie disorders in right-handed subjects, and the subsequent observation made by Broca that right hemispheric lesions generate aphasias in lefthanded subjects, suggested that there is an association between functional latéralisation for language and for manual control. The concept of hemispheric dominance was successively extended to other cognitive functions such as praxes (Liepman, 1900a) and the representation of body schema (Gerstmann, 1930), both linked to the left hemisphere. Data gathered since the 1940s has shown visuospatial and visuoconstructive disorders in patients with focal lesions of the right hemisphere (see Benton, 1988, for a historical reconstruction). The concept of hemispheric dominance, with reference to motor control and cognitive capacities,

1. INTRODUCTORY CONCEPTS

raised great scientific interest due to the establishment of a selective presence only in the human species. If some behavioural characteristics are specific to the species, they must present “a systematic relationship with identifiable states of organisation of the nervous system” (Berlucchi & Tassinari, 1987, p.84). Thus, the hemispheric asymmetry observed in the human species has made necessary an accurate comparison between behavioural characteristics in the various species and organisation of the nervous system. In this perspective, comparative studies (neuroanatomical, radiological, embryological, neuroendocrine, and paleoneurological) have been carried out in various animal species in order to interpret the meaning of hemispheric asymmetries in humans. Without going into the details of studies that will be illustrated in the following chapters, we will only comment on the complex confluence of multidisciplinary notions on this topic by examining motor and cognitive dominance separately. In humans, motor dominance and in particular manual dominance presents as a population characteristic and not as an individual variant. In other words, a proportion of people, variable between 90 and 98%, present right manual dominance; these proportions are largely independent of the populations and cultural factors considered (Warren, 1980); they can be documented through the study of paintings of ancient civilisations or the discovery of utensils with unimanual handles in historical periods going back to several millennia before Christ and even to prehistoric periods (Porac & Coren, 1981). Also, side preference is observable in very early periods of neonatal life (Michel, 1983). In mammals, in particular in anthropoid monkeys most similar to humans, a preference is found in the stable use of one limb in the same individual; but, unlike humans, this is distributed in equal proportions between the two sides of the body in each species. However, examples of lateralisations characteristic of an entire species exist in animals phylogenetically distant from humans; examples of these asymmetries are found in the fiddler crab and in several orthopterans (crickets) that produce their characteristic chirping by systematically rubbing one elytron on the contralateral one, which remains

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immobile. Another example is found in some types of passerines that produce their most modulated song in one of two laryngeal syringes and under the control of song nuclei in only one cerebral hemisphere. These examples of systematic asymmetry in various animal species do not speak in favour of a peculiarity only for the human species; at the same time, they allow for experimental investigation of the characteristics of the nervous system that can explain the functional significance of this organisation. Berlucchi and Tassinari (1987) observed that in all the animal examples cited, including humans, manual preference actually subserves a distribution of tasks between the two sides, which collaborate in the execution of a complex motor performance. Both in the case of bimanual actions, and in the use of elytrons or claws, one limb executes fine, precise, rapid, and phasic (dominant side) movements, while the opposite side maintains a stable position by means of tonic muscle contraction. From the anatomical point of view, it has been shown in many species of mammals that the control of fine movements is often supported by pyramidal neurones directly connecting cortical areas with peripheral motoneurones; motor synergies at the base of postural tone are more supported by pyramidal neurones with greater functional distance from peripheral motoneurones, as intermediate neurones interpose in the direct corticalspinal connections (Heffner & Masterton, 1983). Also, the pyramidal neurones that control the largest claw in the fiddler crab are of greater dimensions and have a larger dendritic tree than the corresponding neurones of the smaller claw (Young & Govind, 1983). Therefore, the motor preference of one side can be traced in part to structural differences of single neurones and in part to different organisational modalities of the nervous system (connections with greater or lesser functional distance between cortex and motoneurones). On the basis of these data, Berlucchi and Tassinari (1987, p.98) speculatively suggest that “in the genesis of the nervous system the differential innervation of neurones with different functional tasks are facilitated if these neurones are separated in space rather than mixed.”

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The basis of hemispheric latéralisation could, however, derive from a need for economy in the organisation of the central nervous system. Passing on to consider the cognitive functions such as language, praxis, visuospatial abilities, memory, etc., more than a century of clinical observations clearly show how unilateral cerebral lesions produce functionally different consequences depending on which hemisphere is lesioned. Comparative research, analogous to that illustrated for manual dominance, has also been carried out in the area of cognitive abilities. However, in this case, with rare and not completely convincing exceptions, lesions of one or the other hemisphere are followed by the same disorders in various animal species, including anthropoid monkeys. Therefore, the human species is the only one that has unilateral decision-making centres, from time to time allocated to one or the other hemisphere, with the probable advantage of making coordination more efficient between structures concurring in the organisation of complex adaptive behaviours. The presence of functional asymmetries in humans has induced searching for a possible structural substrate of this organisation in the human brain. An important step in this direction was made in Geschwind and Levitsky’s (1968) research: examining 100 human brains they found that the posterior and upper portion of the temporal lobe, the part called planum temporalis, was more developed on the left in 65 cases, and on the right in 11 cases. The presence of this anatomical asymmetry, in the Wernicke’s area indicated as basic for linguistic processes, raised great interest and allowed for enrichment of this first important result. First of all the macroscopic asymmetry revealed in autopsies can also be documented in vivo through the radiological study of the sylvian fissure (Le May & Culabras, 1972); the asymmetry of the sylvian course brings diversity to bone casts of the fissure and has therefore permitted the discovery of analogous findings in prehistoric craniums as well (cranium of Peking man, Le May, 1976). Galaburda and colleagues (1978) extended these results, specifying that differences in the extension

of the cytoarchitectonie areas of the region in question correspond to macroscopic asymmetries. Finally, the presence of temporal asymmetries was observed in several-week-old infants (Chi et al., 1977; Witelson & Pallie, 1973). Falzi and colleagues (1982) investigated the same problem in Broca’s area, which is also involved in linguistic functions; the macroscopic asymmetries between the left and right area presented with the same proportion described by Geschwind and Levitsky (1968) for the temporal planum. However, the suggestive similarity between functional and anatomical asymmetries should be considered with caution for two reasons: the first regards the finding of analogous temporal asymmetries in anthropoid monkeys which, as mentioned earlier, do not accompany corresponding functional latéralisations; the second regards the numerical difference between percent of anatomical asymmetries (about 65% of cases in all studies) and functional ones, which are much greater for language. Even with these uncertainties about giving significance to the data summarised up to now, in this context we need only recall the great interest and multidisciplinary effort produced by the development of the concept of hemispheric dominance. Returning to the proposal made by Berlucchi and Tassinari on manual dominance, it may be that also in the case of cognitive processes, the different way of processing information profits from a different functional organisation of the nervous substrates involved. The distribution of the cognitive processes in the two sides of the brain is advantageous for optimal functional performance, maintaining cerebral volume constant. These theoretical topics can be brought closer to the alternative way of conceptualising cognitive processes. Dichotomisations in terms of processes underlying these operations followed a first interpretation of the function of the left hemisphere as prevalently linked to linguistic capacities and the right one to spatial processing. Borrowing some concepts from the verbal labels of computer science, processing in series and analytical processing were adopted for some linguistic processes, while parallel processes and

1. INTRODUCTORY CONCEPTS

global processes were postulated for several spatial operations. The common element in these most recent formalisations of the problem of cognitive asymmetries is the emphasis placed on the different operative modalities with which various aspects of surrounding reality are processed. This explicit reference to the operational modality could require or make more economical a different organisational approach to the neurological structures involved. Therefore, the questions deriving from this move towards verifying whether differences actually exist; for example, in the way in which areas involved in different processes are connected, whether biological factors can be identified that are responsible for this organisation, and when these organisational needs occur during the course of ontogenetic development. Although there is no documentation of a different architecture in the connections between different areas of the two hemispheres, at least two research areas can provide indications about the nature of the biological processes underlying hemispheric differentiation and when they occur during development. These two areas are the behavioural study of subjects with numerical anomalies in sex chromosomes, and by recent suggestions regarding a possible relationship between sex hormones and cerebral development. The common basis of these two approaches is the notion that the two cerebral hemispheres do not mature in a symmetrical way. In fact, anatomical (Yakovlev & Rakic, 1966), behavioural (Corballis & Morgan, 1978) and electrophysiological (Thatcher et al., 1987) evidence indicates that the left hemisphere presents more precocious development than the right and, more in general, that, during the course of ontogenesis, critical periods exist during which one hemisphere shows maturational acceleration. These alternating increases in the two hemispheres can be observed until the end of maturation of the central nervous system. During foetal life, there is more precocious development of the left hemisphere, that is, of the hemisphere involved in verbal or analytical functions; the right hemisphere develops

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successively, which is in turn involved in the control of spatial and global functions. The presence of an excess or of a lack of sexual heterochromatin causes an alteration of the maturational rhythm of the left hemisphere and, as a consequence, of the pattern of latéralisation of hemispheric functions, besides a modification of verbal or spatial processing ability. In particular, a lack of sex heterochromatin, such as in Turner’s (XO) syndrome, brings about an acceleration of cell multiplication (Netley & Rovet, 1982) with resulting rapid development of the left hemisphere. The accelerated maturation of this hemisphere also brings about an extension in the right hemisphere of the organisational modality typical of the left hemisphere. As a consequence of this maturational perturbation, adults with Turner’s syndrome present normal linguistic ability accompanied, however, by a less asymmetrical representation of language, demonstrated by means of verbal dichotic stimuli (Netley & Rovet, 1982). Also the “invasion” of the right hemisphere by “linguistic” type organisational schema brings about a decrease in performance in visuospatial ability, repeatedly observed in this syndrome (Waber, 1979). Speculatively, the excess of heterochromatin present in Klinefelter’s (XXY) syndrome should slow down the development of the left hemisphere in critical developmental periods, leaving development of the right hemisphere unaltered. As a consequence, in individuals with Klinefelter’s syndrome good spatial reasoning capacity is observed, with a normal pattern of cognitive latéralisation, and reduced verbal reasoning ability (Rovet & Netley, 1979). However, this interpretation of the role of sex chromosomes in the development of hemispheric dominance (Levy, 1969) is inadequate for satisfactory explanation of the possible individual variations in the development of dominances in subjects with normal sex chromosomes. Geschwind (1984) and Geschwind and Galaburda (1987) proposed an interpretative mechanism apparently similar to that of Levy (1969) by identifying the biological factor responsible for modifications of the maturational course of the two hemispheres in level of production of testosterone in critical periods of

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cerebral development. In their model, an excess of testosterone in the first 3 to 4 months of foetal life causes a delay in maturational development of the left hemisphere, and a lack of this hormone produces the contrary effect. On the basis of this hypothesis, Hier and Crowley (1982) explained a decrease in spatial abilities observed in a group of patients with congenital hypogonadotrophic hypogonadism. However, this finding was not confirmed by Cappa and colleagues (1988) in an analogous population of subjects with congenital hypogonadism nor in a case of testicular féminisation. The hypothesis of a relationship between testosterone levels and development of spatial abilities linked to the right hemisphere does not therefore seem confirmed. However, these authors described a link between congenital hypoproduction (or insensitivity in the case of testicular féminisation) of testosterone and organisation of cognitive functions, in particular short-term memory, but without relation to hemispheric latéralisation. Today, the attempt to link genetic, endocrinological, and immunological knowledge to the development and organisation of the cerebral hemispheres is based on a very loose and highly imaginative grouping of facts that are still very distant. Even presentation of the hypotheses that have been formulated requires the use of figurative language, for example “invasion of the right hemisphere by linguistic functions”. The explanations deriving from it have more of a metaphorical flavour than of a causal sequence of events. It is also easy to predict that progress of knowledge in this area will be slowed down by the difficulty, or even impossibility, of using animal experimentation, given the lack of convincing cognitive asymmetries. In this line of research, the current explosion of neuroimaging studies has brought a series of behavioural observations to the focus of attention relative to possible differences in hemispheric latéralisation between the two sexes in the human species. Lateralised visual presentation of verbal and nonverbal stimuli showed a systematic superiority of one hemisphere over the other (respectively left and right for the tasks cited) in

males (Rizzolatti et al., 1971); this superiority was much less evident for females (Hellige, 1993; Pizzamiglio & Zoccolotti, 1981; Rizzolatti & Buchtel, 1977). Two recent brain-imaging studies have raised researchers’ interest in the possible different functional organisation of the brain in the two sexes. Gur and colleagues (1995) studied regional distribution of glucose metabolism (using the PET technique) in 61 normal adults of both sexes. In this study a largely superimposable profile of metabolic activity emerged for both sexes but, at the same time, several significant differences also emerged. In particular, males presented greater metabolic activity in the lateral and ventromedial regions of the temporal lobes, in the hippocampus, the amygdala, and the fronto-orbital areas. On the contrary, females presented more intense metabolism in the posterior and medial parts of the cingulate gyrus. These results on the metabolism of the temporo-limbic system and the cingulate gyrus have suggested the possibility that these differences are at the base of a different way of processing emotional experience. The same study also showed other hemispheric differences, independent of sex: metabolic activity of the associative cortical areas is prevalent in the left hemisphere, and the ventro-limbic and medialtemporal regions are prevalent in the right hemisphere. These differences between sexes and between hemispheres were observed in a rest condition. Therefore it would be interesting to study how this diversity changes during the performance of a mental activity. A second study showed sexual differences during the performance of linguistic tasks. Shaywitz and colleagues (1995) studied the level of activation of 19 males and 19 females during the performance of tasks of orthographic, phonological, and semantic recognition through the use of magnetic resonance with eco-planner. Tasks of phonological and semantic recognition activate both temporal (superior and medial temporal gyrus) and frontal (inferior frontal gyrus) areas: however, hemispheric asymmetries were shown in the two sexes only on the phonological task. In particular, males showed a strong activation of the left inferior frontal gyrus, and females a more diffused

1. INTRODUCTORY CONCEPTS

activation involving both left and right inferior frontal gyrus. On the one hand, this finding confirms numerous preceding studies indicating greater bilaterality in the representation of language in women (McGlone, 1980) and on the other it documents that this different hemispheric representation is specific for several components and cannot be extended to all aspects of linguistic processing. In conclusion, we believe that the two neuropsychological problems we have discussed represent clear examples of the complexity and multidisciplinary nature of modern neuropsychology. The following chapters will demonstrate the truth of this statement in greater detail. Before concluding, it is important to note that in contemporary neuropsychology two ways of approaching neuropsychological problems are present, which result in different descriptions of cerebral activities. One description has the concepts

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of cognitive psychology as its base; the other has neurophysiology and anatomy. It is possible that the two descriptions are intrinsically different and have no common base of reference. However, the recent development of techniques and of both psychological and physiological conceptions favour the opposite alternative. Neurones are not only generators of impulses, but inserted in a network they function as stages of progressively more complex information processing. On the other hand there is the concept that the implementation of psychological processes seems correlated with a more complex organisation of the nervous system. The possibility of a unitary description of neuropsychological functions in which the complexity of mental processes is brought out, simultaneously taking into consideration the specific, peculiar way in which these functions are executed, seems to be the most important (and most fascinating) task of neuropsychology at the end of the twentieth century.

Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

2 Behavioural Methods in Neuropsychology Maria Pia Viggiano

behavioural techniques in neuropsychology may be found in some chapters of the book edited by Hannay (1986), as well as in other specific contributions on tachistoscopic stimulation, dichotic listening, reaction times, etc., which will be quoted.

INTRODUCTION When the experimental method was adopted by neuropsychology around the 1960s the problem was to set up research conditions in which the parameters of stimulus presentation and method of data recording and analysis were established accurately. Some experimental sets, based on tachistoscopic visual stimulation or dichotic listening, became paradigmatic for a large number of neuropsychological studies. The experimental approach made it possible to compare the performance of large samples of brain-injured patients and normal subjects. This chapter will describe stimuli, presentation techniques, and experimental paradigms most frequently used in neuropsychology. Reference will be made to studies that have become a starting-point for further research, thanks to their methodological characteristics. A presentation will also be given of the most common problems that emerge with the various methodologies and the solutions adopted to overcome them. A detailed discussion of issues and methodological problems inherent in the use of

STIMULI AND PRESENTATION TECHNIQUES A wide variety of techniques have been used in neuropsychology, which differ both in sensory modality and complexity. One of the most critical problems from the methodological point of view is the lack of homogeneous criteria on the basis of which the complexity of stimuli can be graded. This leads to a certain idiosyncraticity of stimuli used by various investigations. However, the introduction of the computer made it possible to obtain easily reproducible standard sequences of stimulation, and it is now possible to repeat the same experiment in different laboratories. Two large categories of stimuli may be distinguished, meaningful and meaningless (Snodgrass, Levy-Berger, & Haydon, 15

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1985), and these categories can, in turn, be differentiated into visual stimuli, auditory stimuli, and tactile stimuli. Verbal stimuli form a category by themselves, but they will be illustrated in relation to the sensory modality of presentation, visual or auditory. Within each group of stimuli, there may be other differentiations, generally based on physical characteristics and complexity of processing.

Visual stimuli Meaningless visual stimuli (gratings, random patterns, etc.) have been used to study the processing of visual information independently of verbalisation and attribution of meaning. Meaningful visual stimuli (drawings of objects, faces, etc.) have often been used to study the relative information processing and the dissociation between the ability to verbalise the visual stimulus and the capacity to recognise its meaning, for example in the case of split-brain patients. The following account lists the visual stimuli that can be presented by means of slide projectors, tachistoscopes, oscilloscopes, TV monitors, and computers, and can be used in research based on experimental paradigms. Gratings and checkerboards. Gratings and checkerboards (Fig. 2.1) have been employed particularly in research on deficits in the primary processing of visual information due to brain lesions (Hannay, 1986). Gratings are periodic variations of luminance in space: light and dark bars, which alternate regularly. The number of bars contained in a grating may vary, making it possible to study the properties of the visual system in the analysis of spatial frequency (the number of cycles in one degree of visual angle). Gratings may be stationary, or presented by means of periodic variations in the spatial dislocation of the light and dark bars (the light bar becomes dark and vice versa). The temporal frequency with which the bars are alternated is also an important dimension of the visual stimulus. Moreover, the difference in luminance between the bars is another of the basic properties analysed by the visual system: the contrast is properly defined as the difference between the maximum value of luminance of one

bar and the minimum value of the other, divided by the sum of the two luminances. Contrast sensitivity is the reciprocal of the threshold of K, that is, the minimum value of contrast (K) at which a grating of a specific spatial frequency can be detected. In normal adult subjects, the relationship of contrast sensitivity and spatial frequency assumes the shape of an inverted U: at intermediate spatial frequencies (3-5 cycles/ degree), sensitivity is greater than for lower or higher frequencies. Gratings are very suitable for evaluating the integrity of basic visual processes (Spinelli & Zoccolotti, 1992). For example, many studies have demonstrated that in cases of cerebral lesion there may be selective losses of contrast sensitivity for limited ranges of spatial frequency, although the consequences of these deficits at the level of the processing of more complex visual information are not yet clear. Furthermore, no relationship has yet been found between the localisation of cerebral lesions and the range of spatial frequencies for which there is a selective loss of sensitivity (Bodis-Wollner & Diamond, 1976; Hess, Zihl, Pointer, & Schmid, 1990; Mecacci, 1993,1997). Checkboards vary in the dimensions of the squares and the temporal frequency with which the black and white squares alternate. Checkboards, like gratings, have been used in electrophysiological research to control the integrity of basic visual processes in neuropsychological syndromes (Vallar et al., 1991; Viggiano, Spinelli, & Mecacci, 1995), and in relationship to the area and the extension of the lesion (Halliday, 1993). Random patterns. The best-known series of random stimuli is the one produced by Attneave and Arnault (1956). Each stimulus is derived from a matrix of 100 X 100 dots chosen at random to delineate its perimeter (Fig. 2.1). The values of association and content have been measured for 1,100 stimuli of this kind(Vanderplas, Sanderson, & Vanderplas, 1965). These random patterns have also been used in studies with a lateralised tachistoscopic presentation (Hellige, 1978) and they have often been employed in research on brain-injured patients (McCarthy & Warrington, 1992). Other stimuli, derived from matrices made up of black or white

2. BEHAVIOURAL METHODS

FIGURE 2.1

Examples of visual stimuli.

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squares (Attneave, 1955; Kimura & Durnford, 1974) (Fig. 2.1) or of regular and irregular geometrical patterns (Bisiach, Capitani, & Faglioni, 1975; Kimura, 1963) (Fig. 2.1) have been used to study the effects of unilateral lesions on visual perception and recognition memory. Drawings. Outlines of common objects have been used in many studies. At present, a series is available o f260 drawings of objects for which measurements have been made of familiarity, visual complexity, imaginability, and agreement among subjects about the name to be attributed to each drawing (Snodgrass & Vanderwart, 1980) This series of drawings is also available in a version for computer presentation (Fig. 2.1). These drawings can be used not only to study disturbances of perception and recognition (Berti, Maravita, Frassineto, & Umiltà, 1995), but also in research on semantic categorisation deficits in brain-injured patients, and on the problem of the selectivity of such deficits for stimuli representing animate and inanimate objects ( Capitani, Laiacona, Barbarotto, & Trivelli, 1994; Laiacona, Capitani, & Barbarotto, 1993). Fragmented drawings. Another widely used type of stimulus in neuropsychology is represented by drawings from which fragments are missing, making them difficult to identify. Various studies have been carried out on the performance of patients with unilateral lesions in tasks of visual recognition, generally with more serious deficits in cases with right-side lesions. Generally the fragmented pictures of Street (1931) or Gollin (1960) are used. The previously mentioned drawings by Snodgrass and Vanderwart also exist in a series with different levels of fragmentation (Snodgrass & Corwin, 1988) (Fig. 2.1), which may be used to assess perceptual closure in brain-injured patients (Viggiano & Pitzalis, 1998). Faces. One subgroup of visual stimuli which represents a specific category of complex visual information is that of faces (Fig. 2.1). Several studies have been conducted in order to verify the superiority of one visual field (and the specialisation of the contralateral hemisphere) in the processing of faces, in normal and brain-injured subjects.

Studies on hemisphere specialisation in the identification of faces have employed unknown faces (for example, in the work by Rizzolatti, Umiltà, & Berlucchi, 1971), as well as familiar faces (politicians, actors, etc.; for example in the study by Marzi & Berlucchi, 1977), or the faces in the series prepared by Benton and Van Allen, which includes photographs taken from different angles and in different lighting conditions (Farah, 1990; Piischel & Zaidel, 1994). Performance in the processing of faces has often been compared with performance in the processing of verbal material, and differences have been interpreted with reference to various models of hemisphere specialisation (see the later section on tachistoscopic presentation). To make recognition more difficult, chiaroscuro faces prepared by Mooney (1957) have been used, as in the research by Milner, Corkin, and Teuber (1968) on the case of HM (Fig. 2.1 ), or faces filtered on the basis of spatial frequency content, as in the research by Sergent (1987). Sometimes performance in face recognition by prosopagnosic patients has been compared with perception of elementary stimuli such as gratings, in order to evaluate the specificity of the deficit in relation to the damaged cerebral area (Sergent & Signoret, 1992). In this kind of study, the details that can facilitate the recognition of single faces are eliminated. Special series of faces expressing different emotional states have been prepared for studies on the recognition of facial expressions of emotions (Buchtel, Campari, De Risio, & Rota, 1978; Ekman & Friesen, 1975; Hansch & Pirozzolo, 1980; Landis, Assai, & Perret, 1979; Pizzamiglio, Caltagirone, & Zoccolotti, 1989; Pizzamiglio, Zoccolotti, Mammucari, & Cesaroni, 1983). Chimeric pictures. A kind of visual stimulus that recurs in clinical and experimental neuropsychology literature is the “chimeric” picture (each stimulus is divided in half and the parts of different stimuli are recombined to create a new picture; Fig. 2.1). For example, in the work carried out by Levy, Trevarthen, and Sperry (1972), perception was studied in patients with section of the cerebral commissures, using a variety of stimuli (animals, flowers, faces, etc.) which were presented either in their original form or in a chimeric form. The

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chimeric stimuli were presented by means of a tachistoscope at the centre of the visual field, in such a way that each of the two parts stimulated only one hemifield, one half the left hemifield, and the other half the right one. After tachistoscopic presentation, subjects were shown a group of similar figures, and they were asked to indicate which of them they had previously seen. In patients with split brain, in whom the perceptual “completion” of the two halves was not achieved, the picture indicated was generally the one whose half had been presented in the left hemifield (right hemisphere) if the response was given by using the hand, or in the right hemifield if the response was verbal. The drawings of Snodgrass and Vanderwart (1980) have been used to obtain chimeric pictures, and to study the syndrome of unilateral neglect (Berti & Rizzolatti, 1992; Buxbaum & Brauch Coslett, 1994). Verbal stimuli. Verbal stimuli, presented visually, include letters, words and sentences. Most studies have used words, sometimes comparing the processing of meaningful and meaningless words. As regards meaningful words, a large literature exists, dealing with the characteristics that must be controlled for their experimental use. The most important of these characteristics are the following: 1. Frequency of use (for English, Thorndike & Lorge, 1944; Kucera & Francis, 1967: for Italian, Bortolini, Tagliavini, & Zampolli, 1972; Burani & Thornton, 1993; Thornton, Iacobini, & Burani, 1994: for other languages, Lesser & Trewhitt, 1982). 2. Mean age of acquisition: words are classified on the basis of the age of acquisition during development, with the result that certain words (for example, “mother”) are found to be learned before others (a list o f220 drawings with the age of acquisition of the relative names in English can be found in Carroll & White, 1973). 3. Length (Landauer & Streeter, 1973). 4. Degree of concreteness (concrete words compared with abstract words), imaginability (the extent to which a word evokes a corresponding mental image), and meaningfulness (number of associations evoked by the

BEHAVIOURAL METHODS

19

word), (a list o f925 English nouns together with the values of these three characteristics can be found in Paivio, Yuille, & Madigan, 1968). 5. Category of membership (a list of words divided by categories, such as fruits, birds, quadrupeds, etc., can be found in Battig & Montague, 1969; for Italian categories, see Capitani, Laiacona, & Barbarotto, 1993; Capitani, Laiacona, Barbarotto, & Trivelli, 1994; Laiacona, Barbarotto, Trivelli, & Capitani, 1993). See the publications by Capitani et al. for a list of the various characteristics of the words that can be associated with the objects to be named or described (for example, the drawings of the aforementioned series of Snodgrass & Vanderwart, 1980). This characteristic is relevant particularly in research on deficits of naming and semantic memory for limited categories of animate and inanimate objects. As regards meaningless words, there are various ways of generating this kind of verbal material. Generally, words have been generated that either conform to the graphemic and phonemic rules of English (“legal” words) or do not (“illegal” words). In lexical decision tasks, subjects must decide whether the stimulus presented to them is a word or not. In an attempt to study processes of decodification and memorisation of meaningless verbal material, experiments have also been carried out in which subjects had to learn and memorise meaningless words, with different degrees of pronounceability (Bisiacchi, Cipolotti, & Denes, 1989; Goodglass, Hyde, & Blumstein, 1969). Effects o f the physical characteristics o f stimuli. One important problem that arises in the choice of visual stimuli regards the characteristics of their presentation. The intensity, the duration of the visual stimulus, and the interval between one stimulus and the next have crucial effects on primary processing. Although duration is a very important characteristic for the identification of stimuli, it varies considerably from one experiment to another (although it is usually lower than 100-150msec, in order to avoid eye movements). It is possible that the disagreement between data referring to

20

VIGGIANO

hemisphere latéralisation in the processing of visual stimuli may largely depend on the use of levels of intensity and the duration of presentation of different stimuli (Sergent, 1983; Sergent & Hellige, 1986). Another important characteristic is the visual angle subtended by the stimulus. Although the size of the stimulus as a function of observer’s distance is an essential piece of information in order to know the extension of the retinal stimulation, this information is sometimes omitted. The visual angle can be calculated if the dimensions of the stimulus and the distance from the observer are known (one cm of stimulus at a distance of 57cm from the observer subtends a visual angle of about one degree). In research on hemisphere specialisation, the localisation of the stimulus in the visual hemifield also varies considerably in different studies: the stimulus is projected into the hemifield at a distance that varies from 1-2° up to 10° from the fixation point. Gradual and significant effects on performance depending on this distance from the fixation point may be found. Instruments fo r the presentation o f stimuli. In the past, simple and complex visual stimuli were generally presented by means of a slide projector or a tachistoscope, whereas nowadays computer presentations are generally used. In the study by Berlucchi, Rizzolatti, & Umiltà (1971), a slide projector was used with which it was possible to present stimuli with a total exposure duration of 100ms. The stimuli appeared in the left or right visual hemifield (5° to the left or to the right of the central fixation point). In other classic studies, such as that of Kimura and Durnford (1974), a typical tachistoscope with a mirror was used. This apparatus, in the version used for studies on the effects of latéralisation, consists of three fields or exposure channels, one for the fixation point, and the other two for the presentation of stimuli. Thanks to the mirrors, the three fields are superimposed and, depending on the lamp that illuminates one of the three fields, the subject sees that the fixation point is alternated with the stimulus presented in the field of exposure to the left or to the right of the fixation point itself. The exposure time of the stimulus in these classic experiments was between 10 and 150ms.

Lateralised tachistoscopicpresentation. The use of this technique has become very widespread in the research field on hemisphere specialisation in normal subjects and in brain-injured patients. Early studies on patients with “split brain” employed a projector or a tachistoscope with two channels to present a stimulus (for example, the word key case, or a chimeric face), the two halves of which appeared one on the left and the other on the right of the fixation point. If the task consisted of naming the stimulus, the patient generally named the half that appeared in the right visual hemifield (case for the word key case) and was transmitted to the left hemisphere (specialised in verbal functions). If the task did not require the verbalisation of the response, an advantage was found for the left hemifield (stimulus transmitted to the right hemisphere) (Sperry, 1968). The performance was tested in monocular vision (Levy, Trevarthen, & Sperry, 1972). The relationship between the hemifield stimulated, the type of material or task, and hemisphere specialisation was studied systematically in normal subjects starting from the early 1960s (several monographs and reviews are available: Bradshaw & Nettleton, 1983; Bryden, 1982; Davidson & Hugdahl, 1995; Hellige, 1983, 1993; Kim & Levine, 1992; McKeever, 1986). The early work concentrated on the specialisation of the left hemisphere and therefore on the advantage of the right hemifield in the processing of letters and words (for example, in the work of Bryden & Rayney, 1963, where the superiority of the right hemifield in identifying single letters was shown). Other studies aimed to show the superiority of the left hemifield for visual-spatial material which could be processed more rapidly and/or efficiently by the right hemisphere. The main problem that arose during these early studies was that of using stimuli that could not be verbalised and would thus not involve the functions of the left hemisphere. Other studies concentrated on the “shift” of advantage from one hemifield to the other (and thus from one hemisphere to the other), using the same kind of material that could be verbalised only for a limited range of values of their structural characteristics (for example, in tasks discriminating between lines with a different orientation: Fontenot & Benton, 1972; Um iltaetal., 1974).

2.

Rizzolatti, Umiltà, and Berlucchi (1971) found a clear difference between the two hemifields, by comparing performances in a task discriminating between verbal material (single letters) and visualspatial material (unfamiliar faces). This experiment is representative of many other studies on the lateralisation effect. By means of a projector, subjects were presented with “positive” stimuli (for example, the letters F and R, to which they had to respond by rapidly pressing a button) and “negative” stimuli (for example, the letters A and E). The exposure duration of stimuli was 100ms. Vision was monocular (the right eye for some subjects and the left one for others). Motor response was carried out either with the right or with the left hand in an equal number of trials, in order to balance the effects of manual preference in relation to the hemisphere involved. Results (the superiority of the left hemifield for the discrimination of faces, and of the right hemifield for the discrimination of letters) were not related to the hand used for the response. The difference in reaction times for the two hemifields (18.5ms less for the right hemifield in the case of letters; 15.5 ms less for the left hemifield in the case of faces) was used as a measurement of hemisphere specialisation (there is a more rapid “response” from the hemisphere contralateral to the hemifield stimulated and specialised for the material presented). This index proved to be more sensitive than accuracy (the number of correct responses or alternatively, the number of errors, in relation to the hemifield stimulated): the number of errors was, in fact, found to be the same for the two hemifields (for the problem of the relationship between reaction times or speed of response and response accuracy, see later). Starting from the 1970s, the tachistoscopic presentation of stimuli whose processing involved the one or the other hemisphere differentially was used in many neuropsychology studies applying experimental designs comparable to those adopted in normal subjects. Furthermore, different groups of patients, generally with unilateral lesions, were compared in order to verify the effect of the side of the lesion on performance (this kind of approach for the study of the processing of verbal information in the visual mode and visual-spatial information was also followed in research on the processing of

BEHAVIOURAL METHODS 21

auditory and auditory-verbal information, using the technique of dichotic listening, which will be illustrated later). As an example of the use of the tachistoscopic presentation for a comparison between groups of patients, the work of Benton, Hannay, and Varney (1975) on visual-spatial performance in patients with left- or right-side lesions and in normal subjects may be mentioned. The task consisted in identifying the slope of lines or couples of lines presented centrally. After an interval of 2 seconds from the presentation of the stimulus (which lasted 300ms) a second stimulus was presented for 6 seconds, showing the 11 possible slopes of the lines, and the subject had to indicate which one corresponded to the slope of the line or lines previously seen. The performance of patients with left-side lesions was in no way different from that of normal subjects, whereas that of patients with right-side lesions was significantly lower (in particular for the identification of the slope of pairs of lines). These results were in agreement with those obtained in normal subjects (Fontenot & Benton, 1972; Umiltà et al., 1974) as a demonstration of the specialisation of the right hemisphere for visual-spatial tasks. In the application of the tachistoscopic technique, in particular in research on lateralisation effects, various problems of methodological and procedural nature arise (Bradshaw & Nettleton, 1983; Bryden, 1982; Davidson & Hugdahl, 1995; Hellige, 1983, 1993; McKeever, 1986). Problems connected with the presentation of the stimulus and with some characteristics of the subjects are listed next. A special section will deal with the problems inherent in the measurement of responses, reliability, and validity of measure. 1. E c c e n t r ic it y o f th e s tim u lu s w ith r e s p e c t to th e

In order to ensure that the stimulus presented in one hemifield is projected directly to the contralateral hemisphere, the stimulus is placed at a certain distance from the fixation point. However, the distance between the fixation point and the stimulus may have a considerable effect on performance, because an extremely peripheral stimulus may prove to be too “degraded” perceptively. Furthermore, as the value of eccentricity varies considerably from

f ix a t io n p o in t.

22 VIGGIANO

one study to another, it is difficult to compare results, because the effects of the visual “quality” of stimuli interact with field effects. Usually, the distance between the centre of fixation and the side of the stimulus closest to the fixation point is about 4-5° and should not go below 2-1.5° (Sergent & Hellige, 1986). 2. Effects o f physical characteristics o f the stimulus. As has already been said, the effects of physical characteristics of the stimulus are important. In particular, the duration and the luminance of the stimulus have an important effect on performance. Below 100ms, there is an interaction between these two physical variables (Roscoe-Bunsen law), and consequently stimuli with a short duration and a high luminance correspond perceptively to stimuli with a long duration and a low luminance. Control of these variables is important in particular when it is desirable to underline the difficulty of the task by presenting stimuli with low luminance and short duration, bearing in mind that there may be considerable individual differences in the relative thresholds. In order to ensure that all subjects are placed in the same conditions of difficulty, it has been proposed to vary the values of a specific characteristic, for example, duration, until the subject reaches a threshold of recognition, say, of 75%. This level of recognition must be guaranteed to all subjects, determining a suitable duration for each of them (Hannay, 1986). A large part of the disagreement between results about effects of visual latéralisation might depend on the variety of values of physical characteristics of the stimuli in the various experiments. As the two hemispheres, according to Sergent (1982,1983), are sensitive to different ranges of values of the physical properties of visual stimuli (in particular in relation to spatial frequency), the same stimulus might activate either of the two hemispheres depending on the specific values of physical characteristics such as duration and luminance (this problem is discussed in detail in the special issue of Brain and Cognition, 1986, no. 2; see also Hellige, 1993; Grabowska & Nowicka, 1996; Christman, 1997; Mecacci, 1997).

3. Unilateral and bilateral presentation. In unilateral presentation, the stimulus appears in a random order either in the left or in the right hemifield. In bilateral presentation, two stimuli appear simultaneously, one in the left hemifield and the other in the right one. It has long been the object of discussion what the advantages and disadvantages of the two types of presentation are (Beaumont, 1982; Bryden, 1988; Kim & Levine, 1994). In bilateral presentation, there may be a bias of attention towards one of the two hemifields, which may annul the aims of the lateralised presentation. On the contrary, in unilateral presentation, the subject does not know in advance in which hemifield the stimulus will be presented. In some studies with a bilateral presentation, an arrow has been used, situated near the fixation point, indicating the hemifield for which the relative stimulus has to be reported (Schmuller & Goodman, 1979, 1980). 4. Monocular and binocular vision. Both monocular and binocular vision have been used with varying motivations at different times in various studies using tachistoscopic presentation—although the tendency is to prefer binocular vision, in order to balance the effects, due to differences of acuity between nasal and the temporal hemiretina. (Consequently, an advantage of the right hemifield might partly depend on the stimulation of the nasal hemiretina during vision with the right eye, and vice versa an advantage of the left hemifield might stem from stimulation of the left nasal hemiretina.) (McKeever, 1986). 5. Hand side. Several studies have examined the relationship between the hand used for the motor response (reaction times), the hemifield stimulated, and the hemisphere. In the uncrossed condition, the hemifield stimulated and the hand are on the same side; therefore the hemisphere controlling the hand also receives the information directly from the hemifield stimulated (right hemifield-left hemisphere / right handleft hemisphere). In the crossed condition, the hemifield stimulated and the hand are not on the same side, and the hemisphere that receives the

2. BEHAVIOURAL METHODS 23

information directly is different from the one that controls the hand (right hand-left hemisphere /left hand-right hemisphere). In the uncrossed condition, there is no need for interhemisphere transmission in order to produce the motor response (the same hemisphere receives the stimulus and produces the response); in the crossed condition, interhemisphere transmission is required (one hemisphere receives the stimulus and passes the information on to the other hemisphere, which produces the response). In an experimental design in which the two hands alternate in the same lateralised task, it is thus possible to study the interhemispheric transmission time (mean: 2-3ms), by comparing the times of the two conditions, uncrossed and crossed (Bashore, 1981; Berlucchi, Heron, Hyman, Rizzolatti, & Umiltà, 1971 ; McKeever, 1986). This problem has been extended to include the more general question of stimulus-response spatial compatibility, that is, between the hemifield in which the stimulus appears and the hand used for the motor response (Umiltà & Nicoletti, 1990). Considering, above all, individual differences in hand preference (see later), and in order to avoid false results due to an effect of the dominant hand in experiments with lateralised presentation, it is necessary that the execution of responses is balanced within the same subject, alternating groups of trials in which the right or left hand is used. 6. Hand preference and familial left-handedness. As regards the difference between right-handed and left-handed people, and the effects of the presence or absence of left-handed people in the

family of the subject in relation to performance in tasks with tachistoscopic presentation (as well as in dichotic listening; see later), there is an extremely large literature (Bryden, 1982, 1988; Davidson & Hugdahl, 1995; Hellige, 1993) (see Table 2.1). The superiority of the right hemifield for verbal material, and of the left hemifield for visual-spatial material has been confirmed in about 70-80% of right-handed subjects and in about 60-70% of left-handed subjects (the differences between the two groups of subjects are, however, generally lower for visual-spatial material; this finding can be explained by the lower degree of latéralisation of visual-spatial functions). Familial left-handedness has the effect of altering the differences between the two groups, for example, reducing the degree of advantage of the right hemifield for verbal material in right-handed subjects (McKeever, 1986). In order to avoid problems of methodology and interpretation, it is advisable, where possible, to prepare experimental designs in which at least the hand preference factor is balanced (using a similar number of righthanded and left-handed subjects). 7. Sex. There is also large literature regarding sex differences and their effects on performance in tasks with tachistoscopic presentation (effects that are also found for results obtained with dichotic listening). Classical data suggest lower effects of latéralisation in females than in males (McGlone, 1980). Like hand preference, sex represents an independent variable whose effects must be controlled in neuropsychological experimental designs. In

TABLE 2.1 Relationship between left (L), bilateral (B), right (R) hemispheric latéralisation and hand preference.

Right-handed Left-handed I

(Following Bryden, 1988)

V erb al F u n c tio n s

V isuospatial Fu n c tio n s

L a té ra lis a tio n

L a té ra lis a tio n

B

R

33

0

67

30

32

38

L

B

R

L

97 51

0 34

3 15

I

24

VIGGIANO

studies on normal subjects, it is possible to choose a relatively similar number of males and females; in neuropsychological research, the number of male and female brain-injured subjects may not be balanced, creating problems of statistical comparison and theoretical interpretation. 8. Eye movements. It must be guaranteed that subjects do not move their eyes during stimulus presentation, so that the portions of the two retinas projecting to the ipsilateral hemisphere are actually stimulated. To control eye movements and to eliminate, if necessary, contaminated trials, various methods can be used, including fixation by means of a mirror reflecting eye movements (Umiltà et al., 1978) or a telecamera, or else electroculographic recording (in this case the electric signals recorded indicate “false” responses: Butler & Norsell, 1968). Furthermore, the use of brief exposures of the stimulus, not more than 100-150ms, reduces the interference of eye movements (Pirozzolo & Rayner, 1980). To force subjects to stare at the centre of the screen, and not to move their eyes into the left or right hemifield, before the stimulus appears, subjects may be asked to identify the figure or the symbol that appears at the centre of fixation. It has been objected, however, that this task might involve the verbal functions of the left hemisphere, preactivating this hemisphere with respect to the material subsequently presented (with an increase of the advantage for the right hemifield; seeMcKeever, 1986).

Auditory stimuli Many kinds of auditory stimuli have been used in neuropsychological research: tones, words, sentences, musical sounds, etc. The evaluation of auditory deficits by means of audiometrie techniques and psychophysical methodologies has often been used to verify the presence of peripheral disorders in aphasic patients (Hannay, 1986; see Chapter 10 by Denes, Semenza, & Caldognetto in this book). The most widely used auditory stimuli in experimental research on disturbances of

auditory and, in particular verbal, information processing have been the following: 1. Lists of numbers and words transmitted in groups of three pairs (for example Kimura, 1967). 2. Consonant-vowel syllables, transmitted as a pair, in which only the consonant changes, (for example, /ba/ to the left ear and /ga/ to the right ear) (Shankweiler & Studdert-Kennedy, 1967); this type of stimulus reduces the effects of memory and semantic analysis compared with numbers and words, and makes it possible to study the phonological competence of the two hemispheres more directly. 3. Monosyllabic words (consonant-vowelconsonant) similar except for the initial letter, presented in pairs with a rhyming effect (for example, “coat” / “goat”, in which the first word is transmitted to the left ear and the second to the right ear, “pig” / “dig”, etc.: Wexler and Halwes, 1983). 4. Musical stimuli (strings: Gordon, 1970; tunes: Kimura, 1964). 5. “Environmental” noises (starting up the engine of a car, the sound of a toothbrush in contact with teeth, etc.: Curry, 1967; a telephone ringing, the ticking of a clock, etc.: Knox & Kimura, 1970). The presentation of auditory stimuli in neuropsychology has generally been carried out by means of the dichotic listening technique. Dichotic listening. The technique of dichotic listening was initially developed to study selective attention and it has gradually become a widespread tool to determine hemisphere functional specialisation in normal and brain-injured subjects (the most systematic description of the various issues related to this technique is in Hugdahl, 1988). In early experiments (Broadbent, 1958; Kimura, 1961), groups of three pairs of numbers (or words) were transmitted simultaneously to the two ears: one stimulus of each pair was directed to the right ear and the other to the left ear. After each group of three pairs, subjects were invited to repeat as many stimuli as they remembered in the order they chose. The typical result was that subjects repeated the

2.

numbers transmitted to the ear to which they paid more attention. In the condition of free attention, in which the subject did not have to pay attention to one of the two ears, subjects generally repeated first, or to a greater extent, the material transmitted to the right ear (Kimura, 1961). The advantage of the right ear for verbal material (letters, numbers, words) was explained on the basis of the following anatomicalfunctional aspects: the larger number of projection fibres from one ear to the contralateral hemisphere (in this case the “privileged” path is right ear-left hemisphere); the specialisation of the left hemisphere for the processing of verbal information; the partial or complete suppression of the input transmitted along the ipsilateral pathway (left ear-right hemisphere) by the “stronger” contralateral pathway. Similar explanations have been used to account for the advantage of the left ear (right hemisphere) for musical material and auditory stimuli like environmental noises, the emotional tone of language, etc., considering the superiority of the right hemisphere for this kind of processing. Various procedures have been adopted to evaluate the effects of dichotic listening. In early experiments, subjects were invited to recall stimuli after each group of three pairs; then, in order to reduce the possibility that subjects might shift their attention from one ear to the other during the presentation of the three pairs, the choice was made to present one pair of stimuli at a time, and invite subjects to recall them immediately. Another procedure consists in presenting a first pair of dichotic different stimuli and subsequently another pair of dichotic stimuli in which the same stimulus is transmitted to the two ears; the subject is then asked to indicate if a stimulus of the first series is present in the second (Kimura, 1964; Kimura & Folb, 1968). Or, a pair of stimuli can be transmitted and then a single probe stimulus follows; the subject has the task of deciding whether the probe stimulus is the same or different (verbally or by pressing a button to measure reaction times) (Sidtis, 1981, 1982) The widespread debate about results regarding the advantage of the right ear for the recall of verbal material presented dichotically essentially contrasts two hypotheses: one based on the aforementioned

BEHAVIOURAL METHODS 25

anatomical-structural model, and the other on the shifting of attention towards a specific source of stimulation, generally the one contralateral to the hemisphere specialised for the type of information that the subject is engaged in processing (for the various models introduced in order to explain the data of dichotic listening, see the reviews in Hugdahl, 1988; see also Bryden, 1982, 1988; Kim & Levine, 1992). Considering the enormous heterogeneity of the stimulus material used, the types of tasks, the types of measurements, the order and the mode of response, the various indices of latéralisation, etc., Bradshaw, Burden, and Nettleton (1986) called for a certain caution in interpreting the results of dichotic listening in order to determine hemisphere specialisation. One of the most recent studies on the reliability of dichotic listening (Jâncke, Steinmetz, & Volkmann, 1992) compared the performance of 52 normal subjects in four tests: recall of digits, presented in groups of three pairs each (the recall took place at the end of each group); recall of consonant-vowel syllables presented in pairs (the recall took place after each pair); detection of a consonant-vowel syllable presented at random in the series of pairs of syllables (the technique of “dichotic monitoring”: Geffen & Caudry, 1981); and recall of pairs of Morse signals. As the correlation between performances in the various tests was found to be very low, it is clear that the type of task significantly influences the performance in dichotic listening and the extent of the advantage of one ear compared with the other. The relationship between hand preference and the advantage of the right ear for verbal material has been studied by comparing right-handed and left-handed subjects in various tasks of dichotic listening. As can be seen from Bryden’s review (1988), in which the results of numerous studies were examined, and on the basis of other studies (see Table 2.2), the advantage of the right ear is present in a greater number of right-handed (about 81%) than left-handed (about 64%) subjects, even if the difference between the two groups depends largely on the kind of task. In many studies, the advantage of one ear over the other is determined by comparing the percentages of correct answers for the two ears. According to Wexler and Halwes (1983), the difference between the two ears must be

26

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TABLE 2.2 Percentage of right- and left-handed subjects having right ear dominant for dichotic verbal stimuli in different tasks. Task

Recall of lists1 Recall of lists2 Recall of single pairs1 Recall of single pairs2 Dichotic monitoring1 Dichotic monitoring2 Pairs of rhyming words3

R ig h t-h a n d e d

L e ft-h a n d e d

81.1 85 79.7 77 90.9 65.5 85

59.3 61 68.2 61 70.4 57.5 71

1Review by Bryden (1988) 2Jancke, Steinmetz & Volkmann (1992) 3Wexler & Halwes (1983)

determined statistically. The percentage of subjects presenting an advantage of one ear compared with the other varies depending on the level of significance chosen. The relationship with sex has been studied in order to verify the hypothesis of a different hemisphere asymmetry between males and females. On the basis of Bryden’s review (1988), the advantage of the right ear (left hemisphere) for verbal material was present in 75% of right-handed females and in 81 % of right-handed males (see also Hiscock & Mackay, 1985). Thus the advantage of the right ear seems to be associated more with hand preference rather than with sex. The technique of dichotic listening was applied in neuropsychology by Kimura (1961) to study hemisphere specialisation for verbal material in patients with unilateral temporal lobectomy. In order to verify the degree of reliability of the results of dichotic listening as an index of the dominance of the left hemisphere for language, Kimura compared the data of dichotic listening with the effects of an injection of sodium amytal. The drug was found to block the verbal functions in the hemisphere contralateral to the ear that presented an advantage in dichotic listening (the dominant hemisphere for language on the basis of dichotic listening was correctly predicted in 80% of cases). In a similar comparison between the results of dichotic listening and the effects of sodium amytal, Strauss, Gaddes, and Wada (1987) found that 86%

of subjects with language centres in the left hemisphere had an advantage of the right ear. Zatorre (1989), using pairs of rhyming words, found an advantage of the right ear in 33 (94%) out of 35 patients whose language was represented in the left hemisphere on the basis of the sodium amytal test, and an advantage of the left ear in all four patients with language centres in the right hemisphere. In the work by Hugdahl and Webster (1992) four patients with lesions in the left hemisphere (one patient was left-handed) were tested with the dichotic listening technique (pairs of consonant-vowel syllables). The reduction of the normal advantage of the right ear over the left ear was explained by the effects of the lesion in the left hemisphere. Grote et al. (1995) argue that data of dichotic listening, obtained statistically in relatively large samples of patients, should not be used directly as a generalised index of the hemispheric functional localisation of verbal functions, but that data referring to single cases, in which there may be remarkable individual differences, should also be considered, at least in a complementary manner. The technique of dichotic listening was also used in the study of cognitive functions of patients with split-brain (Milner, Taylor, & Sperry, 1968; Sparks & Geschwind, 1968). Results were interpreted as evidence of the anatomical-structural model: due to the section of the interhemispheric callosal commissure, only contralateral transmission was possible, and interhemispheric

2. BEHAVIOURAL METHODS 27

transmission was destroyed. For this reason, the information that arrived at the right ear could be transmitted to the contralateral left hemisphere and adequately processed, whereas the information from the left ear arrived at the right hemisphere and could not pass over from there to the left hemisphere in order to be processed (as happens in normal subjects). Thus, in situations of dichotic listening with competing verbal stimuli, callosal patients tend to have an advantage of the right ear to a greater degree than normal subjects. In fact normal subjects can partially pass on the material transmitted to the left ear, which arrives at the left hemisphere from the right hemisphere via callosal pathways. In the study of Sugishita et al. (1995), carried out on 5 patients with partial section of the callosum and 50 control subjects, it was found that only in the case of lesions to the splenium might a strong suppression of the left ear during dichotic listening of consonant-vowel syllables be found. In other patients, in whom the splenium was intact, it was possible for auditory information to be transferred from the left ear to the right hemisphere and from there, via the intact callosal connections, to the left hemisphere, with the result that the advantage of the right ear over the left one was not so evident as in cases with the section at the level of splenium. Besides research and diagnosis, the technique of dichotic listening has been employed to study the processes of recovery of cognitive deficits, generally verbal, following surgery and/or a rehabilitation programme. In some cases, a recovery of the advantage of the right ear for verbal material has been demonstrated in aphasic patients. In the study of Castro-Caldas, Guerreiro, and Confraria (1984), it was observed that only four out of nine aphasic patients displayed a recovery of the advantage of the right ear, which had been compromised because of a lesion. In the other five patients, no such recovery was observed. CT scans showed that the two groups differed in the site of lesions. The five patients in whom there was no recovery had lesions in the Heschl’s gyrus, and in the geniculo-temporal pathways, whereas there were no lesions in these pathways in the four patients who displayed a recovery (see also Hugdahl & Webster, 1992; Moore & Papanicolau, 1988).

MEASURES OF PERFORMANCE The performance of subjects in the tasks listed earlier is measured by evaluating the accuracy of responses (correct responses or errors), and recording reaction times. In neuropsychological research, the choice of these measures is often determined by the condition of the patient. For example, in the case of paralysis of an arm, the measurement of reaction times can be carried out only with the unaffected hand, without the possibility of balancing the trials with respect to the hemifield-hemisphere-hand relationship; in cases of aphasia, it is obviously impossible to ask subjects to produce accurate verbal responses. The main measures used in neuropsychological research are the following. Tachistoscopic presentation: Test—retest reliability o f measures. The limited number of studies dealing with the problem of the stability of behavioural measures (reaction times, correct responses, errors) obtained in tasks with tachistoscopic presentation have examined both the variation of measures themselves within a block of trials (in the same experimental session), and the variation between one session and another after an interval of days (Brysbaert & d’Ydewalle, 1990; Fennell, Bowers, & Satz, 1977; McKeever, 1986; Resnick, Lazar, Gur, & Gur, 1994). Generally, there is a greater correlation between the two or three sessions following the first one than between the first session and the following ones. This finding has been partly explained by effects due to familiarisation with the task. The recommendation is to administer a relatively high number of trials to the subject, in different blocks or in different sessions, analysing the stability between the measures obtained in different blocks or/and sessions statistically. If the subjects have performed different tasks (for example, a verbal task and a visual-spatial one), it may be interesting to compare the values of stability in the two tasks, in order to detect any differences not only in the field effects, but also in the stability of performance. Obviously, this aspect involves specific problems for brain-injured patients,

28

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for whom it may be more tiring to endure repeated long sessions. Correct responses and errors. A large number of neuropsychological research studies evaluate the performance of brain-injured patients by measuring the number of correct responses or errors produced during the clinical examination or experimental test. For example, in the study of Graf and Schacter (1985) on amnesic patients and normal subjects, the performance in tests of implicit memory (completion of fragmented words) and explicit memory (recall of words) was evaluated on the basis of the number of correct responses. In general, many studies on memory in normal and brain-injured subjects measure the number of correct responses, especially when recall is tested. When recognition tests are used, subjects may be asked to respond by pressing a button if they remember previously seeing or hearing the stimulus presented. The reaction time for correct responses may then be compared with the reaction time associated with errors in recognition. Indices of laterality (lateralised tachistoscopic presentation anddichotic listening). The choice of indices of laterality has been (Bradshaw, Burden, & Nettleton, 1986; Sprott & Bryden, 1983) and still is much debated. Although the simple difference (D) between the percentage (P) of correct responses (or errors) for the right side (r) and for the left side (1) D = Pr-P/

has often been used as an index, it is considered appropriate to correct the difference in relation to the overall performance achieved by each subject. Among the various correction formulas (Repp, 1977), the following formula is often used for correct responses (POC = percentage of correct responses)

POCnj( ~~

Pr

(Pr+P/)

and for errors (POE = percentage of errors)

POE =

d-PQ

(2-Pr-P/)

The laterality quotient (LQ) corresponds to the ratio between the difference between the two sides, right and left, and the sum of the two performances: LQ =

(r-Q (r+D

X100

Other indices of laterality include phi (Kuhn, 1973) associated with overall performance (Repp, 1977), and A, (Bryden, 1982; Bryden & Sprott, 1981; Brysbaert & d'Ydewalle, 1990; Sprott & Bryden, 1983), which is independent on overall performance. The various indices are closely correlated both among themselves and with overall performance, as has been demonstrated, for example, for dichotic listening by Hellige, Zatkin, and Wong (1981). Reaction times. The technique of reaction times has undoubtedly been the most widely used in experimental psychology and neuropsychological research in recent decades. It is based on the measurement of the interval of time between the presentation of a stimulus (visual, auditory, or tactile) and the execution of a response (generally pressing a button with one finger). The technique of reaction times has been applied with reference to different methods: the subtractive method, the additive method, and the double task method (Massaro, 1975; Snodgrass, Levy-Berger, & Hay don, 1985; Sternberg, 1969). The subtractive method determines the differences in the time of information processing in relation to the complexity of information itself and to requirements of the experimental task. The time taken to respond to the presentation of a stimulus (the condition of the "simple reaction time") is less than the time required in the condition in which one must respond to a particular stimulus, for example, a very intense flash of light, and not to another one, for example, a less intense flash of light ("choice reaction time"). The difference between the choice reaction time and the simple reaction time (subtraction method) indicates the time required by the increase in complexity of the information

2. BEHAVIOURAL METHODS 29

processing, passing from a simple process of detection of the stimulus to a relatively more complex process of discrimination between two stimuli. In the additive factor method, two or more factors or independent variables are manipulated, and one dependent variable (reaction time), or more than one, can be measured (for example, in psychophysiological research, it is possible to measure both reaction times and variations of electrophysiological indices). Using the additive method, interactions between independent variables can be revealed. For example, in research on hemisphere specialisation for visual material, there may be at least three factors: type of stimulus, hemifield stimulated, and hand for the execution of the response. By means of an experimental design of this kind, additive or interactive hypotheses may be made about the effect that the factors have on reaction times, and therefore about the time required for the information processing (“mental chronometry”). In the use of reaction times, the following problems arise (Snodgrass, Levy-Berger, & Hay don, 1985): 1. Anticipation of responses in simple reaction times, if the subject can foresee the moment of stimulus presentation (reaction times lower than 100ms may be considered as errors of anticipation; to eliminate this inconvenience, the interval between the warning stimulus and the test stimulus may be varied randomly, so that the subject cannot foresee the moment of presentation; this problem is not relevant for reaction times in a choice task, because the anticipations are randomly distributed among the various stimuli). 2. “Too long” reaction times (outliers), due to a variety of reasons (distraction, complex processing, uncertainty about the button to push), which involve a distortion of the subject’s mean. In order to avoid this problem, various expedients may be adopted: rejecting times that exceed a value fixed in advance by the experimenter (for example, one second); rejecting times that differ by more than two or three standard deviations from the subject’s mean, or substituting the mean with the median,

thus eliminating the effects of too long (and too short) times. 3. Relationship between reaction time and errors: speed of execution may penalise accuracy (with a consequent increase in the number of errors) and vice versa. Errors should not exceed 5% for any experimental condition. In order to avoid an increase in the number of errors during a session due to fatigue it is advisable, above all in research on brain-injured patients, not to go beyond 300 trials per session, distributing them into groups of 30 trials with brief intervals of about two minutes (McKeever, 1986). 4. Relationship between detection and criterion: some works on reaction times with lateralised presentation have applied the signal detection theory (Green & Swets, 1966) in order to determine the effects on performance of subjective criteria and instructions. In other words, it is possible to evaluate the sensitivity of the subject independently of nonsensory factors (Bryden, 1976; Hannay, 1986). The same approach has been followed for the study of recognition memory, for example in aphasic and non-aphasic brain-injured patients (Riege, Metter, & Hanson, 1980). All these problems are more complicated when reaction times are used with brain-injured patients: reaction times are globally longer, and the number of errors and anticipations increases. Thus, mental chronometry presents some specific critical aspects in neuropsychology (Milner, 1986). The lengthening of reaction times has been studied in detail in brain-injured patients, to verify whether it depends on the extension or the severeness of the lesion and on the type of task (Benton, 1986; Dee & Van Allen, 1973; De Renzi & Faglioni, 1965). Furthermore, an attempt has been made to verify the importance of the interaction between age and effects of the lesion, considering the known positive correlation between lengthening of reaction time and ageing (Hicks & Birren, 1970; Vrtunski, Patterson, Mack, & Hill, 1983). Some studies have pointed out differences in reaction times depending on the side of the lesion (Dee & Van Allen, 1973; Howes & Boiler, 1975), and the involvement in the lesion of one or two hemispheres (Newcombe & Ratcliff, 1979).

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Furthermore, it has been studied whether, in braininjured patients, a long sequence of trials produces a further lengthening of reaction times due to fatigue, or a decrease due to practice (Schweinberger, Buse, & Sommer, 1993). Various criteria have been adopted in connection with the correction of outlier reaction times, which are very frequent in brain-injured patients. Milner (1986) compared the effects of various calculation criteria on the results of simple reaction times, using visual stimuli with three levels of luminance in patients with callosal agenesis and controls: (a) calculation of the arithmetic mean excluding reaction times shorter than 150ms and longer than 1000ms (these “cleaned-up” reaction times are the basic data for subsequent analysis); (b) calculation of the arithmetic mean rejecting from the basic data reaction times that differ by more than three standard deviations from the mean; (c) calculation of the geometric mean from the basic data; (d) calculation of the harmonic mean from the basic data; (e) calculation of the median from the basic data. The analysis of variance results have been relatively similar for the five calculation methods, although the exclusion of the values that are too low or too high, or the calculation based on the median, produce more informative results.

EXPERIMENTAL PARADIGMS Various paradigms present in experimental psychology have been adopted in neuropsychology, among which the following are the most common. Simple task and choice task. Reaction times associated with simple tasks are obtained in a condition in which there is a single stimulus, to which a response is to be given (for example, pressing a button with the right hand every time a particular target stimulus appears on the screen in front of the subject, and not pressing it in response to other stimuli; the so-called go-no-go condition). In choice tasks, subjects must press, for example, a button on the right in response to a stimulus X and a button on the left in response to a stimulus Y. Brain-injured patients display a generalised delay

in simple reaction times, and this delay is considerably accentuated for choice reaction times. Furthermore, it has been found that the delay in choice reaction times is greater in cases of left-side than right-side lesion (Benton, 1986; Dee & Van Allen, 1973). Double task. In a double task, the subject is invited to carry out two tasks simultaneously (Gopher & Donchin, 1986). The two tasks may interfere with each other because they involve the same process or processing stage (listening to the news on TV and at the same time listening to music on the radio) or they require paying attention to two different tasks (listening to the news and typing out a text). The following is an example of a double task: a series of visual stimuli is projected and the subject’s task is to press a button at the presentation of a given target stimulus; the same subject is also invited to perform a second task at the same time as the first one (for example, counting backwards). One particular procedure of the double task method is that of the “secondary task”. A primary task, to which the majority of attention resources are dedicated in order to achieve an optimal performance, is joined to a secondary task, on the hypothesis that the latter will be carried out using the attention resources not engaged in the first task. The resources are thus distributed between the primary task and the secondary one. The double task method has been widely used in research on subjects’ ability to control and distribute their attention during the execution of two tasks. Interest has also focused on the way in which attention is distributed; that is to say, whether the two tasks are performed in a parallel way or there are shiftings in attention from one task to the other, thus presupposing a serial chaining. The results of these studies tend to show that the mind has limited processing capacities or resources, and that the subject’s performance in a double task depend on the characteristics of the task itself, whether the two tasks use the same resources or not. The relationship between performances in the primary and secondary tasks may be represented by a curve of the “performance operating characteristics” (POC) (Gopher & Donchin, 1986). This curve indicates that the engagement of resources in one task (with a relative increase in

2. BEHAVIOURAL METHODS 31

performance) makes the performance in the other task decrease proportionally. The paradigm of the double task has been applied in order to study the effects of hemisphere overloading. Kinsboume and Cook (1971) studied the effect of verbalisation on the simultaneous motor performance of the right hand or the left hand. Their results revealed that performance with the right hand was lower than that with the left hand, probably because the same hemisphere was involved in two tasks that interfered with each other (for the development of this kind of research, see Hiscock, 1986; Kinsboume & Hiscock, 1983). Masking. Experiments on the effects of masking have been conducted by means of tachistoscopic presentation: after presentation of the stimulus, for example a word, a second stimulus follows, composed of dots, gratings, etc., with the function of interfering with the processing of the first stimulus. This condition is called “backward masking”; however, the masking stimulus may also precede the target stimulus (so-called “forward masking”). By varying the time interval between a target stimulus and the masking stimulus, it is possible to measure the time needed to complete the processing of the first stimulus (Humphreys & Bruce, 1989). Posner paradigm. Subjects have the task of deciding whether two stimuli, presented simultaneously or at variable time intervals, are the same or different on the basis of certain characteristics; the aim is to establish the levels of information processing in relation to the physical characteristics of the stimuli, their cognitive meaning, and instructions. In the classic experiment of Posner and Mitchell (1967), the stimuli were letters of the alphabet which could be physically identical (AA, aa), differ physically but have the same name (Aa,aA), or be different both in their name and their physical characteristics (AB, ab). The task was to decide whether the two stimuli were “the same” or “different”, on the basis of one characteristic: physical identity, or the same name. Results indicated that the time required to compare the two stimuli on the basis of their physical characteristics was about 7 0 -100ms lower than the

time needed to compare them on the basis of their name. Two stages of processing could thus be distinguished, the first related to the analysis of the physical characteristics of the stimuli and the second to their meaning. Priming. Performance in a task, for example the recognition of a word or an object, is facilitated if the word has previously been seen. The effects of priming have been studied in particular in connection with tasks of explicit and implicit memory. Generally, a priming experiment consists of a study phase in which some stimuli are presented, for example words such as “TYPEWRITER”, “LAKE”, “ELEPHANT”, etc., and a subsequent test phase in which the subject is asked to recall the words previously seen, or fragments of words to be completed are presented, such as “T—EW—T-R”, or “-AK-”. Subjects are invited to complete the words on the basis of the words seen in the previous study phase (explicit memory) or to complete them freely, using words that come into their mind (implicit memory). Also in the latter case, albeit unconsciously, subjects often complete the fragments with words previously seen. Furthermore, in both cases, completion takes place more rapidly compared with completion of fragments belonging to words not previously seen. Priming experiments have also been carried out on neuropsychological patients in order to study whether a brain lesion produces differentiated effects on explicit and implicit memory, in agreement with the hypothesis of the existence of two memory systems (Tulving & Schacter, 1990). Graf and Schacter (1985) conducted priming experiments comparing the performance of amnesic patients with that of normal subjects. The experimental design included a study phase during which words like “MOTEL”, “ELEMENT”, etc. were presented, and a test phase in which some subjects had to recall the words seen in the study phase, while others had to complete fragments of words freely. Results showed that the level of performance of amnesic patients in the completion task (implicit memory) was no different from that of normal subjects. However, when amnesic patients were asked to recall the words previously seen (explicit memory), their level of performance

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was lower than that of normal subjects. The priming paradigm has been applied for the study of other neuropsychological disturbances, for example, unilateral hemineglect (Berti & Rizzolatti, 1992; Làdavas, Paladini, & Cubebi, 1993). Stroop test. As is known, the Stroop test reveals interference in the processing of incongruous information; it has been used to study performance in tasks that require a “global” or “local” processing of letters made up of elements that are congruous or otherwise. This version of the Stroop test is also known as the Navon paradigm (Navon, 1977). This paradigm has been used to verify the hypothesis that global analysis is carried out by the right

hemisphere and local analysis by the left hemisphere (Van Kleeck, 1989). For example, in the study of Doyon and Milner (1991), local processing was evaluated by asking patients to pay attention to the single letters that made up the large letter (Fig. 2.2), and to indicate as quickly as possible whether the letters presented were the same or different, compared with a target letter. Global processing, on the other hand, was evaluated by asking patients to carry out the same task, focusing their attention on the whole of the large letter, and ignoring the single components. A comparison between the performance of patients with unilateral left- and right-side lesions allowed the authors to verify the hypothesis of local-global hemisphere dichotomy.

FIGURE 2.2

Large letters (global level) created by small letters (local level) in a congruent (left side) and incongruent (right side) condition (Doyon & Milner, 1991).

3 Electrophysiological Methods in Neuropsychology Luciano Mecacci and Donatella Spinelli

between the two series of phenomena, we acknowledge that this method has a great meaning for psychology.

INTRODUCTION Psychophysiology: A historical overview

This perspective was later defined as “psychophysiology”, i.e. the investigation of effects produced by independent psychological variables on dependent physiological variables (Stem, 1964). Skin electrical activity was investigated in relation to psychological phenomena by the French physician Fere (1888) and the Russian physiologist Tarchanoff (or Tarkhanov, 1890). In particular, Tarkhanov observed that variations in skin electrical potentials might be generated even when external stimuli were absent, that is, following images and thoughts produced spontaneously by the subject. The “psychogalvanic reflex” became the most frequently investigated physiological response, in relation to emotions. A classic example are the studies on free associations by Jung and his coworkers collected in the second volume of Jung’s Works (Jung, 1907). The basic turning-point in the study of brain electrical activity was represented by Berger’s discovery of the human electroencephalogram

In the second half of the nineteenth century, a new perspective was developed in research on the physiological bases of psychological processes. This approach was different from other contemporary types of investigation, which were based either on electrical stimulation and ablation of cerebral areas in animals or on clinical investigation of brain-injured patients. The method was noninvasive and was based on the study of electrical activity recorded on the skin or scalp during psychological activity. The first interesting results from this approach were obtained by Russian physiologists. Danilevsky (1891, p.629) wrote that: the study of brain electrical phenomena represents a possible way for investigating the objective material processes which are the substrate of subjective, psychological phenomena. By knowing the existence of a regular, strictly connected relationship 33

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(Berger, 1929). Berger became interested in brain electrical activity as a consequence of his studies on the relationships between brain and mind (he wrote the book Psychophysiologie on this topic in 1921). He distinguished two groups of brain electrical waves recorded on the scalp: “alpha” and “beta” waves. In 1934, Adrian and Matthews showed the blockage or desynchronisation of the alpha rhythm when the organism passes from a state of relaxed wakefulness with eyes closed to a state of arousal with eyes open. Research on electrophysiological correlates of psychological processes was reinforced by the work published by Moruzzi and Magoun (1949) on the functions of reticular formation. In 1949 the journal Electroencephalography and Clinical Neurophysiology was founded. From then on, electroencephalography became the main technique for studying the wakefulness-sleep cycle and activation levels. The work by Aserinsky and Kleitman (1955) was also very influential, as it showed that rapid eye movements are present during the so-called paradoxical sleep when dreams are produced. In 1951, Dawson introduced a new technique that made it possible to obtain what was then called “averaged evoked potential”. If a stimulus was presented repeatedly and the brain electrical activity was simultaneously recorded, it was possible to compute the correlated averaged evoked activity. These potentials had already been described in 1939 by Davis, who observed that auditory stimuli produced remarkable voltage variations in the electroencephalogram, but the technique for extracting them by averaging became available only later. In addition to indices of cerebral and autonomic activity, muscular electrical activity was also soon considered a physiological index of psychological processes. In the works by Darrow (1929), Jacobson (1930), and Davis (1939), muscular electrical activity was correlated with “mental work” and performance level. Classical works on psychophysiology are collected in Porges and Coles (1976).

Psychophysiological investigation in neuropsychology Differences in the theoretical and methodological approaches between neuropsychology and

psychophysiology have probably impeded the application of electrophysiological techniques in neuropsychology. In the 1950s and 1960s, psychophysiology was influenced by the behaviourist model. Physiological responses were considered, in the same way as behavioural responses, as expressions of the organism’s activity in response to external stimuli (for instance, in Ax’s classic work in 1953, the physiological responses to stimulus-situations producing fear and rage were recorded). The mind and the brain were considered as a “black box”, and processes inside the box, such as sensory analysis, attention etc., were generally not investigated. Only later, in the 1970s, were electrophysiological data used as a tool to study the inner processes that precede behavioural responses. Moreover, psychophysiological research was generally carried out on healthy subjects and less on patients with neurological and psychiatric disorders (for more details on the theoretical and methodological principles of psychophysiology, see Coles, Donchin, & Porges, 1986; Martin & Venables, 1980). In contrast, the main interest of neuropsychology has always been the anatomy and the function of the central nervous system; thus, most research was devoted to the inside of the “black box”, which was ignored by psychophysiology until the 1960s. Furthermore, neuropsychology favoured the investigation of the central nervous system over the autonomic nervous system and the muscular system. Moreover, subjects were brain-injured patients, rather than healthy persons. These differences between the two approaches, and the fact that the equipment necessary for electrophysiological recording was rarely available in hospitals, might well explain why psychophysiological works with a neuropsychological perspective are relatively few and often not very relevant for understanding neuropsychological disorders. This situation has rapidly evolved in the last few years and the number of psychophysiological studies on neuropsychological themes has increased. Moreover, at present, there is a promising perspective of linking electrophysiological data with results gathered by means of the powerful new neuroimaging techniques such as PET and fNMR.

3. ELECTROPHYSIOLOGICAL METHODS

A general review of the applications of electrophysiological techniques to neuropsychological research is given in this chapter. As these applications are very heterogeneous, we have grouped them according to the psychophy siological indices investigated. Skin and heart electrical activity, eye movements, and brain activity recorded on the scalp are the most commonly used measures. Examples have been selected almost exclusively from studies on patients with brain lesions.

THE AUTONOMIC NERVOUS SYSTEM Electrodermal activity is probably the neuroautonomic function most used in psychophysiological studies. Electrodermal activity is associated with the functions of sweat glands, richly innervated by fibres of the autonomic nervous system. This activity is a complex reaction modulated by several control centres of the central nervous system, and in particular reflects the functions of the autonomic nervous system. Variations in electrodermal activity in relation to various sensory, cognitive, and emotional processes have been investigated since the end of the nineteenth century (Fere, 1888; Tarchanov, 1890). The term “psychogalvanic reflex”, introduced by Veraguth (1907), was used to indicate these electrodermal variations and acquired a large popular following. In current research, other terms are preferred in order to distinguish between the basic activity of the skin (tonic activity) and activity in reaction to stimuli (phasic activity). Moreover, a distinction is made in relation to the type of recording: recording of spontaneous variations in electric potential between two electrodes applied on the skin (endogenous variations or skin potential) or recording of skin resistance to a weak current between electrodes (exogenous variations or skin conductance). Electrodes are placed on the skin of the fingers, palm, or arm. Skin potential and skin conductance are measured in millivolts and micromhos/cm2, respectively (general reviews may be found in Andreassi, 1995; Edelberg, 1972; Martin & Venables, 1980; Prokasy & Raskin, 1973; Roy, Boucsein, Fowles et al., 1993).

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Cardiac activity is also a commonly used neuroautonomic index. Electromyocardic signals are recorded by skin electrodes placed close to the heart and on the arms. In psychophy siological research, the number of beats in the time unit or interbeat intervals (in msec or sec) are generally used. Other neuroautonomic indices are blood pressure and respiratory frequency (see reviews in: Andreassi, 1995; Brener & Connally, 1986; Cacioppo & Tassinary 1990; Obrist, 1981; Turner, 1995). Early research hypothesised that all neuroautonomic responses varied in the same direction as a function of activation. For instance, an increase in skin conductance and heart frequency was thought to be associated with an increase in the activation level. In the 1950s, the Laceys introduced the principle of “directional fractionation”, which indicates that the values of different neuroautonomic responses may increase or decrease differentially depending on the type of stimuli and tasks. In particular, when the subject’s attention is directed towards external inputs, such as visual or auditory stimuli, skin conductance increases while heart frequency decreases. On the other hand, when the subject is instructed to ignore external stimuli and concentrate on a cognitive task, such as mental computation, both skin conductance and heart frequency increase (Lacey, 1967). In the past, electrodermal activity has been studied mainly in the area of emotions; for example, see the works by Jung and co-workers on free associations collected in Jung (1907). In the 1960s, “perceptual defence” was investigated with these techniques in several works (Andreassi, 1980). However, arousal, orienting reflex, and emotional reactions are also studied today in both normal subjects and patients. One example of research in this sector with neuropsychological patients is related to the idea of hemispheric specialisation for emotional responses, an hypothesis proposed by Gainotti (1972). In a series of studies, autonomic indices (electrodermal activity and heart frequency) and behavioural responses (facial expressions and avoidance behaviour) were recorded during the viewing of film sequences with high or neutral emotional value. In patients with right brain lesions, variations in electrophysiological indices were not related to

36 MECACCi AND SPINELLI

the emotional content of films, contrary to what was found in control subjects and patients with left lesions. This result could not be due to a cognitive deficit, because patients with right lesions were able to describe and to understand the film content. Moreover, as all patients exhibited emotional facial expressions, they were actually able to express their emotion. However, avoidance behaviour (such as gaze-shifting during very difficult sequences) was present only in normal subjects and in patients with left lesions. Overall, these results were interpreted as evidence that patients with right brain lesions have a specific disorder of autonomic nervous reactivity to emotional stimuli, and that the right hemisphere plays a crucial role in the production of responses suitable for coping with emotional stimuli, such as avoidance behaviour and variations in neuroautonomic parameters associated with emotions (Caltagirone, Zoccolotti, Originate et al. 1989; Mammuccari, Caltagirone, Ekman et al., 1988; Zoccolotti, Caltagirone, Benedetti et al., 1986; Zoccolotti, Caltagirone, Pechinedda et al., 1993). These researches show the advantage of simultaneously collecting both behavioural and electrophysiological responses. Performances and concurrent physiological variations in a specific condition or task are documented, thus allowing more in-depth conclusions. Moreover, an interesting possibility offered by this approach is that of studying unconscious processes of stimuli in brain-damaged patients. Two examples of this will be presented, one regarding the study of heminattention (or neglect) and the other prosopagnosia. Hemianesthesia is commonly caused by defective sensory processing; however, unilateral neglect may also produce contralesional defects in the perception of tactile stimuli. In these cases it is difficult to separate the attentional deficit (heminattention) from the primary sensory deficit (hemianesthesia). Vallar, Bottini, Sterzi et al. (1991) used the electrophysiological technique to discriminate between these two alternatives in one case of right-brain damage with left neglect and left hemianesthesia. Somatosensory stimuli were delivered to the left and right hand. About 50% of the nonreported stimuli to the left hand produced skin conductance responses, indicating that the

early somatosensory processing of stimuli was not entirely disrupted. Thus, the patient’s hemianesthesia was due to a defective access of relatively saved early analysis to the conscious processes required for verbal response. Other studies showed a dissociation between recognition performance and electrophysiological data in prosopagnosic patients. The patients did not distinguish between familiar and unfamiliar faces and could not associate a correct name with a familiar face. However, electrodermal data gave evidence of some kind of discrimination without awareness (Bauer, 1984; Tranel & Damasio, 1985). In particular, in a study by Tranel and Damasio (1988), larger-amplitude skin conductance responses to familiar than to unfamiliar faces were recorded in four patients. On the other hand, none of the patients was able to give discriminatory verbal ratings of these faces. Autonomic responses proved discriminatory even for faces that the patients came into contact with only after becoming agnosic. The authors suggested that the processing responsible for formation and maintenance of a new face “trace” can be independent of conscious experience. Thus, information relative to faces would be submitted to normal processing, but the output of this processing would remain beyond awareness (see also Damasio, Tranel, & Damasio, 1990a). Another example of studies of neuroautonomic indices on patients further illustrates the potential contribution of this technique to the understanding of brain functions. Patients with ventromedial frontal brain damage may show severe defects in decision making and planning, especially evident in abnormal social behaviour. In these patients the autonomic responses to socially meaningful and emotional stimuli (such as pictures representing social disaster, mutilation, nudity etc.) were abnormal, while elementary unconditioned stimuli (such as loud noise) produced normal autonomic responses. It was proposed that, as a consequence of brain damage, social stimuli failed to activate somatic states at the most basic level. According to the authors, the presence of intact responses to unconditioned stimuli indicated that a different network exists to cope with stimuli that do not require the complex processing required by social

3. ELECTROPHYSIOLOGICAL METHODS

stimuli (Damasio, Tranel, & Damasio, 1990b). The ability to discern the outcome of social behaviour in terms of punishment and reward would depend on visceral feedback mediated through interactions between ventromedial frontal cortex and autonomic centres. This pathway would be disrupted in patients with damage to the prefrontal cortex (Bechara, Tranel, Damasio et al., 1996).

RETINAL ACTIVITY AND EYE MOVEMENTS Electrical activity of the eye is recorded in two different forms: electroretinogram (ERG) and electro-oculogram (EOG). ERG is generally picked up with a corneal electrode, which records the activity following a flash of light. This activity consists of various components which arise in different layers of the retina (i.e. photoreceptors, cells in the inner nuclear layer etc.). The first evidence from an electroretinogram was given by A.F. Holmgren in 1865, but ERG clinical applications were due to the pioneering work by Riggs (1941) and Karpe (1945). This technique is commonly used in clinical ophthalmology to assess retinal functioning. Simultaneous recordings of ERG and evoked potentials make it possible to have a complete evaluation of the functions of the visual system and to localise the site of the deficit (e.g. Maffei & Fiorentini, 1990). For detailed reviews on ERG, recording techniques and clinical application, see Ikeda (1993) and Halliday and Kriss (1993). EOG is based on the fact that the anterior part of the eyeball is electrically positive compared with the posterior part. When illumination is constant and the eyes are fixed straight ahead, a steady voltage is recorded from electrodes located on the periocular region (or on the cornea); if the eyes move, variations are recorded (EOG). Thus, the EOG is associated with the exploratory functions of eye movements (Carpenter, 1977). The EOG is often replaced by a nonelectrophysiological technique, based on infrared rays. This technique has been used to investigate visual perception, cognitive strategies, and reading

37

(e.g. d’Ydewalle & van Rengsbergen, 1993, 1994; O’Regan & Levy-Shoen, 1987; Rayner & Pollatsek, 1989; Yarbus, 1967). Most of the studies measure the number, amplitude (degrees), direction, and velocity (degrees/sec) of saccades, while the subject is performing a visual task. Recent technological advances make it possible to superimpose the pattern of eye movements on the visual scene, in order to study the subject’s scanpath. Next, some research will be reported to illustrate the variety of investigations on neuropsychological themes afforded by eye movement recording. In all cases the main information offered by this technique is an accurate description of exploratory behaviour. This reveals phenomena that would otherwise remain undetected, such as the dissociation between conscious perception of the stimulus and the ability to fixate it (see agnosia) or the use of different strategies in exploring the visual scene (see between-objects and within-objects neglect) or accomplishing visual linguistic tasks (see aphasia). Moreover, other phenomena already observed can be properly quantified, such as the presence/ absence of compensatory strategies in relation to the type of brain damage (see hemianopia and neglect).

Hemianopia In research on reading and visual exploration, eye movements have been investigated in patients affected by hemianopia. In a recent study on a large group, Zihl (1995a) showed that degree of reading impairment depended on the extent of visual field damage; patients with right-sided loss were more impaired. The amplitude of saccades was reduced and fixations were longer. Further, saccade length, which is typically very flexible in expert readers, seems to have a reduced variability in right hemianopic patients, indicating a sort of “automatic pilot” in their reading (De Luca, Spinelli, & Zoccolotti, 1996). Compensatory exploration strategies in a visual searching task have been shown in hemianopic patients: their eyes move to pick up information from the blind hemifield; scanning is normal, although in some cases it is slow (Zihl, 1995b). When hemianopia was associated with unilateral spatial neglect, no compensatory strategies were present (e.g. Girotti, Casazza, Musicco et al., 1983).

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Neglect Research on eye movements during reading in patients with neglect showed that the pattern is characterised by return sweeps with a landingpoint half-way along the line; then a series of regressive saccades followed until a reasonable continuation of the sentence is found, independently of the real beginning of the line (Kamath & Huber, 1992). Eye movement recordings were used to support the view that the ability to orient between-objects or within-objects can be independently damaged in patients with neglect. Scanning of simple visual scenes or line drawings composed of various objects were compared with scanning of one single face or object. The patients failed to move their eyes to locate objects positioned in the contralateral side of the scene; on the contrary, they were able to make contralesional saccades when looking at a single object, i.e. fixating both left and right eye of the face (Kamath, 1994). One patient with the symmetric defect has also been described. This involved the failure to scan the right side of individual objects, while scanning of the contralesional side of the visual scene was intact (Walker, Findlay, Young et al., 1996). Eye movements in patients with neglect have also been studied during sleep. During wakefulness, saccades towards the left were comparable to saccades towards the right; during sleep, saccades towards the left were almost totally absent. On the contrary, they were present in patients with right brain damage but without neglect. These results suggest that attentional areas damaged in neglect have control over rapid eye movement production during sleep (Doricchi, Guariglia, Paolucci et al., 1993). Improvement of neglect due to rehabilitative training did not affect REM asymmetry (Doricchi, Guariglia, Paolucci et al., 1996).

Agnosia In pioneering studies (e.g. Luria, PravdinaVinarskaya, & Yarbus, 1962; Tyler, 1968) of cases of simultaneous agnosia, eye-movement paths were reported to be disorganised with respect to the

typical pattern observed in healthy subjects. However, it is possible that in these cases brain lesions were very large, also involving oculomotor cortex and frontal and parietal lobes (see Girotti, Milanese, Casazza et al., 1982). On the other hand, Rizzo and Hurtig (1987) reported dissociation between the capacity to look at the stimulus and its conscious perception. The patients studied had lesions limited to the bilateral superior associative occipital cortices and were suffering from simultaneous agnosia, i.e. they complained that the objects in the visual environment would “disappear” from view. Eye movements were measured by EOG and showed normal fixation, normal tracking, and normal scanning of visual images. Thus, the processing was sufficient to permit accurate driving of oculomotor mechanisms, but conscious experience of the stimulus was intermittent.

Aphasia In aphasic patients, analysis of the patient’s gaze during reading may be more informative than a simple description of reading errors (see Huber, Luer, & Lass, 1988a, b). Distinct reading behaviours have been described in patients with Wernicke’s and Broca’s aphasia. In the former, saccades were very short, showing a kind of “step by step” reading, while in the latter, fixation times were longer and many regressions were present. Special strategies used by Broca’s patients in processing sentences were discovered. Moreover, by using pictorial material, aphasic patients were investigated in tasks involving recognition of semantic relationships between words, and recognition of images and sentences. Results suggested that the understanding of single information elements and the choice of problem-solving strategies were not grossly modified in patients compared with controls. However, difficulties were observed in aphasic patients. At the end of tasks they often gave incorrect responses and had very long reaction times. The authors suggested that difficulties depended on the necessity to integrate many decisions to solve the task. A behaviour typical of these patients was the repetitive control of relevant elements; however, the correct solution was not reached.

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Developmental dyslexia In dyslexics, eye movements in reading are altered, with longer fixation duration, shorter rightward saccades, and a higher number of regressions (e.g. Adler-Grinberg & Stark, 1978). In some cases, the pattern of eye movements was so altered, that it was proposed that the disorder can be considered one of the main causes of developmental dyslexia. This hypothesis was tested by studying eye movements in non-reading tasks in dyslexics. Results were contradictory: Pavlidis (1981) reported eye movement disorders both in reading and in non-reading visual tasks. On the contrary, many other studies (e.g. Olson, Kliegl, & Davidson, 1983) have shown normal saccades in non-reading tasks. This supports the view that the abnormality of eye movements is secondary to the linguistic problems.

BRAIN ACTIVITY Electrical brain activity is generally recorded by means of electrodes placed on the scalp. Sometimes, during surgical operations, intracranial recordings are also made. Electrical activity is recorded as electroencephalogram (EEG), evoked potentials (EPs), event-related potentials (ERPs), and slow potentials (SPs). In this review, EPs and ERPs will be considered. Only brief information will be given about EEG, brain mapping, intracranial recording, transcranial magnetic stimulation and magnetoencephalography. (For a discussion of the SP technique, see Birbaumer, Elbert, Canavan et al., 1990; McCallum & Curry, 1993.)

EEG The EEG is the recording of electrical potential variations generated by millions of cerebral neurones. These variations are associated with the wakefulness-sleep cycle, ongoing psychological processes, etc. To record EEG, several electrodes are usually placed on the head. To permit comparison of data from different subjects (with different head sizes), a standard system for placing electrodes on the scalp was adopted.

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Location of electrodes is based on the length of two reference lines measured in each subject: the inion-nasion and left-right ear distances (10-20 international system; Jasper, 1958). Electrodes located above occipital, temporal, parietal, frontal, and central areas are labelled O, T, P, F, and C, respectively. Even and odd numbers indicate right and left sides; Fz, Cz, Pz, and Oz are electrodes placed on the midline. Recorded activity is amplified and filtered. EEG rhythms are classified in relation to the frequency band of ongoing electrical potential oscillations (expressed in cycles/sec or Hz). The alpha rhythm, with a frequency between 8 and 13 c/sec and an amplitude of around 10 microvolts, is typical of a relaxed state with eyes closed. Opening the eyes, and also mental activity, produce blockage of the alpha rhythm (desynchronisation reaction) and presence of the beta rhythm, with a smaller amplitude and a higher frequency (between 13 and 35 c/sec). The theta rhythm, with a frequency between 4 and 8 c/sec and a large amplitude (up to 100 microvolts) is usually associated with sleepiness; the delta rhythm characterised by a very low frequency, less than 4 c/sec, and a large amplitude (about 100 microvolts) is recorded in deep sleep states. Since Berger’s (1929) early research on the human EEG, this brain electrical activity has been considered the main physiological index of psychological processes. A lot of work has been published on the relationship between EEG rhythms and sensory-motor performance, perception, conditioning, learning, memory, intelligence, etc. (see Andreassi, 1995). However, the EEG is less employed nowadays in psychophysiological research since the spread of the EP technique, which makes it possible to detect more precisely the correlation between brain activity and psychological processes. The EEG reflects the overall activity of the brain or of wide cerebral areas, and it is a general index of activation level. In the past, the EEG was an important means for localising brain lesions; for this purpose today it has largely been replaced by anatomical techniques, such as CT scanning and MRI. Description of the cellular basis, measurements, and correlates of EEG can be found in

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Barlow, 1993; Duffy, Iyer, and Surwillo, 1989; Fish, 1991; Pilgreen, 1995. In the clinical routine, searching for alterations of electrical activity is often performed through computerised EEG analysis. The computer, more efficiently and reliably than the human eye, divides the brain electrical activity into frequency domains; then it analyses the temporal consistency of this activity for each electrode, creates a map of the spatial distribution of the activity and, in some cases, performs a statistical comparison with normative data (Rossi & Tecchio, 1994). Thus, for the purpose of clinical diagnosis, quantified EEG is a more powerful instrument with higher reliability than the traditional EEG. Data on the use and validity of computerised techniques for EEG analysis in neuropsychology are growing. Advantages have been stressed (Chiappa, 1986; Duffy, 1986) and also critical remarks have been made (Epstein, 1994; Tyler, 1986). One typical example of the application of EEG in neuropsychological research is the study of the functional asymmetry of the two hemispheres. The prevalent electrical activation of one of the two hemispheres should indicate that it is involved in the ongoing process for which it is specialised. In patients with left brain damage and aphasia the activation of the two hemispheres during a verbal task was studied. Compared with controls, the right hemisphere appeared to be more activated. This sort of “compensatory” activation of the right hemisphere suggested that language recovery in patients with aphasia may be guided through a progressive involvement of the non-language hemisphere (see: Moore, 1984,1986; Papanicolau, Moore, Levin et al., 1987; Papanicolaou, Moore, Deutsch et al., 1988).

Evoked potentials (EPs) and event-related potentials (ERPs) Evoked potentials recording is based on the EEG technique with some modifications. A single EP is a very small signal, masked by the overall ongoing brain electrical activity (EEG), and it has to be extracted from this noise to become visible. This result is obtained by averaging. Averaging is carried out in the time immediately following stimulus

presentation and for the duration desired (e.g. one second). Stimulation is repeated many times (50-300), and each time the concurrent electrical activity is recorded and averaged. Averaging cancels waves not synchronised with the stimulus, while synchronised waves sum up. Thus the evoked electrical sign becomes evident. An example of the morphology of the final brain electrical activity is presented in Fig. 3.1. The latency of the peak is measured from stimulus onset. Positive and negative peaks can be well distinguished. Note that in the figure, positive is up; however, in the literature both positive up and negative up may be found. Evoked potential morphology is related to the physical characteristics of the stimulus, but may also depend on the tasks the subject has to accomplish. Barrett (1993) distinguishes between sensory EPs and cognitive EPs. Another widely used term is “event related potentials” (ERPs) for the entire class of non-spontaneous electrical potentials, distinguishing between exogenous (produced by external stimuli) and endogenous (produced by operations performed by subjects) components. Waves evoked by external stimuli are called exogenous (“obligatory”, “sensory”, “primary”); waves associated with cognitive operations are called endogenous (“cognitive”, “secondary”). According to the time course of the ERP, endogenous components are earlier, while endogenous components are later. In this chapter both terms will be used. When exogenous components have to be measured, a few electrodes (at least one active and one reference electrode plus the ground electrode) are placed on the scalp in appropriate positions. For instance, in the case of auditory stimulation, the active electrode is generally placed on the vertex; in the case of visual stimulation, electrodes are placed on the occipital lobes etc. However, different montages of electrodes are used by different laboratories. For instance, the reference electrode can be on mastoids, earlobes, Fz, etc. For investigations on brain-injured patients, the socalled Queen Square montage (from the name of a London hospital) is widely applied; a set of active electrodes are placed on the scalp and the reference electrode on Fz (for the techniques of recording and measuring, see Picton, 1988). This is much

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discouraged nowdays due to the fact that the frontal lobes are often activated by the sensory stimulus; thus, frontal leads are far from being neutral as an ideal reference should be. As a general rule, therefore, reference electrodes on the earlobe, mastoid, or shoulder are encouraged. When research is devoted to endogenous components, a larger number of electrodes are used, generally placed along a central line on Fz, Cz, Pz, and Oz, and laterally to left and right. Of course, more complex procedures for data analysis are required when several electrodes are used (see brain mapping). The reader interested in the literature on EPs and ERPs can consult the section “Evoked potentials”, as well as the Supplements and Handbooks, of the journal Electroencephalography and Clinical Neurophysiology entirely devoted to research carried out by means of this technique. Technical aspects may also be found in Brain Topography.

Relevance of EPs and ERPs for neuropsychological research It is generally assumed that a given number of morphological components, such as P I00, P300 etc., related to ongoing sensory and cognitive processes can be identified in the EPs. The different time onsets of these components tap the timing of the various sensory and cognitive processing.

Research should describe these components and localise their cerebral generators. Disentangling EP or ERP components corresponds to identifying the portion of electric wave (a peak) produced by a single source (see Naatanen, 1982). This task is not easy: a voltage peak may be the output of the activity of several generators, each involved in different operations, summed at the electrode. The method of separating (discriminating) different components summed up into the same peak, is based on the analysis of latency, on the amplitude distribution over the scalp, and on differential sensitivity to experimental manipulations; principal component analysis may also be applied (Rugg, 1992). In general, the larger the number of active electrodes scanning the activity of various brain areas from the scalp, the higher the chance to discriminate different components and their characteristics. Investigation of patients, particularly with focal brain damage, may make a remarkable contribution towards solving this problem. For instance, it may be found that a component is missing after a specific type of brain damage, suggesting that the injured area is relevant in producing such a component. On the contrary, it may rule out that one brain area is the main source for a specific component when the morphology (amplitude, latency) of the wave is not altered after the lesion. Thus, neuropsychological

FIGURE 3.1

Sketch of visual EPs. Main exogenous (continuous line) and cognitive (dashed and dotted lines) components are indicated. Note a family of negative (N) waves around 150-200msec, P300 and N400.

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research in the damaged brain may contribute to a better understanding of electrical phenomena in the healthy brain. However, other aspects are particularly relevant for neuropsychology. Disorders in brain activity are directly investigated instead of being deduced in relation to impairments in behavioural performance. In fact, while neuropsychological techniques investigate overt behaviour, EPs and ERPs reveal processing stages that do not have access to conscious experience and remain covert. This opens two possibilities. On the one hand, ERPs may reveal functional abnormalities even in the absence of perceptual impairment and anatomical damage. This was the case in studies on multiple sclerosis, where abnormalities of the visual ERP were documented despite normal visual acuity, visual field, and colour vision (Chiappa, 1983). On the other hand, in cases of defective perception, ERPs might show that stimulus processing can be preserved, at least in part (e.g. see the case of hemineglect). The technique has very good temporal resolution (in the order of milliseconds). The latency and the amplitude of components depend on the timing and synchronicity of firing of the neuronal pools underlying sensory and cognitive processing. In the next sections it will be illustrated that these processes (at least some of them) have been related to particular components. This makes it possible to localise the deficit at various stages of processing. Abnormalities of the various components may indicate disorders at various stages of processing (sensory, attention, memory, etc.). Finally EPs and ERPs are not invasive and there are no impediments for repetition of the test; thus they may be important for prognosis and monitoring of the illness. The main limits of the EP and ERP techniques are essentially the insensitivity in the spatial localisation of neural generators, and the great variability in the healthy population. A typical example of failure in spatial resolution is given by the so-called “paradoxical latéralisation”. It is generally assumed that maximal ERP amplitudes are recorded at the scalp electrodes closest to its source. However, it has been shown that a stimulus presented to

one visual hemifield evokes a paradoxically larger potential over the ipsilateral occipital scalp (Barrett, Blumhardt, Halliday et al., 1976; Blumhardt & Halliday, 1979). Such a paradox stemmed from the limited amount of recording electrodes and has been solved by mapping out the scalp distribution of hemifield VEPs and by tridimensionally localising their dipolar source within the calcarine cortex (see Onofrj, Bazzano, Malatesta et al., 1991). The spatial resolution may be improved by using special techniques for recording and data analysis utilising dedicated algorithms for Equivalent Current Dipole localisation (see brain mapping). However, not all processes are equally represented at the level of electrodes: processes occurring deep in the cortex and subcortical activity might not be measurable on the scalp. Overall, neural generators cannot be assessed on the basis of single ERP information, and additional information is required such as brain-damaged patients’ data, magnetoencephalographic data, intracranial recording, fMRI etc. Individual variations in the healthy population may be partly ascribable to differences in the anatomy of the cortex and its circumvolutions, as well as to conduction volumes (e.g. thickness of skull bones). This variability may be an obstacle for the reliability of between-comparisons in the patient population; thus, within-designs appear to be a better experimental approach in many cases (Barrett, 1993). However, in recent years, combined electrophysiological and structural approaches have partly overcome the individual anatomical variabilities by integrating EPs with MRI (e.g. Rossini, Narici, Martino et al., 1994; Rossini, Rossi, & Tecchio, 1996). Another point of interest concerns the duration of electrophysiological testing. It is assumed that EP and ERP components are stable over time, but this is just a necessary simplification of what really occurs from trial to trial. Indeed, during testing with patients one should expect remarkable fluctuations. Applying techniques of signal analysis, such as that introduced by Woody (1967), might reduce the testing duration. This might be an advantage for patients unable to hold their attention for long sessions.

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Finally, the usefulness should be stressed of methods for evaluating the reliability of the electrical signals recorded, such as the statistics developed by Victor and Mast (1991) or the measurement of the standard deviation of the amplitude and phase of the signal, and the simultaneous recording of signal and noise (at a temporal frequency uncorrelated with the stimulus) in order to evaluate the signal-noise ratio (technique developed by Porciatti, Burr, Morrone, & Fiorentini, 1992). These methods are particularly useful in research on patients, where signals are often weak and variable.

Sensory components EP and ERP morphology is characterised by a sequence of positive (P) and negative (N) peaks. The component’s latency is measured with respect to stimulus onset. Thus, P I00 indicates a positive peak about 100msec from stimulus onset. Sensory (or primary, exogenous, early, obligatory) components are present in the first 100-150msec. Auditory EPs (AEPs) are generated by auditory stimuli such as clicks, tones, words, etc. AEPs are characterised by a series of waves produced at subcortical (brainstem potentials) and cortical level. Brainstem potentials are recorded in the first 10msec and are used for the diagnosis of disorders in the auditory pathways. Subsequent components, produced at the cortical level, at middle (10-50msec) and long (100msec or longer) latency reflect the processing of physical properties of the auditory stimuli (frequencies, loudness, duration, etc.). Visual EPs (VEPs) are generated by visual stimuli such as flashes of light, gratings, checkerboards etc. VEPs are characterised by components produced at the cortical level (Fig. 3.1). The component most frequently considered is P I00; its amplitude and latency are modulated by the physical properties of a visual stimulus (such as intensity, duration, contrast, etc.). Somatosensory EPs (SEPs) are evoked by electric shocks of moderate intensity, generally applied to the wrist medial nerve. SEPs are characterised by subcortical components (up to N18, probably related to thalamus and sensory radiation activities) and cortical components with

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short (up to 30msec, generated at parietal, rolandic and frontal areas), middle (up to 70msec) and long (beyond 70msec) latencies. Two main types of EP recording are used. Transient EPs are recorded when relatively long interstimulus intervals are used. This should permit brain activity to return to resting conditions after each stimulus. Steady-state EPs are recorded when the stimulus rate is high. In this case, as the response becomes sinusoidal in shape, Fourier analysis is generally used for data analysis. AEPs, VEPs, and SEPs are widely used for diagnosis of neurological disorders. Overviews of the rich literature on sensory EPs and their use in neurological and psychiatric research can be found in Picton (1988), Regan (1989), Halliday (1993) and Rossini (1994).

Attentional modulation of sensory components The possibility of peripheral gating as a mechanism of attention in humans has been investigated by studying brainstem waves, the short latency components of the somatosensory evoked potential and ERG. Results have generally been negative (for a review, see Hillyard & Picton, 1987). However, more recently effects of attention have been reported on a variant of brainstem potential—that is, the frequency following potential (FFP), termed thus because its power-spectrum peak is placed very close to the stimulation frequency. FFP latency (latency is about 6msec) is shortened if subjects pay attention to the stimulus (Hoorman, Falkenstein, & Hohnsbein, 1994). On the other hand, many works have shown that cortical sensory evoked potential components are influenced by attention in auditory (Hillyard, Hink, Schwent et al., 1973; MeCallum, Curry, Cooper et al. 1983; Woldorff, Gallen, Scott et al., 1993; Woldorff, Hansen, & Hillyard, 1987), visual (Hillyard, 1993; Mangun, 1995; Morgan, Hansen, & Hillyard, 1996; Rugg, Milner, Lines et al. 1987) and somatosensory (Desmedt, Tran Huy, Bourget et al., 1983) modalities. However, negative results have also been reported (for example, see Linden, Picton, Hamel et al., 1987). Overall, consistent with the idea of a perceptual facilitation of the attended input, these data suggest that attention— and the

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related changes induced in the ongoing EEG—may modify the early cortical processing of the stimulus, an effect that is shown by modulation of the amplitude of the component itself. A different mechanism was proposed by Naatanen and Picton (1987) for the auditory modality. In this case, the enhancement of the N 1 component results from the effect of another negative-going wave (“processing negativity”, see next section) which overlaps in time with N 1. Some studies have tried to localise the early ERP attention effects. For instance, in the visual domain, studies with various techniques (scalp current density topography ERP, MRI, and cerebral regional blood flow), based on Posner’s cueing paradigm, have argued that the enhancement of P I00 evoked by inputs from pre-cued attended locations take place at the level of the extrastriate area (see review by Mangun, 1995). Effects of early sensory modulation in attentional tasks have also been shown in patients with brain lesions. Positive components with a latency of about 30msec (produced by the primary auditory cortex and areas 1 and 2 of postcentral gyrus) appeared to be disinhibited after a lesion in the dorsolateral prefrontal cortex (Knight, Scabini, Woods, 1989a; Yamaguchi & Knight, 1990). Further research confirmed that sensory modulation of the auditory cortex was impaired in patients with frontal lesions: P 1 amplitude, with a latency around 50msec, was not modulated by attention (Alho, Woods, Algazi et al., 1994). Thus, it was proposed that in healthy subjects these early attentional effects are controlled at the dorsolateral prefrontal level. The advantage of this early control in normal subjects would be to avoid processing of nonrelevant information. On the contrary, as a result of the chronic absence of this modulatory activity, all external events would appear equivalent and would not be filtered. It is likely that changes in the modulatory activity of the prefrontal cortex would contribute to attention disorders typical of prefrontal patients (Knight, 1991).

Cognitive components The main cognitive components will be briefly described; more information can be found in the reviews by Kutas and Hillyard (1984a), Hillyard

and Kutas (1983), Hillyard and Picton (1987), Picton (1988), Rugg (1992), Barrett (1993), Rugg and Coles (1995), Gevin and Cutillo (1995). As in the case of sensory components, cognitive components are indicated by referring to peak polarity and latency. However, whereas the latency label of sensory components is generally very close to the latency really recorded (that is, P I00 actually has a latency around 100msec, with variations of about 10msec, depending on stimulus features and individual variations), the latency values of the cognitive components vary much more, as an effect of cognitive tasks and individual characteristics. Thus, what is known as P300 may be recorded also at 600msec or later. It is possible to describe the time course of brain information processing on the basis of the latencies of ERP components. For instance, the semantic analysis reflected in a negative component around 400-600msec (N400) occurs later than the selective attention operations shown by negative components whose peak is around 200msec (N200). This temporal sequence does not necessarily mean that operations are performed sequentially: they might also be performed in parallel by distributed neural networks requiring that different time durations be completed. Components with a latency of less than 150msec are relative to primary analysis of stimulus features. Moreover, there is a negative wave (labelled processing negativity PN, or Nd negative displacement) which begins very early (5 0 -100msec) and lasts for several hundredths of msec. This component reflects the shifting of selective attention. For instance, in a task of dichotic listening where instructions are to pay attention to stimuli transmitted to one ear and to ignore stimuli transmitted to the other ear, processing negativity is larger for stimuli to which attention is paid (Naatanen, 1990). A set of negative waves with a latency around 200msec (N2) follows. These components emerge especially in an oddball task, where rare target stimuli are randomly presented within a series of more frequent and non-target stimuli; occasionally new stimuli (i.e. stimuli different from target and non-target) are also presented, without subjects having been previously informed of them. Two

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subcomponents have been described. The N2a component, also called mismatch negativity (MMN), is produced by novel stimuli irrespective of whether they are noticed by the subjects. N2a is thought to be an index of pre-attentive mechanisms of sensory memory and to reflect a system of controlling and evaluating variations of ongoing auditory information (e.g. Naatanen, 1992; Tervaniemi, Maury, & Naatanen, 1994; Tiitinen, May, Reinikainen et al., 1994). The N2b component is produced by rare target stimuli and its amplitude is inversely proportional to the stimulus frequency. Around 300msec, a positive wave emerges, the so-called P300 or P3, widely investigated by research on ERPs and cognitive processes. The peak latency of this component may vary between 300 and 800msec in relation to the type and/or difficulty of the task; in some cases, particularly in memory tasks, a different label is used, that is P600. In experiments using the previously described oddball paradigm a distinction was made between two sub-components: P3a, with short latency (250-550msec) in response to unexpected stimuli, novel enough to attract attention; and P3b with longer latency, associated with processing of target stimuli. Thus, the P3a component, larger over frontal areas, often following the N2a, is associated with the presence of a new signal, and is a marker of involuntary automatic attention (orienting response). Using another paradigm (a serial picture recognition memory task) it was shown that P3a is an index of a rapid working memory system. In this experiment, P3a amplitude evoked by a picture is enhanced, with respect to the first presentation of the same figure, only if it immediately follows the first trial. If a delay longer than four seconds is given, P3a amplitude is reduced to the value recorded in the first presentation. Thus, P3a would be an index of a frontally mediated rapid working memory system for stimuli held in memory for less than four seconds (Nielsen-Bohlman & Knight, 1994). In the same experiment, a clear dissociation was observed with the later component N400, not present at short delay and enhanced at long delay. This component results from the activity of limbic areas, and reflects long-term memory processes (see later).

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The P3b component (or P3), particularly large over the parietal midline, relates to operations necessary for processing target stimuli in the oddball condition. Although the meaning of P3 is debated (see the discussion by Verleger, 1988 and Donchin & Coles, 1988), this component is generally considered to be an index of processes associated with phasic voluntary attention and complex categorisation operations. Indeed, P3 peak latency correlates with the time required to categorise the evoking stimulus (Kutas, McCarthy, & Donchin, 1977). However, it seems that P3 characteristics are also partly determined by fluctuations in the arousal state of the subject due to various biological and environmental factors such as circadian rhythms, intake “common” drugs, e.g. caffeine, etc. (for a review, see Polich & Kok, 1995). Many experiments have shown that P3 is related to memory tasks. In Sternberg’s (1966) procedure, items are presented for memorisation and later an item is presented that the subject must classify as being part of the memory set or not. A positive potential is generated by the probe; its latency is about 400msec and increases with increased set size (e.g. Pratt, Michaelewski, Barrett et al., 1989). In word recognition memory tasks, ERPs show the repetition effect. Thus, after a study phase, old words (previously seen or heard by the subject) presented to the subject produce a phasic positive deflection with onset at 300-400msec, larger than that evoked by new words. The effect is larger over the left hemisphere and most marked at parietal sites and is closely tied to processes necessary for recollection (see a review in Rugg, 1994). Overall, the general finding is that more positive P3 is generally associated with more efficient memory. Most research on the negative component around 400msec is related to semantic processing, such as semantic priming (e.g. Rugg, 1985). N400 is produced by verbal stimuli incongruent at the semantic level with previous information (e.g. Kutas & Hillyard, 1984b). For example, the word “socks” will produce an ERP with a large N400 if this verbal stimulus follows the words “He spread the bread with ...”, while the word “butter” will not have the same effect because it is semantically congruent. The amplitude of N400 is inversely

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proportional to the coherence of the stimulus with the context. This phenomenon would not be confined only to the linguistic domain, but also to the cross modal conceptual domain (e.g. pictures: Nigam, Hoffman, & Simons, 1992). For a review on N400, see Kutas and Van Petten (1994).

EPs and ERPs in neuropsychology Compared with neurological and psychiatric research, a lower—but increasing—number of works have been devoted to studying neuropsychological disorders (reviews may be found in Barrett, 1993; Knight, 1991; Papanicolaou, 1987; Rugg, 1992; Viggiano, 1996). In the following sections, some examples will be presented of the applications and the contribution of EP and ERP techniques in neuropsychological investigations. Dissociation o f components and data on neural generators As discussed earlier, work on brain-damaged patients might be informative for assessing neural generators of EP and ERP components. An example can be given by the investigation of the P300 source. One hypothesis was that P300 is produced by the interhemispheric comparison of information through the corpus callosum. However, a study of P300 distribution in patients with section of the corpus callosum showed that this component was spared (Kutas, Hillyard, Volpe et al., 1990). Studies with intracranial electrodes showed the presence of locally generated potentials in the temporal lobe structure, functionally similar to the scalp-recorded P300 (e.g. Stapleton & Halgren, 1987). This suggests that P300 reflects activity of bilateral temporal lobe generators. Thus, a reduction in the amplitude of P300 was expected in patients with damage to this cerebral region. However, patients with unilateral anterior temporal lobectomy (e.g. Stapleton, Halgren, & Moreno, 1987; Sheffers, Johnson, & Ruchkin, 1991) and one patient with extensive dysfunction of the left medial temporal lobe (Rugg, Pickles, Potter et al., 1991) did not show any significant differences in P300 amplitude, topography, and latency with respect to controls. Thus, these results contrast with the idea that the

temporal lobe (and particularly the anterior portion of it) make a substantial contribution to the scalp P300. Other studies have dissociated P3a and P3b components. Two groups of patients were studied: one with prefrontal lesions and one with parieto-temporal lesions. P3b was normal in patients with prefrontal damage (Knight, 1984) and it was absent in patients with temporo-parietal damage (Knight, Scabini, Woods et al., 1989b; Yamaguchi & Knight, 1990). On the other hand, P3a was reduced in both groups of patients, suggesting that stimulus novelty activates widely distributed circuits. More recently, it has been shown that P3a was specifically reduced in patients with posterior hippocampal lesions, while P3b was intact. It was concluded that the hippocampal region makes an important contribution to P3a generation, while parieto-temporal regions are most involved in P3b production (Knight, 1996). Developmental disorders and ageing Several developmental neuropsychological syndromes have been investigated using EP and ERP techniques; see for instance the recent studies on autism (Lincoln, Courchesne, Harms et al., 1995), Down syndrome (Karrer, Wojtascek, & Davis, 1995) and attention-deficit hyperactivity disorder (Satterfield, Schell, & Thomas, 1994). One of the questions these studies might help to solve is whether deficits are due to damage in cerebral centres responsible for cognitive functions, or to basic processing impairment, or both (see review by Steinschneider, Kurtzberg, & Vaughan, 1992). Many works have been devoted to developmental dyslexia. This syndrome has been considered from two points of view: as a specific cognitive disorder in the processing of verbal material, or as a disorder determined at least in part by a sensory deficit. The latter hypothesis was supported by EP studies showing abnormality of early visual components in many children with reading disability. For instance, the morphology of EPs by checkerboards was found to be altered (Mecacci, Sechi, & Levi, 1983); abnormalities of binocular processing were found (Solan, Sutija, Ficara et al., 1990); the response of the transient system was

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impaired (e.g. Lehmkuhle, Garzia, Turner et al., 1993; Livingstone, Rosen, Drislane et al., 1991; May, Lovegrove, Martin et al., 1991). Recently, a deficit in the early auditory processing of dyslexics was shown: the MMN component to changes introduced in trains of sounds (such as “da-da-dada” and “da-da-da-ga”) present in controls was absent in these children (Kraus, McGee, Carrell et a l , 1996). The hypothesis has been advanced that a deficit in the transient visual system (Lovegrove, 1991) or the magnocellular pathway (Livingstone, Rosen, Drislane et al., 1991) may be at the root of dyslexia (on this point, see also Frith & Frith, 1996; Mecacci, 1997). However, other works have failed to confirm the presence of EP abnormalities in dyslexics (e.g. Victor, Conte, Burton et al., 1993; Johannes, Kussmaul, Munte et al., 1996). The hypothesis that specific deficits in processing language are present in children with reading disability has been investigated (e.g. Ackerman, Dykman, & Oglesby, 1994). An alteration of the N400 component during a rhyming task was found in dyslexics. Moreover, priming effects on N400 were shown to be different in dyslexics compared with controls (Miles & Stelmack, 1994). The conclusion that no single factor can be isolated as the cause of reading disorders was drawn by Neville, Coffey, Holcomb et al., (1993). These authors studied basic processing of visual and auditory information and linguistic processing of sentences. Abnormalities were found in both of them. The use of MEG provided further information on processing of words in dyslexics (Salmelin, Service, Kiesila et al., 1996). Finally, the hypothesis was also advanced that the reading disorder depends on an attentional deficit. Many works have investigated N200, P300, and N400 in children with learning disorders (including dyslexia) and have found some morphological abnormalities in tasks requiring subjects’ attention (e.g. Harter, Anllo-Vento, Wood et al., 1988; Harter, Diering, & Wood, 1988; Klorman, 1991; Satterfield, Schell, Nicholas et al., 1988). Sensory and cognitive components of ERPs have also been used to investigate the effect of

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ageing. The latency of sensory components was found to be longer in aged subjects (e.g. Allison, Hume, Wood et al., 1984; Fiorentini, Porciatti, Morrone et al., 1996). However, the delay was more marked for late components related to cognitive processes. P300 has been particularly studied as a function of ageing and a progressive increase in latency has been found during the lifespan from age 15. Some authors have also found a decrease in P300 amplitude (for reviews, see Barrett, 1993; Polich, 1996). Memory decay in ageing has been associated with changes in P300. For instance, in auditory oddball tasks, elderly people performed poorly and a modification of the scalp foci of P300 with respect to younger subjects was present (Fabiani & Friedman, 1995). Also, P300 amplitude was decreased in a visual recognition memory task when delay between stimuli was long; the electrophysiological change was associated with poor performance (Nielsen-Bohlman & Knight, 1995). Overall, cognitive components are altered in the elderly. However, their involution is more evident in the case of pathologies responsible for cognitive impairment, indicating abnormal slowing of mental functioning (see the study by Goodin, Squires, & Starr, 1978 on patients with various types of dementia, showing very long latencies in 80% of cases). On the other hand, stroke by itself does not seem to produce a specific delay in cognitive components. According to Ladurner, Schimke, Wraneck et al. (1990), stroke patients without cognitive disorders have the same latency of P300 recorded in controls, whereas patients with stroke and dementia have a clear latency delay. In patients with cerebrovascular accident, amplitude and latency measurements were also made by Gummow, Dustman, and Keaney (1986). These authors found that amplitudes were reduced, but latencies were normal. The reduction in amplitude was present both for target and non-target stimuli, suggesting an aspecific effect. According to these authors, the amplitude reduction by itself cannot be considered an index of cognitive deterioration, but might reflect decreased cortical intercommunication associated with damage to subcortical brain structure.

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Disorders in auditory processing and language Integrity of auditory pathways and primary auditory cortex is assessed by inspection of brainstem potentials and middle-long latency components, respectively. Bilateral temporal lobe lesions produce a variety of disorders ranging from auditory threshold elevation to cortical deafness (i.e. the inability to perceive sounds, in the absence of a peripheral deficit). Brainstem potentials were normal in all patients; however, middle- and long-latency cortical components showed remarkable variability. For instance, in a case of cortical deafness middle- and long-latency components were absent (e.g. Ozdamar, Kraus, & Curry, 1982). On the other hand, in a case of auditory agnosia (i.e. inability to interpret both verbal and nonverbal sounds, even though the patient can hear them) middle- and late-latency EP components were present but slowed (e.g. Rosati, De Bastiani, Paolino et al., 1982). A review of the effect of bilateral lesion of the auditory cortex on the long-latency auditory EP components was presented by Woods, Clayworth, Knight et al. (1987). In some cases, responses were reduced or abolished whereas in other cases they were unaffected. The authors noted that the infarction responsible for bilateral lesion of the superior temporal plane commonly extends outside the auditory cortex. They proposed that abnormalities in middle- and long-latency auditory EPs do not reflect damage to primary auditory cortex per se, but rather the degree of damage of adjacent regions. Abnormalities in the middlelatency component would be associated with subcortical lesions; abnormalities in the longlatency component would reflect lesions extending to the multi-modal areas of the inferior parietal lobule. To investigate verbal information processing, the relevant wave is N400, associated with semantic evaluation of congruity between verbal stimuli and their context. As already mentioned, this late component appeared to be abnormal in dyslexic children with learning disorders. An example of dissociation between brain activity (N400) and behavioural response was shown in a case of global aphasia (Revonsuo &

Laine, 1996). Congruous and incongruous words were given at the end of a sentence. Normal N400 variations were recorded as a function of congruity (i.e., N400 was more negative to incongruous final words). On the contrary, the patient’s performance was at the chance level. This finding suggests that implicit semantic activation of the conceptual level can take place even in the absence of conscious, explicit comprehension of the meaningfulness of linguistic stimuli. The difference between the two hemispheres in processing semantic properties of verbal information emerged in comparing two groups of patients, one with left hemisphere lesions and aphasia, and the other with right hemisphere lesions without aphasia (Hagoort, Brown, & Swaab, 1996). Pairs of words were auditorily presented: some were unrelated, some belonged to the same semantic category (e.g. church-villa) and some were associatively related (e.g. bread-butter). The latter relationship is the closest. In control subjects, N400 amplitudes varied as a function of the distance between the words in a pair; unrelated words produced the largest N400 effect. As expected, the size of this effect on N400 was reduced in left-injured patients with severe aphasia. In right-injured patients, N400 effect was normal for associative pairs, while a trend in amplitude reduction was observed for semantic pairs. This suggests that the right hemisphere is involved in processing of semantically distant relationships between words. In addition to N400, other ERP components, such as MMN and P300, have been studied in patients with language disorders. For example, MMN was investigated during vowel processing in aphasics with anterior and posterior lesions. The component was found to be absent in the case of posterior lesions and normal in the case of anterior lesions. Overall, the left temporo-parietal area seems to be crucial for vowel discrimination (Aaltonen, Tuomainen, Laine et al., 1993). In a study of P300 component it was shown that P300 to positive probes was altered in patients with conduction aphasia and severe deficit in verbal short-term memory, particularly for auditory stimuli. On the other hand, morphology and latency of P300 recorded in a

3. ELECTROPHYSIOLOGICAL METHODS

classic oddball task were normal. The authors suggested that the disorder in conduction aphasia is one of memory rather than response selection (Starr & Barrett, 1987). Disorders in visual information processing and visual perception Integrity of retinal function is investigated by means of ERG, while the integrity of visual pathway and early cortical processing is based on the evaluation of P100 component or on steady-state VEPs. Typically, in hemianopic subjects, the stimuli presented to the blind hemifield do not produce activity. Different patterns of results were reported in cases of “blindsight”, cortical blindness, and residual vision. In one case of “blindsight”, PI 00 to target stimuli in the blind hemifield was absent, while the late component P300 was present. It was proposed that stimuli presented to the blind field activate associative cerebral areas through pathways different from geniculo-striate ones (Shefrin, Goodin, & Aminoff, 1988). In patients with cortical blindness due to bilateral damage of occipital lobes a dissociation was found where EPs were normal, at least in some experimental conditions, in the total absence of vision. The analysis of cerebral blood flow in these patients suggested that visual EPs were due to the activity of small spared regions of area 17: the larger these spared portions of visual cortex were, the more reliable were the EPs. Moreover, residual vision was present in patients when the spared portion of area 17 was large enough. It was proposed that “blindsight”, like residual vision, could be due to small spared portions of area 17, rather than to the contribution of the extrastriate visual system (Celesia, Bushnell, Cone Toleikis et al., 1991). Recently, ffytche, Guy, and Zeki (1996) studied a patient with residual vision. The lesion involved most of the striate cortex of one hemisphere, leading to homonymous hemianopia. An earlier PET study (Barbur, Watson, Frackowiak et al., 1993) showed that when the subject was aware of a moving stimulus in the blind hemifield, V5 area was active. Moreover, high-speed moving stimuli could be detected better than slow-moving stimuli. In the

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electrophy siological study, EPs were recorded from stimuli presented in the blind hemifield. The speed of the stimulus was critical. At low velocity, EPs were absent and the subject did not perceive the stimulus; at high velocity, EPs were present and the subject could discriminate stimulus onset and direction of motion. Moreover, the use of anatomical MRI data for precise localisation of the electrodes confirmed previous PET data: the signals were not generated in area V I, but in V5. The conclusion of this work is that in this patient conscious experience was correlated with electrical activity in V5. The presence of parallel pathways specialised for fast motion to areas V 1 and V5 was also confirmed in a study based on EP, MEG, and PET data on normal subjects showing that signals evoked by fast-moving stimuli are present in V5 before V 1 (ffytche, Guy, & Zeki, 1995). Another neuropsychological disorder investigated by recording brain electrical activity is prosopagnosia. Small (1988) reported that ERPs for faces recorded over both hemispheres were normal, while P I00 latency to checkerboards was longer over the right hemisphere. These results suggested a deficit in sensory processing rather than a specific defect in face processing. Renault, Signoret, Debruille et al. (1989) found a variation of P300 in relation to face familiarity. In the experiment, known and unknown faces were presented in two different probability conditions (familiar faces were presented with the probability of 33% and 50% respectively). Although faces were not recognised, P300 amplitude for known faces varied as a function of the probability of presentation. Moreover, the latency was longer for familiar than for unfamiliar faces, and even longer for relatives’ faces and the patient’s own face, suggesting slower processing. Electrophysiological data were interpreted as an index of covert recognition in the absence of overt behavioural recognition. In cases of visual agnosia, dissociation between electrophysiological data and perception have also been reported: patients could not recognize visual stimuli, but EPs could be recorded (Bodis-Wollner, Atkin, Raab et al., 1977; Celesia, Archer, Kuroiwa et al., 1980; Kooi & Sharbrough, 1966; Onofrj, Fulgente, & Thomas, 1995; Spehlmann, Gross, Ho et al., 1977).

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Disorders in attention Much work on attention in patients with brain lesions has been carried out by Knight and coworkers. A part of this research, on the modulatory role of the frontal area on sensory processing, has already been summarised in the previous section. Disorders in sustained focused attention and disorders in phasic attention have to be distinguished. The Nd component is the index of sustained attention directed towards a stimulus coming from a given channel, i.e. from one of the two ears or the two limbs, or from one of the two visual hemifields. The presence of Nd is correlated with improvement of performance for that channel. A remarkable difference is shown in cases of left or right brain damage. Patients with focal damage to the dorsolateral frontal right cortex did not exhibit the Nd component to contralesional ear stimuli in a task of sustained attention. The electrophysiological impairment is associated with the behavioural deficit. On the contrary, patients with left frontal lesions do not show any Nd abnormality either to left or right ear attended stimuli and they do not have any behavioural deficit (Knight, Hillyard, Woods et al., 1981). Thus, ERPs in patients support the hypothesis that Nd is the index of focused attention. Frontal lobes are thought to make an important contribution to the production of this component. Moreover, results are in agreement with neuropsychological data on the asymmetry of effects of right and left lesions in human subjects as regards attentional mechanisms (Knight, 1991). The hypothesis that frontal lobes are important for orienting attention is confirmed by data on another ERP component. The MMN component (produced by deviant tones, to which subjects— engaged in another cognitive activity—were not to pay attention) was found to be reduced in patients with frontal lesions, especially in recordings from the injured hemisphere and for deviant tones presented to the ipsilesional ear (Alho et al., 1994). As regards phasic attention, the subcomponents P3b, related to voluntary attention, and P3a, index of automatic involuntary attention, should be considered. As already described in the previous section on dissociation of components, P3b was normal in patients with prefrontal damage (Knight, 1984), although it was absent in patients with

parieto-temporal damage (Knight et al., 1989b; Yamaguchi & Knight, 1990). However, P3a was reduced in both groups of patients. Thus, the response to stimulus novelty is widely distributed in the brain, although a crucial role seems to be played by the hippocampal region. According to Knight (1996), the possible role of this region may be to maintain a template of the recent past for comparison with incoming sensory information. Hemispheric asymmetry for control of spatial attention was also shown by recordings in one splitbrain patient. Shorter RTs and larger P300 potentials to stimuli falling in the rightmost space were observed; further, the right hemisphere, unlike the left hemisphere, gives P3b responses of about the same magnitude to stimuli falling in either visual hemifield (Proverbio, Zani, Gazzaniga et al., 1994). Overall, ERP data support the view that the right hemisphere has bilateral control of visual space, while in the left hemisphere control is restricted to the contralateral space (Kinsboume, 1987). Visual agnosia restricted to one hemispace (generally the left one) is typical of patients with unilateral spatial neglect. In this case a dissociation between electrophysiological data and perception was shown: the EP exogenous component (PI00 ) to stimuli presented in the left hemifield was normal, while perception was absent (Vallar, Sandroni, Rusconi et al., 1991). On the other hand, the endogenous component P300 appears to be altered for stimuli generated in the neglected hemifield, at least for the visual modality (Lhermitte, Turell, Le Brigand et al., 1985). These data support the interpretation of neglect as a disorder that concerns exclusively the postsensory level (see also Garcia-Larrea, Brousolle, Gravejat et al., 1996, for a study on “Parkinson’s neglect”). On the contrary, other works have found abnormalities in steady-state visual EPs that indicate the presence of disorders also at sensory levels (Angelelli, De Luca, & Spinelli, 1996; Spinelli, Burr, & Morrone, 1994; Viggiano, Spinelli, & Mecacci, 1995). In particular, EPs to stimuli presented in the neglected hemifield had latencies longer than EPs to ipsilesional stimuli. Other studies showed that manipulation of both visual stimulus properties (luminance and contrast) and subject condition (head-trunk rotation) had a

3. ELECTROPHYSIOLOGICAL METHODS

similar effect on performance and EP quality (Doricchi, Angelelli, De Luca et al., 1996; Spinelli & Di Russo, 1996). In particular, the longer latencies to stimuli in the neglected hemifield were present only to luminance stimuli, while they were absent for equiluminant stimuli, that is, chromatic patterns (Spinelli, Angelelli, De Luca et al., 1996). These data supported the proposal that the delay of EPs to contralesional stimuli might result from disruption of the fast response of the magnocellular pathway, not active in the case of isoluminant stimuli. As anatomical damage to the occipital lobes of patients could be excluded in many cases, it was suggested that changes in the top-down modulation of the higher cortical centre on the occipital lobes might be responsible for the phenomenon (Spinelli et al., 1996). Disorders in memory In patients with memory disorders the positive late component P300 (with a peak of450-600msec) has been mostly investigated. For instance, the P3 amplitude was decreased compared to controls when patients with disorders in recent memory were engaged in phonemic and semantic processing of spoken words. On the other hand, in the same patients, the P3 evoked by tones during a tone discrimination task was normal. Therefore, the P3 components elicited by tonal and verbal discriminations may reflect different neural processes and may be differentially affected by the memory disturbances. The abnormalities of P3 suggested a failure of elaboration of the stimuli that might cause an encoding disorder (Meador, Hammond, Loring et al., 1987). In normal subjects, there is a large effect of word repetition: P3 evoked by repeated words is more positive-going than that evoked by non-repeated words. In patients with a verbal memory deficit following left temporal lobectomy this repetition effect was eliminated (Smith & Halgren, 1989). Right temporal lobectomy did not affect the repetition effect on ERP (Smith & Halgren, 1989). However, in patients with damage in the right parahippocampal and lingual gyri, extending to posterior hippocampus and occipital cortex, the repetition effect was eliminated (Swick & Knight, 1995).

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Auditory ERP abnormalities were observed in amnesic patients. Abnormalities of P3 were related to dipole orientation (rather than dipole strength) and were present only when lesions involved the hippocampus (O’Donnel, Cohen, Hokama et al., 1993). Abnormal topography of P3 was reported also by Onofrj, Fulgente, Nobilio et al. (1992) in patients with bilateral temporal lobe lesions and amnesia. On the other hand, Rugg, Pickles, Potter et al. (1991) did not find any modification of P300 in one patient with a severe disorder in verbal longterm memory due to extensive damage to the left medial temporal lobe. Discrepancy between results might be due to different etiology of the brain damage. Polich and Squire (1993) studied a relatively large group of amnesic patients with bilateral hippocampal lesions using the same paradigm. P3 component evoked by targets was of smaller amplitude and longer latency than in control subjects. However, the component was identifiable, indicating that the hippocampus is not the major source of P3b. This was confirmed by recent work: the posterior scalp P3b was not affected by hippocampal lesions while P3a was specifically reduced (Knight, 1996).

Monitoring and prognosis by means of EP and ERP techniques EPs and ERPs may represent a useful technique for prognosis and for monitoring the course of patients’ illnesses. For instance, follow-up with somatosensory EPs in cases of stroke and cerebral ischaemia is a good diagnostic tool for measuring the evolution of the cerebral dysfunction (de Weerd, Looijenga, Veldhuizen et al., 1985). The presence or absence of somatosensory ERPs has been used as a prognostic criterion in patients with heminattention (Ring & Finnegan, 1989). The prognostic reliability of brainstem, somatosensory, and visual EPs has been assessed in closed-head injury patients (e.g. Anderson, Bundlie & Rockswold, 1984; Campbell, Suffield, Deacon et al., 1987). Other examples of application are the monitoring of individuals at risk for cognitive dysfunctions, such as in the case of pre-term newborns (Kurtzberg & Vaughan, 1986), or

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children whose neurological evaluation at birth is below normal (De Sonneville, Visser, & Njiokiktjien, 1989). EPs may also be used for monitoring treatment effects. For instance, performance improvement in a selective attention task in patients submitted to rehabilitative treatment has been associated with changes in the N200 component (Baribeau, Ethier, & Braun, 1989). Predictive capacities improve if a high number of electrodes are used (e.g. in patients with closedhead injuries: Thatcher, Cantor, McAlaster et al., 1991).

Brain mapping The technique is based on recording electrical brain activity with a large number of electrodes. When the number of electrodes increases, data analysis is very complex and computerised programs are necessary. A development of the technique is the topographical description of the EEG or EPs or ERPs recorded on the scalp. Very high numbers of electrodes are used (21,32,64, or more); the recorded activity is stored with a high-capacity device and processed. At each time each electrode gives a data point; interpolation methods are used to estimate the electrical potential values at scalp locations between actual recording sites (generally between four electrodes). A topographic map is created, where voltage values, measured and interpolated, are transformed into colours, according to a colour code. The same colour is attributed to areas with the same voltage. Other ways of presenting such a large amount of information are grey scale, contour maps with isopotential lines (e.g. Ragot & Remond, 1978), and three-dimensional head models with spherical interpolation (spline map topography; e.g. Perrin, Pernier, Bertrand et al., 1987). In any case, the topographic map represents the voltage distribution on the scalp at a given instant in time. Besides the description of voltage distribution, another type of topographical analysis is the current source density (CSD), which estimates the head ingoing and outgoing current flow (e.g. Pernier, Perrin, & Bertrand, 1988). The description of the relation of ERPs recorded at different scalp locations may help to understand the functional coordination between different brain

areas. There are various measurements of the similarity (or interdependence) between the activity at the various electrodes, for instance the correlation (e.g. Gevin, 1987) and the covariance (e.g. Gevin, Bressler, Morgan etal., 1989). One of the main goals of EP or ERP studies is to localise the sources of the electric waves. The problem is to compute the equivalent brain sources from the voltage difference measured at the scalp. The method is based on two assumptions. The head is modelled as a spherical volume, and the sources are modelled as equivalent dipoles. Source estimation calculates the location, strength, and direction of the dipoles. Two methods are used for transforming scalp-recorded brain activity in brain source imaging: the single-timepoint and spatio-temporal methods. In the first case, which is more diffuse, dipoles are computed at a single instant of time. In the spatio-temporal case, two kinds of images are computed. One is related to the spatial image of the discrete multiple sources and the other is related to the temporal image of a source current waveform reflecting the time course of the local activity in circumscribed brain areas (e.g. Sherg & Ebersole, 1993). Thus, the localisation and the time course of the neuronal generators are estimated using a method that combines topographic profile analysis and spatio-temporal source analysis (brain electrical source analysis, BESA by Berg & Sherg, 1990). The temporal accuracy of the technique is very high and the poor spatial accuracy has been improved by these recent methods. Further improvement may be obtained by associating electrophysiological data with individual anatomical data (from MRI) and with magnetoencephalographic technique, which is peculiarly sensitive to tangentially oriented dipoles and, unlike EEG, is blind to the effects of the extracerebral layers (skull, meninges etc.; see for a review Hari, 1996).

Intracranial stimulation and recording In some clinical cases (e.g. surgically treated epilepsy) electrical stimulation of cortical regions and/or recording with surface or deep electrodes is performed. These experiments provide more direct information about brain electrical activity than EPs

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recorded on the scalp (limited by the fact that placement of intracranial electrodes is determined by clinical necessity). The specialisation of one cortical region for a specific stimulus can be tested. For instance, specific waves in response to faces have been recorded in small regions of the fusiform gyrus and inferior temporal gyrus. Electrical stimulation of the same regions produced temporary impairment in naming faces. Interestingly, individual differences in the localisation of these areas were evident (Allison, Ginter, McCarty et al., 1994). Different responses for familiar and unfamiliar faces were recorded in amygdala, hippocampus, and temporal lobes, showing that limbic and temporal structures are involved in recognising the familiarity of faces (Seek, Mainwaring, Ives et al., 1993). More complex processing (e.g. memory functions) can only be studied by intracranial recording. For instance, it was shown that the posterior temporal cortex is specifically involved in short-term processing, whereas the amygdala, hippocampus, and anterior temporal cortex are involved in both short-term and long-term memory (Guillem, N’Kaoua, Rougier et al., 1996). ERP sources have been investigated by intracerebral studies. For instance, it was found that the intracranial recordings associated with the scalp P3 were widely distributed in the brain (Wood, Allison, Goff et al., 1980). The presence of large potentials, showing polarity reversal during oddball tasks which evoke P3 at the scalp, were observed in association with changes in unit activities in the medial temporal lobe (e.g. Stapleton & Halgren, 1987). The hippocampal region involvement in P3 generation has also been shown (McCarthy, Wood, Williamson et al., 1989; Smith, Halgren, Sokolik et al., 1990).

Transcranial electromagnetic stimulation Magnetic stimulation is a new and safe method of interfering with brain activity in humans. The technique, developed in the 1980s (Barker, Jalinous, Freenston et al., 1985) is noninvasive and is based on the application of a brief and strong magnetic field to a specific region of the subject’s head. The induced electric current crosses the scalp, the skull, and the meninges with minimal activation of the

pain receptors and transiently blocks the function of cortical neurones (for details see Wasserman, Grafman, Berry et al., 1996). Magnetic stimulation of brain (and spinal roots) have been widely used to study the motor cortex and nervous propagation in various neurological diseases, and to describe the reorganisation of neural connections after brain damage (for a review see Rossini & Rossi, 1997). Moreover, transcranial stimulation has been used to study other brain functions, such as visual perception (Amassian, Cracco, Maccabee et al., 1989), language (Pascual-Leone, Gates, & Dhuna, 1991), attention (Pascual-Leone, Gomez-Tortosa, Grafman et al., 1994), and memory (Grafman, Pascual-Leone, Alway et al., 1994). In all cases magnetic stimulation temporarily inactivates the cortical region to which it is applied, confirming the functional role played by that area. Thus, according to the site of application, it produces suppression of visual perception (occipital cortex), suppression of colour perception (occipital-temporal areas), speech arrest (left temporal lobes), neglect (right parietal lobe), or recall deficits (left mid-temporal and bilateral dorsofrontal lobes). Recently, magnetic stimulation has been also applied to the left prefrontal cortex, showing effects on mood regulation (Pascual-Leone, Catala, & Pascual-Leone, 1996).

Magnetoencephalography (MEG) Brain electrical activity produces a magnetic field that can be measured close to the head by means of a special recording system. Magnetoencephalography (MEG) measures the spontaneous variations of this magnetic field in time, while the Evoked Fields represent the MEG variations with respect to an external stimulus. Waves of Evoked Fields are indicated by the same label used for Evoked Potentials, followed by an m; for example, MMNm is the magnetic counterpart of the mismatch negativity. This technique, used for the first time by Cohen (1968), is very complex from a technical point of view; it is sensitive only to events that take place near the scalp, but is noninvasive and has a better capacity for spatial localisation than EEG (of the order of 2-3mm), at a parity of temporal resolution.

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On the other hand, EEG may show currents that are not visible for the magnetometer because they originate in too deep portions of the brain or have a radial direction. Thus, the simultaneous recording of EEG and MEG might be useful. MEG reliability has improved through the use of new detector devices. Biomagnetic signals have to be extracted from noise. To increase the signal to noise ratio, evoked signals are averaged and filtered. Multichannel recording developed from single channel recording, with detector devices distributed on the scalp surface, in order to record the whole distribution of the brain magnetic field (helmet or whole-head systems). Spatial resolution is a function of the number of sensors. Data from the various channels are integrated to build up the spatial distribution of the magnetic field, as in electric brain mapping. The intensity, position, and direction of the source or sources are then calculated on the basis of the dipole (or multidipole) fitting algorithm and spherical head model (Romani & Rossini, 1988). To localise sources accurately, individual brain anatomical data are necessary; these can be obtained through brain imaging techniques such as MRI, which provide excellent spatial resolution. A review by Naatanen, Ilmoniemi, and Alho (1994) shows the value and results of the MEG technique and underlines the advantages offered by the simultaneous use of MEG (to improve the localisation of generators) and EEG (to detect activities not revealed at the magnetic level), as well as the opportunity to associate these techniques with neuroimaging ones (PET and fNMR). MEG has been applied in topographic studies of brain activity. The retinotopic map of the occipital lobes (Ahlfors, Ilmoniemi, & Hamalainen, 1992), the tonotopic organisation of the auditory cortex (Romani, Williamson, & Kaufman, 1982), and the somatotopic organisation of the somatosensory cortex (Okada, Tanenbaum, Williamson et al., 1984) have been described. MEG has also been applied to the study of cognitive components, generally with localisation aims. For instance, the auditory cortex was found to generate both Ndm in attention experiments (e.g. Arthur, Lewis, Medwick et al., 1991; Woldorff, Gallen, Scott et al., 1993) and MMNm evoked by

pitch deviant stimuli (Tiitinen, Alho, Huotilainen et al., 1993). The primary auditory cortex was found to offer the neural basis of the echoic memory, as measured by N lm characteristics (Lu, Williamson, & Kaufman, 1992), and languagespecific memory traces were localised in the left auditory cortex through the MMN paradigm (Naatanen, Lehtokoski, Lennes et al., 1997). Moreover, short-term brain plasticity phenomena have been documented (Rossini, Martino, Narici et al., 1994). An interesting example of application of MEG to neuropsychological problems can be found in the study of dyslexia. Different time courses of cortical activation were found in dyslexics and control subjects during passive viewing of words briefly presented. The maximal difference was localised in the left temporo-occipital region which was not activated (or was activated later) in dyslexics, while a sharp firing was displayed at about 180msec following word presentation in controls. This supports the view that perception of a word as a single unit is impaired in dyslexics. On the other hand, dyslexics showed, earlier than controls, an activation of the left inferior frontal lobe which is involved in the silent noun generation task. This suggests that dyslexics use a different processing system in reading (Salmelin, Service, Kiesila et al., 1996). The number of studies using MEG in neuropsychological patients is low at present, probably because there are few hospitals equipped with this instrument. Studies should increase following the spread of whole-head MEG systems in research and clinical departments devoted to functional brain imaging.

Summary The recording of sensory EPs is routinely used in clinical research to investigate all sensory modalities. Broad experience ensures high reliability of results obtained with this technique. For this reason, one of the most interesting contributions of EP recording to neuropsychology is probably that of assessing the presence/absence of deficits at a sensory level, dissociating pure cognitive disturbances from impairment due, at least in part, to sensory disorders.

3.

On the other hand, ERPs also offer the possibility of detecting specific impairments at different levels of cognitive processing (e.g. attention, memory, semantic analysis, etc.) or in different aspects of a cognitive function (e.g. sustained and phasic attention). This approach represents a promising prospect for neuropsychology. However, in some cases, results show considerable variability. This is probably due to the great difference in the nature and extent of brain damage, which may have highly differentiated effects on ERP morphology. The association of electrophysiological recordings with the new

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imaging techniques more accurately assessing brain damage could reduce this variability in the future. At present, EPs and ERPs are the most powerful method for tapping the timing of sensory and cognitive processing. On the other hand they have poor spatial resolution. The systematic association of electrical brain recording with anatomical and functional neuroimaging techniques may lead to a more powerful spatio-temporal description of brain activity. Finally, the potential value of ERPs in prognosis and monitoring, both in patients and in individuals at risk, should be underlined.

Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

4 The Evaluation of Experimental Data in Neuropsychology Erminio Capitani and Marcella Laiacona

2. Sampling, i.e. how many experimental units are needed and how we can sample them in order to obtain results of general validity.

INTRODUCTION

Psychometric data may be collected for prognostic, diagnostic, or research use (Cronbach, 1949). For prognostic (or predictive) use, it is not necessary to study the factors behind the score obtained, as only this latter is used for predicting other variables (e.g. the capacity for some task or professional duty). However, the aim of a neuropsychologist is often to discover what lies behind a given behaviour, and to verify if, among the causative factors, there is a disease present. Moreover, neuropsychological scores are increasingly considered as the measure of clinical trials, both when treatment is psychological, as in language rehabilitation, and when it is pharmacological, as in the drug therapy of dementia. Before discussing some of the problems encountered in clinical practice, it might be useful to elucidate two preliminary aspects:

Thereafter we shall review some common problems in the analysis of data, with special reference to the diagnostic process, experimental designs in clinical trials, and some new approaches to statistical analysis.

MEASUREMENT

Objects and processes

Psychometric scores may have different relationships with the underlying psychological reality. Following the standard approach, we can assume either (a) that this relationship is deterministic, in analogy with the mathematical concept of "function": the underlying psychological variable is an object that determines the expected value of the measure. Due to the faulty reliability of the measure, to this value should be added a variable error (with an expected value of

1. The measurement process, i.e. the relationship between the underlying ability and its actual measure. 57

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zero), which causes the inconsistency among repeated measures of the same subject. Alternatively (b) we may conceive the underlying psychological reality as a process ruled by probabilistic laws. An example is the actual retrieval of a word from the phonological lexicon, after a process of research, which at each subsequent trial may be successful or not (Faglioni & Botti, 1993). In this case, the variability among the different trials carried out by the same subject simply derives from the probabilistic nature of the phenomenon. The classical psychometric theory conforms to the former approach. The latter approach is a more recent one, and applies well to the study of certain processes, such as learning and forgetting. Probabilistic models allow us to estimate the parameters corresponding to different stages of the underlying psychological process, and will be discussed later in this chapter. We will now discuss some aspects of the classical approach that are relevant for the neuropsychologist.

Problems concerning measurement scale Measurement signifies mapping from the values of an underlying variable (that may be very complex) to a simpler measurement variable (a digit or a label). The general problem of measurement (e.g. Narens & Luce, 1986) is to define the function that associates the measure with what is measured (which we will hereafter call the object or ability). According to Stevens (1946) and subsequent authors (e.g. Suppes & Zinnes, 1963), numbers are assigned to objects, so that the interesting empirical relationships among the objects should be reflected in the numbers that express their measure. These numbers lie on a scale endowed with certain properties; we should ascertain what these properties are in order to know whether a given statistical analysis is allowed. Stevens maintains that the admissible statistical processing also depends on the properties of the measurement function, and not only on the distribution of the collected data and on other statistical considerations. This limitation, (generally recognised by many scholarly textbooks of statistics, e.g. Siegel, 1956), has led several researchers to confine themselves to the so-called

“non-parametric” methods, given that measures have only ordinal scale properties. According to the classical system of classification, measurement scales are of four types: nominal, ordinal, interval, and rational, (i) In nominal scales, numbers are simply labels or names (e.g. the numbers on football players’ jerseys), (ii) With ordinal scales, measures have an intrinsic quantitative value and can be arranged in increasing or decreasing order. However, let us suppose that the same interval separates different measures (e.g. 5 is the difference between scores of 15 and 10, but also of 25 and 20). With the ordinal scale we cannot be sure that equal differences in scores reflect equal differences between the underlying abilities. It follows that, if the average measure of two groups is the same, the means of the underlying abilities need not be the same. Therefore, all the statistics and operations based on the arithmetical mean will not be allowed, and we should restrict ourselves to nonparametric statistics or to the analysis of frequency tables, (iii) When equal intervals between the measures imply equal intervals between the objects, the scale has an interval property: we can resort to statistics based on arithmetical mean, such as the analysis of variance and related procedures, (iv) The limitation of interval scales is that the origin of the scale does not correspond to a true absence of the object; this latter property only applies to physical or time scales, which are defined “rational scales”. Only with rational scales does the ratio between different measures correspond exactly to the ratio between the underlying objects. These points were first criticised in a delightful and provocative paper by Lord (1953), and more recently by other authors whose positions are summarised by Gaito (1980) and Michell (1986). In short, numbers resulting from a measurement process would become in some sense independent from the underlying objects, (“the numbers do not know where they come from”) and the measurement scale limitation should not influence the statistical analysis of data. Other authors (e.g. E.W. Adams et al., 1965) support in general Stevens’ statement, but consider psychological tests as a special case. It is extremely difficult to decide if a scale has an interval property. In the psychological and still more in the neuropsychological field, the

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underlying objects can be known only through other measures to which exactly the same problems apply. Moreover, most tests are designed with questions or sets of questions of increasing difficulty. With such tests, not only is the interval property in doubt but, strictly speaking, so is the ordinal one (Michell, 1986). We believe that the ultimate choice of whether or not to use parametric methods should be left to the researcher. When constructing a new test, one should empirically optimise its scale properties, but even if the interval properties are not known with certainty, in our opinion, the analysis of data by means of parametric methods may be allowed, if the other statistical conditions permit their use. As a matter of fact a deviation from the interval property could, by chance, favour one of the experimental groups and give rise to possible biases. However, this likelihood is evenly distributed among the groups and is a matter of chance. In the comparison among groups, biases arising from a faulty knowledge of the scale properties may introduce a further source of statistical error (whose expected value is zero) that can mask the systematic effects and their experimental transparency. The effect is, as with low reliability, to lower the power of the experiment rather than impair its protection against type I errors. Accordingly, the differences actually observed largely retain their significance. Other problems of relevance to neuropsychology are the intrinsic restrictions of scores that are upper- and lower-limited. For instance, we cannot conclude that two groups present deficits of equal severity when both average scores fall near to zero. Another constraint concerns the comparison among different tests whose scores have been standardised on the basis of the mean and standard deviation (SD). With the common standardisation procedure (difference from the mean in SD units) the standard scores are also often upper- or lowerlimited. For instance, if in a given test the mean is 7 and the SD 4, it is not possible to achieve a standard score lower than (0 - 7)/4 , i.e. -1.75; whereas in a different test with mean 13 and SD 4, the poorest subjects could get a standard score of (0 - 1 3)/4, i.e. = -3.25. It would be obviously wrong to conclude that the standard score o f-1.75 in the former test is better than the score o f-3.25 in the latter; a similar

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argument applies to top scores. This can be a source of biases when the qualitative diagnosis in a given patient is based on a comparison among different tasks. The combination of the asymmetrical distribution shape with the closed scale can give rise to a biased prevalence of some types of diagnosis. Experiments affected by such biases are studies of the parallelism of the multivariate profiles between a group of severe patients (e.g. suffering from Alzheimer’s disease) and a group of less severe patients. We may be interested to verify whether the two groups are wrong on the same tasks, although at different levels of severity. The profile of Alzheimer patients may depend on the present availability of a scale of sufficient extent, and the profile may be artifactual if this space does not coincide in the different tests. Upper and lower limits of the scale also influence the dispersion of the scores. For instance, if we want to verify the hypothesis of an increasing variability of the scores with age (Rabbitt, 1981), we could artifactually observe the opposite pattern: with a closed scale test, the performances of elderly subjects could be flattened around zero (with a consequent low variability), if the test is very difficult for old subjects.

Measurement errors and reliability The theory of measurement errors has been widely studied and is discussed in standard textbooks of psychometrics (e.g. Lord & Novick, 1968). We will consider here only variable errors, that arise from random inaccuracies due to many causes. The expected value of variable errors is zero for each observer and subject, and variable errors constitute a kind of “background noise” of the measurement: test reliability is the relative freedom from variable errors. We can evaluate reliability in different ways (Guilford, 1965; Gulliksen, 1987; Helmstadter, 1966; Lord & Novick, 1968): most of the methods derive from correlation assessments between two measurements of the same subject. After having estimated the reliability, which ranges between 0 and 1, we should evaluate whether it is satisfactory. In brain-damaged patients a low consistency between two subsequent examinations could arise from fluctuations in the underlying ability; for this reason it is better to evaluate the reliability with

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normal subjects, even if the regions of the scale that are tested in the two samples may be different. The reliability can be measured against a fixed reference, considered the minimal acceptable level (e.g. 0.60 or 0.70), but this approach is not entirely satisfactory. The classical psychometric theory (e.g. Gulliksen, 1987) studies the relationship between the test reliability, the score variability between subjects, and the confidence limits of the true score o f a single subject. On this basis, we can compute the confidence limits of the true score of each subject, with a controlled risk. If a test is imperfectly reliable, but its variability between subjects is low, the confidence limits of the true score and of the underlying object variable may be still acceptable for clinical use. The combined use of a statistical consideration (the correlation between two measures) and of a metric consideration (the range of the object variability) is of more general interest. Sometimes the statistical significance is wrongly interpreted as implying a relevant and meaningful difference between the underlying objects. This is not always true: when the variability is very low, there can be significant effects even when the difference between the objects, although systematic, is quite negligible in practice. In some experiments, particularly in clinical trials, the discussion of this point probably tends to be overlooked. For a further discussion of this subject, the reader is referred to Wilcox (1987). The importance of considering reliability in aphasia diagnosis is widely discussed by Willmes (1985). Finally, it has been shown (Chapman & Chapman, 1973) that, in studies involving tests of differing reliability, the most reliable test can disclose a greater impairment than the others. This could introduce a further bias in the comparison of different tests in a group of braindamaged patients.

SAMPLING: GROUP VS. SINGLE CASE STUDIES Quantitative and qualitative problems In the last few decades group studies have been a standard practice in neuropsychology. This is

largely due to the fact that single performances, besides including systematic effects, are also influenced by some random components whose expected value (their hypothetical mean) is zero. The analogy with what was said concerning measurement and reliability is evident. Very recently, however, the use of group studies has been criticised as inappropriate for testing finergrained hypotheses about the structure of the cognitive system. It has been claimed that defects presented by the subjects of the group under scrutiny may not be homogeneous. Consequently, averaging over the group cannot provide useful information, as no “systematic effects” are shared by the subjects. Accordingly, only single case studies (or at least “multiple-single-cases” studies) are considered informative. This debate is treated elsewhere in this book and is well represented in the recent literature. However, it should be borne in mind that, even for single case studies, there are substantial statistical problems concerning the reliability and comparability of different tasks. We discuss this point later. In some experimental situations, group studies cannot be disposed of, e.g. the construction of diagnostic tools and clinical trials. In group studies, there are several criteria for choosing the sample size: 1. The representative criterion: at least p% of the population, with a controlled risk, should be included between the extremes observed in the sample. This size is best ascertained through non-parametric tolerance limits, as reported by several authors (e.g. Ackermann, 1985; Gibbons & Natrella, 1966; Owen, 1982). Normative studies, where the extreme observations are the main interest, generally conform to this criterion. To correctly estimate the outer values of a distribution, as a general rule, samples of considerable size are needed. As an example, at least 93 subjects are needed if we want at least 95% of the population to be included between the extremes of the sample with a 5% error risk. 2. The need for fair protection and a sufficient power in the statistical analysis of the experiment. Here we should evaluate and check the power of the experiment, i.e. the risk of a

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type II error (the missed detection in the sample of differences existing in the population). In some instances, the experimenter can estimate a priori the power of the comparison on the basis of the number of subjects, the desired protection against type I error, and the size of the differences considered interesting. A more extensive presentation of this subject is found in Cohen (1988) and in Wilcox (1987). However, studies with brain-injured patients are faced with further problems and peculiar restrictions, which also concern the qualitative aspects of the sample: 1. Subjects sampled in experimental studies are often different with respect to age, education, and length and severity of disease, and these variables can influence performance. Therefore, big samples and specific statistics are needed in order to rule out the influence of unbalanced concomitant variables. 2. Samples may be unrepresentative because of selection, and in studies aimed at comparing the severity of different groups we must be sure that the most severe subjects of each group have not been excluded. This can be done as follows: (i) Sampling a continuous series of patients. We should register the dropouts (due to death, or the fact that they were too severe to be tested) and compare their incidence among groups. If the percentage of dropouts is higher in a given group and this group is performing better, such an outcome could be artifactual. The same could be possible in experiments where groups are performing at the same level, but with a different dropout rate. (ii) The source from which patients are sampled should be homogeneous. Mixed recruitment is dangerous. Concerning in-patients and out-patients, for instance, the former are generally more severe at onset, but are less selected with respect to their prognosis; regarding the latter, the length of illness is greater and sometimes patients are sampled as out-patients because they did not recover in the early stages of illness. If the sampling

is mixed, subjects with a greater length of illness may have, on the whole, more severe brain damage. Further sampling problems concern longitudinal surveys, such as the study of improvement of an acute illness or of the worsening of a progressive pathology. If the aim is to individuate which variables influence improvement (e.g. rehabilitation) or decline (e.g. the onset age of Alzheimer’s disease), we should consider that in their evolution subjects start from different baselines. To compare their follow-up, we should assume (a) that the scale of the scores has the interval property, and (b) that each subject should have the real possibility to change his/her score, especially if the scale is upper-limited and a subject starts with a rather high score (being only slightly damaged). In a strict sense, the upper limit of recovery is the premorbid (unknown) level, which could be as low as the mere normality threshold. In this case, the difference between the first and the second examination of a moderately impaired subject who recovers could be similar to that of a subject who starts from a much lower score but improves little. This point would make it problematic in evolutive studies to consider all the originally observed subjects. It would be better to take into account only subjects with a given degree of severity. This selection limits the generality of the results, in as much as they are restricted to a subgroup of the former sample. A remedy for this problem is to match subjects for initial severity in the different treatments of the trial. We need to split the possible initial scores into different regions, and, within each region, to randomly assign the subjects to different treatments according the usual rules of experimental designs. The onset severity bias may affect the comparison of different groups (e.g. left and right brain-damaged patients, or amnesic and demented patients): left brain-damaged patients are generally seen earlier by a doctor, because language may be impaired, sometimes even after a very small lesion; right brain-damaged patients may be less disturbed by small lesions and may not want to see a doctor, also because of the greater frequency of anosognosia.

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In addition to the choice of the group (or groups) of brain-damaged patients on which to verify the experimental hypothesis, we generally need a control group. This can consist of: (a) normal subjects, in order to get norms for a diagnostic approach to single patients; (b) patients not affected by cerebral damage, in order to see, with group studies, if a given task is specifically hampered by a cerebral lesion. Very often we resort to in-patients not suffering from central nervous system diseases, as these are similar to neurological in-patients for all general and environmental conditions apart from the specific cerebral lesion; (c) brain-damaged patients, when the aim is to define the characteristic profile of impairment with reference to a group of tests. As an example, to classify a case of fluent aphasia such as Wernicke, or Conduction or Sensory Transcortical aphasia, we should compare the patient’s performance on comprehension and repetition tasks with that of a large sample of nonselected fluent aphasics.

Single case studies Also with single cases, a rigorous quantitative evaluation of the data is needed in order to distinguish real from random effects. We report just a few of the most useful methods suitable for single case studies. 1. When dealing with continuous measures (e.g. reaction times), repeated in different experimental conditions, one can resort to the usual variance and covariance analyses, which provide information about the interaction of the different factors controlled by the experiment. When the data structure calls for a frequency analysis, we can use contingency tables of two or more dimensions, following the standard procedures based on generalised linear models (Aitkin et al. 1989). 2. In some tasks, such as confrontation naming, it may be interesting to evaluate which variables significantly influence the performance of a subject; relevant variables may be continuous (e.g. word frequency and familiarity or visual complexity of the stimulus) or categorical (e.g. the semantic category). In these cases one can make use of logistic regression analysis (Aitkin

et al. 1989), a transformed linear model where the correct response is scored 1 and the wrong response 0. The variables included in the model can be evaluated, ruling out their overlap. For applications concerning the study of semantic memory, see Laiacona et al., 1993a, b; Capitani et al., 1993. 3. Sometimes it is possible to analyse the patient’s performance by means of a binomial model, i.e. as a sequence of trials, independent of each other and governed by a general success probability. This is the case when the patient responds with a forced multiple choice paradigm. We can calculate the success probability expected by chance, and the score region where the responses are significantly different from chance. After a given number of correct responses, we can estimate the confidence limits of the rate of correct responses, which may be asymmetric (“likelihood profile”, Aitkin et al., 1989): this avoids the inclusion of impossible values, i.e. above 1 or below 0. 4. On the basis of the reliability of a given test, we can set the confidence limits of the score for a single subject, by means of the rules that link the variability between subjects with that within subject (Gulliksen, 1987; Huber, 1973). In this way we can verify if the performance of a subject at two different and subsequent examinations has really improved. We find the best example of this approach in the standardisation of the Aachener Aphasie Test (Willmes, 1985; Willmes et al., 1988). 5. In analysing single subjects, it is interesting not only to verify if performances vary from one examination to another, but also if they are consistent. For example, in repeated confrontation naming, it is useful to study if right or wrong responses always concern the same stimuli or not. Recently Faglioni and Both (1993) have criticised the methods used to date in approaching this problem, and have suggested a solution based on the analysis of stochastic models and Markov chains. Their paper reports an example of this method applied to naming analysis. Stochastic methods based on Markov chains are a very interesting method,

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recently made available to the neuropsychologist. Working on single cases, they enable a powerful analysis of qualitative and quantitative models of cognitive impairment, particularly of learning and forgetting (Faglioni et al., 1992; Kingma & Van den Bos, 1987a, b).

NEUROPSYCHOLOGICAL TESTS AND DIAGNOSTIC PRACTICE Normality and mastery Neuropsychological tests are used in clinical practice to assess the normality of a given subject. It is worth underlining the difference between two concepts that sometimes are not adequately differentiated: mastery and normality. The former is the ability with which a given task is accomplished, independent of how many subjects are able to do it. On the contrary, normality is a judgement concerning a reference sample. It tells us if the performance of a subject is explained (with the limit of chance deviation) by a given model (more or less complex). For example, on the basis of a reference sample and by means of multiple regression analysis, we can determine the expected score on the Token Test of a healthy subject whose age and education are known: if their actual score is lower, we should wonder if the observed discrepancy results from chance or if we need to add to the basic model a factor (e.g. an illness) that lowers the performance. From the mastery perspective, the effects of age and education are not relevant, but they are fundamental from the normality perspective. Elderly and less well educated subjects can show performances that are normal with respect to their reference sample, but nevertheless below the level necessary to master a given task.

Scores adjusted for other variables If we want to adjust a score, e.g. for age and education, we need to estimate the contribution of these variables by means of a linear covariance model (Aitkin et al., 1989) and then we can adjust the observed score in order to remove the influence of the concomitant variables. As an example, in

Raven’s progressive matrices (PM47, Basso et al., 1987) the best linear model of the expected score of a subject (j) is: yj = 29.69 + 5.18[ln (100 - agej) - 4.03] + 2.98[(Veaucationj) - 3.21], 29.69 is the average PM47 in the reference sample; 4.03 and 3.21 are the means of In (100-age) and of education (square root); agej and educationj are age and education. The adjustment brings the observed score back to the value expected if age and education had been at their average; this adjustment can be made simply by reversing the sign of the parameters of the regression equation, and adding the obtained value to the raw score. Some important consequences of adjustment on the scale properties of the tests are discussed by Capitani and Laiacona (1988, 1997).

Outer and inner tolerance limits We will now consider the normality judgement. Generally, a threshold is fixed on the score distribution of a test, under which performances are judged to be not normal. From the perspective of inferential statistics, we should evaluate the risk of error associated with this judgement. Tolerance limits can be used to find the optimal threshold on the basis of the number of subjects in the sample and of the risk we want to control. Tolerance limits may be parametric or nonparametric (Ackermann, 1985), and only the latter are reliable when the shape of the scores’ distribution is not strictly normal. Moreover, the use of nonparametric tolerance limits is in order when working with scores adjusted for age and education (Capitani & Laiacona, 1988, 1997). We should distinguish between two types of tolerance limits: the outer and the inner limit. The error risks in declaring that a subject is not normal or that a subject is normal cannot be controlled with a unique threshold. We need two thresholds: the outer limit, under which the subject’s score can be declared not normal with a controlled risk, and the inner limit above which the subject’s score can be declared normal with a controlled risk. If we take as a reference the tail corresponding to the worst 5% of the population, the outer limit will be more peripheral, and the inner limit more central than the 5th percentile of the sample. In the score range included between these different thresholds the

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error risk is not controlled for either the normality, or non-normality judgement. The width of this “uncertainty region” is inversely proportional to the number of subjects belonging to the reference sample. An example of this procedure applied to a screening test for cognitive decline is reported by Brazzelli et al. (1994).

Normality judgement and test reliability As pointed out earlier, there is a certain oscillation of the observed score around the true score, due to imperfect test reliability. Some authors have stressed the relevance of this point when tests are used for diagnostic purposes (Willmes, 1985). If the test reliability is low and the confidence limits of a single subject’s true score are wide enough, a given patient could score, by chance, sometimes above and sometimes below the thresholds, and repeated examinations would give rise to inconsistent diagnostic judgements with respect to the critical region of the outer 5% of normal sample. If we use outer and inner tolerance limits, it is possible for the subject to score sometimes within the uncertainty region, and sometimes in a region where the risk is controlled. In principle, to judge that a given subject is not normal, we could require that even the upper confidence limit of his/her true score should be below the outer threshold, and vice versa for judging a subject as normal. However, according to this policy, the scale extent where no definite judgement is possible would further expand. We should conclude that the simultaneous control of all risks is expensive and can be obtained only with very reliable tests and large reference samples.

Univariate and multivariate tolerance limits When two constructs have a special link (e.g. word comprehension and repetition), it may be interesting to assess whether the combination of their measures is normal as a whole. Even if both measures taken separately are within the norm, it does not follow that they will be still normal when considered together. For instance, a systolic blood pressure of lOOmmHg is still in the normal range, and the same applies to a diastolic pressure of 90mmHg; however, a blood pressure of 100/90 is certainly unusual. There are methods for

constructing tolerance limits for the set of two or more variables (Ackermann, 1985), which may be useful when a diagnosis stems from the comparison between two or more measures.

Normality judgements and discriminant analysis Discriminant analysis is a group of different techniques that allow us, on a probabilistic basis, to classify subjects into groups providing that we have previously collected enough observations for each of these groups. If the groups are only two, we can use logistic regression analysis; when groups are more than two, other statistical methods must be applied, parametric or nonparametric, which are generally included in the standard statistical libraries (see later). In principle, we could also use discriminant analysis when we wish to classify subjects as “normal” or “not normal”. What are the differences between classifications based on discriminant analysis and on tolerance limits? In the first place, for constructing tolerance limits of the normal population we need only one reference group, composed of normal subjects, whereas for discriminant analysis at least two reference samples should be available. In the former case (tolerance limits) it follows that the judgement of “not normal” is a “negative” diagnosis and does not require that subjects be classified in any precise diagnostic category. With discriminant analysis, on the other hand, the predetermined reference samples should cover all the diagnostic alternatives. The different approaches of discriminant analysis and tolerance limits can be better clarified through an example. Let us assume that in a pathological group, for instance of AD patients, 30% of the subjects are not impaired in a given cognitive ability. As the best threshold between normality and AD should optimise the number of correct group assignments, this threshold will be influenced by the percentage of AD patients that are normal on this cognitive task. Consequently the diagnostic threshold between AD and normal subjects will be higher than the normality threshold obtained through tolerance limits. It follows that some normal subjects with low but still normal performances on

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this task, as regards tolerance limits, will be classified as AD patients by discriminant analysis. It should be borne in mind that some true pathological subjects can still score within the norm on a given cognitive ability, albeit the latter may be statistically impaired in the group as a whole. It is clear that the two methods are very different. Discriminant analysis is useful where the need is to classify subjects among different nosographic groups, but can be misleading when used for normality judgements, where tolerance limits are more appropriate.

EVALUATION OF THE EFFECTS OF TREATMENTS Experimental designs for assessing drug effectiveness Clinical neuropsychologists utilise both pharmacological treatments (e.g. the therapy of Alzheimer’s disease) and behavioural (“cognitive”) treatments. As a general rule, in neuropsychological studies neither the patient nor the doctor should know whether the patient has been given the treatment under scrutiny or an inert treatment (placebo). It should be remembered that the doctor’s expectation about a treatment’s efficacy often also has a significant effect on the patient’s performances (Rosenthal, 1985). The experiment can be based on either groups or single cases: for a general review see Der Simonian et al. (1982), Pocock (1993), and Longstrath et al. (1987). Group studies entail a homogeneous treatment within each group. One can distinguish between parallel studies (each group undergoes one treatment only) or crossover studies, where the same subject is given different treatments at different moments, and each subject acts as his or her own control. Choosing between parallel or crossover designs depends on different factors: the crossover approach is more powerful and needs fewer subjects, but, in general, is feasible only if the effect is fully reversible, i.e. if we assume that the improvement stops with the end of treatment, and if the underlying pathology does not evolve

with time. In general, studies of Alzheimer patients are of a parallel type. Several neuropsychological measures are used in clinical trials concerning Alzheimer’s disease: they range from general, compact, and comprehensive tests, such as the MMSE (Folstein et al., 1975) or the MODA (Brazzelli et al., 1994), to more detailed tests focused on single abilities. The tests used for assessment should have normative data, good reliability, and should have been previously used for determining the natural evolution of the disease. This allows us to evaluate the rate of decline of the scores over time: only in this way is it possible to convert the difference between treated and nontreated subjects into a slowing of the expected decline. In judging the efficacy of a given treatment it is important to take into account the real size of the effect and not just its statistical significance.

Experimental designs for behavioural treatments The experimental design for the evaluation of behavioural treatments is more complex. First of all, as with psychotherapeutic treatments (Prioleau et al., 1983), there is the problem of the control group and of the placebo effect. This is particularly a problem in the study of aphasia treatment. If we take as the control group those patients who cannot participate in the treatment because of practical problems (e.g. the distance from the clinical structures), we could select the subjects on the grounds of severity, economical status, motivations, cultural background, and their use and knowledge of the language. The placebo effect is what is shared by the treatment given by trained therapists and the treatment given by untrained volunteers. Some authors have considered as control subjects patients rehabilitated by untrained volunteers who acted in the same setting as the trained therapists (e.g. David et al., 1982; Hartmann & Landau, 1987). However, even in this case, we cannot exclude the intervention of the operator’s expectations, as the therapists obviously know their qualification level. Current studies of aphasia treatment follow different approaches, and often conform to single case or crossover designs. Howard et al. (1985) studied the effect of naming rehabilitation taking

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into account “multiple baselines”: two different groups of words were rehabilitated consecutively, one group acting as a control for the other. We can further complicate the study using different treatment strategies in the different stages of the experiment. For this approach we must assume that it is possible to treat only part of the words, so that we can envisage a selective effect. This approach will be more informative if we observe stabilised patients: in this case all changes can be attributed to the treatment (both to its specificity and to the placebo effect) and not to the natural evolution of the patient. The main problems of this approach are (i) the selection of the sample, as it is rather problematic to include acute patients that are still spontaneously recovering, and (ii) statistical problems resulting from the comparison of scores possibly lying on different scales. The debate concerning the single case approach with regard to the rehabilitation of aphasic disturbances is very interesting. We refer, for a review, to Coltheart (1983) and to the debate, published in the British Journal o f Disorders o f Communications (1986), in the Forum “Evaluating intervention”: Howard and Pring criticise group studies and support the single case approach, whereas Fitz-Gibbon underlines the limits of this approach and suggests resorting more extensively to other methods such as evaluating the size of effects (and not only their significance) and metaanalysis. In any case we should underline the different implications deriving from group studies and from single case studies. With the former approach the implications of a positive result are general, i.e. it applies to all patients of that type rehabilitated in that way; whereas with the single case approach we can infer only that the patient studied shows a significant improvement. The conceptual advantage of group studies seems obvious, but problems arise when results are negative. Negative results could arise simply from having studied patients who are too heterogeneous and from the fact that questions such as “is language rehabilitation effective?” are underspecified. Metaanalysis is a useful method that allows the results coming from different studies to be pooled. With this method, perhaps, we can overcome the lack of

power of single experiments and can take into account all the positive and negative results published. As an example of meta-analysis we refer to the study by Robey (1994) on aphasia rehabilitation, where one can find an illustration of the method used, a debate on the power of the experiments, and updated references on this topic.

ADVANCES IN DATA ANALYSIS New methods of data analysis In the last 10 years the broad use of personal computers (PCs) has radically changed data management in all experimental fields. Nowadays all researchers have at their disposition high computational power and comprehensive statistical libraries. The standard statistical methods (such as variance, covariance and regression analysis, contingency tables analysis, simple nonparametric methods, factorial analysis, etc.) are available in easy-to-use statistical packages, such as the SAS, the SPSS, the GENSTAT etc. The evolution in statistical methods can be considered from two points of view: (a) better choice of the methods appropriate for simple problems, such as the comparison of two groups, so that the computation of the significance level is closest to the real probability evaluation of the risk of being wrong in claiming a given result; (b) the possibility of coping with more complex problems, for which, previously, no satisfactory methods were available to non-specialists. Until the last few years, the most accurate solutions for simple problems were hampered by a shortage of programs. As an example, in comparing two groups very often the researcher automatically uses the Student’s i-test, even when this method is not appropriate and allows only a rough evaluation of the error risk. An interesting review of these problems and of the available solutions has been made by Wilcox (1987), to whom the reader is referred for a careful discussion of this topic. Myers (1990) is another useful textbook. Controlling the power of the experiment is very often a neglected aspect. The missed rejection of a null hypothesis (lack of effects or differences)

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prevents us from deciding, with a controlled risk, if the two groups under consideration really belong to the same population. With rather simple experiments, however, we can effectively control this risk. With this approach, the size of the effect to which the experiment should be sensitive must be defined. For a wide discussion on this topic we refer the reader to Cohen (1988). Finally, we will mention a recent example of the radical improvement in the analysis of “simple” problems. For a set of nonparametric methods, such as the Wilcoxon test, the analysis of contingency tables 2 x n, etc., some procedures (Mehta & Patel, 1992) allow us to compute not only the asymptotic, but also the exact probability of having sampled by chance the observed data under the null hypothesis. These programs can work by simulation methods (Monte Carlo estimates) and can sample in a very short time a huge number (in the order of tens of thousands) of simulated cases with which they compute the probability of observing the data in question. This is a new approach to the computation of significance, and in the near future it could be widened to include more complex and general statistical models. Coming now to more complex problems, we should remind the reader of the advantages of the procedures based on generalised linear models. The general structure of these models enables unification, from a more abstract perspective, of variance, covariance, multiple regression analyses, the analysis of multidimensional contingency and of the survival tables, and logistic regression analysis. For these types of analyses, the GLIM is a standard program. Its theoretical basis and applications are presented by Aitkin et al. (1989). As already mentioned, logistic regression allows us to analyse more deeply and satisfactorily some problems that are common in clinical and experimental neuropsychology. For example, in the analysis of confrontation naming, if we want to reveal which factors influence the patient’s performance, we can design a linear model, with a binomial error, where the answers have a dichotomic value (1 for the right and 0 for the wrong response). Taking into account all the pictures, we can check the influence of a set of variables (e.g. the name frequency, its category, the visual complexity

of the corresponding picture etc.) disentangling the exclusive effect of each variable from its overlap with the others. An example of this procedure and the GLIM macro instruction for the automatic analysis of a naming task is reported by Laiacona et al. (1993b) and by Capitani et al. (1993). We feel it useful to introduce another procedure that might foster neuropsychological research even if it is still marginally represented in the literature: the analysis of LISREL models (Joereskog & Soerbom, 1989), which consists of different subgroups of simpler models, among which confirmatory factorial analysis (CFA) has some interesting applications. CFA is a generalisation and an extension of the classical factorial analysis (exploratory) and enables the formulation of clearcut hypotheses about the relationships between observed and latent variables that are explicitly declared at the outset of the study. For example, we can assume that, within a given neuropsychological battery, certain tasks are influenced by some latent variables and not by others: we can statistically verify this hypothesis, testing the significance of the connections between observed and latent variables, as well as those between the latent variables themselves. For these methods, which because of their complexity cannot be further elucidated in this chapter, we refer the interested reader to some introductory texts (Byrne, 1989; Hayduk, 1987) and to the statistical program LISREL (Joereskog & Soerbom, 1989) that is available singly or is assembled in some standard statistical packages. Finally, we would like to recall the potential impact on neuropsychological analysis of stochastic models based on Markov chains, with particular reference to the study of memory (Kingma & Van den Bos, 1987a, b; Faglioni et al., 1992). Recently, Faglioni and Botti (1993) applied this method to consistency analysis in a picture confrontation naming task; we refer the reader to this paper for a critical review of the different methods formerly employed for this problem. The method suggested by Faglioni and Botti hypothesises that words are in two possible states (inside or outside the lexicon) and, in the former case, that they can be retrieved at each trial on a probabilistic basis. Taking into account the performance of a given subject on repeated trials

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we should consider how many words are always retrieved, how many are never retrieved, and how many are inconstantly retrieved. Statistical analysis calculates the percentage of words still present in the lexicon and the probability of their actual retrieval with the value of the corresponding parameters and confidence limits. In this way, we can judge whether the subject presents a storage degradation, or access difficulties or both. The model suggested by Faglioni and Botti is a very general one, and allows the introduction of some other interesting parameters in order to quantify, for example, if the fraction of words that are retained within the lexicon changes over time or after

treatment. However, we should remember that the general analysis of these models, apart from some rather simple instances presented in the paper by Faglioni & Botti, requires complex mathematical programs that are not yet available for personal computers.

ACKNOWLEDGEMENTS We are deeply indebted to Professor P. Faglioni for his invaluable teaching. Dr. R. Allpress revised the English text.

5 Neuroimaging Methods in Neuropsychology Daniela Perani and Stefano F. Cappa

scientific status to the study of anatomo-clinical correlations altogether. The renaissance of interest in the neurological side of neuropsychology is relatively recent, starting from the 1960s, and can be considered as the consequence of several factors. In the first place, developments in neurophysiology, showing the high degree of specialisation present at each level of the nervous system, have finally discredited the idea of “equipotentiality” of nervous tissue. The influence of several researchers worldwide, such as Hecaen, Luria, and Geschwind, must not be neglected: besides their personal contributions, they prompted a rediscovery of the large body of anatomo-clinical knowledge that had disappeared from the scientific arena during the “globalist” period. Finally, a major breakthrough has been the development of neuroimaging methods. These tools have provided a new impulse to the study of the neural basis of cognitive function, and have extended the field of inquiry from lesions to functional investigations of brain activity in normal subjects engaged in cognitive tasks. The aim of this chapter is to provide an overview of neuroimaging methods in cognitive research.

INTRODUCTION The date of birth of neuropsychology as a specialised field of inquiry is often said to coincide with the publication of the first case study of a cognitive disorder (aphasia), which included a postmortem study of the brain. Paul Broca, reporting in 1865 the case of a patient with a severe disorder of language production, whose brain was shown at autopsy to harbour a softening centred on the third frontal convolution, inaugurated the anatomoclinical method in neuropsychology. The importance attributed to the investigation of the neural basis of cognitive functions has since waxed and waned in the history of neuropsychology. The early period (from Broca’s observation to the First World War) was, with a few exceptions, characterised by “localisationist” doctrines. These tended to ascribe complex functions, such as auditory language comprehension, to circumscribed cerebral areas, which were localised on the basis of anatomo-clinical correlation studies in patients. This era was followed by a period of supremacy of “globalist” theorising, which denied 69

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Technical information has been kept to the minimum required for a correct interpretation of the practical applications of the different methodologies. Neurophysiological methods, which represent the main complementary resource for cognitive neuroscience, are discussed in Chapter 3 by Mecacci and Spinelli.

Historical aspects The anatomo-clinical method is based on the observation of a patient’s clinical picture, combined with the results of the macroscopic and microscopic pathological examination of the brain post-mortem. This type of investigation of course provides a precise morphological definition of a cerebral lesion. However, the limitations are self-evident: as a rule, the time of the clinical observation is distant from the moment of pathological evaluation, making the symptom-lesion correlation difficult to interpret. In the case of vascular lesions, the patient’s demise is often due to neurological complications, such as brain oedema, or to further strokes, which modify both the clinical picture and the pathological findings. With a few exceptions, this approach can be applied only to single cases, as the lack of homogeneity in the collection of clinical and neuropsychological data and in the pathological examination itself hampers the comparison between individual patients. The development of neurosurgery seemed to open a new avenue of investigation. Actually, the characteristics of some of the neurosurgically relevant pathologies, such as brain tumours, sometimes prevent useful anatomo-clinical correlations, because of their progressive nature. Furthermore, intra-operatory definition of anatomical localisation was often imprecise. The most remarkable exception to these limitations is functional neurosurgery, in particular for epilepsy. Studies of patients with localised cortical ablations are one of the most productive areas of neuropsychological investigation (Milner, 1971). Another important source of information has been the study of war injuries, in particular penetrating bullet wounds, in large series of veterans (Luria, 1970; Newcombe, 1969; Teuber, 1962). Also in this case the precision of lesion localisation was limited in the older series, in which

the only methods for assessment were the plain skull x-ray, showing the penetration point, and the surgical reports. The birth of neuroradiology in the 1920s, with the introduction in clinical use of cerebral angiography and pneumoencephalography, initially had a limited impact on neuropsychological research. The methods were invasive, preventing any pure research application. Furthermore, as already observed, the prevailing theoretical climate in psychology between the two world wars was largely hostile to cerebral localisation. Until the 1960s, the only method that was sometimes used for a gross localisation of brain lesion was the electroencephalogram. It was at this time that the isotopic scan (brain scintigraphy) began to be applied to the study of lesion site in aphasic patients (Benson, 1967; Karis & Horenstein, 1976). The landmark study by Frank Benson tried to correlate lesion site with the clinical dichotomy between nonfluent and fluent aphasias proposed by Harold Goodglass and his colleagues (1964). The results were that nonfluent aphasics, whose speech is characterised by reduced output, short phrase length, frequent hesitations, and articulatory impairment, had lesions that involved the anterior, prerolandic region of the left hemisphere. Fluent aphasics, whose speech production rate was normal or supernormal, without articulatory impairment but with profuse phonological and/or lexical errors, had lesions limited to the retrorolandic regions of the left hemisphere. The historical importance of this study for cognitive neuroscience cannot be overemphasised, as it represents one of the first examples of application of a neuroimaging method to the study of a cognitive model. The results of this study have been repeatedly confirmed, which is remarkable given that bidimensional brain scintigraphy was a rather gross method, both from the point of view of sensitivity (a pathological permeability of the blood-brain barrier was a necessary requirement for the accumulation of the tracer) and of the precision of localisation. The following years have been characterised by an unprecedented development in brain imaging techniques, due to the rapid progress in radiological sciences and in computerised methods of data handling. The first result of these developments has

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been Computerised Tomography (CT), which, until the introduction in clinical use of Magnetic Resonance Imaging (MRI), has been the gold standard for lesion localisation in vivo. Largely in parallel with methods for the in vivo study of brain anatomy, the assessment of the functioning of the human brain (functional brain imaging) has become gradually possible. The original methods for the assessment of cerebral blood flow were the first steps of a progression that has led to emission tomographic methods (single photon emission computerised tomography— SPECT—and positron emission tomography—PET). Nowadays it is possible to measure in vivo multiple parameters of regional cerebral physiology, such as blood flow and oxidative and glucose metabolism. The most recent adjunct to the array of functional imaging methods is functional magnetic resonance (fMR), which will be discussed later in this chapter.

ANATOMICAL IMAGING Computerised tomography (CT) Technical aspects CT was the first radiological method to allow a direct visualisation of brain tissue and of its modifications induced by disease. The formation of a CT image depends on the transmission of an x-ray beam through a thin section of the brain. The transmission results in an attenuation of the radiation beam, which depends on the tissue absorption coefficient, and is measured by external detectors. These measurements are repeated for multiple entry points, at different angles. An algorithm, implemented on a dedicated computer, calculates from the attenuation data the absorption coefficients of the tissue volumes (voxels), into which the section can be subdivided. The corresponding CT image represents these elements bidimensionally (pixels): the absorption coefficient is expressed as a density unit according to an arbitrary scale (named after the CT scientist and Nobel Prizewinner Hounsfield), where 0 corresponds to the density of water, 1000 to bone

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density. These numerical values are then represented with a colour scale (usually black to white, with different shades of grey). The CT images usually reach the clinician in this form, on radiological films or as computer printouts. Significant technical developments have taken place from the introduction of CT in the early 1970s: scanning times are reduced, the sections are thinner, spatial resolution is increased and artefacts have been reduced. A crucial factor for these ameliorations has been the modification of the radiation beam/detector ratio, from the single beam/single detector of the first-generation CT to the detector ring with a rotating radiation source of fourth-generation CT. The increase in spatial resolution is due to the decreasing size of the voxels, leading to a reduction of partial volume effects (the averaging of the densities of tissues with different absorption coefficients, within the same volume of tissue). Neuropsychological applications Schematically, CT scan has been used in neuropsychological research as a tool to localise the site and extent of focal lesion, to assess and quantitate brain atrophy, and to measure hemispheric asymmetries. Focal lesions. Cerebrovascular lesions (infarctions and haemorrhages) are the localised brain lesions most frequently responsible for neuropsychological disorders in adult patients. On CT, infarcted brain is usually apparent as a focal decrease in tissue density 12-24 hours after the onset of clinical symptoms. The lesion borders are indistinct in the acute phase, which is characterised by perilesional oedema. They become more evident with the passage of time, as the CT lesion comes to reflect the circumscribed area of parenchymal necrosis (Goldberg & Lee, 1987). A CT obtained in the period between two and three weeks post stroke can give false negative results, due to the transient lesion isodensity (fogging effect: Becher, Desh, & Hacker, 1979). The ideal period for the definition of lesion site and extent in the case of infarctions is thus the chronic phase (Damasio & Damasio, 1989). On the other hand, haemorrhage lesions are evident immediately after stroke, due to

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the large difference in density between blood and brain tissue. The minimal size of a lesion visible on CT depends on the spatial resolution of the equipment, as well as on its location with reference to areas of different intensity (partial volume effect) and the quality of the examination, which requires patient collaboration. For research purposes, it is usually necessary to localise the area of altered density shown by CT with reference to anatomical structures, i.e. the main gyri or, in further detail, Brodmann’s areas (Ba). In the case of an individual patient, the accuracy of lesion localisation depends in the first place on the spatial resolution of the equipment and on the possibility of identifying “landmark” anatomical structures, such as the main sulci (Ebelin, Huber, & Reulen, 1986; Seines, Knopman, Niccum, & Rubens, 1983). It is then usually necessary to make reference to an anatomical atlas, in particular if the aim is to compare lesion location in different patients. The crucial problem is the large inter-individual variability in the size and configuration of the brain surface structure (see Thompson, Schwartz, Lin, Khan, & Toga, 1996, for a recent approach to post-mortem cortical morphometry). Several methods, with different degrees of complexity and claims to accuracy are available: • Axial diagrams: the early methods used in neuropsychological-CT research were based on the transfer of the area of altered intensity from the CT image to a standard axial diagram. Ventricular landmarks were used as references to help the manual mapping (Kertesz, Harlock, & Coates, 1979; Naeser& Hayward, 1978).The inclination of the axial CT section and its width were assumed be the same as the diagram, and the differences between the actual CT sections and the diagram from the point of view of size, sulcal pattern, etc., were disregarded. The mapping to axial section has subsequently been refined, making reference to more adequate atlases, which, while leaving open the problem of inter-individual differences have provided sections with different degrees of inclination with respect to the orbito-meatal line (Damasio & Damasio, 1989; Matsui & Hirano, 1978).

• Lateral diagrams: another simple method for lesion localisation is based on the transfer of the lesion from the CT sections to a diagram that represents the lateral convexity of the brain. Several procedures have been published and largely employed in neuropsychological research: they share the advantage of taking into account the slice inclination with respect to the orbito-meatal line, and using multiple reference landmarks, besides ventricular structures (Luzzatti, Scotti & Gattoni, 1979; Mazzocchi & Vignolo, 1978) (Fig. 5.1). These methods however, still fail to take into account the problem of inter-individual variability in gyral pattern. • Semiautomatic methods have also been proposed for a more objective and precise lesion quantification, such as the one developed by the Aachen group (Blunk, De Bleser, Willmes, & Zeumer, 1981). The lesion is first transferred to an axial diagram, with a superimposed grid. Each square of the grid is computed as damaged (1) or intact (0). These lesional scores can be manipulated in different ways: their sum provides an index of lesion size; or they can be plotted in a 3-D graph, providing a representation of the frequency of involvement of a given structure. It is possible to define a priori regions of interest on the grid, which are conventionally considered as involved by a lesion if more than 30% of the component “squares” are damaged (for examples of applications, see Poeck, De Bleser, & Graf von Keyserlingk, 1984; Willmes & Poeck, 1993). • Stereotactic mapping: stereotactic methods have been developed for functional neurosurgery, with the precise aim of taking into account individual variation in size and overall shape of the brain. The cornerstone of stereotaxy is the so-called “proportional method” (Talairach & Tournoux, 1988). This method takes as reference three lines, which have been shown to hold a constant and proportional relationship with subcortical and (to a lesser degree) cortical structures: the intercommissural line, which joins the anterior (AC) and posterior (PC) commissure, and two vertical lines perpendicular to the AC-PC line, anterior to the

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PC and posterior to the AC. Several standard proportional grids, based on this reference system and reproducing the most common brain sizes are available. The stereotactic approach is presently incorporated in most PET data analysis methods (Friston et al., 1989); Evans et al., 1992). It has also been applied to the analysis of CT images (see for example the study of von Cramon, Hebei, & Schuri, 1985, on lesion localisation within the thalamus). Vanier et al. (1985) have suggested and validated the utilisation of the lateral scannogram provided by the standard CT procedure to locate the lines of reference, with the help of bony landmarks such as the external auditory meatus. It is then possible to apply a proportional fractionation to each CT slice and make reference to the stereotactic atlas for lesion or structure localisation. The procedure is of course much simpler with MRI, which allows the direct visualisation of the AC and PC on a sagittal section (Steinmetz, Fuerst, & Freund, 1989). Dementia. CT has an important clinical role in the diagnostic evaluation of mental deterioration, because it allows clinicians to rule out potentially

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treatable causes of dementia, such as subdural haematoma or low-pressure hydrocephalus. Its usefulness in the positive diagnosis of degenerative dementia is more limited. It has been clear since the introduction of CT in clinical practice that the presence of dementia in individual patients cannot be predicted on the basis of the presence or degree of brain atrophy (except in severe cases). Several methods have been employed for atrophy evaluation. Visual inspection by a radiologist does not differentiate probable Alzheimer’s disease (AD) from normal ageing (Jacoby & Levy, 1980). Using a planimetric quantitative method, Damasio, Eslinger, Damasio, Rizzo and Huang (1983) have shown that demented subjects had significantly more atrophy than controls. The atrophy indexes were inversely correlated with the neuropsychological test scores both in AD and multiinfarct dementia (MID) patients (Eslinger, Damasio, Graff-Radford, & Damasio, 1984). Automated computed morphometry methods, which can measure the size of other cerebral structures, besides the ventricular system, have been suggested to be an effective tool for AD diagnosis (Ichinuya, Kobayashi, Arai, Ikeda, & Kosaka, 1986), but its complexity has probably prevented widespread application. Much interest

FIGURE 5.1

An example of a lateral diagram of the left hemispheric convexity, used to map CT lesion (method of Mazzocchi and Vignolo). The area of maximal lesion overlap (9 subjects out of 10) in patients with impaired sentence comprehension as assessed with the Token test, lies in the posterior part of the left superior temporal gyrus. I = insula; L = lenticular nucleus; IC = internal capsule.

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was aroused by the report that thin CT slices parallel to the main axis of the temporal lobe showed a dilatation of the transverse fissure and of the adjacent choroido-hippocampal sulcus in AD patients (De Leon, George, Stylopoulos, Smith, & Miller, 1989). The discriminative power with normal ageing was not elevated, but may be improved by simple linear measurements (Jobst, Smith, & Szatmari, 1992). A diffuse hypodensity of white matter (leucoaraiosis) can also be observed in elderly subjects, and is frequently associated with cognitive deterioration (Tarvonen-Schroder et al., 1996). Hemispheric asymmetries. The seminal anatomical observation that the planum temporale (PT) is asymmetric, with a larger left extension in most brains (Geschwind & Levitsky, 1968) was followed by many studies, which have confirmed that the two hemispheres are not the mirror image of each other. The neuropsychological interest of these observations resides in the relationship of PT asymmetry with hemispheric specialisation. Le May and Kido (1978) were the first to suggest that hemispheric asymmetries could be studied in vivo, using CT. They showed that in right-handers the most frequent asymmetry pattern was longer left occipital and right frontal lobes, while left handers failed to show any consistent asymmetry pattern. The original observation, however, was not replicated (Chang Chui & Damasio, 1980; Koff, Naeser, Pieniadz, Foundas, & Levine, 1986): the prevalent left occipital-right frontal asymmetry pattern seems to be the most frequent CT pattern in the general population, including left handers. A CT-pathological correlation study in 15 righthanded subjects (Pieniadz & Naeser, 1984) has shown a good correlation between occipital length and PT asymmetry. This observation has led to the hypothesis that the “typical” asymmetry pattern on CT is not related to handedness, but to hemispheric dominance for selected aspects of language function, such as language comprehension. This was supported by clinical observations: for example, a global aphasic with “atypical” asymmetry pattern showed an unexpectedly fast recovery of auditory comprehension (Pieniadz, Naeser, Koff, & Levine, 1983). Furthermore,

left-handers who had become aphasic after a left or right hemispheric stroke were found to have a milder disorder of auditory comprehension if the longer occipital lobe was contralateral to the lesion (as, for example, in the case of a “typical” asymmetry in a patient with a right hemispheric lesion—Naeser & Borod, 1986). These data must be considered with caution, given the evidence that the pattern of asymmetry has a limited usefulness in predicting language latéralisation in crossed aphasies: Henderson, Naeser, Wiener, Pieniadz, and Chang Chui (1984) found a typical pattern in 11 out of 15 crossed aphasies, while Naeser and Borod (in the study just mentioned) found “typical” asymmetries in 3 out of 4 left-handers who had become aphasic after a right hemispheric lesion. The reliability of planimetric measurements of hemispheric asymmetries is limited, as minimal variations in the incidence angle can result in large variations (intra-subject correlation with CT and MRI was, respectively, only 0.78 and 0.79 in a study by Chu, Tranel, & Damasio, 1994). Threedimensional morphometric MRI methods seem to provide more robust measurements of hemispheric asymmetries (see next section).

Magnetic resonance imaging Technical aspects The physical principles responsible for magnetic resonance image formation are different from those of traditional radiology, and are clearly described in several publications (see, for example, Brown & Semelka, 1995; Villafana, 1987). The present introduction will be limited to basic concepts. MRI is based on the properties of some atomic nuclei which, when exposed to a magnetic field and stimulated by a radiofrequency of defined wavelength, re-emit part of the absorbed energy as a radio signal (Fig. 5.2). Hydrogen is presently the most extensively employed nucleus for clinical applications. Whereas CT is based on a single property of the tissue (electron density), the determinants of the MR signal are multiple. Besides proton density, two other parameters, the T1 and T2 relaxation times, are essential. They express the time required by the radiofrequency-excited atomic nuclei to return to the baseline energetic level. The

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T1 relaxation time reflects the time course of the recovery of magnetisation along the longitudinal axis, while T2 reflects the decay of magnetisation on the horizontal plane. T1 and T2 depend, respectively, on the energetic exchanges of the atomic nuclei with the surrounding molecular milieu, and among themselves. In water, where the protons are dispersed in a homogeneous milieu, and the chances of energetic exchange are low, both T1 and T2 are long. The situation is reversed in fat tissue. The T1 and T2 relaxation times of the different components of the central nervous system are thus different, and reflect closely the chemical composition of the tissue (grey matter, white matter, cerebrospinal fluid) (Fig. 5.3). The T1 recuperation time (called also spin-lattice relaxation) is exponential, and its length is in the

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order of hundreds of msec, while the T2 decay time (also called spin-spin relaxation) is shorter, and is measured in tens of msec. They are conventionally expressed, respectively, as the time required to reach 63.2% of maximal magnetisation (Tl), and the time required to reach 36.8% of initial magnetisation (T2). The MR signal intensity of the different normal and pathological components of brain tissue depends on these intrinsic parameters; an important role is also played by the modalities of application of the radiofrequency, which are manipulated by the examiner. In particular, it is possible to modify the interval between the successive applications of the radiofrequency (repetition time—TR), and the timing of the detection of its “echo” (echo time—TE), in order to magnify the intrinsic differences of the

FIGURE 5.2

(A) Schematic drawing representing the excitation of an atomic nucleus within a magnetic field by a radiofrequency. This results in the emission of a “resonance” frequency. (B) Spatial resolution is provided by the superimposition of a magnetic gradient on the field: the atomic nuclei in different spatial locations can be localised according to the characteristics of the emitted frequency.

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FIGURE 5.3

Time course of the recuperation of magnetisation on the longitudinal axis (T1-A), and of the decay of magnetisation on the transversal plane (T2-B) for the main constituents of the central nervous system.

components of the tissue, and thus to increase image contrast. Fig. 5.4 shows the relative intensities of brain and CSF using a long (2s) or short (0.5s) TR. In the case of a short TR, given that the brain T1 is shorter than that of CSF, the recuperation after 0.5s will be larger, and decay will start from higher values; with a long TR (2s) this difference disappears, brain and CSF will start to decay from the same energetic level and the time course will reflect only the different T2. The echo time can make use of this difference: at 50ms the brain will appear more intense than CSF, whereas at long echo times the CSF will be more intense. The sequences used for cerebral imaging (such as multiple spin-echo) allow the manipulation of these parameters in order to differentiate optimally the components of cerebral tissue, such as grey and white matter, or to increase the sensitivity for the presence of pathological areas. As a memory aid, it is useful to remember that when an image is principally influenced by T1 (T1 weighted; short TR and TE), the signal intensity is inversely related to the length of T l, whereas with T2 weighted images (long TR and TE), the signal intensity is directly related to the length of T2.

Besides intensity, the other important parameter of the MR signal is frequency. The difference in frequency allows the spatial localisation of the resonating protons, thus providing the basis of image formation. Differences in frequency can be produced by the superimposition of a magnetic gradient on the baseline magnetic field. It is possible to perform MR sections according to any plane, both orthogonal and oblique, which represents a remarkable advantage in comparison to CT. In order to increase spatial resolution, it is necessary to detect small differences in frequency. This requires the repetition of the excitation process hundreds of times to form a complete image. With spin echo (SE) sequences, based on the application of pairs of radiofrequency stimuli, the time required for the acquisition of a series of images ranges from 3 to 15 minutes. A family of sequences called “gradient echo” (GRE), based on the superimposition of gradients to the main magnetic field, reduce effectively acquisition time. The main difference between SE and GRE is that in the latter case the magnetisation decay on the transversal plane does not depend only on “true” spin-spin relaxation, but is largely influenced by the

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dyshomogeneities of the magnetic field: this is called “effective” T2 or T2* (T2 star). The characteristics of the many commercial GRE sequences allow optimal image contrasts for different clinical indications (for an accessible introduction see Elstir, 1993). The reduction of time between sequential excitations is extremely important for functional MR (fMR) (see later): at the cost of some loss in signal to noise ratio, images can be acquired in about one second. Because the field of application of fMR is functional imaging, it will be discussed after PET. Neuropsychological applications Focal lesions. Areas of cerebral infarction appear as hypointense areas in T1-weighted images, whereas they are hyperintense in T2 (De Witt, 1986). This is due to the lengthening of both relaxation times induced by the tissue ischemia. MR is superior to CT in the early detection of cerebral infarction, even in the first few hours after

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onset (Kertesz, Black, Nicholson, & Carr, 1987). Chronic infarctions are surrounded by a hyperintense “halo”, which has been ascribed to Wallerian degeneration (Kertesz et al., 1987). Periventricular hyperintensity and clinically silent areas of altered intensity are frequently observed in patients with focal ischemic lesions. They are significantly more frequent in patients with hypertension, or other risk factors for cerebrovascular disease (Kertesz, Black, Tokar, Benke, Carr, & Nicholson, 1988), but ageing perse appears to play an important role (Ylikoski et al., 1995). In normal, elderly subjects their presence predicts poorer performance on attentional tasks and slowed information processing (Ylikoski, Ylikoski, Erkinjuntti, Sulkava, Raininko, & Tilvis, 1993). Haemorrhages are characterised during the acute phase by a short T1 area surrounded by a long T1 border. They are hyperintense in T2 weighted images (De Witt, 1986; Kertesz et al., 1987). CT thus maintains its role in the early diagnosis of

FIGURE 5.4

Dfferentiation of cerebrospinal fluid and brain tissue by the manipulation of repetition and echo times (for full explanation see the text).

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haemorrhagic lesions. In the chronic phase, MR is useful to differentiate a post-haemorrhagic area from ischemia, because of the short T1 of the former. The advantage of using MR for the topographical diagnosis of lesions associated with neuropsychological deficits lies in the excellent spatial and tissue resolution, which allows the direct detection of sulci and gyri. Anatomical MRI is the best available instrument for the in vivo study of brain morphology. It allows a detailed assessment of the morphology of neuropsychologically crucial structures, such as the hippocampus and the parahippocampal gyri (Press, Amaral, & Squire, 1989) and the mammillary bodies (Chamess & De La Paz, 1987), which can then be submitted to quantitative evaluations. Several 3D reconstruction algorithms, which can be applied to thin, high-resolution MR slices, have been developed for brain morphometry (Filipeck, Kennedy, Caviness, Rossnick, Spraggins, & Starewicz, 1989; Steinmetz et al., 1989). The most recent methods provide an accurate reconstruction of the gyral anatomy of individual subjects (Andreasen et al., 1994; Damasio & Frank, 1992): this is an aspect of practical significance, given the large intersubject variability in sulcal and gyral structures (Thompson et al., 1996), and the fact that sulcal boundaries separate functionally different areas (Rademacher, Caviness Jr, Steinmetz, & Galaburda, 1993). Stereotactic normalisation of MRI in 20 normal subjects has been shown to leave a residual variability in the perisylvian region in the order of 1.5-2cm, due to the different course of the sylvian fissure, in particular of the anterior and posterior ascending rami (Steinmetz & Seitz, 1991). A study of the parietal opercular region by the same group (Steinmetz, Ebeling, Huang, & Kahn, 1990) showed four different patterns of sulcal topography, both within subjects and within hemispheres. Dementia. MR plays an important role in the study of dementing conditions. The first investigations (Erkinjuntti, Sipponen, Livanainen,

Ketonen, Sulkava, & Sepponen, 1984), which employed low magnetic field machines, underlined the lack of white matter lesions in Alzheimer’s disease (AD) and suggested that MR could be the choice method for the differential diagnosis with vascular dementia. Subsequent investigations have indicated a more complex picture, with AD subjects showing areas of altered signal intensity, especially in the T2 weighted images. Periventricular hyperintensities and small hyperintense foci cannot be considered characteristic either of AD or of vascular dementia, as they can be found in normal elderly subjects (Erkinjuntti, Gao, Lee, Eliasziw, Merskey, & Hachinski, 1994; Fazekas, Chawluk, Alavi, Hurtig, & Zimmerman, 1987). The burden of hyperintense brain areas has been reported to be negatively correlated with regional blood flow in the hippocampus in AD subjects (Waldemar, Christiansen, Larsson, Hogh, Laursen, Lassen, & Paulson, 1994). The measurement of atrophy has been the focus of a large number of investigations, with the aim of providing a useful tool for the differential diagnosis of early AD from normal ageing. Simple methods, based on linear measurements of the mesial temporal regions, have shown fair specificity and sensibility (Frisoni, Bianchetti, Geroldi, Trabucchi, Beltramello, & Weiss, 1994; Scheltens et al., 1992). Volumetric measurements have indicated an inverse relationship between age and hippocampal volume (Bhatia, Bookheimer, Gaillard, & Theodore, 1993); a further correlation with performance on memory tests has been found in elderly, nondemented subjects (Soininen et al., 1994; Launer et al., 1995). Hippocampal, temporal horn (Killiany, Moss, Albert, Sandor, Tieman, & Jolesz, 1993), and amygdala volume (Cuenod et al., 1993) have all shown some discriminative value between AD and normal ageing. Semiautomatic methods, based on image segmentation algorithms, allow a more precise measurement of the volumetric variation of different brain structures with age (Pfefferbaum, Mathalon, Sullivan, Rawles, Zipursky, & Lim, 1994), and appear to be promising tools for early AD diagnosis (DeCarli et al., 1995). In the progressive focal neuropsychological syndromes MRI usually shows focal areas of

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atrophy (for example, of the left hemispheric language areas in progressive aphasia cases— Karbe, Kertesz, & Polk, 1993), which corresponds well with the areas of hypoperfusion and hypometabolism shown by functional imaging. A focal frontal and temporal atrophy is typically found in patients with Pick’s disease and fronto-temporal dementia (Frisoni et al., 1996; The Lund and Manchester Groups, 1994). Besides AD and vascular dementia (Corbett, Bennet, & Kos, 1994), MR has been used in other neurological conditions associated with cognitive deterioration, such as multiple sclerosis (Anzola et al., 1990) and HIVassociated encephalopathy (Hall et al., 1996). Hemispheric asymmetries. The in vivo study of hemispheric asymmetries, which began with CT scan, has been successfully approached with MRI. Kertesz, Black, Polk, and Howell (1986) have shown a marked asymmetry in the sulcal demarcation of the posterior parietal operculum, which was correlated with handedness. Steinmetz, Rademacher, Jaencke, Huang, Thron, and Zilles (1990) using MR morphometry have shown that the left hemispheric prevalence of the planum temporale is associated with a larger extent of the intrasylvian cortex behind the planum in the right hemisphere. With the same method, Steinmetz, Volkmann, Jaencke, and Freund (1991) have confirmed quantitatively the correlation between planum asymmetry and handedness, with lefthanders’ brains being less asymmetric, especially if the left-handedness was familial. This finding has been confirmed using a different methodology (Rossi et al., 1994): in this study there was also a trend towards lesser asymmetry in females. Musicians with perfect pitch have been shown to have stronger PT asymmetry than non-musicians or musicians without perfect pitch (Schlaug, Jaencke, Huang, & Steinmetz, 1995). The asymmetry of the PT (Foundas, Leonard, Gilmore, Fennel, & Heilman, 1994) and also of the pars triangularis (a portion of Broca’s area—Foundas, Leonard, Gilmore, Fennel, & Heilman, 1995) assessed with MRI has an excellent concordance with hemispheric language dominance as indicated by the Wada test.

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FUNCTIONAL IMAGING Regional cerebral blood flow (rCBF) Technical aspects The global measurement of cerebral blood flow (CBF) became possible with the Kety and Schmidt (1948) technique, based on Fick’s principle. Given that the flow can be calculated from the arteriovenous difference in the concentration of a metabolically inert and freely diffusible gas, its substitution with an isotopical tracer (such as 133Xe) allows the external measurement of the variations in local concentration (Lassen & Ingvar, 1961). Practically, what is measured is the clearance of the tracer from the different cerebral areas, which depends strictly on regional cerebral blood flow. The tracer can be given directly in the carotid artery, by inhalation, or by venous infusion. The clearance curves can be analysed with different methods: the simplest is the assessment of the initial slope (Initial Slope Index). The calculated values are to be considered as relative perfusion indexes, because of the tracer recirculation and the shunting from extracerebral flow from the external carotid artery. Neuropsychological applications The measurement of rCBF has been applied to patients with cerebrovascular lesions associated with neuropsychological disorders, and has shown that the areas of reduced perfusion are larger than the regions of structural damage shown by CT (Skyhoj Olsen, Larsen, Herning, Bech Skriver, & Lassen, 1983). These earlier observations have been corroborated with tomographic methods, such as SPECT and PET (see later). The main novelty of rCBF studies was the possibility of performing functional activation investigations in normal subjects engaged in sensorimotor and cognitive tasks, and measuring the associated modifications in regional cerebral perfusion. These pioneering investigations in the field, of, for example, language, have given interesting and somewhat unexpected results, such as the presence of a bihemispheric activation with left hemispheric prevalence (see the chapter on the neurological

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foundations of language). A predominantly right hemispheric activation was found with visuospatial tasks, such as judgement of line orientation (Hannay, Falgout, Leli, Kathaly, Halsey, & Wills, 1987) or mental rotation (Deutsch, Bourhon, Papanicolaou, & Eisenberg, 1988). The activation paradigms could also be applied to patients. In aphasics, they have been used in order to investigate the neurological basis of recovery (still an open question). Knopman, Rubens, Klassen, and Meyer (1984) showed an activation of right frontal areas in patents with temporo-parietal strokes who had shown partial recovery. The patients with good recovery had spared left temporo-parietal areas, and showed right hemispheric activation only in the early phase; later, the activation was prevalent in the left temporo-parietal region. Demeurisse and Capon (1987) found that, during a naming task, aphasics subjects had a more bilateral activation than normal subjects. However, the patients with larger left hemispheric activation had a better prognosis. Although technological advances in the last decade have made these techniques obsolete, their importance remains to be underlined, not only for historical reasons. Their results have been largely confirmed and refined with newer functional imaging techniques, such as PET and fMR: in particular, the fact that all cognitive tasks do not engage a single brain area, but complex, differentiated networks of cerebral regions.

Single photon emission computerised tomography (SPECT) Technical aspects This technique represented a major methodological advance in rCBF measurements, allowing the tomographic assessment of cerebral perfusion and its representation according to axial, coronal, and sagittal slices. Clinical applications were developed by Kuhl and Edwards (1963): SPECT is based on the use of gamma emitters, which can be inserted in appropriate molecular complexes to produce radiotracers. The acquisition of emitted radioactivity is performed by a rotating gamma camera, in line with a dedicated computer, which reconstructs the collected data and computes the

tomographic images of tracer distribution. The ideal rCBF tracer should freely cross the blood-brain barrier, have a high cerebral extraction coefficient, and display a stable captation during the time of the exam. A group of molecules belonging to the family of lipophilic amines (IMP and HIPDM with 1231), and, more recently, 90mTc HMPAO have been widely used (Lucignani et al., 1987). The distribution of these tracers, in the absence of rediffusion from brain to blood, is proportional to regional cerebral blood flow. Inhaled 133Xe can also be used for SPECT (Stokely, Sveinsdottir, Lassen, & Romner, 1980): while the previous tracers allowed only steady state measurement, the Xe SPECT can also be used to perform activation studies (see, for example, Rezai, Andreasen, Alliger, Cohen, Swayze, & O’Leary, 1993). Neuropsychological applications SPECT with [1231] HIPDM has been used in particular in patients with cerebrovascular lesions, and has confirmed tomographically the presence of areas of hypoperfusion which are larger than the structural damage shown by CT (Perani et al., 1988): for example, subcortical lesions can be associated with hypoperfusion of the overlying undamaged cortex, and supratentorial lesions can be accompanied by hypoperfusion of the contralateral cerebellar hemisphere (crossed cerebellar diaschisis—Baron, Bousser, Comar, & Castaigne, 1981). These reductions of blood flow in structurally unaffected areas probably depend on different mechanisms: particularly interesting from the neuropsychological standpoint is the possibility that the decrease in flow might be the consequence of a reduction of local metabolism, due to a “deactivation” following on from the distant lesion (diaschisis). This deactivation might be responsible for clinical events: for example, patients with aphasia or hemineglect due to a subcortical lesion have been shown to have a more severe cortical hypoperfusion than patients with subcortical strokes unassociated with cognitive impairment (Perani, Vallar, Cappa, Messa, & Fazio, 1987). This finding has been confirmed by other studies (Okuda, Tanaka, Tachibana, Kawabata, & Sugita, 1994; Skyhoj Olsen et al., 1986; Weiller, Ringelstein, Reiche, Thron, & Buell, 1990). The

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follow-up study of the same patients showed a parallelism between the recovery of neuropsychological disorders and the regression of cortical hypoperfusion (Vallar et al., 1988). SPECT with [1231] HIPDM and with [90mTc] HM-PAO has been also extensively applied to the study of dementing conditions, in particular of AD, and has consistently shown a reduction of perfusion in temporo-parietal associative cortex (see Perani & Cappa, 1995, for a review). The results are in excellent agreement with PET (Messa et al., 1994) (Fig. 5.5), and indicate that SPECT has an important role in the early diagnosis of AD (Karbe, Kertesz, Davis, Kemp, Prato, & Nicholson, 1994). The reduction is usually bilateral, but can sometimes be asymmetric, with a good correlation with verbal/nonverbal asymmetries in neuropsychological impairment (Perani et al., 1988). A good correlation of the site of hypoperfusion with the neuropsychological presentation has also been found in progressive, selective neuropsychological impairments, such as progressive aphasia (Cappa et al., 1993; Snowden, Neary, Mann, Goulding, & Testa, 1992) and frontal lobe dementia (Elfgren, Ryding, & Passant, 1996; Miller et al., 1991).

Positron emission tomography (PET) Technical aspects Positron Emission Tomography (PET), the leading method for the investigation of brain physiological processes in vivo, is based at the most general level

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on three components (Powers & Raichle, 1985): (1) a positron tomograph which allows the precise measurement of regional radioactivity in vivo; (2) a positron emitting tracer which can be used for human studies; (3) a mathematical model of the tracer kinetics which establishes the quantitative relationship between the regional radioactivity measured by the tomograph and the physiological variable under investigation. These three aspects, rooted in different fields of science, from physics to chemistry to mathematics and computer science, are in continuous, rapid development. PET tomographs include a system of detectors that can take advantage of the fundamental property of positron emitters, i.e. the interaction of positrons with electrons, resulting in the creation of two gamma photons travelling in opposite directions. The registration of these coincidence events by two opposite detectors allows the precise determination of the spatial location of the annihilation. This basic mechanism, associated with absorption correction procedures, according to the general principles of tomographic techniques, allows the measurement of local radioactive tracer concentrations which can be represented as images of brain radioactivity. In this field the advances have been in particular from the point of view of improving spatial resolution and signal to noise ratio. The recent developments of 3-D data acquisition techniques, with the retraction of the septa used for collimation (septa out) have been extremely successful from this point of view (Townsend et al., 1991).

FIGURE 5.5

Comparison of MRI, PET, and SPECT in the same AD patient. Although the structural image is not characteristic of the condition, both PET and SPECT show the “typical” AD pattern of posterior (temporo-parietal) metabolic and perfusional reduction.

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PET tracers can be isotopes of biological elements (such as oxygen 15) or of nonbiological elements which can be combined to biological molecules as markers (such as fluorine 18 in the deoxyglucose molecule). All positron emitting isotopes have a short half-life, from less than a minute to a few hours: this characteristic dictates the necessity to have isotope production by cyclotron available in the proximity of the PET tomograph. The main development in this area is the availability of smaller, dedicated cyclotrons (baby cyclotrons), which are less costly (relatively speaking) and easier to operate and maintain. The third, non-hardware area of PET development, mathematical and statistical modelling, is in a state of continuous evolution. Although most of the following discussion will be limited to modelling aspects of metabolic and blood flow measurements, it must be underlined that the field of application of PET techniques to the in vivo study of brain physiology is much broader, including other parameters, such as protein turnover or neuroreceptor binding. Although these potentialities have not, with a few exceptions, been applied to the study of cognitive function, it appears likely that they will become more and more important as the field of cognitive neuroscience moves from the system to the cellular and molecular levels of investigation. When we wrote this chapter for the first Italian edition of this textbook (1988), we could be confident that we had reviewed all the PET literature devoted to the study of cognitive function. It is a matter of satisfaction for researchers in the field to note that now any effort to cover exhaustively even a single area, such as language or memory, would be doomed to certain failure: new PET studies appear continuously, not only in specialised journals, such as Neuroimage or Human Brain Mapping, but also in publications dealing with every other discipline related to the study of cognitive function. Our endeavour will thus be limited to providing the basic information about the main methods of PET investigation, including some technical aspects that we deem necessary for the appropriate interpretation and planning of cognitive experiments. The review of specific research will be limited to the exemplification of

different approaches. The discussion will cover resting state methods, i.e. the assessment of physiological parameters, such as cerebral blood flow, while the subjects are not engaged in a predetermined cognitive activity, as well as the now prevailing field of functional activation methodology. Resting state studies Methodologies. The 18-fluorodeoxy glucose method (18F-FDG) is based on a modification of the in vitro autoradiographic method originally described by Sokoloff et al. (1977). Deoxyglucose is transported to the brain and phosphorilated as glucose, but cannot enter further metabolic pathways and is trapped in the tissue. If marked with a positron emitter, its local concentration can be measured with PET. This is one of the variables that are entered in the equation to calculate the local glucose metabolic rate, together with three constants (influx, efflux, and phosphorilation) and a “correction” constant to account for kinetic differences between glucose and deoxyglucose (Reivich et al., 1985). The oxygen dynamic steady state method (Frackowiak, Lenzi, Jones, & Heather, 1980) allows the measurement of rCBF, of local oxygen consumption (rCMR02), and oxygen extraction ratio (OER). The assessment of rCBF requires the inhalation of C 02 labelled with 150. In the lungs carbonic anhydrase converts it to circulating water, [150] H20. After a few minutes a steady state is reached, which allows the calculation of regional cerebral blood flow. The measurement of oxygen consumption requires the inhalation of molecular oxygen marked with 150. The tracer binds to haemoglobin and enters the systemic circulation: in the brain part of the oxygen is extracted for normal aerobic processes, and is transformed in labelled water, whose regional concentration at steady state depends on the oxygen extraction ratio (rOER). The rCM R02 can be calculated by multiplying rOER with rCBF and blood oxygen concentration. Both the oxygen and the glucose steady state methods are characterised by an excellent spatial resolution. They are both based on steady state

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measurements (in the case of [18F] FDG, 60 minutes after intravenous injection of the tracer, in the case of oxygen 15,10 minutes after inhalation) that must be pursued until sufficient radioactivity counts have been collected. Given these characteristics, they are not suitable for the assessment of the fast and short-lived changes of regional blood flow and metabolism due to sensorimotor and cognitive activity, but only for the study of “resting” brain function in patients with cognitive disorders due to central nervous system impairment. They allow the measurement of lesioninduced “functional” derangement, which often does not coincide with the “structural” damage shown by CT or anatomical MRI. This is of course typical of conditions that are not associated with gross tissue necrosis, as most degenerative diseases; but can also be true of vascular lesions, as already discussed for other rCBF measurements (see previous section). Neuropsychological applications. The resting state PET studies in the field of aphasia are discussed in the chapter on the neurological foundations of language (Cappa & Vignolo, Chapter 8 this volume). Recent applications include the study of recovery. Metter, Jackson, Kempler, and Hanson (1992) have shown a significant positive correlation between changes in temporo-parietal metabolism and auditory comprehension recovery, while Heiss, Kessler, Karbe, Fink, and Pawlik (1993) have shown that the glucose metabolic rates in undamaged left hemispheric areas had the best predictive value on the recovery of auditory comprehension four months after stroke. In general, there is a positive correlation between the regression of functional depression in structurally undamaged areas in both hemispheres and aphasia recovery in the early period (from one to three months post stroke) after a left hemispheric stroke of limited extent (Cappa et al., 1997). The same phenomenon has been observed in right hemispheric lesion patients with unilateral neglect (Perani, Vallar, Paulesu, Alberoni, & Fazio, 1993; von Giesen, Schlaug, Steinmetz, Benecke, Freund, & Seitz, 1994). Recovery was associated with regression of functional impairment in areas not only in the ipsi-, but also in the contralateral hemisphere.

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Resting glucose metabolism has also been investigated in a group of amnesic patients who had lesions of different aetiologies, sometimes unassociated with any structural damage on MRI (anoxia, Korsakoff’s syndrome) (Fazio et al., 1992). This study showed a widespread metabolic depression which involved all structures connected in Papez’s circuit—hippocampal regions, thalamus, cingulate cortex, and fronto-basal areas— underlining the role of this network in episodic memory. Perhaps the most important area of application of resting state methods is the study of dementing conditions (see Perani & Cappa, 1995, for a review). The original observation of decreased temporo-parietal rCMR02 and rCBF, paralleling dementia severity (Frackowiak et al., 1981) has been confirmed and refined by many [18F] FDG studies, which have indicated that this pattern is “typical” of AD (Foster, Chase, Fedio, Patronas, Brooks, & Di Chiro, 1983; Haxby, Duara, Grady, Cutler, & Rapoport, 1985). The correlation between the pattern of metabolic impairment and the neuropsychological picture has been addressed by many investigations: an excellent concordance exists between right-left asymmetries and predominant “verbal” or “visuospatial” patterns of impairment (for a review, see Rapoport, 1991). Specific correlations between different aspects of memory in AD and local glucose metabolism have also been found (Perani et al., 1993) (Fig. 5.6). In particular, this study confirmed the association of episodic memory with the structures of Papez’s circuit, and showed correlations between, respectively, short-term and semantic memory and language areas, and procedural learning and a network including cerebellum, basal ganglia, and dorsolateral frontal cortex. PET is also useful to identify the pattern of metabolic impairment in other dementing conditions associated with mostly subcortical involvement, such as progressive supranuclear palsy (D’Antona, Baron, Samson, Serdaru, Viader, Agid, & Cambier, 1985; Leenders, Frackowiak, & Lees, 1988) and Huntington’s chorea (Young et al., 1986), as well as in other diseases that can be associated with cognitive decline, such as multiple sclerosis (Brooks, Leenders, Head, Marshall, Legg,

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& Jones, 1984; Paulesu et al., 1996), or the AIDS dementia complex (Rottenberg et al., 1987). In general, these investigations have confirmed the involvement of the frontal lobe in the so-called “subcortical” dementias. Activation studies The introduction of dynamic methods for the rapid measurement of regional cerebral blood flow while subjects were engaged in a specific task has played a crucial role in the development of cognitive activation studies. These methods require the intravenous injection of a bolus of water labelled with positron emitting 150, which has a half-life of 2.1 minutes (H2150) (Herscovitch, Markham, & Raichle, 1983), or the inhalation of C1502 (Lammertsma et al., 1990). Another tracer that has been used recently is 150-buthanol (Herscovitch, Raichle, Kilboum, & Welch, 1987). PET is used for the dynamic measurement of the cerebral uptake of the tracer, which will reflect the conditions of

cerebral activity, being proportional to blood flow (Fox & Mintun, 1989). Several different data analysis methods have been developed to identify the site and extent of the modifications in cerebral perfusion associated with specific, localised cerebral activation. They are based on different approaches to the same set of problems; that is, to detect and evaluate the significance of differences or modifications in the spatially extended maps of cerebral radioactivity reflecting genuine changes in function related to the experimental paradigm. These must be separated from the noise due to different confounds, and localised with reference to brain anatomy (Fox, Mintun, Reiman, & Raichle, 1988; Poline & Mazoyer, 1993; Roland, Levin, Kawashima, & Akerman,1993; Worsley, Evans, Marret, & Neelin, 1992). This is a field in constant evolution: while the details of the different procedures can be of considerable complexity, some basic understanding of the problems of data analysis, and of the possible

FIGURE 5.6

Images of regional cerebral metabolic rate for glucose for similar axial and coronal sections in a normal subject, an amnesic patient, and an AD subject. The axial image shows the reduction of thalamic and mesial temporal metabolism in the amnesic patient, and the “typical” temporo-parietal metabolic depression in AD. The coronal images show the mesial temporal hypometabolism in both amnesia and AD (see arrows).

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solutions, are mandatory for proper experimental design and results interpretation. In this chapter, the discussion will be limited to Statistical Parametric Mapping (SPM) a comprehensive and continuously evolving set of data analysis procedures developed by the Wellcome Department of Cognitive Neurology group (Friston et al., 1989; Friston et al., 1990; Friston, Frith, Liddle, & Frackowiak, 1991a, b; Friston et al., 1995b). The reason for this choice is that SPM is the most diffuse data analysis methodology in cognitive neuroscience. SPM takes into careful consideration all the problems summarised earlier, proposing an open set of solutions within the framework of statistical theory, from the general linear model (Friston et al., 1995), to nonparametric (Holmes, Blair, Watson, & Ford, 1996) and multivariate approaches (Friston, Poline, Holmes, Frith & Frackowiak, 1996). This general approach has been also fruitfully applied to fMR (see later). SPMs are spatially extended statistical processes, which are based on the following data analysis steps: 1. Stereotactic normalisation: PET data acquired for each subject are oriented according to the bicommissural line and transformed to the standard stereotaxic space (Talairach & Tournoux, 1988). With 2-D data acquisition techniques, normalisation was a necessary step for inter-subject averaging. The low signal to noise ratio resulted in signals of limited intensity: it was thus necessary to average data from multiple subjects studied in the same experimental conditions (Fox, Mintun, Reiman, & Raichle, 1988), making any direct correlation with the individual anatomy impossible. The new 3D tomographs allow single subject studies, which allow direct (within-subject) coregistration with anatomical MRI (Watson et al., 1993). However, multiple subjects are still generally used to improve statistical power, given the low magnitude differences elicited by most cognitive paradigms (for recent developments and a general approach to normalisation, see Friston et al., 1995a). 2. Smoothing, using a Gaussian filter, in order to suppress the effects of individual anatomical

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differences and to increase the signal to noise ratio. 3. Analysis o f covariance (ANCOVA): this preliminary normalisation procedure removes global variations of regional perfusion among individual subjects and among different conditions, which are independent from the local cerebral modifications induced by the experimental manipulations. 4. Hypothesis testing, which can be performed according to several experimental designs. The most widely used, and simplest, design, is the so-called subtraction method, based on Donders’ mental chronometry approach in experimental psychology (Donders, 1969). The subtraction method requires a baseline condition (usually rest), which can be compared to an “activated” condition. In the most basic form, the radioactivity images collected during baseline and activation conditions are subtracted, and the resulting differences submitted to some form of statistical test. Within SPM, the evaluation of significance is based on an estimate of error variance in each point (voxel). A typical PET study with a 10cm field of view in the axial direction, yields about 10,000 voxel measurements: the SPM procedure measures the differences in perfusion and the error variance for each voxel, and tests them against the null hypothesis (lack of differences between baseline and activation) using a known distribution, such as Student’s t, F, or chi square). The recent versions of the SPM include also a formal evaluation of the significance of the size of the activation in number of pixels, based on the theory of Gaussian fields (Friston, Worsley, Frackowiak, Mazziotta, & Evans, 1994). This “categorical” approach, which has been extensively used in cognitive PET research, is based on a large number of assumptions: in particular, it requires what has been called the “pure insertion hypothesis” (Friston et al., 1996), i.e. cognitive processing components are considered as separate and simply additive, not interacting with each other. Only this assumption allows the (now) classic decomposition of cognitive tasks into

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multiple components, which is the prerequisite of any subtraction. A prototypical example of this approach is the Petersen, Fox, Posner, Mintun, and Raichle (1988) word processing experiment, described in detail in another chapter (Cappa & Vignolo, Chapter 8 this volume). While this approach may be perfectly legitimate at a “functional” level of analysis, it appears extremely unlikely that the set of underlying assumptions apply to actual brain function. Other approaches are, within the general linear model, the parametric and the factorial (Friston et al., 1995b). The former is based on the computation of correlations between regional cerebral activity and continuous or graded stimulation parameters: for example, Grasby, Frith, Friston, Frackowiak, and Dolan (1993) found that the activation of the hippocampus was correlated with the increase in word list length that the patients had to memorise. Price, Wise, Ramsay, Friston, Howard, Patterson, and Frackowiak (1992) have reported a linear relationship between the regional perfusion in auditory areas, and the rate of word presentation (see Buechel, Wise, Mummery, Poline, & Friston, 1996, for the results of nonlinear correlations applied to a similar experimental paradigm). Factorial design allows the study of interactions: this has been applied to combined pharmacological-cognitive paradigms (Friston et al., 1992), but might prove a fruitful approach to cognitive processing (Friston et al., 1996). The most recent proposal within SPM is the multivariate method of data analysis, which does not require the probably untenable assumption of linearity in brain response (Friston et al., 1996), and seems to be ideally suitable for the study of functional connectivity, which previously could be approached only descriptively through principal component analysis (Friston, Frith, Liddle, & Frackowiak, 1993) Neuropsychological applications. The first PET activation studies in normal subjects were performed using the [18F] FDG method, which required a protracted presentation of repeating stimuli, and thus measured a brain response averaged over a long lapse of time, i.e. in totally unphysiological conditions. It was nevertheless possible using this method to show functional

asymmetry in the temporal cortex. Verbal stimuli activated the left fronto-temporal cortex and the thalamus, while nonverbal stimuli were associated with a predominant right hemispheric response (Mazziotta & Phelps, 1985). As already observed, the availability of dynamic methods, allowing the measurement of brain responses within a more adequate time range (in the order of a minute with standard activation techniques) has resulted in a real explosion of cognitive activation studies. All the domains of cognition have been explored: language (see Cappa & Vignolo, Chapter 8, this volume), attention (Corbetta, Miezin, Dobmeyer, Shulman & Petersen, 1990; Corbetta, Miezin, Shulman, & Petersen, 1993), mental imagery (Decety, Perani, Jeannerod, Bettinardi, Tadary, Woods, Mazziotta, & Fazio, 1994; Kosslyn, Alpert, Thompson, Chabris, Rauch, & Anderson, 1994), and some of the results can be found in the relative chapters. The following examples, taken from the study of memory, are not intended to provide a full review (see Vallar, Chapter 15 this volume), but only to illustrate different approaches. Working memory is an active field of PET investigation, and has been particularly focused on the role of the frontal lobe. An interesting integrative approach has been taken by the McGill group. This is based on the selection for PET studies of tasks that are known to be impaired in patients with frontal ablations, and which have “monkey” versions for which a link with specific lesion sites within the frontal lobe has been shown. These included a visual working memory task, requiring the continuous monitoring of the responses (self-ordered pointing task), and the learning of arbitrary associations (conditional task). PET showed distinct location of frontal activation, compatible with animal studies: Ba 9 and 46 for the former, Ba 8 for the latter, bilaterally with a left sided prevalence (Petrides, Alivisatos, Meyer, & Evans, 1993a). A verbal task similar to the one used in the visual working memory experiment activated the same areas in the left hemisphere, with the addition of a ventral frontal region (Ba 10) when monitoring of externally ordered stimuli was required (Petrides, Alivisatos, Meyer, & Evans, 1993b). The role of the latter area in working memory has been recently confirmed in another

5.

investigation with the Tower of London test (Owen, Doyon, Petrides, & Evans, 1996). A complementary approach to the PET study of working memory is based on Baddeley’s model (Baddeley, 1986). Paulesu, Frith, and Frackowiak (1993) have shown that an auditory-verbal working memory task was associated with a left peri sylvian activation pattern. Comparing this activation with the one observed during a letter rhyming judgement task, it was possible to separate the areas related to the rehearsal process (mainly Ba 44) from those involved with phonological storage (supramarginal gyrus—Ba 40). Visual working memory has been associated with the activation of a network of frontal, parietal, and occipital areas in the right hemisphere (Jonides et al., 1993). Another extremely active area of investigation has been the study of long-term retention. One of the leading research problems in this field has been the discrepancy between the well known role of hippocampal lesions in producing human amnesia (Squire & Zola-Morgan, 1991), and the relative difficulty of observing hippocampal activation during PET studies of normal subjects engaged in long-term memory tasks. The hippocampus was activated in an early study (Squire et al., 1992), which contrasted a cued recall condition of word lists with a priming (stem completion) task. During retrieval, a right frontal and hippocampal activation was observed with the former, while the latter was associated with a flow decrease in the right occipital lobe. Grasby et al. (1993) found that when the activation observed with digit sequences exceeding the span was compared with that associated with a digit span task, activations were found bilaterally in the dorsolateral frontal cortex, in the precuneus and in retrosplenial areas. Hippocampal activation could only be observed with a parametric design (see earlier), i.e. correlating the blood flow response with list length (Grasby et al., 1993). Subsequent studies have found that hippocampal activation is associated with high recall conditions, due to repeated exposure and deep encoding (Schacter, Alpert, Savage, Rauch, & Albert, 1996), and in general to successful recollection (Nyberg, McIntosh, Houle, Nilsson, & Tulving, 1996). Specific correlates have also been assigned to the multiple neocortical areas associated with memory

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tasks. There is ample evidence that left dorsolateral frontal cortex activation is related to semantic encoding (Kapur et al., 1994; Shallice et al., 1994; Tulving et al., 1994); the right prefrontal cortex has been shown to be related to intentional retrieval (Shallice et al., 1994), although it is still debated whether its activation increases with successful retrieval (Rugg, Fletcher, Frith, Frackowiak, & Dolan, 1997), or is simply related to retrieval attempt (Kapur et al., 1995). The precuneus is activated in high-imagery memory tasks (Fletcher, Shallice, Frith, Frackowiak, & Dolan, 1996). This set of results is remarkable, because it has suggested important roles in memory processing for several areas, which were not predicted on the basis of neuropsychological investigations in amnesic patients. In particular, the role of the frontal cortex in “strategic” or “cognitive mediation” (Warrington & Weiskrantz, 1982) aspects of memory seems to be amenable to empirical investigation with PET. It is noteworthy that a “reverse” approach (i.e. neuropsychological investigations in patients primed by PET results) is appearing in the neuropsychological literature (see, for example, Swick & Knight, 1996, for a partial failure to find encoding and retrieval defects in patients with frontal lesions). Although the results of this integrated approach may be sometimes difficult to reconcile (see Vallar, this volume), they clearly show that PET does not simply have a confirmatory role regarding the results of lesion-based neuropsychological investigations. Other interesting insights have been provided by the study of semantic memory. Perani et al. (1995) found that animal picture recognition activated the posterior visual areas, including the left inferior temporal gyrus. For artefact picture recognition, all activations were left hemispheric and dorsal through the temporal and frontal lobes, with the exception of ventral activation seen bilaterally in the inferior temporal/fusiform gyrus and left hippocampal gyri (Fig. 5.7). Similar results have been reported by Martin, Wiggs, Ungerleider, and Haxby (1996) for a picture discrimination task, supporting different anatomical activations depending on the category of picture (living or nonliving) presented. The neural corre-

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lates of access to semantic knowledge from pictorial or verbal material have been compared by Vandenberghe, Price, Wise, Josephs, and Frackowiak (1996) using a word and picture matching task: the main finding was an extensive area of common activation for words and pictures, which included several left hemispheric areas: the temporo-parietal junction, the fusiform gyrus, the middle temporal gyrus, and a left inferior frontal area. Damasio, Grabowski, Tranel, Hichwa, and Damasio (1996) reported activations from a PET study where subjects named from pictures, famous people, animals, and tools. Naming famous people activated an area in the left ventrolateral temporal pole, while naming animals and tools activated different areas in the left posterior inferotemporal and left temporal pole. Taken together, these studies have provided evidence for an important role of temporal lobe structures (in particular, for inferior temporal cortex) in semantic memory.

Another area of extreme interest for the clinical neuropsychologist is the PET activation study of patients. This approach has to date been limited by several technical problems, which have however been largely solved by the possibility of performing single subject experiments. Group studies have been performed using simple motor tasks in patients who have recovered from motor impairment, and have shown evidence of extensive brain reorganisation (Chollet, Di Piero, Wise, Brooks, Dolan, & Frackowiak, 1991), with large inter-individual variability (Weiller, Chollet, Friston, Wise, & Frackowiak, 1992). A group of patients who had recovered from Wernicke’s aphasia has been studied with single word repetition and controlled association tasks (Weiller et al., 1995). This study showed evidence of a recruitment of right hemispheric frontal and parietal areas, not activated by normal subjects during these tasks. Examples of the single case approach can be found in Engelien et al. (1995).

FIGURE 5.7

Areas of differential activation during the recognition of (A) living (animals) and (B) non-living (tools) entities.

5.

Functional magnetic resonance (fMR) The most important recent addition to the field of functional imaging is certainly functional magnetic resonance (fMR). From the discussion of the principles of MR image formation, it should be clear that any modification in the chemical milieu of the brain, as in the metabolic changes induced by neuronal activity, will affect water molecules and, consequently, the MR signal. The main source of these modifications is the variation in cerebral blood flow coupled with the regional increases in cerebral activity associated with motor, sensory, and cognitive tasks (Raichle, Grubb, Gado, Eichling, & Ter-Pogossian, 1976). The blood-flow changes, however, are short-lasting and are quantitatively modest. A crucial role in the development of functional imaging with MR has been played by the ultrafast image acquisition techniques called Echo-Planar Imaging (EPI) (Stehling, Turner, & Mansfield, 1991). In contrast with GRE sequences, EPI does not require the repetition of the application of the radiofrequency, as the whole image is acquired within the time frame of the decay of a single MR signal (about 50 milliseconds). The EPI technique, which is based on the ultrafast application of alternating magnetic gradients, requires specific hardware, which is not included in standard clinical machines. The first functional MR study (fMR) was performed using a paramagnetic contrast agent (gadolinium DPTA), given to the subjects intravenously; the activation condition was an intermittent visual stimulation (Belliveau et al., 1991). The local concentration of the contrast agent influences tissue T2*. Using a T2* sensitive EPI sequence it was possible to acquire a series of images showing the passage of the injected bolus during a 15-second period (blood volume maps). The comparison of resting state maps with the maps acquired during photic stimulation showed a localised increase in the primary visual areas. The general principle that the rate of T2* decay is influenced by local variation in magnetic field intensity caused by changes in magnetic sensibility was then extended to endogenous molecules, leading to totally noninvasive fMR methods. In particular, blood and brain tissue differ in magnetic susceptibility because of the

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paramagnetic properties of deoxyhemoglobin. The variation in the content of oxygenated and deoxygenated haemoglobin can thus be used to acquire different MR images (Fig. 5.8). Ogawa, Lee, Nayak, and Glynn (1990) were the first to show that a reduction in oxygen content increased the contrast between blood vessels and surrounding tissue. Turner, Le Bihan, Moonen, Depres, and Frank (1991) were able to detect the temporal variation in the level of oxygenation in the living animal. The first in vivo human studies based on the level of blood oxygenation were performed by Ogawa et al. (1992), and by Kwong et al. (1992). The increase in MR signal in the occipital areas associated with photic stimulation was interpreted as the consequence of the relative uncoupling between the increase in blood flow and the increase in oxygen consumption. Given that the flow increase exceeds the increase in oxygen use by the tissue, the venous blood draining from an activated cerebral region has more oxyhaemoglobin and less deoxyhaemoglobin, which thus can act as an endogenous contrast agent. Similar results were obtained by Bandettini et al. (1992) using a motor activation task.

FIGURE 5.8

The principles of functional MR imaging using the BOLD technique (explanation in the text).

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The BOLD technique is based on the modification of the T2* signal, most likely in the venous district. However, the influx of arterial blood can also affect the T1 signal (Kwong et al., 1992), and is at the basis of the EPISTAR technique (see Cohen & Bookheimer, 1994). The application of a preparatory radiofrequency stimulus or “saturation” to reduce the signal coming from a section is used for MR angiography. This allows the detection of incoming blood in the saturated region, which results in a signal increase, and can be used to measure the differences between a baseline and an activated condition. Several groups have attempted to perform functional imaging studies with less rapid, non-EPI, imaging techniques (based on GRE sequences) on clinical scanners. Convincing results have been obtained with high magnetic fields (4.0 Tesla: Ugurbil et al., 1993), or for sensory and motor activations (Cao et al., 1994; Schneider et al., 1994), while cognitive activations seem to be more difficult to detect. The impressive development of fMR has awakened great interest in the neuropsychological community: in comparison with PET, fMR is non invasive, less expensive and more widely available, and seems thus to be the ideal candidate for cognitive activation studies. However there are still several problems with data analysis and interpretation which remain to be solved. A few seconds (5 to 10) are necessary after stimulus presentation for the signal to reach its peak: this interval represents the limit of temporal resolution, which, although superior to PET, remains far from the time window of neurophysiological techniques. The ability to study the entire brain is still limited to a few centres: usually the acquisition is limited to a number of sections. The activation-induced modification of the MR signal is modest, in the order of 2-5% at 1.5 Tesla, and thus difficult to disentangle from noise and temporal fluctuations. The most serious problem is caused by the presence of artefacts. The high spatial resolution of the technique has a consequence that even minimal head movements produce huge variations in pixel intensities. In the case of image subtraction, these movement artefacts can produce false areas of activation. Image co-registration algorithms are

effective in reducing this risk (Woods, Cherry, & Mazziotta, 1992). Signal from venous vessel not related to the activation is another problem, which can be solved by preliminary MR angiography. Activation studies As in the case of PET, methods of data analysis are in constant evolution. The high spatial resolution and good signal-to-noise ratio are ideally suited for single subject studies, which are however usually associated with some form of group analysis As in the case of PET, the activation studies can be analysed with image subtraction (activation minus control), followed by some form of statistical testing. The areas of significant activation are then usually mapped on anatomical images from the same subject. fMRI allows another class of analyses, based on the time series of the activation. Each pixel response can be cross-correlated over time with a reference function representing the time course of the expected activation, taking into account the latency between the stimulation and the haemodynamic response. As most of the artefactual signal over time is due to events, such as head movements, blood pulsation, etc., which occur at random with respect with the time course of the activation, these methods can be useful to remove artefacts (Bandettini, Jesmanowicz, Wong, & Hyde, 1993). A similar approach, within the general SPM framework, is based on multiple regression analysis (Friston, Jezzard, & Turner, 1994; Friston et al., 1995). Nonparametric statistical approaches have also been recently proposed (see, for example, Stem et al., 1996). The anatomical location of the activations shown by fMRI have been “validated” with the comparison to those observed with PET using the same paradigm (auditory-verbal short-term memory: Paulesu et al., 1995; face matching: Clark et al., 1996). Neuropsychological applications The characteristics of the MR setting require the development of dedicated methods for stimulus presentation (for a discussion, see Cohen, Noll, & Schneider, 1993). It is thus not surprising that the first applications were devoted to simple motor

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tasks: for example, Kim et al. (1993) studied subjects while they were performing sequential thumb opposition movements. An asymmetry was observed in the primary motor cortex activation: left finger movements were associated with a strict contralateral cortical activation, while on the right side both ipsi- and contralateral activation could be observed, in particular in right-handers. Rao et al. (1993) have shown a contralateral activation for simple flexion-extension movements, while complex, sequential movements were associated with a more extensive activation, which included the somatosensory cortex, the supplementary motor area, as well as premotor areas bilaterally; the latter areas were also active during imagined execution of the movement. Visual perception and visual imagery have also been areas of intensive investigation (see Tootell, Dale, Sereno, & Malach, 1996, for a review). An exquisite specialisation has been shown to exist in the inferior temporal cortex, with a region in the fusiform gyrus selectively activated by faces and a nearby temporo-occipital area activated by letter strings (Puce, Allison, Asgari, Gore, & McCarthy, 1996). Visual cortex activation has been reported during visual imagery tasks (Le Bihan, Turner, Zeffiro, Cuenod, Jezzard, & Bonnerot, 1993). Language studies initially focused on word generation tasks (Hinke et al., 1993; McCarthy, Blamire, Rothman, Gruetter & Shulman, 1993;

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Rueckert et al., 1994). These were mainly confirmatory studies, which indicated a left hemispheric frontal opercular activation. A more complex pattern is shown by the comparison of letter and semantic fluency (Paulesu et al., 1997) (Fig. 5.9). In comparison with resting state, both tasks activated the anterior triangular portion of the left inferior frontal gyrus (IFG) and the left thalamus. There were also areas activated in one task but not in the other: the posterior opercular portion of the left IFG for phonemic fluency, and the left retrosplenial region for semantic fluency. The passive presentation of meaningful and meaningless verbal stimuli activates both superior temporal lobes, with an extension superior to that associated with nonverbal noise (Binder et al., 1994); the response amplitude was correlated with presentation rate (Binder, Rao, Hammeke, Frost, Bandettini & Hyde, 1994). Left-lateralised activation in the frontolateral and parieto-occipital cortex was associated with semantic monitoring of single words (animal names) (Binder et al., 1995). This activation was shown to be reliable across subjects and task repetitions, indicating that fMRI is a promising tool for the assessment of language dominance. The size of left hemispheric activation, elicited by a sentence comprehension task, has been suggested to be related to syntactic complexity (Just, Carpenter, Keller, Eddy, & Thulborn, 1996).

FIGURE 5.9

Brain activation during a word fluency task measured with fMRI: (A) phonemic verbal fluency; (B) semantic verbal fluency (adapted from Paulesu et al., 1997).

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In the memory field, Paulesu et al. (1995) have replicated the results of a PET study of auditory-verbal and visuo-spatial short-term memory with fMR, with a good correlation in two out of three subjects (Fig. 5.10). Prefrontal activation, with a right-sided prevalence, has been observed during a spatial working memory task (McCarthy et al., 1994). D’Esposito et al. (1995) have shown prefrontal cortex activation during dual task performance, but not during single working memory conditions, supporting the role of the frontal lobe in the central executive component of the working memory model. Stern et al. (1996) have been able to show bilateral hippocampal and parahippocampal activation during novel picture encoding in a recognition memory task. fMR studies have also shed new light on the functions of the cerebellum: rather unexpectedly, dentate nucleus activation has been observed during cutaneous stimulation and discrimination (Gao et al., 1996), and even during problem solving (Kim, Ugurbil, & Strick, 1994)

fMR has also been applied to the study of clinical populations. Hemiparetic subjects after a perinatal lesion showed a similar activation in the healthy hemisphere for both ipsi- and contralateral hand movements (Cao, Vikingstad, Huttenlocher, Tolwe & Levin, 1994). The V5/MT activation induced by visual motion (Tootell et al., 1996) was absent in developmental dyslexics (Eden et al., 1996).

Magnetic resonance spectroscopy (MRS) The modifications in cerebral metabolism induced by neural activity can also be assessed with in vivo magnetic resonance spectroscopy (MRS), using the 1H nucleus. In vivo spectroscopy allows the measurement of substances such as lactate, glutamate, and glucose, providing information on the glycolitic processes. The analysis is performed on regions of interest with a volume in the order of one cubic centimetre, and requires long acquisition times (several minutes) (Shulman, Blamire, Rothman, & McCarthy, 1993). Using this method, Chen, Novotny, Zhu, Rothman, and Shulman

FIGURE 5.10

Comparison of the regional activations during an auditory-verbal (a) and visuo-spatial (b) working memory task assessed with PET. Activation foci associated with phonological (c) and visuo-spatial (d) store. (Kindly provided by E. Paulesu.)

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(1993) have been able to measure variations in glucose metabolism induced by photic stimulation in the occipital cortex. Recent developments include multislice techniques, which have been already applied to clinical populations (Tedeschi et al., 1996).

CONCLUSIONS The application of neuroimaging methods to the study of cognitive functions has enjoyed an unprecedented development in the last few years, and is presently one of the cornerstones of cognitive neuroscience. This chapter has tried to provide an overview of the different research tools that are presently available to this field of research (with the exclusion of electrophysiological methods, which are described by Mecacci and Spinelli, Chapter 3 this volume). Our major aim has been to emphasise the strength and weaknesses of the different imaging tools from the point of view of the cognitive researcher or neurologist. To summarise, we can conclude that anatomical MRI represents at the moment the gold standard for in vivo lesion localisation and for studies of normal human anatomy. Methods for 3D reconstruction are now widely available; the areas of developments are automation of image segmentation and methods for cortical surface modelling (Loftus, Tramo, & Gazzaniga, 1995; Tootell et al., 1996). In the field of functional imaging, PET is the reference method. Recent methodological developments have remarkably simplified data analysis, and allow the activation study of single subjects, normal and lesioned. However, the high costs of the method are probably not going to decrease remarkably in the short term, and PET will remain the privilege of a few centres. Many cognitive researchers are entering the field of functional magnetic resonance, because of the wider availability and lower maintenance costs, and it appears possible that in the near future fMR will become the privileged method for cognitive activation studies. SPECT is widely available, and has been used in the neuropsychological field quite extensively. If used appropriately, it can provide important information

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supplementing structural imaging modalities, in particular in the study of dementing disorders. The relationship between the results of PET and fMRI imaging and the corpus of knowledge derived from anatomo-clinical and, more recently, clinicoradiological correlation study is not straightforward, and is the focus of a lively debate (see also Vallar, Chapter 6 this volume). The results of these different research methods are not directly comparable, but need to be integrated in a comprehensive framework that takes into account the strengths and weaknesses of each approach, and its unique contribution to the understanding of the neural basis of cognitive function. Functional imaging techniques allow the investigation of brain activity in normal, undamaged individuals, directly during the actual performance of a cognitive task that has been selected by the experimenter on the basis of a predicted relationship with brain function. It is hardly surprising that this type of investigation provides results that are not totally coincident with the findings of patient correlation studies, which are based on the observation of a lesion site, and of the accompanying modifications in cognitive processing (some examples have been discussed in relation to PET memory studies). In the first place, a total coincidence of the results between the two approaches would make the contribution of functional imaging largely trivial, and confine it to a confirmatory role. The reproducibility of PET results has been addressed experimentally. Although it is now well known that minimal modifications in the experimental paradigm, such as rate of stimulus presentation (Price et al., 1994), or practice with the stimuli (Raichle et al., 1994) can result in significant modification of the site and size of brain response, a recent European community study has shown excellent reproducibility across Centres, PET scanners, and cultures using a standardised experimental procedure (Poline, Vandenberghe, Holmes, Friston & Frackowiak, 1996). The main theoretical problem remains the interpretation of the regional patterns of activation or deactivation of brain areas. It must be underlined that the interpretative issue will remain crucial, even if all the technical limitations of functional imaging methods, such as spatial and temporal

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resolution, data analysis, and reliability, could be eliminated. Important advances can be expected from the integration of different imaging modalities in order to obtain optimal spatial and temporal resolution, for example by combining PET with neurophysiological techniques, such as MEG, which have exquisite temporal resolution (see, for an example of this approach, Heinze et al., 1994). The information processing models that have been prevalent in cognitive neuropsychology were typically compatible with the compositional analysis of PET tasks, and have informed a general approach to PET activation studies that tried to map

the boxes and arrows of cognitive models to specific brain regions. This type of approach has provided interesting results, but is not directly connected with any neurobiological theory of how the brain implements cognitive functions. The most influential alternative to this approach is related to connectionist (neural networks) modelling, and might find its PET methodological counterpart in nonlinear data analysis. Although it is too early to evaluate this approach, there is no doubt that the time is ripe to consider seriously the need for neural modelling as a necessary intermediate step between cognitive theory and behaviour.

6 The Methodological Foundations of Neuropsychology Giuseppe Vallar

Roger W. Sperry, who is well known to neuropsychologists for his seminal investigations of split-brain patients. A main feature of the recent developments of neuropsychological research, in addition to the production of a great deal of empirical data, has been a debate on the methodological foundations of the discipline. This chapter will discuss some main methodological issues, even though, when appropriate, reference will be made to specific historical periods in the development of neuropsychology. Neuropsychology, since its inception, has had two main aims. As a medical discipline, neuropsychology investigates the pathological modifications of cognitive and emotional processes, produced by brain damage or dysfunction, with diagnostic and therapeutic aims. Neuropsychology, however, has never been confined to this clinical dimension, developing instead a main heuristic component, which takes advantage of brain-damaged patients in whom mental processes are defective, treating them as experiments o f nature (see an early discussion of this method in Bernard, 1865).

In the last 30 years, a considerable development of human neuropsychology has been taking place. An indication of this is the number of journals specifically devoted to this discipline. In the 1960s, Neuropsychologia (1963) and Cortex (1964) were founded, in the following decade Brain and Language (1974), and in the 1980s Brain and Cognition (1982), Cognitive Neuropsychology (1984), Aphasiology (1987), the Journal o f Cognitive Neuroscience (1989), and Neuropsychology. In addition, neurological journals such as Annals o f Neurology, Archives o f Neurology, Brain, Journal o f Neurology, Journal o f Neurology Neurosurgery and Psychiatry, Neurology, and Revue Neurologique, still publish neuropsychological articles, which also appear in psychological journals (e.g. Cognition, Quarterly Journal o f Experimental Psychology, Journal fo r Experimental Psychology). This is also the case of neuroscience journals such as Behavioral and Brain Sciences, Experimental Brain Research, and Neuroreport. The role of neuropsychology within the human behavioural sciences is also witnessed by the Nobel Prize 1981 awarded to 95

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Two heuristic distinguished.

related

scopes

may

be

1. The investigation of the neural bases o f mental functions, through the anatomo-clinical correlation method, used since the early 19th century, and with the recent functional neuroimaging methods. 2. The investigation o f mental functions p erse; the study of patients with specific deficits may provide useful information to elucidate the functional architecture of mental processes, also independent of their neural correlates. The chapter comprises five sections.The first discusses the anatomo-clinical correlation method. A useful reading of this section presupposes a minimal knowledge of the basic technological foundations of the main neuroimaging techniques: Computerised Tomography (CT), Magnetic Resonance Imaging (MRI), Single Photon Emission Computerised Tomography (SPECT), Positron Emission Tomography (PET), functional Magnetic Resonance Imaging (fMRI) (see Perani and Cappa, this volume).The second section considers the contribution of connectionist modelling.The third is concerned with the method that, after World War II, replaced the traditional clinical assessment: group studies in braindamaged patients, whose performance on standardised tasks is compared with that of normal subjects, matched for relevant neurological and demographic variables. The fourth section considers the approach of cognitive neuropsychology, which has been very influential in the last 30 years. The fifth section discusses a number of specific controversial issues raised in the preceding sections: associations and dissociations among neuropsychological deficits, the concept o f syndrome, and group vs. single case studies.

THE NEURAL BASIS OF MENTAL ACTIVITY The anatomo-clinical correlation method The birth of scientific neuropsychology took place in the second half of the 19th century, as the

neuropsychology of aphasia (see also Gainotti, Chapter 7 this volume). In the early 19th century the anatomist Franz-Josef Gall (1758-1828) proposed a cerebral localisation of mental faculties (see ZolaMorgan, 1995). It was however the anatomoclinical correlational approach of the French physician Bouillaud (1825) and, most of all, of Paul Broca, which revealed a relationship between the damage to specific brain regions and dysphasia (see Hecaen & Dubois, 1969). The German neurologist Carl Wernicke (1874/1966-1968) then put forward an anatomo-functional model, in which the faculty of language was fractionated into discrete, though connected, components with different anatomical correlates. Wernicke drew a distinction between a centre for acoustic-verbal images, localised in the temporal lobe, and a centre for motor-verbal images, localised in the frontal lobe (Fig. 6.1). Many neurologists took the view that language was a multi-componential function. The most influential was Lichtheim (1885), who, following Kussmaul (1877), added to Wernicke’s model a component concerned with concepts, and accounted for the existence of reading and writing disorders, assuming the existence of specific centres for visual images and for the innervation of the peripheral organs involved in writing (Fig. 6.2).1 On the basis of models of this sort, in the second half of the 19th century the paradigmatic (Kuhn, 1970) research programme in neuropsychology aimed at localising different mental functions in specific brain areas or centres. The classical anatomo-clinical correlation method comprised these main steps. A behavioural analysis of the patient’s deficits (e.g. aphasia) was followed by a localisation of the cerebral lesion. The presence of an association between a specific behavioural deficit (i.e., the impairment of a given function) and the damage to a cerebral area allowed the inference that the neural basis of the function of interest was localised in that brain region (see discussion in Kosslyn & Van Kleek, 1990; Von Eckardt Klein, 1978). This kind of inference made use, since its inception, of the principle of dissociations between symptoms and signs. Bouillaud’s conclusion that the centre for words was localised in the frontal regions of the cerebral hemispheres was based on two related observations: patients with defective

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FIGURE 6.1 Wernicke’s (1874/1966-1968) anatomo-clinical model of language function.

FIGURE 6.2

An anatomo-clinical model of language function. A: centre of auditory images; M: centre of motor images; a: afferent branch; m: efferent branch; B: centre for the elaboration of concepts; 0: centre of visual representations; E: writing centre (redrawn from Lichtheim, 1885).

speech production had lesions in the frontal regions, that was spared in patients in whom the function was preserved. The inference from the pathological association (the abnormal behaviour, the symptoms or signs, manifestations of the impairment of function F, are associated with a lesion of brain region R) to the

normal state (F is localised in R) is not free from problems, however. The British neurologist Hughlings-Jackson (1879) pointed out that localising the lesion that disrupts a given function and localising the function are not the same thing. There may be different readings of this warning: 1. According to an holistic approach, in which all cerebral regions (at least as far as higher mental functions are concerned) are functionally equivalent, localising a specific mental function is simply meaningless. The investigation of the neural correlates of complex mental processes, such as language, spatial abilities, and memory, has clearly shown, however, that such nonlocalisationist positions (e.g. Lashley, 1929) are untenable, at least in their more extreme versions (see discussion in Benton, 1988; Phillips, Zeki, & Barlow, 1984). Many chapters of this book illustrate this conclusion. 2. A second problem derives from the fact that different brain regions are interconnected by white matter fibre tracts. A lesion of area A, therefore, might bring about a specific deficit disrupting the operation of brain circuit C, of which A is just one component. According to this view the correlation is to be, rather than with the damaged region only, with the whole circuit made dysfunctional by the focal lesion. The idea that a cerebral lesion may produce a functional impairment in far removed, but

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connected, regions is not novel (Monakow, 1914). Only in the last 20 years, however, has this concept of diaschisis been adequately specified, through functional neuroimaging techniques, which provide in vivo measures of the functional activity of the brain, in terms of regional blood flow and metabolism (see Perani & Cappa, Chapter 5 this volume). For more than a century the correlation has been based on methods such as post-mortem examination, surgical exploration, and, more recently, neuroradiological techniques with a higher and higher spatial resolution (brain scan, CT, MRI), which provide anatomo-pathological information, concerning the site, size, and aetiology of the cerebral lesion, but are unable to detect functional changes that do not produce neuronal death. Functional neuroimaging techniques (SPET, PET) have shown that cortical and subcortical lesions may bring about, in addition to the focal structural damage, a reduction of neural activity, without neuronal death, in far removed unaffected regions (at least at the current level of spatial resolution of CT and MRI) (see review in Feeney & Baron, 1986). Reductions of regional cerebral blood flow (rCBF) and metabolism are indexes of this pathological hypoactivation. This diaschisis is produced by the interruption of afferent projections from the damaged region to connected, far removed, areas. Mechanisms of this sort are, by and large, in line with the view that the neural basis of mental processes should be conceived in terms of complex neural circuits (e.g. Fazio, Perani, Gilardi et al., 1992; Mesulam, 1990; Metter, Riege, Kuhl et al., 1984). 3. Finally, it should be considered that the localisation of a given function in a specific cerebral region may imply an adequate neurobiological description (or reduction, according to physicalist materialism). The typical inference drawn from the anatomoclinical correlation studies discussed in this chapter is instead that specific cerebral regions are the neural basis of discrete mental functions.2 With these caveats in mind, the anatomo-clinical correlation method may be used independent of the

type of functional description of both the neuropsychological deficit and the normal mental function. Consider, for instance, aphasic disorders. According to research approaches using the Wemicke-Lichtheim model of the aphasias, the functional counterpart is a taxonomy of normal linguistic processes based on Wundt’s associationism (see Boring, 1950). The correlation may also be referred to more recent psycholinguistic models, which distinguish different levels of processing, such as phonological, syntactic, lexical-semantic. The functional description, finally, may be in terms of the box-andarrow information processing models of cognitive psychology, in which the dysfunction of specific components is correlated with the localisation of the lesion.3 Four anatomo-clinical studies illustrate these possibilities. Mazzocchi and Vignolo (1979) correlated the lesion sites of aphasic patients, as assessed by CT, with the traditional aphasic syndromes, confirming the classical localisations, even though relevant exceptions were found, such as the so-called subcortical aphasias (Vallar, Cappa, & Wallesch, 1992). Cappa et al. (1981) through a correlation between the type of error made by aphasic patients in a confrontation naming task, and the site of the lesion, suggested that the perisylvian regions of the left hemisphere are the neural basis of the phonological level of speech production, and the marginal ones (farther from the sylvian fissure) of the lexical-semantic level. Shallice and Vallar (1990), on the basis of a metaanalysis of the lesion sites of 10 patients with a selective impairment of auditory-verbal span, suggested that the inferior parietal lobule (supramarginal gyrus) of the left hemisphere was the neural correlate of the phonological short-term store component of verbal short-term memory. The anatomo-clinical correlation method has also been applied to non-verbal disorders, such as hemineglect. In humans, a lesion of the inferior parietal lobule (supramarginal gyrus) of the right hemisphere is the more frequent anatomical correlate of this disorder (Vallar, 1993). In principle, then, the anatomo-clinical correlation method may be applied within a given functional model, both to a series of single case

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studies, and to groups of patients. The significance of the correlation depends not only on the validity of the functional model, but also on both the adequate control of some neurological parameters (lesion aetiology, temporal interval between the onset of the disease and the correlation) and the specific imaging techniques (see Perani and Cappa, this volume) that are being used. The role of temporal parameters and of imaging techniques is illustrated by a study by Bosley et al. (1987), concerning a primary sensory deficit (lateral homonymous hemianopia), which may be produced by a contralateral lesion involving the occipital cortex. In a series of five stroke patients with hemianopia, CT showed in three a lesion in the occipital regions, which were spared in two cases. PET performed shortly after the ictus, by contrast, revealed occipital hypometabolism in all five patients. In the two patients in whom the lesion spared the occipital lobe, recovery from hemianopia paralleled a reduction of occipital hypometabolism. In the three patients with occipital damage no functional recovery took place. This study illustrates the role of two factors that may modify the interpretation of the anatomo-clinical correlation: the time of the correlation, and the imaging technique. First, had the correlation been done in the chronic phase only (at least one month after stroke onset) the erroneous conclusion would have been that only lesions involving the occipital lobe may bring about hemianopia. The study in the acute phase shows instead that extra-occipital lesions involving the afferent projections to the visual cortex may also produce a visual field disorder, which may recover over time. Second, PET revealed a functional derangement in the occipital regions, undetected by CT. The role of the factor aetiology is illustrated by the differential effects of neoplastic and vascular lesions. In the former, the natural evolution is one of progressive worsening of the deficit. In the latter some spontaneous recovery may occur. The factor length o f illness has, therefore, a very different role in the two types of deficits. In the case of neoplastic lesions, for instance, growth rate and type of tumour are relevant factors. Vallar and Perani (1987), reviewing published cases and personal observations, noted that hemineglect is more

frequently produced by rapidly growing malignant tumours, such as glioblastomas. By contrast, the association with slowly developing tumours, such as meningiomas, is less frequent. This difference might reflect the rapid growth of a tumour, which prevents the development of compensatory mechanisms by undamaged cerebral regions. Anderson et al. (1990) found that the association between visuo-perceptual deficits and right hemisphere damage was less systematic in the case of CT, or MRI-assessed tumours (gliomas, meningiomas), compared to stroke lesions with a similar localisation. Similarly, neoplastic lesions in the left hemisphere bring about aphasic deficits that are less severe than those produced by strokes. Qualitative differences also exist. Anomic aphasia is more frequently associated with tumours than with vascular lesions (Haas, Vogt, Schiemann et al., 1982; Miceli, Caltagirone, Gainotti et al., 1981). Autotopoagnosia in the pure form (i.e. the patients’ selective inability to indicate parts of their own body, to a verbal command, in the absence of aphasic disorders) is usually associated with left parietal neoplastic lesions (Denes, 1989). Finally, demographic factors such as sex, age, and socio-cultural differences (i.e. years of schooling) may affect the neuropsychological deficit, and, therefore, the anatomo-clinical correlation (see Basso & Cubelli, Chapter 9 this volume, for a review of the differences between fluent and nonfluent aphasia, related to age and sex differences). For instance, the mean age of patients with fluent aphasia has been found to be higher, compared with that of non-fluent aphasics (Basso, Capitani, Laiacona et al., 1980; De Renzi, Faglioni, & Ferrari, 1980; Miceli et al., 1981). Also the patients’ sex may influence the clinical manifestations of aphasia. The incidence of nonfluent aphasia has been reported to be higher in males (De Renzi et al., 1980), but the empirical evidence is not univocal (e.g. Basso et al., 1980), while recovery is better in females (Basso, 1992). These effects of sex may be related to differences in the anatomo-functional organisation of the brain (Kimura, 1983, Shaywitz et al., 1995; Witelson & Kigar, 1988). To summarise, anatomo-clinical correlation studies should take into account both neurological

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and demographic factors. The optimal strategy is to compare groups of patients, who differ only in the variable under investigation (e.g. the behavioural deficit, or the site and size of the lesion), all other parameters (e.g. age, sex, aetiology, and duration of the disease) being comparable.

Cerebral activation methods Even though pioneering investigations date back to the first half of the century (Fulton, 1928), and early rCBF activation studies were performed since the late 1960s (e.g. Lassen & Ingvar, 1990, for areview; Risberg & Ingvar, 1973), only in the last 15 years has the study of the neural basis of mental processes through activation methods undergone a major development, due to the availability of new functional imaging techniques (Frackowiak, Friston,Frithetal., 1997;Perani& Cappa,Chapter 5 this volume). The logic underlying this approach is complementary to that of the anatomo-clinical correlation method. The relevant correlation here is between the localisation of the variation (usually the increase, but also the decrease) of rCBF and the task performed by the subject, rather than between a defective performance and the site and size of the lesion. This method has been used mainly in normal individuals, but in a few studies the neural basis of functional recovery or residual performance has been assessed (e.g. Bottini, Paulesu, Sterzi et al., 1995). In PET studies, the conclusion that a given task is associated with the activation of one or more cerebral areas is based on the comparison between the experimental condition and an appropriate control condition, which differs from the former only in the process or task under investigation. This method was based on a procedure originally used in mental chronometry (Bonders’ subtraction method) (Meyer, Osman, Irwin et al., 1988; Posner, 1978). For example (Petersen, Fox, Posner et al., 1988), the cerebral areas activated during listening to words may be revealed by subtracting from the rCBF activation values of this condition the activation pattern of the control condition, in which subjects do not receive any stimulation, but just look at the fixation point, as in the experimental condition. As the two conditions differ only in the auditory-verbal stimulation, their difference gives the activation

pattern that is specific to word listening (see also Cappa & Vignolo, Chapter 8 this volume). More recent developments make use of nonsubtractive paradigms, which do not make the additivity assumption (see Frackowiak & Friston, 1994, for a review; Friston, Price, Fletcher et al., 1996). According to one procedure, the experimental tasks can be directly compared: the Task-1 minus Task-2 subtraction provides the pattern of activation associated with Task-1, the Task-2 minus Task-1 vice versa. The self-ordered and externally ordered working memory tasks of Petrides et al. (1993) provide an illustrative example. The amount of neural activity in specific cerebral regions may be correlated with a behavioural measure: for instance, hippocampal rCBF with a measure of long-term auditory-verbal memory, but not with a short-term memory score (Grasby, Frith, Friston et al., 1993), verbal episodic retrieval with activation of medial temporal structures (Nyberg, McIntosh, Houle et al., 1996b). The whole set of brain regions in which rCBF is positively and negatively (increased vs. decreased brain activity) correlated with a behavioural or physiological condition may be identified. Recent studies concerning human rapid-eye-movement sleep and dreaming (Maquet, Peters, Aerts et al., 1996) and episodic memory retrieval (Nyberg, McIntosh, Cabeza et al., 1996a) provide illustrative examples. Finally, interaction and factorial designs are also used. A study by Paulesu et al. (1996), who investigated the brain areas activated by a phonological short-term memory task in normal and dyslexic subjects, provides an illustrative example. Using these paradigms, the neural bases of functions such as verbal memory, language, and attention have been explored (Frackowiak, 1994; Petersen & Fiez, 1993; Posner & Raichle, 1994; Posner & Raichle, 1995). Over and above the specific results of different studies, and the discrepancies among them, the general emerging pattern is one of a high degree of functional specialisation in the brain, at the level of both sensory-motor processes and higher mental functions. Most activation experiments have provided results that confirm and extend findings from

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anatomo-clinical correlation studies in humans and animals. The lack of activation of a cerebral region, which, on the basis of correlation studies in braindamaged patients, has a specific functional role, raises interpretative problems, however. For instance, Shallice et al. (1994) did not detect activation in the hippocampal region during a verbal long-term memory task. This negative finding was unexpected on the basis of lesion studies, which have repeatedly shown that hippocampal damage produces anterograde amnesia (see Vallar, Chapter 15 this volume). On the basis of a negative result of this sort (“the ambiguity of a null result”, see Farah, 1994a), the conclusion that a given cerebral region does not participate in the operation of a specific function may be premature, if such a role is suggested by lesion studies. In the study mentioned earlier, Shallice et al. (1994) cautiously hypothesised that a comparatively low neuronal activity might account for their negative results (see Skaggs & McNaughton, 1992). Other studies have however revealed an association between specific long-term memory processes, such as successful recollection, and activation in the hippocampal region (Nyberg et al., 1996b; Schacter, Savage, Alpert et al., 1996). This type of difficulty does not apply to anatomo-clinical correlation studies. If the lesion of a specific cerebral region does not disrupt a given mental process, it is very unlikely that the damaged area plays a substantial role. Studies in brain-damaged patients, however, suffer from other problems, such as the patients’ selection (see Group and single case studies), and the size and the site of the lesion, which, being natural (e.g. a tumour, a stroke), may have effects that are not selective, but disrupt more than one function, producing multiple deficits (see an early discussion in Lichtheim, 1885). The observed impairments, therefore, may reflect damage to multiple components, making the pattern more complex and the interpretation more difficult. Patients with selective deficits (the so-called pure cases) are specially valuable in this respect. Since the early days of scientific neuropsychology, such cases, which show dissociated patterns of impairment (see Dissociations among symptoms), have been providing the main source of pathological evidence

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for a multi-componential organisation of mental processes and their neural bases. A final problem with activation studies is one opposite to the failure to detect the activation of a relevant cerebral area. Paulesu et al. (1996) have suggested that in normal subjects engaged in a given task, not only the critical or necessary areas may be activated, but also additional or incidental regions. In their study they teased apart the necessary and incidental regions by examining both normal subjects and a pathological population (developmental dyslexics), who were able to perform the critical task. To summarise, cerebral activation methods and anatomo-clinical correlation studies in braindamaged patients may provide complementary results, concerning the neural and functional architecture of mental processes.

A SIMULATION APPROACH: CONNECTIONIST MODELLING In the last 15 years, there has been a considerable development of an approach to the investigation of mental architecture, which—unlike its immediate predecessor, artificial intelligence (Newell, Rosenbloom, & Laird, 1989; Woodhouse, Johnstone, & McDougall, 1982)— aims at providing an abstract and general model of the computational organisation of the brain. This approach, like those developed in the past (mechanic and hydraulic, telephone central, and computer models) offers analogies and metaphors taken from the more advanced technologies of the time. As with artificial intelligence, connectionist modelling provides a computational simulation of mental processes. Its distinctive feature is however that the architecture differs from that of the present computer generation (von Neumann), but is broadly similar to the structure and function of the real brain. The computational activity of connectionist models is, then, neural-like, with the computer metaphor being replaced by the brain metaphor (Rumelhart, 1989). In connectionist neural networks, the basic processing unit is a sort of abstract neurone, which

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receives inputs and sends signals (numbers) to other neurones. Three main neurones may be distinguished: (1) input units, which receive signals from outer sources (sensory stimuli, other networks); (2) output units, which send signals out of the system, e.g. to motor effectors, or to other networks; (3) hidden units, with efferent and afferent projections internal to the system (e.g., from input to hidden units). Figure 6.3 shows an example of a connectionist network (Rumelhart, Hinton, & Williams, 1986). Other types of units (icontext or memory) may be useful under specific circumstances, such as learning of sequences (Elman, 1990; Nolfi, Parisi, Vallar et al., 1991). A representation of the state of activation of the different components of the network is also needed. Finally, the activation function of the units (identity, threshold, stochastic, non-linear, such as sigmoid), the organisation of the connections, and their weight (a positive weight indicates an excitatory connection, a negative an inhibitory one) should be specified. Each unit transforms the received inputs into an output signal, which is forwarded to connected units. The process has two components: each input signal is multiplied by the weight of the connection, and the sum of all signals is the total input, which, in turn, is converted into the output signal by the activation function.

FIGURE 6.3

An illustrative example of connectionist network, which includes input, hidden , and o u tput units (reproduced from Vallar, 1996, with permission of Zanichelli Editore).

The procedures whereby a neural net may learn a task, and become able to perform it on new stimuli (generalisation) are also to be defined. The training of the net (e.g. learning to recognise numbers or letters) is performed by sending appropriate signals to the input units, and by computing the discrepancy between the output signal and the target (in the example, correct recognition). On a trial-and-error basis, the weights of the connections are continuously modified, with the procedure (learning cycles) being repeated until the net becomes able to perform the task with a given level of accuracy. A widely used learning procedure is the back-propagation algorithm: a signal concerning the error made by the net in responding to a given stimulus is sent backwards from the output to the input units, modifying the weight of the connections. In this type of architecture, knowledge (long-term memory) is stored in the connections, whereas the activation of the units produced by a given stimulus may be considered as a temporary representation. To summarise, artificial networks are an abstract and relatively simplistic model of real neural circuits, constituted by dendrites and axons. The synaptic function is simulated by the changing weight associated with each connection. The output electric signal generated by each neurone is

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represented by a number, which denotes its activity (Hinton, 1992). Given their close reference to the real brain (Crick, 1989), connectionist models may be of interest to neuropsychologists more than the preceding analogies or metaphors. Neural networks have been used to simulate the activity of specific cortical neurones. For instance, neurophysiological studies in the monkey suggest that the inferior parietal lobule includes three types of neurones: cells with retinotopic receptive fields; cells that code eye position; cells with retinotopic receptive fields, in that the size of the response is modulated by eye position. The latter neurones generate a headcentred representation, as their response to stimuli in a given location with reference to retinotopic coordinates is maximal when the eyes have a specific position in the orbit. A representation of this sort is required for the execution of movements directed towards targets in personal and extrapersonal space (Andersen, 1989; Andersen, Snyder, Li et al., 1993). Zipser and Andersen (1988) trained a neural network to code visual targets according to head-centred coordinates, providing inputs concerning the retinotopic coordinates of the stimulus, and the position of the eyes. After learning through back-propagation, Zipser and Andersen (1988) found in the hidden units a pattern of activation similar to that of parietal neurones responding to both the visual stimulus and eye position. Within its receptive field, each unit had a maximal response when the eyes were in a specific position. Some aspects of the model could differ from the real brain, however. For instance, it is unclear whether or not in animals and humans head-centred coordinates are, wholly or in part, learned, and, if so, by backpropagation. In any case, the existence of similarities between neurophysiological and connectionist sets of data suggests that the model is a plausible architecture, and generates working hypotheses. Zipser and Andersen (1988) concluded their paper by noting that there was no empirical evidence for a head-centred spatial representation, independent of the position of the eyes. Such a representation would not exist in the brain, being instead a behavioural manifestation, when the animal fixates a target, or points to it. Some years later, however, neurones with non-retinocentric,

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eye-position independent, receptive fields, have been found in the premotor (area 6) (Fogassi, Gallese, di Pellegrino et al., 1992; Fogassi, Gallese, Fadiga et al., 1996; Graziano, Tian Hu, & Gross, 1997), and in the posterior parietal (Battaglini, Galletti, & Fattori, 1996; Galletti, Battaglini, & Fattori, 1993) cortex. These cells could constitute a neural basis of spatial egocentric (e.g. head-centred, arm-centred) representations of objects. A second use of neural networks is to study the effects of lesions after the learning of a specific ability. The performance of the damaged network may be compared with that of brain-damaged patients, who are impaired in that task, in terms of both accuracy, and qualitative patterns of errors. Relevant aspects of deficits such as optic aphasia (Plaut & Shallice, 1993b), and surface (Plaut, McClelland, Seidenberg et al., 1996), deep (Plaut & Shallice, 1993a), and neglect (Mozer & Behrmann, 1990) dyslexia have been successfully simulated, even though the correspondence with the patients’ behaviour may be not complete. The results of these simulations suggest that the network may be a plausible architecture of the system damaged in patients. The results of simulation studies may stimulate a critical reappraisal of the traditional box-andarrow models, which have been widely used by cognitive neuropsychologists in the last 25 years. Plaut et al. (1996), for instance, found that networks using a single procedure (orthographic and phonological representations) were able to learn to read both regular and irregular words, and non words. Lesions to these networks reproduced some aspects of the error pattern of patients with surface dyslexia; however a more successful simulation required the introduction of a semantic component. Both dual-route (Whitney, Berndt, & Reggia, 1996; Zorzi, Houghton, & Butterworth, in press) and one-route (Plaut et al., 1996) connectionist models of reading have been developed (review and discussion in Denes et al., this volume). The plausibility of these models is related to their ability to simulate successfully behavioural patterns in normal subjects, and pathological deficits after experimental lesions (in the examples discussed here, reading and the different varieties of dyslexias). A third relevant

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factor is the relationship between the architecture of the network and the organisation of the brain (see related discussion in Plaut, 1995). In this respect, it may be noted here that some PET activation studies have been interpreted in the light of an anatomo-functional dual-route model of reading (Petersen & Fiez, 1993; Petersen, Fox, Posner et al, 1989). A connectionist approach has been used by Farah (1994b) to challenge the view that the functional architecture of the mind is multicomponential, or modular, supporting instead an account in terms of distributed and interactive representations. Neural networks too, however, may have a multi-componential architecture: multiple, connected systems, each including input, inner and output units (see Schneider & Detweiler, 1987; Zorzi, 1994). Furthermore, the learning process may induce a functional specialisation of some units. For instance, in a model of reading, hidden units may become specialised for reading exception words (Zorzi et al., in press); in a model of visuo-spatial processing the retinotopic receptive fields of hidden units may be differentially modulated by specific eye positions (Zipser & Andersen, 1988). Connectionist models differ from computational models such as, for instance, production systems, in that the network is not programmed a priori, through explicit instructions, in order to be able to perform a given task. The network's skills, which are initially rather poor, progressively improve through learning. The observation that a neural network becomes able to reproduce specific features of the human behaviour may be taken as a strong case that its architecture is a plausible simulation of the human system. Similarly, in lesion experiments the network is damaged in a relatively nonspecific fashion, interrupting connections or removing different amounts of units, but, at least in some cases, the localisation of the lesion may be critical (e.g. the concreteness effect in deep dyslexia: Plaut & Shallice, 1993a, pp.456-460). In the traditional computer simulations, by contrast, the damage should be specified much more precisely

(Kimberg & Farah, 1993; Kosslyn, Flynn, Amsterdam et al., 1990). Also in the case of lesion studies, the finding that a quantitative damage to the network brings about patterns of performances (and of impairment) similar to those observed in brain-damaged patients would provide a greater support to the conclusion that the net is a plausible simulation of the human system under investigation. Connectionist models, however, cannot be regarded as entirely atheoretic, as the architecture of the virgin network (i.e. before training) is a priori defined (e.g., Burgess & Hitch, 1996; Mozer & Behrmann, 1990). This argument is even stronger in the case of modular connectionist systems, including more than one network. The relevant role of the architecture of the network is suggested by the finding that putatively minor variations may be associated with different deficits, when a lesion is made (Plaut & Shallice, 1993a). The precise relationships between the locus of the lesions within a network and the resulting pattern of impairment remains far from transparent, however (see the concreteness effect in reading: Plaut, 1995). Finally, the a priori definition of the architecture of the network, and of the connections among networks in the case of multiple systems, may be used to simulate innate or genetically determined aspects of the neural bases of mental processes. To summarise, simulation may provide useful suggestions, which should be evaluated in the context of the results of lesion and activation studies in humans and animals. If a connectionist network or a computational model successfully simulates human behaviour (and the deficits produced by a lesion) in a given domain, but its structure differs from that suggested by experiments performed in humans, it is the latter architecture that should be considered the real one; that is, actually implemented in the brain. For instance, the computational model of phonological memory of Brown and Hulme (1995) does not include a discrete rehearsal process, but neuropsychological findings support the view that the phonological short-term store and the articulatory rehearsal process are functionally and

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anatomically separate (see review in Vallar, Di Betta, & Silveri, 1997).

THE NEUROPSYCHOLOGICAL METHOD Clinical observation The anatomo-clinical correlation is a main feature of classical neuropsychology. The qualitative and nonsystematical psychological analysis of the patients’ pathological behaviour, often confined to clinical observation (e.g. Moutier, 1908), was however a main weakness of the traditional approach. This contrasts with the relatively high level of the post-mortem examination. A perusal of the series published by Henshen (1920-1922) and Nielsen (1946), which included both personal cases and previously reported observations, illustrates this dissociation between the psychological and neuropathological levels of analysis. The clinical method, based on qualitative and nonsystematic observations, may favour the selection of patients with severe and immediately apparent deficits. These observations constitute a series of single cases, who attracted the examiner’s attention due to the severity or the peculiar features of the neuropsychological disorder. The traditional clinical method has had a crucial role in the birth and early development of scientific neuropsychology. The discovery that cerebral lesions may produce selective cognitive deficits was based on clinical observations. This method has limitations too, however, being inadequate to elucidate the precise psychological features and anatomical correlates of the deficit, and its relationships with other disorders. As a result of the limits of the classical clinical descriptions, some clinical syndromes, such as constructional apraxia (Gainotti, 1985, see also Grossi & Trojano, Chapter 19 this volume), are not precisely defined. In the absence of a precise definition, furthermore, a given disorder may be investigated by different methods, which may involve different abilities. The long-standing controversies concerning the putative existence of some clinical syndromes (e.g. Gerstmann’s syndrome; see Denes, Chapter 22 this volume), and the basic

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nature of some deficits (e.g. visual agnosia) (Bay, 1953; Bender & Feldman, 1972; Humphreys & Riddoch, 1987; Lissauer, 1890) provide another indication of the limitations of the clinical method. Finally, clinical observations do not usually take into account relevant variables, such as sex, age, and education of the patients, which may affect their normal and pathological behaviour. The final result is often a pattern of contrasting observations, in which a comparative analysis is made difficult by a lack of precision and definition, which concerns both the clinical deficit, and the behavioural tasks, that should be used for its assessment.

Quantitative and standardised tasks A solution to the unsatisfactory state of affairs discussed in the previous section is the use of clearly defined and standardised methods. After World War II, since the late 1950s, many neuropsychologists (Benton, 1966; De Renzi, 1967; Poeck, 1969), well aware of the limitations of clinical methods, took the view that standardised and quantitative paradigms should be used. This approach differs from the clinical examination used by neurologists in the second half of the 19th century. It does not necessarily challenge the classic anatomo-clinical models, however. Such a critique may be done, provided the results of studies performed using standardised and quantitative methods differ from those obtained through the traditional clinical assessment. Benton’s (1961) critique of Gerstmann’s syndrome (Denes, Chapter 22 this volume) is an illustrative example. Ennio De Renzi (1967) clearly stated the main features of this new method, which may be summarised in three points. Studies are performed in groups o f patients According to the traditional anatomo-clinical method the conclusion that the lesion of cerebral region R brings about a deficit of function F, producing the symptom or sign X , is based on the existence of positive cases, namely patients in whom R is damaged and X is present. This approach, however, does not take into consideration both patients in whom X is present, but R is unaffected, and patients in whom X is absent, but

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R is damaged. The traditional method, which considers only the positive cases, is therefore unable to rule out the possibility that X is produced by a nonspecific effect of brain damage, independent of its localisation. A similar line of reasoning may be applied to the analysis of functional syndromes. Consider the hypothetical syndrome S (see also Group and single case studies), comprising the symptoms A, B, C, and D, produced by a deficit of function F, and possibly associated with left hemisphere damage. The study should not be confined to the positive cases; that is, to patients who show the four symptoms of S. The investigation should include a continuous series of left and right brain-damaged patients, looking for the association of the four symptoms of S. The conclusion that S indeed exists is possible only if the positive cases show the four symptoms, which are absent in the negative cases. In the case of an anatomo-functional syndrome, S should be associated with left hemisphere lesions only. Clinical observations in single cases may provide interesting suggestions. A scientific investigation, however, can be performed only in a series of brain-damaged patients, who enter the study simply because they have a cerebral lesion, independent of the presence or absence of the symptom or the syndrome of interest. Using this method, it becomes possible to verify whether or not the co-occurrence of a set of deficits, and, possibly, their association with a specific lesion site, is significant; that is to say, represents a syndrome. An implication of this approach is that large samples of patients should be tested, as they better represent the corresponding population. In these large series, the demographic (age, sex, education) and neurological variables (length of illness) should also be taken into consideration. The examination is standardised The traditional clinical examination is not specified in full detail. In different patients, therefore, the examiner (or different examiners) may inadvertently modify more or less relevant aspects of the assessment. In addition, the conclusions concerning the patients’ performance reflect qualitative observations, which are not analysed by

statistical methods. The clinical descriptions usually do not report in full detail the tasks used by the examiner. This prevents a proper replication of the study by another researcher. These problems can be overcome using tasks precisely defined in full detail: administration procedures, scoring of the responses, error analysis, etc. Brain-damaged patients should be compared with normal subjects The clinical approach considers the patients’ errors as an indication of defective function. This conclusion may be correct when the deficit is severe, or clinically apparent. Some errors, however, may be interpreted as pathological only because the patient has a brain lesion. On the other hand, milder deficits may not be detected through the clinical exam. Finally, it should be considered that in virtually all tasks normal subjects commit some errors. Their amount and type is affected by many factors, including age, education, and sex. The patients’ performance, therefore, must be compared, by means of adequate statistical methods, with that of a series of normal subjects (the so-called control group), similar in age, education, sex, handedness, etc. (see Capitani & Laiacona, Chapter 4 this volume). Many neuropsychological studies, which have used this approach, have been performed both in the United States and in Europe, since World War II up to the 1970s. This methodological programme for neuropsychological research is well illustrated by studies performed in Italy by Ennio De Renzi, and Luigi Amedeo Vignolo, in France by Henry Hecaen, in Germany by Claus Poeck, and in the United States by Morris Bender, Arthur Benton, Hans-Lukas Teuber, and their co-workers (De Renzi, 1982b; Mountcastle, 1962; Vignolo, 1982). The typical structure of this type of study was the following. A number of neurological patients was subdivided in different groups on the basis of the side (left, right) of the lesion, and often of its intra-hemispheric localisation (pre-, retro-rolandic, frontal, parietal, etc.). The performances of the different groups of patients in a number of tests were compared with those of a group of normal controls, matched for demographic variables.

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These studies aimed mainly at establishing a correlation between a defective pattern of performance and the lesion of one side of the brain, and, if possible, of a specific cerebral region within one hemisphere. The relationship with experimental psychology concerned the method used to assess the behavioural deficit, rather than the functional architecture of mental processes. The main aim was to establish an anatomoclinical correlation between the cerebral hemispheres and specific mental abilities, not to investigate, using brain-damaged patients as experimental tools, the functional architecture of mental processes. As the main focus of the studies concerned the anatomo-clinical correlation, it is not surprising that: (1) the psychological categories were relatively underspecified (e.g. verbal vs. nonverbal abilities, perceptual vs. memory processes); (2) reference was often made to the classic neurological models (e.g. Wernicke’s model of language; Lissauer’s model of object recognition); (3) the interaction with psychological research in normal subjects was limited. At least up to the 1970s, the results of neuropsychological studies were typically not quoted in textbooks and handbooks of psychology. This lack of interest in neuropsychology on the part of psychology was what one might expect, considering that the main aim of this approach was to investigate the neural basis of mental processes. In this respect, psychology was useful to neuropsychology, providing functional models of mental function, based on the behaviour of normal subjects. The advantage, however, was not mutual. The anatomo-clinical correlations, resulting from the neuropsychological studies, were of limited interest to the student of normal psychological processes.

COGNITIVE NEUROPSYCHOLOGY In the last 25 years a novel neuropsychological approach has undergone a remarkable development: the main aim of cognitive neuropsychology is to explore the functional architecture of normal mental processes, through

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the investigation of the abnormal behaviour of patients with brain damage or dysfunction. The early seminal studies in cognitive neuropsychology can be traced back to the late 1960s and early 1970s, when in Canada, in the United States, and in Great Britain, scientists such as Brenda Milner (1966), Drachman and Arbit (1966), Elizabeth Warrington, Tim Shallice, and Alan Baddeley (Baddeley & Warrington, 1970; Warrington & Shallice, 1969), John Marshall and Freda Newcombe (Marshall & Newcombe, 1973) investigated in single cases or in very homogeneous small series of patients the specific patterns of impairment of short- and long-term memory, and of reading processes (the dual-route model). In the following years, this approach rapidly became a relevant component of neuropsychological research. This is also witnessed by a journal (Cognitive Neuropsychology, 1984), which aims to publish experimental studies and theoretical papers, based on this paradigm. At present, an interim conclusion is that the cognitive approach has produced a remarkable amount of work, concerning all areas of neuropsychology. The cognitive neuropsychological approach has been based, since its inception, on the so-called information processing or flow-chart diagram types of models of the mind, developed by cognitive psychologists in the 1960s. Briefly, the mental faculties comprise a number of connected components, with specific functional properties. For instance, memory was subdivided into shortand long-term components (Vallar, Chapter 15 this volume), the reading skills into phonological, visual, and semantic pathways (Denes, et al., Chapter 14 this volume). If the mind is a multiple-component system with specific features and connections, some of them may be selectively affected by brain lesions. Brain-damaged patients, therefore, may be investigated with a two-fold aim: (1) interpreting their impairment in terms of the defective function of one or more components or connections of the system; (2) increasing knowledge concerning its functional architecture. The methods used by cognitive neuropsychologists derive largely from those used by experimental psychologists. As in the quantitative

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and standardised approach discussed in the preceding section, and unlike the traditional clinical method, cognitive neuropsychologists make use of tasks, in which the materials and the procedures are precisely defined, and the patient’s performance is compared with that of an appropriate control group (Shallice, 1979).

Three basic assumptions The cognitive neuropsychological approach makes three basic assumptions, which were also present in the diagrams proposed by clinical neurologists in the second half of the 19th century (see Figs. 6.1 and 6.2). Modularity Quoting Marr (1982, p.325): “... any large computation should be split up into a collection of small, nearly independent, specialised subprocesses.” The postulate that the mind is modular has been widely present in the neuropsychological approach, at least since Gall (Finger, 1994), both in the 19th-century anatomo-clinical (Figs. 6.1 and 6.2), and in the information processing models of the 1960s (e.g. Norman, 1970, and Fig. 6.11). Its precise features, however, were not clearly defined. The problem was reconsidered by Jerry Fodor (1983) in a brief essay, which, if anything, made neuropsychologists fully aware of the relevance of the problem. According to Fodor, the modules are genetically determined computational mechanisms, which have a specific representational domain and localised neural correlates. The operation of the modules is fast and automatic, and relatively unaffected by other components of the system (using Fodor’s terminology, they are informationally incapsulated). Their content has little access to conscious processes. These modules are domain-specific computational mechanisms, similar to reflexes, which may be referred to as vertical faculties. Examples of modular systems of this sort are some auditory, linguistic (the syntactic and phonological analysers), and visual perceptual processes. By contrast, central processes, such as memory, reasoning and problem-solving are nonmodular, and mediated by horizontal faculties. As such, these central processes are not domain-

specific, do not have localised neural correlates, and are bad candidates for scientific enquiry (see comments in Fodor, 1985). This view is similar to the one taken by Lichtheim (1885, p.436), who localised all perceptual and motor linguistic functions, but not “... the part where concepts are elaborated”. According to most neuropsychologists, however, not only the input perceptual analysers are modular, namely multiple-component systems, with localised neural correlates (see Marshall, 1984; Moscovitch & Umiltà, 1990; Shallice, 1984). Response-production systems (Paillard, 1982), and faculties, which in Fodor’s view are non-modular (memory, Vallar, Chapter 15 this volume, and control processes set up to attain a particular goal, Shallice, 1994) are also conceived as multicomponential. Finally, modules may be not innate, as in the different components of the reading processes (Coltheart, 1985). The modular architectures of different aspects of the mind are often depicted as flow-chart diagrams of information processing (Figs. 6.1, 6.2 and 6.11), with a non-hierarchical organisation of the different components. When a specific part of the system is damaged, e.g. the grapheme-tophoneme conversion process (Fig. 6.11), the patient will make use of the components spared by the lesion. The architecture may be also hierarchical. A classical example is the distinction between the automatic vs. voluntary or propositionising aspects of language (Hughlings-Jackson, 1915; Kennard & Swash, 1989). A more recent example of hierarchical model is Tulving’s (1985) tripartite distinction of memory processes, in which the systems have different kinds of consciousness, or noesis (Fig. 6.4). The existence of episodic memory implies, or presupposes, that of semantic memory, which, in turn, implies procedural memory. A feature of hierarchical architectures which is relevant to neuropsychologists is that a damage to the superordinate systems produces a selective dysfunction, which does not affect the subordinate components. The automatic/voluntary dissociation of Flughlings-Jackson and the interpretation of amnesia as a deficit of episodic memory in a system such as that shown in Fig. 6.4 (see also Vallar, Chapter 15 this volume) are illustrative examples.

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FIGURE 6.4

Hierarchic organisation of three memory systems and forms of consciousness (noesis). The arrows denote im ply (redrawn from Tulving, 1985).

Finally, in hierarchical systems a dysfunction of the subordinate components also produces a defective function of the superordinate ones. Correspondence between functional and neurological architectures If computationally independent processes were implemented, at least in part, in physically discrete structures (brain regions), a cerebral lesion might selectively damage one (or more) of them. If the correspondence assumption aims only at accounting for the observation that brain damage can selectively disrupt specific aspects of mental processes, the precise neural level at which the implementation takes place does not require any further specification (see chapter 1 in Ellis & Young, 1988; Shallice, 1981). If, however, the neural basis of mental processes is of interest, then this level of analysis becomes relevant. In the anatomo-clinical models of the 19th century, then the correspondence was between specific functional centres and regions of the cerebral hemispheres (Figs. 6.1 and 6.2). The neural correlates of mental process are likely to be better conceived in terms of complex cortico-subcortical neural circuits, which may include different cerebral regions (Crick, 1984; Mesulam, 1990). At a fine-grain level of analysis these neural correlates may be referred to as cell assemblies (Hebb, 1949). The correspondence may also be at the level of single neurones (Barlow, 1985). For instance, in the monkey some neurones in the region of the superior temporal sulcus exhibit selective responses to faces,

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or to parts of them (eyes, mouth), or to specific orientations of a face (profile, back), or to an individual face (e.g. the experimenter) independent of orientation, size, expression, etc. (Perret, Mistlin & Chitty, 1987). It is likely, however, that such a specific knowledge is not stored in a single neurone, but in networks or assemblies, of which the single cell is a component part. The only state of affairs in which the cognitive neuropsychological approach would be not practicable is that of a putative correspondence between a modular functional architecture and a non-modular neurological organisation. If this were the case, a brain lesion would not produce specific deficits, decreasing instead the overall level of performance of the system, and these effects would be proportional to the amount of brain damage (Lashley, 1929). Accordingly, the modular architecture of the mind could not be investigated in brain-damaged patients. However, little empirical evidence supports this hypothesis. Constancy A research programme, which aims at investigating the multi-componential organisation of the normal mind through brain-damaged patients, is possible only if, after a cerebral lesion, mental processes do not undergo a functional reorganisation that involves the generation of new components, or of new connections. If this were the case, the mental processes of a brain-damaged patient would be qualitatively different, in terms of functional architecture, from those of a normal subject. Accordingly, any inference from the pathological to the normal behaviour would be impossible. To summarise, if the experimental study suggests that the patients are making use of functional components that are not present in the normal subject, their behaviour may be relevant in order to understand how the system may cope with a pathological situation, through a modification of its organisation, but not to investigate the normal system per se. After damage to a specific component, patients may develop specific strategies, which are not typically used by normal subjects. Also in this case the constancy or transparency (Caramazza, 1986, 1988a) assumption remains valid, provided such strategies are a part of the behavioural repertoire

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Modularity, correspondence, and constancy: Their plausibility Neuropsychological research does not aim at a direct verification of these assumptions, which have been regarded as a basic core (Caramazza, 1984; Ellis & Young, 1988). The following paragraphs briefly discuss their plausibility.

modifications affecting the whole system. This may be an evolutional disadvantage. Ellis and Young (1988) put forward the analogy with current hi-fi systems, which comprise different components (turntable, CD player, integrated amplifier, loudspeakers). In these systems a new module (e.g. a tuner) can be added, a damaged component can be repaired or replaced, and upgrading is possible. These changes were not possible in the so-called radiograms, built in the 1950s, which were much less modular, including tuner, turntable, loudspeakers. Developing the hi-fi analogy, it is of interest to note that the higher the level of the system, the more modular is its architecture. Accordingly the integrated amplifier splits into the preamplifier and the power amplifier, the integrated CD player into the transport, responsible for disc handling and accessing the data, and the digital to analogue converter. Another analogy is provided by the architecture of ships’ holds, and of submarines’ bodies, which include many discrete modules. If a local lesion of the keel occurs, the water inundates only the nearby modules. By contrast, if the structure was nonmodular, the water would spread all over the hold. Many empirical observations concur to support the modular view. An anatomical example is the organisation of the efferent and afferent connections of the different regions of the occipital-temporal visual cortex (DeYoe, Felleman, Van Essen et al., 1994). Furthermore, neurophysiological studies suggest that discrete areas of the visual cortex are involved in processing different aspects of a complex visual pattern (shape, colour, movement) (Cowey, 1985; Lueck, Zeki, Friston et al., 1989; Zeki & Shipp, 1988). Finally, many studies in normal subjects argue for the functional independence of some mental abilities, for instance: some visuomotor processes (e.g. to hit an approaching ball with a bat: McLeod, McLaughlin, & Nimmo-Smith, 1985), speech perception and production (Shallice, McLeod, & Lewis, 1985), verbal short- and long-term memory processes (Baddeley, 1966a, 1966b; Kintsch & Buschke, 1969).

Modularity. Non-modular architectures undergo only global changes, with even minor local

Correspondence. The existence of some correspondence between the neurological and the

available to normal subjects; that is to say, they are based on components of the normal system spared by the lesion. An illustrative example of the compensatory use of strategies, that are also available to normal subjects was provided by patient PV, who suffered from a selective deficit of auditory-verbal shortterm memory (Vallar, Chapter 15 this volume). PV, in a task requiring the immediate free recall of supra-span lists of words, adopted a serial order strategy, producing first and best the initial items. These represent the output of verbal long-term memory processes, which were spared in the patient. Normal subjects, by contrast, recalled first the final stimuli, which are stored in auditoryverbal (phonological) short-term memory. Normal subjects probably use this strategy because the lability of the short-term memory trace makes it advantageous to recall the final items first, with a subsequent production of the material held in longterm memory. In PV’s case, conversely, due to the pathological reduction of the capacity of phonological memory, a strategy that assigns a recall priority to the final stimuli was unlikely to improve her memory performance. In line with this view, her performance remained defective even when she was explicitly required to recall the final items first. Finally, the normal repertoire includes both strategies: normal subjects are able to recall the initial items first (the strategy spontaneously used by PV), and PV was able to recall the final items first (the recall order preferred by normal subjects). Under these conditions, the assumption of constancy is not broken, and the inferences from the pathological behaviour to the organisation of the normal functional architecture are legitimate (Vallar & Papagno, 1986).

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functional architectures, both modular in nature, has been a main feature of human neuropsychology, which, since its inception, has been concerned with selective deficits of cognitive functions, associated with focal brain damage.4 The data mentioned in the previous section support this view. Constancy. The postulate that, at least in adult subjects5 , the reorganisation of the system after a brain lesion does not include qualitative changes, such as novel components or connections, cannot be easily verified. A variety of neurobiological mechanisms may participate in functional recovery, such as reduction of diaschisis, and new synaptic connections (Basso & Pizzamiglio, Chapter 35 this volume, see also Cappa & Vallar, 1992; Chollet & Weiller, 1994). In the case of sensory-motor functions, both sensory de-afferentation (Pons, Garraghty, Ommaya et al., 1991), and peripheral (Cohen, Bandinelli, Findley et al., 1991) and central (Weiller, Chollet, Friston et al., 1992) lesions may induce a reorganisation of cortical maps. Data of this sort indicate that some degree of plasticity is a feature of the central nervous system, in order to cope, at least in part, with the damage produced by a lesion (see Basso and Pizzamiglio, Chapter 35 this volume). This ability does not necessarily imply, however, that the post-lesional organisation is qualitatively different from the normal system. To summarise, the assumption that, after a cerebral lesion, mental processes do not undergo qualitative changes, which modify their architecture, is to be treated with caution and pondered in each specific case. The significance o f observations in brain-damaged patients Even if the three postulates just discussed (modularity, constancy, correspondence) are true, this does not necessarily imply that the pathological deficits produced by brain lesions can be interpreted in terms of the selective impairment of one, or more, components of the normal system. The possibility should be considered that the neuropsychological observations are contradictory, and cannot be analysed from this perspective (Postman, 1975). This is a plausible view, as the localisation of naturally occurring lesions is

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determined by factors such as the organisation of the vascular system (in the case of stroke lesions), which are not related to the functional architecture of interest. In addition, even if neuropsychological deficits can be interpreted in the light of the functional architecture of normal processes, this does not necessarily imply that the data from pathology are relevant to our knowledge of the normal system. Similarly, the best method for understanding the architecture of a man-made object such as a car, is probably to disassemble it in an orderly fashion, rather that to beat the car with a hammer, or to study it after a crash. If the latter approaches were used, the localisation of the damage would not be related to the functional properties of the object. Under these conditions, neuropsychology parasitises psychology, making use of models of mental function based on studies in normal subjects, without providing any heuristic information on their architecture and properties (Crowder, 1982, p.38). A perusal of neuropsychological studies performed in the last 30 years shows, however, that these reservations are unfounded. Not only the deficits of patients with brain lesions are interpreted in the light of models of normal processes. Such pathological studies have also contributed to settling controversies concerning their architecture. An illustrative example is the issue, discussed in the 1960s, as to whether or not memory was a single- or multi-componential process (Atkinson & Shiffrin, 1968; Melton, 1963). The observation that brain-damaged patients may display selective memory deficits lends support to the multiplesystems view (see Vallar, Chapter 15 this volume; Fodor, 1983, pp.99-100 for a related discussion of memory and amnesia—as a non-domain specific, horizontally organised faculty). A second example is the debate concerning the analogical vs. propositional features of mental images (Anderson, 1978; Bisiach & Luzzatti, 1978). The observation that brain-damaged patients may neglect the left side of mental images has been taken as evidence for the existence of analogical representations. A third example is the contribution provided by the investigation of amnesic patients to the elucidation of non-conscious memory processes (Vallar, Chapter 15 this volume). In amnesia, the selective

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damage of conscious, explicit memory, makes it possible to study unconscious, implicit memory in isolation, without interference from the former components. A final example concerns the putative distinction between the phonological short-term store and the rehearsal process components of phonological memory. On the basis of experiments in normal subjects and simulation modelling, interpretations in terms of a single component have been put forward (Brown & Hulme, 1995; Gupta & MacWhinney, 1995). However, experiments in brain-damaged patients and PET activation studies in normal subjects provide support to a bipartite architecture (see Vallar, Chapter 15 this volume). Evidence from patients with cerebral lesions may then provide a relevant contribution to our knowledge of the organisation of mental processes (Caramazza, 1992; Kosslyn & Intriligator, 1992).

Functional and neurological architectures The functional architecture of mental processes may be investigated, both in normal subjects and in brain-damaged patients, without any direct reference to the structures that constitute its neural basis, even though this issue may be relevant on its own. Seen from this perspective, investigation of the anatomical correlates of mental processes is not necessary to a research approach, which aims at expanding our knowledge as to “how the mind works” (Editorial: Cognitive Neuropsychology, 7: 1, 1984). One view, which has been popular among cognitive neuropsychologists, is that (taking for granted the postulate of correspondence, accounting for the existence of selective neuropsychological deficits produced by brain lesions) the neurological and neuropsychological levels of description are very different (see discussion in Mehler, Morton, & Jusczyk, 1984). Accordingly, it is unlikely that the investigation of the neural basis of mental processes provides data relevant to our understanding of their functional architecture. The limitations of a purely functional approach are apparent in a recent review concerning phonological dyslexia, of which the most prominent manifestation is a selective impairment of nonword reading. Coltheart (1996) discusses at length the case of patient LB (Dérouesné & Beauvois, 1985),

who does not show any associated phonological impairment, in a variety of tasks requiring the manipulation of phonemic constituents. By contrast, most patients with defective nonword reading have some phonological impairment in tasks not involving any orthographic processing. Although the latter cases suggest an interpretation of phonological dyslexia as a more global phonological deficit, the data from patient LB are not compatible with this view and have been explained by a specific dysfunction in the reading process itself, for instance at some orthographic level. After a long discussion concerning functional patterns of impairment and computational and connectionist models, Coltheart (1996, p.761) wonders whether the hypothesis of an anatomical contiguity of the brain areas involved in nonword reading and phonological processing might help to explain the observed dissociations, and “Should any significance be attached to the fact th a t...” patient LB was a right-handed individual who became aphasic after a lesion in the right hemisphere. The latter neurological fact raises in this patient the possibility of an idiosyncratic anatomo-functional organisation of the systems under investigation. Even though a strict functional approach remains possible in principle, the integration of neurological and psychological sets of results may have synergetic effects. The observation, in different patients, of a relationship between the site of the lesions and the patterns of behavioural deficit may be taken as evidence for a functional dissociation. This is the case, for instance, for the distinction between short- and long-term memory processes, drawn in the 1960s: patients with selective deficits of such systems differ both in the pattern of memory impairment, and in the site of the cerebral lesions. In the following years, the neurological analysis of the lesion sites of patients with memory disorders became more and more precise, localising the neural bases of specific components of short- and long-term memory systems (Vallar, Chapter 15 this volume). Another illustrative example is the association of perceptual hemineglect with parietal lesions, and of premotor neglect with frontal damage, which suggests a distinction between input and output processes in the stimulus-response chain (Vallar, 1993).

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A main reason for the relevance of behavioural experiments in brain-damaged patients and of cerebral activation studies in normal subjects (and in patients) is that data concerning the actual organisation of the neural bases of cognitive processes may help to eliminate possible alternative and plausible architectures, suggested by purely behavioural experiments in normal individuals, and by simulation studies. This procedure may in the end reduce the competing hypotheses to the single functional architecture implemented in the human brain. The lack of an adequate anatomical correlation between a specific deficit and lesion of a cerebral region does not, however, diminish the importance of a functional dissociation, revealed through behavioural experiments. For instance, in humans neglect may be confined to distant or to close extra-personal space, but this behavioural dissociation does not have a clearly defined anatomical counterpart at present (Vallar, 1993). These observations in humans are, however, in line with studies in the monkey, which have shown that experimental lesions of different cerebral areas may bring about selective forms of hemineglect for the distant, peripersonal, and peribuccal space (Graziano & Gross, 1995, for related evidence; Rizzolatti, Matelli & Pavesi, 1983). A cognitive neuroscience approach (see also Schacter, 1992), which integrates neural and behavioural data sets, may at present take advantage of three main methods: (1) the traditional anatomo-clinical correlation; (2) functional activation; (3) animal studies. The first and the second paradigm, have greatly benefited from the development of neuroimaging techniques (TC, MRI, SPET, PET, fMRI). The third approach provides relevant data concerning a variety of perceptual, mnestic, and motor functions, but cannot be used to investigate language and its disorders. These three sources, together with psychological experiments in different populations without brain damage (children, adults, elderly subjects) and simulation modelling, may provide evidence that, through converging operations,6 elucidates the functional and neural aspects of the mind’s architecture.

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SOME SPECIFIC METHODOLOGICAL PROBLEMS In this section some specific issues, which concern all the approaches previously discussed, are considered. In the last 20 years neuropsychologists have become more and more aware of the relevance of the assumptions that underlie their research work. These postulates and their implications have been extensively debated in specialised journals and books (Caramazza, 1988a; Ellis & Young, 1988; Shallice, 1988; Vallar, 1991).

Dissociations among symptoms Since its inception (see Bouillaud, 1825) neuropsychological research has made use of the paradigm of dissociations among deficits, in order to interpret sets of experimental data. Two forms of dissociation may be distinguished (Teuber, 1955; Weiskrantz, 1968). Simple dissociation The behavioural tasks A and B, which assess the functions F¡ and F 2 are given to a group of patients (or a single patient), selected according to the side or, the intra-hemispheric localisation of the lesion, or both features. The patients’ performance may be defective in A and, within the normal range in B. One interpretation of this result is that the damaged hemisphere or cerebral region is the neural correlate of function F 1 , which has been disrupted by the lesion. At a purely functional level, this pattern denotes the damage of Fi, while F2 is preserved. In the classical (strong) form of the simple dissociation, the patients’ level of performance is normal (presumably not different from the premorbid level, and, in any case, comparable with that of an appropriate control group) in one of the two tasks, and defective in the other (Fig. 6.5a). The simple dissociation may be less clear-cut (or weak). The patients’ performance may be more defective in one of the two tasks, even though they are impaired in both, compared with normal subjects (Fig. 6.5b). In this case the type of inference just mentioned should be treated more carefully: the defective performance in both tasks suggests a multiple-component disorder. The strength of a

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weak simple dissociation is related to two main factors: the difference between the levels of performance in the two tasks, and, in the task in which performance level is higher, the magnitude of the impairment in comparison with the control group. The greater is the difference, and the smaller is the impairment, the stronger is the dissociation. It remains possible, however, that a simple dissociation, both in the weak and in the strong form, is produced by a greater difficulty of task A, in comparison with B. Normal subjects might need to allocate a greater amount of resources in order to perform A (Norman & Bobrow, 1975). The cerebral lesion might have reduced the total level of available resources (e.g. attention, memory), so that only the easier task (B) may be performed at a normal level, or, in the case of a weak dissociation, below the normal level, but nevertheless better than A (Fig. 6.6). According to this view, a single function (e.g. Fi), is involved in the execution of both tasks, with B being easier than A. A parsimony criterion supports this conclusion, which requires a minor number of functional components (F7, but not F 2 ).

FIGURE 6.6

Resource/performance curves for two hypothetical tasks. A brain lesion may reduce the available amount of resources to a level R 1 , so that the patient’s performance is defective in the more difficult task, even though a single function is involved in both tasks (redrawn from Norman & Bobrow, 1975; Shallice, 1988).

FIGURE 6.5

Simple dissociation, (a) In the classic or strong form the level of performance is within the normal range in task B, defective in A. (b) In the weak form the levels of performance may be defective in both tasks, but there is nevertheless a difference between A and B (reproduced from Vallar, 1996, with permission of Zanichelli Editore).

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Double dissociation The problem of interpretation mentioned in the previous section is overcome by the existence of two groups of patients, or two single cases (Pi and P 2 ), who show this pattern of impairment. Compared with the performance of control subjects, Pi is impaired in task B, but not in task A, and P2 vice versa (Fig. 6.7a). This is the double dissociation in the classical or strong form. Under these conditions, the patterns of impairment cannot be interpreted in terms of task difficulty, and the conclusion may be drawn that two independent functions F 1 and F2 are involved in tasks A and B. This conclusion is tenable even when the patients’ levels of performance are below the normal range in both tasks (double dissociation in the weak form, Fig. 6.7b). In this case, the interpretation is more complex, however. It is likely that multiple deficits, a global impairment, or both types of disorders are also present, producing the general reduction of performance level (see also a discussion of double dissociations as cross-over interactions in Jones, 1983).

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The absence of significant differences in the severity of the dissociated deficits indicates both that the experimenter has used tasks with comparable sensitivity to the operation of the functions of interest, and that the overall severity of the neurological damage is similar in the two groups (Weiskrantz, 1968). This comparison may be easy when simple functions are assessed by psychophysical methods, such as sensory thresholds or discrimination skills (Teuber, 1955). In human neuropsychology more complex functions (e.g. language) are frequently investigated, however. The difficulty of the different tasks cannot be directly compared, even though raw scores can be converted into z or equivalent scores (see for example Albert, Goodglass, Helm et al., 1981; Spinnler & Tognoni, 1987). In the vast majority of studies in humans, levels of performance within the normal range vs. clearly defective are usually regarded as sufficient evidence to support a strong double dissociation.

FIGURE 6.7

Double dissociation, (a) In the classic or strong form patient or group P-j has a defective performance in task B, normal in A, P2 vice versa. With reference to the tasks, P-|’s performance level is higher than that of P2 in A, while an opposite pattern occurs in B. Finally, the levels of preserved and impaired performances are comparable across patients, (b) In the weak form the patients’ level of performance is below the normal range in both tasks (reproduced from Vallar, 1996, with permission of Zanichelli Editore).

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The inference suggesting the existence of discrete and independent components can be drawn only if the double dissociation is between patients. The level of performance of Pi is higher than that of P 2 in task A, lower in task B. Under these conditions, if only a single function were involved in both tasks, Rpi and R p2 being the resources available to the two patients, two contradictory inequalities would occur: task A: RPi > R P 2 task B : R P 2 > R pi The double dissociation, however, may take the form of complementary neuropsychological deficits, and occur between tasks and not between patients. As shown in Fig. 6.8, patient Pi has a higher level of performance in task A, compared with B, and patient P 2 vice versa. In both tasks, however, the level of performance of P 2 is higher. This pattern is compatible with an interpretation in terms of a single function, involved in both tasks, provided one performance/resource curve is steeper than the other (Shallice, 1988). The history of neuropsychology provides many instances of double dissociations. An illustrative example is the observation of De Renzi et al. (1969) that lesions in the left hemisphere are associated with agnosic disorders of the associative type, and right-sided lesions with apperceptive disorders. In Complementary double dissociation. The performance of patient or group P-| is better in task A compared to B. In P2 an opposite pattern is found. This dissociation, however, differs from the classical one in that it considers only the sign of the differences between tasks (dissociation between tasks), but does not require that each patient has a level of performance higher than the other in one task (dissociation between patients, see Fig. 6.7). It is therefore possible that P2’s performance is higher than that of Pi in both tasks, even though Pi performs A better than B, and P2 vice versa. This complementary pattern is compatible with the hypothesis that a unitary function is affected, but the two tasks have different resource/performance curves, and the two patients different amounts of resources available (redrawn from Shallice, 1988).

this study, apperceptive tasks, requiring a difficult visual discrimination (naming of overlapping figures, face identification, colour discrimination), and associative tasks, requiring the extraction of the meaning of the stimulus (object-figure matching) were given to a series of 168 brain-damaged patients with unilateral lesions. The performance of right brain-damaged patients with visual halffield deficits was defective in the three apperceptive tasks, compared with that of both right braindamaged patients without visual half-field deficits, and left brain-damaged patients. The latter group, by contrast, was impaired in the associative task. Faglioni et al. (1969) reported a similar double dissociation in the acoustic modality. The performance of right brain-damaged patients was defective in an apperceptive task requiring the discrimination of meaningless sounds, while left brain-damaged patients exhibited a deficit in an associative task requiring the identification of meaningful sounds (see Fig. 6.9). In the studies by De Renzi et al. (1969) and Faglioni et al. (1969) the behavioural double dissociation had an anatomical counterpart in terms of left vs. right latéralisation of the lesion. These results were confirmed by a study in which the site of the lesion was assessed by CT. Furthermore, in line with the conclusions mentioned earlier, patients with bilateral lesions displayed a defective performance in both tasks (Vignolo, 1982).

FIGURE 6.8

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FIGURE 6.9

An example of classical double dissociation: the performances of right (R) and left (L) brain-damaged patients and of control subjects (C) in two auditory tasks (APP: apperceptive; ASS: associative) (reproduced from Vallar, 1996, with permission of Zanichelli Editore; data from Vignolo, 1982, Table 1).

Another example of double dissociation is provided by the reading deficits of brain-damaged English speakers. Patients with phonological dyslexia are severely impaired in the case of pronounceable meaningless letter strings (nonwords, or novel words). They are however able to read both regular and irregular words with a higher level of performance, which, in some cases, may be nearly errorless. Patients with surface dyslexia, by contrast, are able to read non words, but their performance is defective in the case of irregular words (Denes et al., Chapter 14 this volume). This type of inference may be also drawn when the comparison is not between two tasks, but between the effects of two variables on the performances of two patients (method of the critical variable: Shallice, 1988). A crossover interaction for one of the two variables provides a classical double dissociation, which suggests the existence of independent functions. Also non-crossover interactions may allow a similar inference. An illustrative example is a study by Derouesne and Beauvois (1979), who investigated the effects of phonemic and graphemic variables. The reading

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performance of one patient with phonological dyslexia was affected by the graphemic variable, but not by the phonemic one. A second patient showed an opposite pattern: effects of the phonemic, but not of the graphemic variable (Fig. 6 . 10). In normal subjects, the paradigm of the concurrent tasks, which may selectively interfere with the operation of specific functional components, may provide results related to those obtained in brain-damaged patients (e.g. Shallice et al., 1985). The behavioural dissociations produced by brain damage are more clear-cut, however. In addition, concurrent tasks typically have global disruptive effects, which should be taken into consideration. To summarise, the double dissociation in its strong form is a powerful tool, which elucidates the multi-componential architecture of mental functions and their neural bases.

Associations among symptoms and signs The concept of syndrome (“a group of symptoms and signs of disordered function, related to one another by some anatomic, physiologic, or biochemical peculiarity”, Isselbacher, Braunwald, Wilson et al., 1994, p.3) is widely used in clinical medicine. A syndrome “embodies a hypothesis concerning the deranged function of an organ, organ system, or tissue ... A syndrome usually does not identify the precise cause of an illness, but it narrows the number of possibilities and often suggests certain special clinical and laboratory studies.” For instance, “in dementia, deterioration of memory, incoherent thinking, impaired language functions, visual-spatial disorientation, and faulty judgement are related to the destruction of the association areas of the cerebrum” (ibid, p.3). The associations among symptoms have had a main role in defining the taxonomy of the main neuropsychological disorders. A well known example is the traditional classification of language disorders, which defines entities such as Broca’s and Wernicke’s aphasias as the co-occurrence of a set of symptoms, signs, or both. The syndromic approach is not confined to language. Associations of deficits such as Gerstmann’s syndrome and

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Balint’s syndrome have a conspicuous position in the history of neuropsychology (Denes, Chapter 22 and Nichelli, Chapter 20 this volume). Deficits such as visuo-spatial hemineglect, extinction, anosognosia, which are often associated, constitute the clinical syndrome of spatial hemineglect (Heilman, Watson, & Valenstein, 1993; Vallar, 1998). In clinical practice, associations such as the aphasic and neglect syndromes have a diagnostic value, providing indications concerning the side and the site of the cerebral lesion (Adams & Victor, 1994; Mohr, 1994). Three different anatomo-clinical relationships may bring about an association of n symptoms and signs, giving rise to three different types of syndromes (Brain, 1964; Ellis & Young, 1988; Lichtheim, 1885;Poeck, 1983). Anatomical syndrome The cerebral regions or circuits A/, A2 , A 3 , A4 ..A n, in which the functions Fi, F2, F j, F4...Fn are localised, are anatomically contiguous. The

conjoint damage of these regions produces the association of symptoms Ni, N2, N3, N4..M1. This type of syndrome has an anatomical localising value, related to the probability (determined by neurological factors, such as the distribution of the vascular territories of the cerebral arteries) that adjacent cerebral areas are conjointly damaged by the lesion. The higher this probability, the higher the localising value. The anatomical syndrome allows for partial associations, or dissociations among deficits. These are produced by lesions confined to some of the contiguous regions. For instance, a lesion of Ai and A2 would bring about Ni and Afe, without N 3 and N 4 ; damage to A 3 and A 4 N 3 and N4, without Ni and N2. The anatomical syndrome may be considered weak, as its probabilistic features makes it compatible with incomplete or partial associations of deficits (for a discussion of the traditional aphasic syndromes as weak syndromes, see Benson, 1979; Poeck, 1983).

FIGURE 6.10

Performance of two patients in a task requiring reading aloud nonwords with different (a) graphemic and (b) phonemic complexity. The performance of patient A was affected by the graphemic variable. The patient made more errors in the complex grapheme-to-phoneme correspondence condition (a sound corresponds to two letters), compared with the simple condition (a one-to-one letter-to-sound correspondence). The phonemic variable (nonwords, homophones, or non-homophones of real words) did not influence A’s level of performance. In patient D, an opposite pattern was found: the phonemic, but not the graphemic variable affected the patient’s performance (reproduced from Vallar, 1996, with permission of Zanichelli Editore; data from Derouesne & Beauvois, 1979).

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Another example of an association of deficits produced by the anatomical contiguity of relevant cerebral areas is Gerstmann’s syndrome. The association of finger agnosia, left-right disorientation, acalculia, and agraphia has a localising value, suggesting a left parietal posterior-inferior lesion (Denes, Chapter 22 this volume). The syndrome, however, has no functional significance, as partial associations may occur. This indicates that these deficits are produced by the impairment of discrete functions, even though their neural correlates are contiguous. Functional syndrome The symptoms and signs Ni, Afc, N3, N4 ...Nn are associated because they are produced by the impairment of function F. Accordingly, the syndrome is always complete. Exceptions—that is, non-complete patterns—can be explained only in terms of individual variability: in some individuals the functional architecture of the mental processes of interest differs from that of the majority of the population. In this respect, the functional syndrome may be considered strong. Anatomo-functional syndrome The symptoms and signs N i, Afe, Afe, N4...Nn are associated because they are produced by the impairment of function F, localised in the cerebral area R , or in the neural circuit C. The anatomofunctional syndrome differs from the anatomical one in that F has a localised neural correlate. The patterns of aphasic deficits originally described by neurologists in the second half of the 19th century are illustrative examples (Lichtheim, 1885; Wernicke, 1874/1966-1968). The association among a given set of symptoms and signs is produced by the impairment of a specific function, localised in a cerebral area or circuit. Mixed syndrome The association among Ni N2, N3, and N4 reflects both anatomical and functional factors. Ni and N2 are produced by the impairment of function F/, and N3 and N4 of F 2 , giving rise to two discrete functional syndromes. The anatomical association is due to the contiguity of the neural correlates of

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Fi and F 2 , cerebral regions A; and A2 . A lesion involving both A; and A2 brings about the complete mixed syndrome. Lesions confined to either A; or A2 cause partial deficits. Interpretation o f associations The association among symptoms and signs may reflect, as discussed in the previous sections, three discrete patterns of anatomo-functional relationships: the anatomical contiguity of relevant brain regions affected by the lesion, the disorder of a unitary functional component, or both factors. Accordingly, the interpretation of an association is more complex than that of a double dissociation, in its classical or strong form. The study of associations, however, may provide useful insights concerning the pathological mechanisms underlying a neuropsychological deficit. An illustrative example is provided by a set of experiments by Baddeley et al. (1988). Their patient PV, who had a selective impairment of auditory-verbal short-term memory (reduced auditory-verbal span) was unable to learn new words. Two interpretations may account for this association of deficits (reduced span and defective acquisition of new words). The impairment of two independent functions brought about these disorders, and their association reflected the anatomical contiguity of their neural correlates. Alternatively, as suggested by Baddeley et al. (1988), the patient’s defective phonological memory caused an inability to learn new words, in addition to the reduction of auditory-verbal span, in other words: the impairment of a single function underlay both behavioural deficits. The original study by Baddeley et al. (1988) did not adjudicate between these two possible interpretations. However successive experiments in different populations—normal subjects (Papagno, Valentine, & Baddeley, 1991; Papagno & Vallar, 1992, 1995), children (Gathercole & Baddeley, 1989; Service, 1992) and patients with genetically determined cognitive disorders (Barisnikov, Van der Linden, & Poncelet, 1996; Vallar & Papagno, 1993)—have provided converging evidence to the effect that the two deficits reflect the impairment of a single function (phonological short-term memory).

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Another example is provided by a study by Caramazza et al. (1986). Their patient IGR was severely impaired in reading, writing to dictation, and repeating nonwords. The patient’s performance, by contrast, was substantially preserved in the case of words. Furthermore, error analysis revealed a phonological relationship between the stimulus and the response provided by the patient. Caramazza et al. interpreted this association of deficits in terms of the dysfunction of a short-term memory component, the output phonological buffer, which assembles phonological segments and transmits the output of its operation to the peripheral articulatory (for reading aloud and repetition) and graphemic (for writing) processes. These examples illustrate the heuristic role of associations. The presence of dissociations is also needed, however, in order to demonstrate that the conjoint failure in the tasks of interest can be traced back only to the impairment of a specific component. For instance, in patient PV, the inability to learn nonwords was not due to a general learning deficit, as her ability to learn words was preserved (Baddeley et al., 1988). In patient IGR, the repetition deficit was confined to nonwords, and could not be traced back to defective phonological analysis (Caramazza et al., 1986). The efficacy of the conjoint utilisation of associations and dissociations is illustrated by an experiment by Grossi et al. (1989). They studied a right brain-damaged patient with left hemineglect, and a left brain-damaged patient who was unable to generate mental images. The patients’ task was to compare the angles formed by the hour-hands of two clocks. In the perceptual task the clocks were printed on a card, one below the other. In the imagery task the patients had received instructions to generate the images of the two clocks, on the basis of a verbal command (e.g. “the time is five to three”). The patient with left neglect had a defective performance in both tasks, provided the angles to compare were in the left side of the clock-face. This patient showed a dissociation concerning the spatial position of the stimuli (left vs. right), but not the tasks (perception vs. imagery). The patient who was unable to generate mental images showed the opposite pattern of impairment: his performance

was defective in the imagery task, but not in the perceptual task, independent of the spatial position of the stimuli. Associations may be also used to evaluate the effects of a specific treatment (drugs, rehabilitation, physiological stimulations) on a neuropsychological deficit. For instance, if function Fi is involved in the execution of tasks A, F, and C, then its damage impairs the patients’ performances in all three tasks. Let us make the following two assumptions: (1) in patient P Fi is selectively impaired (i.e. P ’s defective performance in A, F, and C can be explained only by a deficit of Fj); (2) a treatment T (e.g. a specific rehabilitation procedure) selectively improves F /’s operation. If this is the case, T should improve P ’s performances in all three tasks. The improvement should also be selective. If in P component F 2 , involved in tasks D, F, and F, is also affected, the positive effects of T should not extend to these latter tasks. If F; was involved in tasks A and B only, but not in C, the effects of T should be confined to the first two tasks. In a situation of this sort, an association may be used to explore the architecture of mental processes, to test competing hypotheses. An illustrative example, which made use of a vestibular stimulation, is the study by Cappa et al. (1987), who aimed at assessing in right braindamaged patients whether this treatment induced the temporary remission of not only visuo-spatial extra-personal left hemineglect, but also of related disorders, such as anosognosia for left hemiplegia, and hemineglect for the left side of the body. According to their hypothesis, if these deficits were produced, at least in part, by the dysfunction of spatial processes modulated by the vestibular system, then the treatment should affect all of them in a similar fashion. In line with this prediction, vestibular stimulation improved both personal and extrapersonal hemineglect, and anosognosia.

Group and single case studies Neuropsychologists have made use of data from both individual patients and groups, selected on the basis of neurological (e.g. the side or the site of the lesion) or behavioural (the presence of a specific deficit) criteria. In different historical periods, one or the other approach has prevailed.

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In the 19th century, neuropsychological studies were performed in single cases, in whom the behavioural deficit, assessed through a clinical examination, was correlated with the localisation of the lesion. This method has a number of methodological flaws (see The neuropsychological method) and was replaced by studies performed in series of brain-damaged patients through standardised tests, which, after World War II, became the leading approach, even though relevant exceptions are on record, such as the noted patient HM (Vallar, Chapter 15 this volume). Since the late 1960s, with the development of the cognitive neuropsychological approach, single case studies again became a widely used experimental method. This modern single case paradigm differs from the 19th-century studies in important respects, however, making use of the methods of experimental psychology (Shallice, 1979). Standard tasks are used, and the patient’s performance is compared with that of matched control subjects, through statistical procedures. The dissociations in the patient’s performances in different tasks have to be statistically significant. The reliability of the patient’s performances may be assessed through repeated testing sessions7. A main reason that underlay this flourishing of single case studies in the 1970s and 1980s was the increasing awareness on the part of cognitive neuropsychologists that the functional architecture of mental processes is very complex, including many connected components. Consider for instance the simple model of the reading processes shown in Fig. 6.1 la. A cerebral lesion, the localisation and size of which reflect anatomo-physiological factors, may disrupt more than one component of the system. Accordingly, if a group of patients is selected on the basis of the side or site of the lesion, it remains possible that patients with heterogeneous behavioural deficits, and, by implication, damage to discrete functions, are pooled together. Also a selection on the basis of the presence or absence of a clinical syndrome (e.g. Broca’s aphasia, or spatial hemineglect) is open to this criticism, as patients with non-homogeneous cognitive disorders might be included. Consider, for instance, the functional model of repetition, reading and writing of single words and

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nonwords shown in Fig. 6.11b (Caramazza et al., 1986). These tasks are simple, compared with the complex analysis required by sentence and discourse processing. Nevertheless, they involve a number of discrete functional components, which may be selectively or conjointly damaged, giving rise to a variety of deficits. It seems then to be unlikely, at least a priori, that two brain-damaged patients show an identical functional impairment. This conclusion is even sounder, if one considers that some parts of the model (the perceptual and the more peripheral production components) are not specified in their full detail. Accordingly, the average behaviour of a group of brain-damaged patients might be a statistical artefact, which conceals heterogeneous patterns of impairment. Figure 6.12 illustrates such an hypothetical example in the case of a double dissociation. An experiment by Bisiach et al. (1983) showed how the group analysis of the performance of brain-damaged patients may cover different pathological patterns. In this study, 12 right braindamaged patients with hemineglect were required to set the mid-point of horizontal segments of varying length. A group analysis performed on the patients showed that the extent of the rightward displacement of the subjective mid-point was directly related to the length of the segment. This treatment of the data concealed some relevant differences among patients, however. An analysis in which the relevant parameter was the length of the represented segment (the part of the segment considered by each individual patient in order to compute the subjective mid-point) revealed two discrete patterns (Fig. 6.13). In one patient, RG, the longer the real segment, the greater was the rightward displacement of the left end of the represented segment. This pattern is compatible with the view that RG’s attention was pathologically focused towards the right end of the segment, so that longer segments produced a greater rightward bisection error (see a theoretical account of this behaviour in terms of opposite attentional vectors in Kinsboume, 1993). In another patient, CC, the longer the real segment, the greater was the leftward displacement of the represented segment. This pattern indicates that CC was, to some extent, taking into consideration the total

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FIGURE 6.11 Cognitive models of some mental abilities, (a) A simple dual-route model of reading (redrawn from Coltheart, 1985). (b) A more complex model for repetition, reading, and writing of words and nonwords (redrawn from Caramazza, Miceli & Villa, 1986).

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FIGURE 6.12

Example of double dissociation between groups, which conceals different patterns of impairment in individual patients. The behavioural pattern of group A patients is similar in all cases, while group B (a) includes sub-groups B-| and B2 (b); B-| does not show a double dissociation with respect to A (redrawn from Shallice, 1988).

length of the segments, and this conclusion might have been based on differences in their right sides. Two lessons can be learned through this example. First, the average performance of a group of patients may be misleading, concealing heterogeneous patterns of behaviour. Second, the theoretical model adopted by the experimenters has a crucial role in all the stages of the study (from the design of the experiment to the analysis of the data, see Caramazza, 1986). Previous researchers had made use of the bisection task (a test widely used for the clinical diagnosis of spatial hemineglect), but their theoretical model did not include the concept of representational space (Schenkenberg, Bradford, & Ajax, 1980). The complexity of the multi-componential architecture of mental processes and of their relationships with the neural correlates assigns a relevant role to single case studies. Natural cerebral lesions, in which the side and site of damage is determined by neurological parameters, usually disrupt multiple components of mental processes, and patients with selective (pure) disorders are comparatively rare.

Many relevant theoretical advances have been made possible by the study of patients who showed a dramatic dissociation between the severe and selective impairment of a specific functional component, and other processes, that were entirely preserved. In Broca’s patient the dissociation concerned a defective speech production vs. a preserved comprehension. The patients described by Anton (1899) and Babinski (1914) were anosognosic for a specific neurological deficit. Their lack of awareness for hemianopia or hemiplegia could not be easily interpreted in terms of defective general intelligence. The noted patient HM had a selective impairment of the explicit component of longterm memory (Vallar, Chapter 15 this volume). The investigation of patient PV revealed the role of phonological memory in vocabulary acquisition (Baddeley et al., 1988). The history of neuropsychology includes many examples of seminal single case studies. Single case studies, in addition, have some practical advantages, compared with group studies. There are no problems related to the selection of

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FIGURE 6.13 Average performance (short vertical dashed lines) of a group of 12 right brain-damaged patients with hemineglect, in a line bisection task (200,400, 600 mm). The lines were shown to the patients with their objective mid-point on the mid-sagittal plane of the patients’ trunk (long vertical dashed line). The performance of patient RG and CC (short vertical lines) are shown in the upper and lower halves of the figure. The dotted rectangles denote the “nonrepresented” portions of the segments, while the remaining part of each line indicates the extent considered by each patient in the bisection task (redrawn from Bisiach, Bulgarelli, Sterzi et al., 1983).

an homogeneous series of patients. The design is less rigid. The result of one experiment may immediately direct the successive investigations. In group studies, by contrast, the structure of the experiment cannot be modified, as this would produce noncomparable data. The only possible solution is to repeat the whole experiment, provided all patients are still available for study. Alternatively, a fresh series of patients may be tested. The greater flexibility of single case studies is based on the assumption that the deficit does not change over time. In the case of long-lasting studies, therefore, the stability of the deficit of interest should be assessed from time to time. The low flexibility of group studies can make data collection slower, but does not diminish, in principle, the value of this approach. The problem of patient selection is more complex. When a patient is assigned to a group on the basis of the presence of a behavioural deficit (e.g. neglect, or

aphasia) the potential role of neurological (site and size of the lesion, aetiology, handedness) and demographic variables, which could make the group non-homogeneous, should be taken into consideration (Vallar & Perani, 1987). If the selection criterion is neurological (e.g., side of the lesion) differences across patients in the pattern of behavioural impairment, which can affect their performance in the experimental task, can make meaningless any interpretation based on the average scores. One solution to these problems is statistical. If the patients’ performance (e.g., in an auditory latéralisation task) is affected by factors other than the investigated variable (e.g. the side and localisation of the lesion), the scores may be adjusted for the potentially confounding factors (e.g. age, schooling, overall neurological severity), through analyses of co-variance (Bisiach, Cornacchia, Sterzi et al., 1984). Alternatively the

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criteria of patient selection may be much more stringent. For instance, Vallar et al. (1988), in a study concerning deficits of verbal memory associated with left-sided lesions, set the absence of aphasia (assessed by a standard exam and the Token Test, a task sensitive to minor language disorders: Boiler & Vignolo, 1966) as selection criteria. In addition, each patient was matched with a control subject with a comparable age and educational level. A typical example of the problems of group studies concerns the possible biasing role of aphasia. When the experiment aims at assessing the incidence and the severity of a neuropsychological deficit after lesions of the left and of the right hemisphere, the percentage of patients who are unable to enter the study because they fail to comprehend the task’s instructions should be comparable in the two groups. In the study of the disorders of auditory latéralisation mentioned earlier, Bisiach et al. (1984) were able to verify that only three aphasies out of 107 patients did not take part in the experiment, due to their language deficit. In addition left and right brain-damaged patients with a visual field deficit had lesions with a similar localisation, but only the latter showed a disorder of auditory latéralisation. Another example is a study that aimed at assessing left-right asymmetries in the incidence of motor, somatosensory, and visual half-field deficits contralateral to a hemispheric lesion. Sterzi et al. (1993) examined retrospectively a large series of patients, taken from a community-based epidemiological survey, in which the two groups of patients were comparable as to all relevant neurological and demographic variables. The problems concerning patient selection frequently occur in group studies. De Renzi and Faglioni (1965) found that right brain-damaged patients had longer latencies in a visuomotor simple reaction time task. In order to account for this hemispheric difference in such a simple task, they suggested that patients with right brain damage had larger lesions. If the function involved in this task was represented in the brain in a diffuse, nonlocalised, fashion, the severity of the patients’ deficit would be directly related to the size of the lesion. The bias related to patient selection may be

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relevant: some left brain-damaged patients with extensive lesions could not have been tested, due to the presence of aphasia. By contrast, patients with right hemisphere lesions similar in size might have entered the study, as they were not aphasic and could comprehend the task. If this had been the case, in a series of patients selected for a behavioural study, right-sided lesions might be more extensive, and the deficit more severe. In a later study, Howes and Boiler (1975) investigated this problem through a volumetric measurement of lesion size, on the basis of a brain scan image. They confirmed that patients with right hemisphere lesions had longer latencies in visuomotor simple reaction times, but not that their lesions were larger. This study does not, therefore, support the view that the hemispheric difference found by De Renzi and Faglioni was produced by a selection bias, suggesting instead that the neural basis of the function of interest was, at least in part, lateralised to the right side of the brain (see related PET activation data in Pardo, Fox, & Raichle, 1991). To summarise, single case studies have a number of advantages, in comparison with group studies. The probability of producing significant theoretical advances is perhaps higher8. Single case studies are more flexible, and the problems related with patient selection are minimal. They are not adequate, however, to investigate hemispheric functional asymmetries, and the neural bases of mental functions. If the aim is to assess whether or not a specific brain region or circuit is (or is not) the neural correlate of a given function or set of functions, the study of a series of patients becomes necessary. The observation that an individual patient with a specific cognitive disorder has focal brain damage is compatible with a nonlocalisationist view of the functional organisation of the brain. If this was the case, the lesion, independent of its site, would produce a degradation of the level of performance, related instead to its extension. Let us assume that a patient P, with a cerebral lesion in area A, has a defective performance in task X , but not in tasks W, Y, and Z. On the basis of this single observation, the possibility that the cerebral regions involved in task X are not confined to A, including instead also B, C, and D, cannot be ruled out. In addition, this

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single dissociation does reject an interpretation in terms of allocation of the available resources: damage to A reduces the patient’s performance in task X , because this is easier than W, Y, and Z. Only the replication of the positive observation (a lesion of A affects the patient’s performance in task X), and a negative finding (a lesion involving cerebral area C, and sparing A, does not disrupt the patient’s performance in task X , affecting instead tasks W or Y) fully supports the conclusion that the brain region A is selectively involved in task X. Two examples will illustrate this pattern. In the first study a behavioural selection criterion was used, namely: the presence or absence of left extra-personal visuospatial hemineglect was subsequently correlated with the site of the cerebral lesion. The more frequent anatomical correlate of hemineglect (assessed by a visuomotor exploratory task) is a lesion of the right posterior-inferior parietal regions, which, in turn, are spared in patients without neglect (Vallar & Perani, 1986). In the second study (Risse, Rubens, & Jordan, 1984) the selection criterion was anatomical, namely: in two groups of patients with frontal and temporoparietal lesions, the pre- vs. post-rolandic site of the damage was subsequently correlated with the behavioural disorder. Risse et al. suggested that the main anatomical correlate of deficits of auditoryverbal short-term memory was a left-sided posterior-inferior parietal lesion. Patients with lesions involving this region had a defective auditory-verbal span, which was preserved in patients with damage involving the frontal lobe or the basal ganglia.

Critique of the concept of syndrome and of group studies Limits o f the concept o f syndrome In the last 20 years, the criteria (a specific pattern of behavioural deficits, the side and localisation of a cerebral lesion) that are used to select a sample of brain-damaged patients, who enter an experimental study, and whose performances are analysed as a group, have been widely criticised. The anatomical localisation value of the traditional neuropsychological syndromes has been

questioned. For instance, in the case of the aphasic syndromes (see Cappa and Vignolo, Chapter 8 this volume), TC and MRI studies have shown that lesions outside the classical language area (e.g. subcortical lesions) can bring about aphasic disorders (Vallar et al., 1992). Furthermore, with reference to the traditional syndromes, fluent aphasia may be associated with frontal lesions, and nonfluent aphasia with posterior damage (Basso, Lecours, Moraschini et al., 1985). Finally, relatively small lesions, localised outside the boundaries of the traditional language areas, may bring about global aphasia (Vignolo, Boccardi, & Caverni, 1986). Methods that provide a measurement of regional cerebral blood flow and metabolism have shown that the area of deranged function may involve regions that are structurally intact (Feeney & Baron, 1986; Metter, 1987; Vallar et al., 1992). On the basis of these observations the classical views on the relationships between neuropsychological syndromes and lesions of specific brain regions have been revisited. For instance, Metter et al. (1989) took the view that the traditional syndromes have little theoretical significance, because in both fluent and nonfluent aphasics metabolism was reduced in the temporal regions. Taken together, these findings suggest that the neural basis of mental processes should be conceived in terms of complex cortico-subcortical circuits, rather than as cortical areas connected by white matter fibre tracts (see Fig. 6.1) (Cappa & Vallar, 1992; Mesulam, 1990). Anatomo-clinical correlation studies of spatial hemineglect also support this conclusion (Vallar, 1993). The view that the neural correlates of mental functions are cortico-subcortical circuits modifies the anatomic part of the concept of neuropsychological syndrome, but not necessarily its functional aspects. These, too, have been impugned, however. In the case of aphasic syndromes, which first were challenged, the argument may be briefly summarised as follows (Saffran, 1982; Schwartz, 1984). The traditional syndromes are founded on a 19th-century model of the organisation of linguistic processes, which, of course, cannot take into consideration the advances that took place in the following decades. The study of mental

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processes, and of their pathological dysfunctions, should be based on current (information processing) models. If the traditional groups of symptoms and signs are analysed in these terms, it is clear that they are, at best, anatomical, probabilistic syndromes, useful in clinical practice, but with no functional significance. This is indeed a current clinical application of the concept of syndrome. The detailed study of the individual case, in addition, may reveal a remarkable lack of homogeneity among different patients, previously classified as belonging to a specific syndrome, through either an informal clinical exam, or standard neuropsychological batteries (the Aphasia Examination of the Neuropsychology Centre of Milano, the Boston Diagnostic Aphasia Test: Basso, Capitani, & Vignolo, 1979; Goodglass & Kaplan, 1972). Accordingly, syndromes such as Broca’s (Mohr, Pessin, Finkelstein et al., 1978; Sloan, Bemdt, & Caramazza, 1980) and conduction (Luria, 1977; Shallice & Butterworth, 1977) aphasias have been fractionated into more subsyndromes, in each of which the complex of symptoms and signs has been explained in terms of a specific functional deficit. Also the standard clinical batteries may disclose new associations, provided objective classification criteria are used. For instance, Kertesz and Phipps (1977, 1980) distinguished two subtypes (afferent and efferent) of the clinical syndrome of conduction aphasia, on the basis of differences in the patients’ performances in verbal fluency and comprehension tasks of the Western Aphasia Battery. Another indication of the limits of the traditional taxonomy is the high number of patients in whom a specific syndromic diagnosis cannot be made. When the assessment is standardised, but the classification is made by the examiner, and not, as in the Western Battery by an algorithm, a high percentage of patients end up not classified: over 40% of the patients on the Boston Diagnostic Aphasia Examination (Albert et al., 1981; Benson, 1979). Cognitive neuropsychologists, therefore, replaced the traditional anatomo-clinical syndromes with new associations, in which the complex of symptoms and signs is analysed in the light of the modem information processing models. In the 1970s and 1980s this revision has generated

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new syndromes, such as deep, phonological, and surface dyslexia (Denes et al., Chapter 14 this volume). More recently the syndrome of spatial hemineglect has been fractionated into a number of discrete components (Barbieri & De Renzi, 1989; Halligan & Marshall, 1992). However, cases classified according to these novel categories may also show relevant differences. This problem was already clear in a review on deep dyslexia, published in the late 1970s (Coltheart, 1980). These differences among patients indicate that any putative functional system, F (the lesion of which produces A7, N 2 , N 3 , and N 4 symptoms, signs or both) may in fact turn out to comprise n subsystems, which may give rise to a number of dissociations. This state of affairs reflects some basic principles of the anatomofunctional organisation of the central nervous system, which possesses a high degree of functional specialisation. An increasing tendency towards fractionation characterises not only the neuropsychological syndromes, but all neurological deficits (e.g. peripheral neuropathies) (see discussion in Vallar, 1994). Only single cases? A solution to these problems is to abandon the very concept of syndrome, which allows patient classification, studying each patient as an individual case (Caramazza, 1986; Ellis, 1987; Patterson, Marshall, & Coltheart, 1985). The alternative would be a multiplication of the syndromes. However, since virtually all skills are based on the cooperation among many functional components (see Fig. 6. lib), the possible defective syndromes produced by brain damage would become so numerous, as to be useless. In the case of dyslexia, for instance, over 16,000 are possible, according to Patterson et al. (1985, p .ll). The view that only the study of single cases provides data relevant to our understanding of the functional architecture of mental processes has been vigorously defended by Caramazza and his co-workers, who, in many papers, have developed this position in some detail (Caramazza, 1986; Caramazza, 1988a). Briefly, given the complex architecture of the cognitive system and the variability of the site and extent of naturally

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occurring lesions, it is very unlikely that two patients have similar functional deficits. It follows, therefore, that a homogeneous group of patients cannot be constituted. Furthermore, even if this were possible, the a priori criteria that define the group concern only the patient’s selection, not the results of the experiments that are to be performed. The functional deficit of each patient, therefore, can be established only a posteriori, after the experimental study (Caramazza, 1988b). Hence, studies in groups of patients which aim at elucidating the neurological and functional architecture of mental processes are useless and harmful, because they provide misleading results. The only appropriate method is to study individual patients, without the aid of any classical or modern syndrome. This extreme position (only single cases), which banishes group studies from the domain of neuropsychology and has been defined ultra (Shallice, 1988) and radical (Robertson, Knight, Rafal et al., 1993), encounters some problems, however. The study o f normal subjects. The arguments against the possibility of forming homogeneous groups of patients can also be applied to the case of normal subjects, showing that group analyses are unreliable, due to individual differences (Caplan, 1988; Shallice, 1988). This is nevertheless the current method of cognitive psychological research in normal subjects. McCloskey and Caramazza (1988) reply to this argument by assuming that normal subjects are homogeneous. Variability reflects a nonspecific background noise, and the behaviour of the majority of the subjects may therefore provide reliable indications as to the architecture of mental processes. Homogeneity, by contrast, can not be taken for granted in brain-damaged individuals, in whom, due to the reasons discussed earlier, it is likely that the functional deficits differ among patients. Differences among normal subjects cannot be accounted for entirely in terms of background noise, however. Let us suppose, for instance, that 10 out of 12 normal subjects show the detrimental effect of word length or of phonological similarity (immediate repetition span is higher for short or

phonologically dissimilar than for long or similar words: Baddeley, Lewis, & Vallar, 1984; Baddeley, Thomson, & Buchanan, 1975), but that in the remaining two subjects the effect is absent or reversed. This untypical behaviour might reflect background noise only, being therefore within the normal distribution of the observations, even though, on the mere basis of the effects of noise, the expected result might be a variability of the overall level of performance, without qualitative effects (i.e. absent or reversed effects). In the latter case, the performance of the two aberrant subjects should show the typical pattern, on repeated testing sessions. The untypical pattern could however be reliable. Such a result could reflect the utilisation by the two minority subjects of strategies different from those employed by the majority, even though the functional architecture of the systems involved is identical. In 251 adults Logie et al. (1996) have recently confirmed that word length and phonological similarity significantly influence the group means in the predicted direction. However 43% of the subjects failed to show at least one of the effects, and a notable number of subjects showed effects in the direction opposite from that of the majority. They also found variability in the presence of the effects on test-retest sessions. Span level was a predictor of the presence of the effects, but exceptions were found (i.e. subjects with high span who did not display the predicted effects). The subjects’ strategies were also relevant, and their effect was independent of span level.9 The untypical subjects might, for some reason, choose to use strategies different from those employed by the majority, but which nevertheless belong to the normal behavioural repertoire (see a related discussion of patient PV’s behaviour in the Constancy section). However, it remains possible that their functional architecture is qualitatively different. Were this the case, the homogeneity assumptions would not apply to normal subjects. That this may indeed be the case, at least for perceptual processes, is suggested by the behaviour of normal subjects in a number of tasks that require the organisation of part of the stimulus in the presence of a background or field. On the basis of their performance in tasks such as the Rod and Frame Test and the Embedded Figure Test, normal

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subjects may be classified along a continuum as relatively field-dependent or independent. These differences are, at least in part, genetically determined, and have been related to hemispheric functional asymmetries. For example, in a choice reaction time experiment, Zoccolotti and Oltman (1978) confirmed the well known superiority of the right visual half-field (left hemisphere) for letters and of the left visual half-field (right hemisphere) for faces in field-independent, but not in fielddependent male subjects. Using a similar paradigm, Pizzamiglio and Zoccolotti (1981) accounted for some hemispheric differences concerning verbal and nonverbal skills in terms of field effects, rather than sex. If group studies of brain-damaged patients must assume a complete homogeneity, in order to be performed, then experiments in normal subjects should also be done as single case studies. As noted earlier in the case of normal individuals, too, homogeneity can not be postulated. Group studies, however, are a current typical paradigm in cognitive psychology. This is because there is no assumption of homogeneity, but the results provided by the statistical treatment are taken as indexes of the behaviour, and of the organisation of the mental architecture, of the majority of the subjects examined. This approach is compatible with the existence of minority patterns. These may be the object of specific studies, and are very interesting in their own right; however, they do not undermine the significance of the conclusions concerning the majority pattern. To summarise, the argument that the selection of a group of patients implies the inclusion of functionally nonhomogeneous individuals (due to the effects of the lesion), applies also to groups of normal subjects. In both cases, the inferences concerning the deranged or normal functions are based on the majority behaviour. Replication. Replication of an observation is a distinctive feature of the scientific enterprise, in all its branches (Popper, 1959). The lack of replication of results (particularly if unexpected on the basis of current knowledge) casts serious doubts on their reliability and is taken as an indication of methodological flaws, or even fraud. The

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controversies (Maddox, Randi, & Stewart, 1988) concerning the reproducibility of the high-dilution experiments (memory of water) (Davenas, Beauvais, Amara et al., 1988) are a noted example. If replication across patients is impossible, as all patients are different from one another, are there alternative methods available to neuropsychologists devoted only to single case studies, in order to evaluate the reliability of an observation? First, replication in the same patient is relevant (Ellis, 1987, but see note 7). Second, the relationships of the new finding with the complete set of pre-existing data and with the theoretical models that have informed the study have an important role (Caramazza, 1986). The relative weight of each single case is therefore determined by the available knowledge in that specific field. In general, the larger the available set, the lower the relative weight of each single observation. A single result is crucial only if (within the context of a specific theoretical model) consistent with the vast majority of data available from other patients. Finally, the results in each single patient should be internally coherent, converging towards a single (the best) available model. The impossibility of replication across patients assigns a most relevant role to the corpus of preexisting experimental data, and to the theoretical models that have directed the study. This may have the effect of favouring studies that produce results in agreement with current knowledge and dominant theories. In other words, novel and unexpected observations, which break current paradigms, are implicitly discouraged. Observations that subsequently proved to be very important were often not based on an explicit project, with a detailed underlying theoretical model. This is the case in new areas, in which replication is the main means by which a novel finding becomes established knowledge. Illustrative neuropsychological examples are the observations that cerebral lesions may produce lack of awareness (anosognosia) for neuropsychological deficits such as cortical blindness, hemiplegia, and hemianopia (Anton, 1899; Babinski, 1914; Bisiach & Geminiani, 1991), and the discovery of the role of the right hemisphere in visuospatial processes (Brain, 1941; De Renzi, 1982a).

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Finally, the impossibility of replicating an experimental result in different patients makes unfeasible any anatomo-clinical correlation. This requires, as previously discussed, series of patients with homogeneous deficits. This limitation may be overcome by “... creating research consortia... This step will permit the accumulation of cases with the desired characteristics for the needed correlational analysis” (Caramazza, 1988b, p.417). This suggestion implies, however, that the difficulty with group studies is not theoretical, but practical, related to the problem of constituting groups of patients who are homogeneous with respect both to the selection criteria and to the results of the experimental study. Conclusion Over and above the specific problems discussed here, the view that only single case studies may be performed is based on the probabilistic assumptions that it is very unlikely that a group includes patients with homogeneous deficits. It is therefore legitimate to consider the results obtained through single case and group studies from the perspective of the advances of our knowledge of the functional and neural architecture of mental processes. A few examples. The view that some internal representations of objects in space have analogical rather than propositional features has been supported by studies in right brain-damaged patients, selected on the basis of the presence of left visuospatial hemineglect (Bisiach, Chapter 21 this volume). In amnesic patients, the study of the preserved and impaired components of long-term memory systems has been performed both in single case and in group studies (Vallar, Chapter 15 this volume). Finally, the selective deficit of phonological short-term memory constitutes an anatomo-functional syndrome, which has been replicated through many single case studies (Vallar, Chapter 15 this volume). To summarise, both single case and group studies contribute to our knowledge of the functional and neurological architecture of mental functions. There is no valid reason to banish one of the two paradigms from the neuropsychologist’s arsenal. Under specific circumstances, however, one approach may be more adequate than the other,

and the appropriate decision is to be taken pragmatically. Both approaches are integral components of neuropsychology.

ACKNOWLEDGEMENTS The author is grateful to Stefano Cappa and Marco Zorzi, who read the sections on the cerebral activation methods and on connectionism, for their helpful suggestions. Usual disclaimers apply.

NOTES 1. As to the centre for the elaboration of concepts, Lichtheim (1885, p.477) wrote: “I do not consider the function to be localised in one spot of the brain, but rather to result from the combined action of the whole sensorial sphere”. By contrast, the centres for motor and acoustic images (M and A in Fig. 6.2) were localised in Wernicke (Brodmann’s area 22) and Broca’s (Brodmann’s area 44) areas. 2. The brain-mind problem is not discussed in this chapter. The interested reader is referred to Bunge (1980), Smith Churchland (1986), Dennett (1991) and Chalmers (1996). 3. Both the 19th-century (see Figs. 6.1 and 6.2) and the contemporary information processing models conceive the human mind as a complex system, including a number of connected components. There is a relevant difference, however, The 19th-century models are anatomo-clinical in the strict sense of the term: any given functional component is (or should be) localised in a specific brain region, and the correspondence is an intrinsic part of the model. Information processing models do not necessarily imply such a correspondence. Their level of description concerns the functional architecture of the mind, rather than its neural correlates (Morton, 1984). Recent developments of cognitive neuroscience, however, are providing a fine-grain description of the neural architecture of a number of components of mental processes (see some illustrative examples concerning memory disorders in Vallar, Chapter 15 this volume). 4. The assumption of a correspondence between the neurological and functional architectures was also a main feature of the 19th-century models of language. By contrast, neurologists such as Pierre Marie, Henry

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Head, and, in the 1960s, Eberhard Bay, took the view that aphasia was a single deficit, and language a unitary process (see Lecours, Lhermitte, & Bryans, 1983; Lhermitte & Signoret, 1982). These positions have been revived by some recent PET studies in aphasic patients (Metter, Kempler, Jackson et al., 1989). 5. In patients suffering from developmental neuropsychological deficits the possibility should be entertained that neurological reorganisation processes take place, giving rise to systems qualitatively different from those of the normal adult subject. The value of extrapolations from data collected in developmental cases to the organisation of the normal system is therefore dubious (McCloskey, 1993; Vallar & Baddeley, 1989). 6. “Converging operations may be thought of as any set of two or more experimental operations which allow the selection or elimination of alternative hypotheses or concepts which could explain an experimental result. They are called converging operations because they are not perfectly correlated and thus can converge on a single concept... Ideally, converging operations would be orthogonal (completely independent), since such operations are the most efficient” (Garner, Hake, & Eriksen, 1956, pp. 150—151). 7. The inconsistency of the patients’ performances across experimental sessions may suggest unreliability, due to nonspecific factors, such as fatigue, lack of motivation, defective global attention, etc. Specific factors may also be involved, however.

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In tasks that assess semantic memory, the variability of the patient’s performance may indicate that the deficit concerns the access to representations, which are nevertheless stored and relatively preserved. By contrast, the repeated observation of a qualitatively and quantitatively stable performance suggests a degradation, more or less severe, of the stored material (Shallice, 1987; Warrington & Shallice, 1979). In psychophysical tasks, the variability of the detection threshold may reflect an attentional, rather than primary sensory, disorder (Tegner, 1989; Vallar, Bottini, Rusconi et al., 1993). 8. A comparative evaluation of the impact of single case and group studies should also consider some social rules of the scientific community. A scientist who makes a relevant discovery in an individual patient is willing to publish his or her finding as soon as possible. If the observation is reliable, replication typically follows. For instance, Bisiach and Luzzatti (1978) described two right brain-damaged patients with left hemineglect for internally generated visuospatial images. The finding was subsequently replicated in a larger series of right brain-damaged patients (Bisiach, Luzzatti, & Perani, 1979). Replication may also occur through a succession of single case studies (Shallice & Vallar, 1990). 9. A related analysis of agrammatic speech production may be found in Bates et al. (1991), who suggested that the patients’ variability may be accounted for by factors such as neurological status, education, and strategies.

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Part II

Language Disorders

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7 Development of the Concept of Aphasia Guido Gainotti

In most cases they were detected through clinical observation (or through congruence between clinical data and theoretical assumptions), based essentially on the systematic co-occurrence of a certain number of linguistic disorders and on the simultaneous integrity of other aspects of language. In other cases, instead, the theoretical model clearly oriented clinical observation, leading to prediction of the existence of clinical syndromes that had not yet been observed empirically. This was the case, for example, for conduction aphasia; its existence was logically predicted by Wernicke’s model even before it was observed on the anatomical-clinical plane (Wernicke, 1874). However, this double valence (classification and interpretation) of the aphasic syndrome construct has repeatedly and in various historicalcultural contexts given rise to a paradoxical situation. On one side, several aphasic syndromes—that is, anatomo-clinical pictures that identify rather well defined regularities in the chaotic data deriving from observation—have been consistently described by authors of various doctrinal orientations and universally used in clinical practice.

So as not to be completely extraneous to the topics in which contemporary researchers in aphasia are interested, it seems important to begin this chapter on the historical development of the concept of aphasia by referring to a construct that has stirred up great controversy throughout its entire history and which is still today at the centre of heated discussions, that is, the aphasic syndrome construct. Its central position probably depends on characteristics of polymorphism and the extreme complexity of aphasic symptomatology; characteristics that led Alajouanine, Ombredane, and Durand (1939, p.l) to say that “in the study of aphasia facts have so little independence from theories that not only their structure, but their very existence is debatable.” Now, the aphasic syndrome construct is probably the one in which facts and theories are most closely connected, as it was developed by associationist authors in the second half of the nineteenth century not only to better isolate clinical facts but also to provide a theoretical justification for isolated clinical pictures. The existence of a double valence (clinical and theoretical/nosographical and physiopathological) of the aphasic syndrome construct is obvious if we consider how the various syndromes were isolated. 135

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On the other side, the physiopathological significance or the existence of these syndromes was repeatedly contested by the authors of the Noetic School in the first half of the twentieth century and in recent years by the cognitivists. With regard to authors of the holistic/noetic approach, we need only think of a striking contradiction present in the work of Goldstein; in the general part of his monograph on language disorders (Goldstein, 1948) he negated the existence of aphasic syndromes on the basis of theoretical considerations and then ended up recognising these syndromes empirically in the special (clinical) part of the same volume. Criticisms of the aphasic syndrome construct by the cognitivists are more methodological and are, in any case, contrary to those of the holistic school. The latter hold that aphasia is one and indivisible and that it is not, therefore, possible to subdivide it into different syndrome pictures, each subserved by a different physiopathological mechanism. On the contrary, cognitivist authors hold that the functional architecture of the linguistic system is extremely complex and articulated into a large number of components. Thus, they do not negate the clinical utility of aphasic syndromes, but hold that they are nonhomogeneous symptomatological agglomerates and cannot be used to clarify the intrinsic organisation of language processing. Obviously, we cannot go into detail about this discussion of principle here, nor about more specific controversies regarding the single aphasic syndromes. Instead, we would just like to note that as the syndromes are the meeting place between facts and theories, different aphasic syndromes have been proposed by all streams of thought marking the development of aphasiology. Therefore, to run over the historical development of the concepts on aphasia means going over the making and unmaking of syndrome proposals in which the gathering of relevant data is oriented by a new reference model. For ease of presentation we will try to analyse this continuous flow by subdividing it into five distinct sections, dedicated respectively to: 1. the principle of localisation and the associationist model; 2. unitary interpretations of aphasic disintegration;

3. empirical classification and Geschwind’s neoassociationism; 4. Luria’s interpretative system and the theory of cortical analysers; 5. linguistic interpretations of aphasia.

THE PRINCIPLE OF LOCALISATION AND THE ASSOCIATIONISTIC MODEL Broca and the birth of scientific aphasiology The discovery that one of the highest functions and characteristics of the human species—language— is not generated by the brain as a whole, but is supported by well defined parts of it, marked the birth of aphasiology. As is well known, this discovery, made by the French neurologist Paul Broca, was not only due to this researcher’s anatomical knowledge and clinical shrewdness, but also to the great debate taking place at that time on the factors causing the emergence of the human “mind” over the course of the evolutionary process. Gall (1810) played an important role in this debate because his phrenological conception, in spite of its obvious arbitrariness, contained two important innovative factors: (a) an attempt to fragment the human mind into relatively autonomous functions, each having its own cerebral localisation; and (b) the recourse to pathology, as a source of empirical data able to confirm or invalidate the phrenological models. Bouillaud was the most eminent of the physicians who held Gall’s ideas in high esteem and tried to compare his theses with pathological data. Bouillaud (1825) was struck by Gall’s affirmation that the “sense of language” was located in the anterior parts of the brain and, as early as 1825, he reported data from clinical research “to demonstrate that the loss of speech corresponds with a lesion of the anterior lobes of the brain.” The clinical and anatomical data on which Bouillaud based his theses were judged as insufficient by his contemporaries and thus he did not influence the scientific thought of his time. However, the idea that the frontal lobes of the brain play a critical role in the development of intelligence and human language continued to stir up controversy in

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medical and anthropological circles of the epoch; and it was during a lively discussion on this topic that Broca’s main observation emerged. The discussion took place in 1861 at the Anthropology Society in Paris. The debate was between Auburtin (Bouillaud’s son-in-law and supporter of his ideas) and Gratiolet, an eminent neuroanatomist and supporter of the thesis that at least with regard to the higher nervous functions, the brain is an essentially homogeneous organ (see Ombrédane, 1951 and Hécaen & Lanteri-Laura, 1977 for a detailed illustration of the topic). Several days after this debate, Broca found a 51-year-old patient in his ward who from the age of 21 had lost the faculty of articulate speech (so much so that to every question he responded with the stereotype, “tantan”) even though he apparently understood what was said to him and demonstrated good intellectual ability. As the patient died several days later for extracranial reasons, his autopsy allowed Broca to make an extremely important check of the theses debated at the Anthropology Society. According to Broca, the autopsy report was clearly in favour of Auburtin because the major damage was in the frontal lobe, although the lesionai context also extended to the lower part of the parietal lobe and to the first temporal gyrus. Broca held that the lesion responsible for the loss of speech in his patient was the one that had destroyed the posterior part of the third frontal gyrus. Further, advancing a physiopathological hypothesis on the nature of his patient’s articulatory disorder, Broca (1861, p.237) held that it was due to the loss of “a particular type of memory, which is not memory for words, but for the movements necessary for articulating words.” In subsequent years, Broca reported other anatomical-clinical observations in support of his thesis and began to understand that not only the frontal location, but also the left hemispheric side of the lesion played an important role in the genesis of disorders of spoken language (Ombrédane, 1951; Hécaen & Lanteri-Laura, 1977). Actually, this latter affirmation was not entirely new, because similar observations had been reported several decades before by another French physician, M. Dax, who had gathered more than 150 cases in which, without exception, a language

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disorder accompanied a left hemispheric lesion (Dax, 1865). However, as these observations were made by a provincial doctor and communicated at a rather unimportant conference, they were completely ignored and even Broca did not know of their existence. On the wave of interest raised by Broca’s reports, this finding also rapidly became an accepted notion in the most qualified scientific community. Without going into the merits of Dax and Broca for the discovery of the relationships between language and the left hemisphere, I will conclude this part by outlining the essential points of Broca’s contribution: a lesion of the foot of the third frontal gyrus of the left hemisphere leads to a disorder in speech production, which Broca attributed to the loss of a particular type of memory, that is, memory of the movements necessary for articulating words.

The discoveries of experimental neurophysiology and the associationist model Several years after Broca’s anatomical-clinical observations, Fritsch and Hitzig (1870) provided for the first time experimental proof supporting the hypothesis that various functions are located in different parts of the cerebral cortex. In fact, these authors showed: (a) that the stimulation of anterior portions of the cerebral cortex of the dog provokes muscular contractions of the contralateral part of the body; (b) that analogous contractions are not obtained by the stimulation of posterior parts of the cortex; and (c) that a point-by-point correspondence exists between the area of cortical stimulation and localisation of the movement provoked by it. These same authors also showed that the destruction of the areas that provoked muscular contractions upon stimulation was followed by a paralysis of the corresponding muscle groups. In the following years, other experimental evidence favouring the principle of localisation was provided, for example by Ferrier (1878), who isolated an ocular-motor centre in the lower part of the frontal lobe; by Luciani & Tamburini (1879), who located the cortical areas of hearing in the temporal cortex of the monkey; and by Munk (1877-1880), who provoked “psychic blindness” in dogs by removing their occipital lobes.

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All of these data (discussed in detail by Hecaen & Lanteri-Laura, 1977) were combined in the model of cerebral functioning proposed by Meynert (1884). This author distinguished areas of projection and areas of association at the cortical level, hypothesising that the first served for analysing sensory information and for giving movement orders and that the second were, instead, a store of images (that is, storages where memories of previously analysed information or of commands given by the corresponding projection areas were grouped). We have already encountered this way of conceiving cerebral functioning in Broca’s hypothesis that lesions of the third frontal convolution destroy memory of the movements necessary for articulating words; and we will find it again in all the major models of aphasia formulated by Wernicke, Lichtheim, and other associationistic authors. Therefore, it seems important to explicitly recall the basic conceptions of associationist thought: 1. Thought is only a combination of images. 2. Images are just the faded trace of sensations received (or of movements executed) previously. 3. When a perceptual centre is again stimulated by a particular stimulus, an automatic evocation of the images formed previously by exposure to the same stimulus is produced. 4. As an object usually stimulates more than one sensory modality (for example, a musical instrument can stimulate sight and hearing simultaneously) the images that are evoked simultaneously in various sensory modalities tend to be associated. 5. An image (for example, the sound of a violin) could, therefore, be evoked not only by stimulation of the corresponding sensory centre, but also by another image associated with it (for example, the visual image of a violin). 6. Concepts of objects are just the corresponding associated images (for example, the concept of violin is just the sum of the visual, auditory, tactile, etc., images provoked by this instrument, and so forth). 7. Language is just a game of verbal images (auditory, visual, articulatory, and graphic)

stored in the associative areas adjacent to the corresponding sensory and motor centres; its reciprocal evocation is assured by the association fibres linking the various unimodal associative areas. 8. Therefore, language pathology depends on the destruction of centres where the verbal images relative to every sensory or motor modality are stored and/or on the destruction of the fibres connecting the various associative centres. According to this general conception, the term aphasia should be broken down into a multiplicity of sectorial disorders, due to the destruction of one or more image centres or to the dissociation of the areas in which these images are stored. These concepts constituted the reference system of all associationist authors and were at the root of the criticisms of those authors who proposed theses different from the associationist ones.

Wernicke’s first model and systematisation of the clinical forms of aphasia Wernicke, who was a disciple of Meynert, was greatly influenced not only by the model of cerebral functioning proposed by his teacher, but also by the notion that the central acoustic pathways terminate in the posterior part of the insula and are associated with an image centre containing auditory images of words. Wernicke clearly separated language from thought on the basis of his observation that deafmutes think, even though they do not know how to speak, and that, vice versa, in the first phases of language development, children repeat words whose meaning they do not know. On the contrary, Wernicke held that language is constructed starting from the auditory afferences and that, thanks to the child’s echolalic tendencies, from an early age important associations are established between auditory and motor images of words, allowing the control of one centre over the other. Combining his conceptions with Broca’s and Meynert’s observations suggesting the presence of a centre of articulatory images in the lower part of the frontal lobe and, respectively, a centre of auditory-verbal images in the posterior part of the insula and the first temporal gyrus, Wernicke

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constructed his first model, which was both simple and influential. According to this model (Wernicke, 1874), the critical structures for language processing are situated all around the left sylvian valley and are articulated into two centres, one frontal (verbalmotor) and one temporal (auditory-verbal) linked by bundles of associative fibres. Different clinical forms of aphasia are provoked by lesions selectively destroying the various parts of this audio-phonatory system. In particular: 1. The destruction of the auditory pathways, before they reach the auditory-verbal centre, causes deafness without aphasia. 2. The destruction of the centre containing the “auditory images of words” make the perceived sound lose all verbal value so that it is perceived as the “indistinct murmer of a foreign language.” Thus, the patient is unable to understand or repeat words. Further, having lost the possibility of controlling oral production with the auditoryverbal centre, the patient has a paraphasic language of which he is unaware. Wernicke named this form of aphasia “sensory aphasia”. 3. Destruction of the association fibres linking the auditory-verbal centre to the verbal-motor centre leaves both articulatory and auditory-verbal images intact. Thus, the patient does not have disorders of comprehension or expressive difficulties but presents disorders in transposing the auditory structure of a word into the corresponding articulatory form. Therefore, the basic deficit of these patients is a repetition defect. To be sure, some deformed words can also be observed in spontaneous language, but unlike what is observed in sensory aphasia, the patient is generally aware of this disorder (being able to control the operation of the verbal-motor centre with the auditory-verbal centre) and tries to correct him/herself. This form of aphasia, which still had no anatomo-clinical demonstration, but which Wernicke’s schemata predicted logically on the basis of the internal organisation of the model, was called “conduction aphasia.” 4. A lesion of the verbal-motor centre produces the clinical form of aphasia described by Broca and characterised by important deficits in verbal

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expression, in the absence of disorders in comprehension. In this form of aphasia, disorders in writing analogous to those seen at the level of oral expression are usually observed, because subjects accustomed to pronouncing the words they write find themselves in trouble because they lack this intermediate process of graphic activity. 5. Finally, a lesion in the fibres extending from the verbal-motor centre to the nuclei of the cranial nerves involved in articulatory activity brings about a primarily parethic type of dysarthria which leaves speech partially understandable.

Criticisms of Wernicke’s first model, and Lichtheim’s synthesis Without mentioning the conceptions of other authors of the associationist school (such as Bastian, 1869; Kussmaul, 1876; Exner, 1881, or Charcot, 1876), who developed models analogous to Wernicke’s, but who are only of historical interest today, in this final part of the section dedicated to the principle of localisation and the associationist model, only two points will be discussed: • the criticisms of Wernicke’s first model; • the schemata used by Lichtheim to try to respond to these criticisms, preserving what was essential in Wernicke’s model. The criticisms of Wernicke’s model were in part theoretical and in part purely empirical. The theoretical criticisms primarily regarded the conception of language proposed by Wernicke, because by considering language only in audiophonatory terms, he neglected the fact that the sounds of language are signs used by man to communicate his ideas and feelings to others (Finkelnburg, 1870; Kussmaul, 1887; Jackson, 1879). Empirical criticism concerned the fact that destruction of the motor and auditory images of the word (or disconnection of the corresponding centres) is not enough to explain the complex range of verbal disorders that can be observed in aphasic patients. For example, Wernicke’s model could not account for patients who repeat perfectly

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even though they show serious deficits in comprehension or serious difficulties in oral production. According to Wernicke’s model, destruction of the auditory images of words would produce linked disorders of comprehension and repetition, just as destruction of the verbal-motor images would provoke a parallel deficit of both spontaneous speech and repetition. To bypass these theoretical and empirical objections, Lichtheim (1885) incorporated Wernicke’s model in a more complex schema, that is, in a two-stage model; the lower level corresponded to the sensorimotor components of language, favoured by Wernicke’s model, and the upper level to the semantic-conceptual components of language, which Wernicke had ignored in his systematisation. Both Lichtheim’s schema and Wernicke’s model in a certain sense anticipated current cognitive models, as both had the following general characteristics: (a) a rather explicit and analytical basic theoretical interpretation of normal functioning; (b) in normal functioning, a series of functionally autonomous components were isolated, which could be destroyed individually by the pathological event; and (c) the changes following the destruction of each of these components could be predicted a priori on the basis of the function carried out by the component in question in normal language. Wernicke’s and Lichtheim’s schema also distinguished two types of functional deficits: • those resulting from the destruction of “centres” in which the functions in question were processed (analogous to what occurs in the “boxes” of the cognitive models); • those resulting from the interruption of “pathways” linking various centres (equivalent to the “arrows” linking the various boxes). Thus, Lichtheim’s model was extremely important for many reasons, which can be synthesised as follows: 1. It constituted the most thorough synthesis of associationist thought. 2. Its system of classification of aphasic disorders is still followed today by many schools of

aphasiology and it constitutes the reference schemata of the most well known test batteries for aphasia, such as the Boston Diagnostic Aphasia Examination (Goodglass & Kaplan, 1972), the Western Aphasia Battery (Kertesz, 1979) and the Aachen Aphasia Test (Huber, Poeck, Weniger, & Willmess, 1983).

3. Its “cognitive” approach is still extremely relevant today. 4. The basic criticism against it (that is, the existence and anatomical localisation of the socalled “centre of concepts”) can perhaps be resolved in light of current conceptions about the anatomical bases of specific semantic disorders by category.

For all of these reasons, it seemed important to dwell a little on this model, and in the following pages I will briefly illustrate: (a) Lichtheim’s model of the normal functioning of language; (b) the components this model is broken down into and the clinical forms of aphasia resulting from lesions of each of these components; (c) criticisms of this model and the possible responses and current conceptions about the anatomical bases of conceptual representations could counter them with. The model o f normal language functioning Lichtheim held that Wernicke’s conception, which reduced language to its audio-phonatory components, was valid only for the first phases of linguistic development, during which an activity of purely reflexive imitation made the acquisition of auditory and articulatory images of words possible. However, in successive phases, when the ability to understand the meaning of words and to produce language with communicative contents appears, it must be admitted that a “centre of concepts,” that is, of the meanings of words, is formed. This centre must be linked to both the “auditory-verbal” centre (to make possible the comprehension of word meanings) and the “verbal-motor” centre (to make possible the utterance of verbal messages able to communicate ideas). Further, with the development of written language, a visual-graphic centre (for reading) and grapho-motor centre (for writing) must be added to the auditory-verbal, verbal-motor,

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and conceptual centres. According to Lichtheim, these centres do not have direct access to the centre of concepts, as the visual information acquired from reading must pass through a phase of auditory-verbal recoding in order to be understood; while the passage from an idea to its graphic expression requires an intermediate oral formulation. For the sake of simplicity, we will not concern ourselves too much with the selective disorders of reading and writing and will focus our attention on the clinical forms of aphasia resulting from lesions of the pathways and centres involved in the various phases of oral language. Components o f the model and corresponding clinical forms o f aphasia In Fig. 7.1, I have tried to schematise the image centres and association pathways proposed by Lichtheim’s model as well as the clinical forms of aphasia that follow a lesion in these pathways and centres. The terminology used to indicate the clinical forms of aphasia is that proposed by Wernicke in his second conceptualisation, which essentially follows the schemata proposed by Lichtheim. This schemata includes seven clinical forms:

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1. Subcortical sensory aphasia (or pure verbal deafness), due to a lesion of the fibres linking the primary auditory areas with the auditoryverbal centre (Wernicke’s area), is characterised by a selective impairment of all linguistic performances (auditory-verbal comprehension, repetition, and writing on dictation), which are based on a correct analysis of the auditory afferences. On the contrary, linguistic performances, apart from the auditory afferences, remain correct, including spontaneous speech and writing, reading aloud, copying, and reading comprehension. 2. Cortical sensory aphasia (or Wernicke's aphasia), due to a lesion of the auditory-verbal centre, has the characteristics stated by Wernicke: disorders of auditory-verbal comprehension and repetition, with paraphasic speech of which the patient is unaware. Also, disorders in reading comprehension, due to the fact that the model does not predict a direct route from the visual areas to the centre of concepts, but holds, instead, that the written images must be first translated into the corresponding auditory-verbal images are present in this form of aphasia.

FIGURE 7.1 Image centres (represented within boxes), associationist pathways (represented with arrows connecting these boxes) and aphasic syndromes resulting from disruption of these centres or pathways according to Lichtheim’s model. ScSA= sub-cortical sensory aphasia; WA (CSA)= Wernicke’s Aphasia (cortical sensory aphasia); CdA= conduction aphasia; TcSA= transcortical sensory aphasia; TcMA= transcortical motor aphasia; BA (CMA)= Broca’s Aphasia (cortical motor aphasia); ScMA= sub-cortical motor aphasia.

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3. Conduction aphasia , due to lesions of fibre bundles linking the auditory-verbal centre with the verbal-motor centre (arcuate fasciculus); clinical characteristics are those thoroughly described by Wernicke. 4. Transcortical sensory aphasia, due to lesions of the fibres linking the auditory-verbal centre with the centre of concepts. In this form of aphasia, auditory-verbal and reading comprehension are impaired, but repetition is unimpaired. Spontaneous speech and writing are preserved but paraphasic, as disorders in comprehension impede the patient from adequately controlling verbal production. 5. Transcortical motor aphasia, due to an interruption of fibres linking the centre of concepts with the verbal-motor centre, is characterised by abolition of speech and spontaneous writing. Instead, both comprehension of oral and written language and repetition and the other forms of transcoding (copying, dictation, and reading aloud) are unimpaired as the relevant structures remain unimpaired. 6. Cortical motor aphasia (or Broca’s aphasia) is obviously due to the destruction of the verbalmotor centre and has the characteristics described by Broca. 7. Subcortical motor aphasia, due to lesions of the fibres linking the verbal-motor centre with the nuclei of cranial nerves involved in phonoarticulatory activity, is characterised by a selective impairment of oral expression and by a relative saving of written expression. This dissociation is due to the integrity of the “motor images of words” and to the selective interruption of the pathways linking the verbal-motor centre to structures carrying out the articulatory activity. Major criticisms o f Lichtheim’s model

There are two major criticisms of Lichtheim’s model: • the first is that it did not take into consideration a very common clinical form of aphasia— nominal aphasia; • the second is due to its hypothesis of the existence of a “centre of concepts”, without

being able to demonstrate that this centre really exists. As I will speak rather extensively about the problem of nominal aphasia later, in the sections of this chapter dedicated to Goldstein’s thought and to Geschwind’s neo-associationist conception, here I will only tackle the problem of the cerebral representation of concepts and their possible anatomical localisation. Actually, this is a rather ticklish problem for Lichtheim’s model, because, if you accept its assumption that anatomical connections exist which relate the auditory-verbal centre and the verbal-motor centre with the area of representation of concepts, then it becomes almost necessary to concede that this area has a rather precise location. However, even if some authors (for example Luria, 1974 and Heilman, Tucker, & Valenstein, 1976) hypothesised that the cortex of the angular gyrus may carry out a critical role in conceptual thought, no one has been able to demonstrate a selective disorder in the processing of concepts in patients affected by lesions in this area or in any other circumscribed portion of the cortex. Perhaps some current conceptions about the anatomical-functional bases of conceptual activity will allow us to approach this problem in a different way, indicating that the concepts are neither stored in a unique “centre”, as Lichtheim held, nor represented in a diffused way on the cortex, as his opponents held. Instead, they may be subserved by different but well-defined parts of the cortex, according to a rule that predicts that the critical zone for the representation of specific conceptual categories could be the same one that processed the most important information for the organisation of the categories in question. These concepts were recently elaborated by Warrington and colleagues (McCarthy & Warrington, 1990; Warrington, 1981; Warrington & McCarthy, 1987; Warrington and Shallice, 1984), who again took up and developed the associationist model of “associated images”, where an integration between different sensory information is at the base of conceptual thought. In fact, these authors point out that even if different information usually converges in the processing of

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a specific concept, the weight of this different information can be remarkably different in different categories. For example, some “biological” categories (such as animals, vegetables, flowers, fruit, etc.) could be primarily based on sensory information and, in particular, on visual information. For instance, the characteristic that best distinguishes a lion from a tiger or from a leopard is homogeneous appearance, stripes or spots. Instead, other categories of manufactured goods (for example, utensils or clothing) could be primarily based on functional information, that is, information relative to the precise function for which the object was made (a knife for cutting solid food, a spoon for bringing liquid foods to the mouth, etc.), besides proprioceptive information, linked to the manipulation of the object. Now, given that different types of information are transmitted by functional systems located in different parts of the brain, it is possible to hypothesise that lesions located in different parts of the cerebral cortex disorganise primarily those conceptual categories that are preferentially based on information processed in that part of the cortex. Anatomoclinical data consistent with this hypothesis have recently been reported by Damasio, Damasio, &

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Tranel (1990a) and by Gainotti, Silveri, Daniele, & Giustolisi (1995). These data seem to indicate that conceptual representations are associated with well defined areas of the cortex (and that anatomical connections may exist between language areas and cortical areas where the concepts are processed). However, they are not concentrated in a unique portion of the cortex, but represented in a multifocal way, in relation to the importance of various sources of information in the organization of different conceptual categories. Although this general conception creates a series of additional problems (which, however, are not important to discuss here) for Lichtheim’s schemata, it is in line with one of the basic assumptions of the connectionist models (see for example Ballard, 1986; Churchland & Sejnowski, 1988) that representations do not exist apart from the data that have contributed to their processing. According to this assumption, in fact, the representations must be considered as patterns of activation in the connections stabilized between the units that processed the information on which the “representations” are based. As Lichtheim’s model has been presented in detail, and can be considered as the most complete

FIGURE 7.2

Schématisation of the main language areas and of the cortical areas which could play a selective role in the representation of different conceptual/semantic categories.

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synthesis of associationist thought for interpreting aphasic disorders, it is now time to present the theses of those authors who proposed different interpretative schemes.

THE NOETIC SCHOOL AND THE UNITARY INTERPRETATION OF APHASIA While associationist thought was obtaining its most convincing results in interpreting aphasic disintegration, some authors were already expressing their dissent over several aspects of this interpretation. The most controversial aspects of the associationist approach were: (a) The importance attributed to sensory and motor components of the aphasic disorder. (b) The adoption of a mosaic conception of the principle of localization in which no distinction was made between basic sensorimotor functions and higher cortical ones, because both were considered to be associated with precise cortical areas. (c) The use of a purely horizontal model (at the cortico-cortical level) of information processing, with a serial treatment of input at the level of the areas of projection, of the associative areas relative to the stimulated modality and to the other sensory modalities, and with final involvement of the associative areas and motor executions. (d) The fragmentation of aphasia into a multiplicity of qualitatively different clinical forms, resulting from the destruction of one or more image centres and/or of one or more association pathways between these centres. Finkelnburg (1870) was among the authors who first contested the validity of the first point (a); he believed aphasia was due to a central disturbance of the symbolic function, that is, the function that permits representation of an idea or a concept (meaning) that is not immediately perceptible with a concrete and immediately perceptible signifier (such as a sound or an image). In Finkelnburg’s conception, the

sensorimotor components of aphasia concern only the system of signifiers, but aphasic disintegration goes much deeper, also impairing the signifier-meaning relationship, as well as the organisation of the meaning. Proof of this is the fact that aphasic patients not only have difficulty in verbal understanding or in verbal expression but also in understanding nonverbal signifiers (for example, symbolic gestures, signs, graphic symbols, etc.) or in nonverbal symbolic expression (for example, in the performance of a pantomime). (b) Gratiolet (1834), whom I mentioned as one of the participants in the discussion at the Paris Anthropology Society and who may have provoked Broca’s main observation, was one of the authors who criticised the extension of the principle of localisation from the study of basic sensorimotor functions, to that of higher cognitive and symbolic (such as language) functions. In fact, Gratiolet held that the principle of localisation was valid only for the basic sensorimotor functions, but not for the higher cortical ones, which were processed by the brain in a unitary way, in conformance with the principle of mass action (Flourens, 1824). (c) The horizontal model of the associationists, based primarily on cortico-cortical connections, was criticised by Baillarger (1865) and by Jackson (1878), who countered it with a vertical model, based on the connections between cortex and subcortical structures and on the theory of functional levels. As is known, this theory, profoundly rooted in evolutionistic thought, conceded that the higher nervous functions are formed progressively during the course of evolution and the concomitant process of telencephalisation. This process consists in the passage: • from the more simple to the more complex; • from lower rigidly organised structures underlying automatic and preprogrammed functional levels to higher structures, organised in a more plastic way, to allow for learned behaviours and behaviours adapted to the changeable needs of the external environment, intentionally processed by the subject.

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Integration has as its inverse phenomenon dissolution, consisting of the passage from the most complex to the simplest, from the most plastic to the most rigidly organised and from the most intentional to the most automatic. This regression from higher cortical levels towards more primitive ones is due to the fact that the higher cortical functions are the most fragile and are, therefore, preferentially stricken by the morbid process, while the more elementary ones are more resistant. Further, given that in normal conditions the higher functions keep the lower ones under control, in the disintegration of higher levels not only negative symptoms are obtained (due to the failure of more elaborate and intentional aspects of use of the function) but also positive symptoms (due to the re-emergence of the more primitive functional levels, which were inhibited by the activity of the higher centres). The aspects of aphasic disintegration that most clearly support this interpretative model consist of the dissociation, observed first by Baillarger (1865), between propositional and automatic uses of language, the former being habitually lost when the latter are preserved. Further, these observations pose problems that are difficult to solve with the doctrine of images, typical of associationist thought. For example, take the commonplace observation of a patient who is completely incapable of pronouncing the word “madonna” if he has to give the name to a religious image, but who immediately afterwards automatically utters the same word, cursing over the interpersonal difficulties caused by his illness. According to Jackson, this commonplace observation shows that there is no destruction of an image (which once destroyed would be lost for any type of linguistic use) at the basis of the aphasic deficit, but rather an inability to use the words to form propositions with communicative value. However, it was primarily the last point (d), that is, the fragmentation of aphasia into many qualitatively distinct syndromes, which provoked the most heated and passionate reactions. Many authors held that this fragmentation, dictated by theory, did not correspond to data from clinical observation and affirmed that, rather than presenting as an archipelago formed by clearly

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separated entities, aphasia presented in general with very similar characteristics from patient to patient. In opposition to the associationist authors, who had isolated different clinical forms of aphasia, underlining the aspects that differentiated one aphasic syndrome from another, authors following a unicistic approach emphasised the common aspects of aphasics classifiable in different syndromes, hypothesising that a common factor underlies most of the deficits of aphasic patients. This orientation is found with different emphasis and formulations in the so-called “Noetic School”, and took on different aspects as a function of the personality and cultural interests of the individual authors. Due to space limitations, here I will only examine the contributions of two of the most important authors of this school: P. Marie (1926), who attacked the associationist models starting primarily from empirical-type considerations, and K. Goldstein (1948), who brought the comparison to the theoretical plane, opposing associationistic models with interpretative schemata derived from “Gestalt Psychology”.

Pierre Marie and his interpretation of Broca’s aphasia The doctrine of mental images had already been criticised by Jackson (1932) and even before by Bergson (1896); the latter had negated their existence as entities which were preformed and deposited in image centres and had affirmed that aphasia was due to a disorder of the faculty of actualising memories of words. Descending from the philosophical plane to the empirical one, P. Marie (1926) attacked: (1) the “deductive” method of the schemata, countering them with the naive examination (without doctrinal preconceptions) of anatomical-clinical facts; (2) the doctrine of images (motor, sensory, etc.) of words, whose disorganisation would result in different forms of aphasia; (3) the conception that the centre of motor images of words was stored in the foot of F3. P. Marie opposed the doctrine of verbal images with a unitary conception of aphasia; that is, qualitatively different types of aphasia do not exist, only one true aphasia exists, which P. Marie identified as Wernicke s aphasia. At the basis of this

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prototypical form of aphasia is a disorder of intelligence (defined by P. Marie as “the set of notions and procedures learned through didactic routes”) not a disorder of auditory images of words. Besides the disintegration of previously learned notions (a disorder that corresponds more with the construct of “semantic memory” than with that of “intelligence”, if we wish to translate it into the terms of contemporary psychology), R Marie identified another characteristic typical of true aphasia in the disorganization of internal language. From aphasia in the strict sense of the word, P. Marie distinguished anarthria, considered a mechanical disorder of the articulation of speech, which leaves internal language and intelligence unimpaired and which, therefore, does not accompany disorders of comprehension, writing, reading, etc. According to P. Marie, anarthria rarely exists in its pure form, but is usually combined with an aphasia, giving rise to Broca’s aphasia, according to the formula: Broca's Aphasia = Wernicke's Aphasia + Anarthria. According to P. Marie, the anatomical structures responsible for anarthria are subcortical (basal ganglia, internal capsule, external capsule, etc.) not cortical and not necessarily involving the foot of the third frontal gyrus. Rather, Marie upheld that the foot of F3 did not carry out any particular role in linguistic function and provided concrete evidence in support of this affirmation. In fact, he re-examined the brains of the two main cases described by Broca and demonstrated that in the first one the lesion extended well beyond the foot of F3 and in the second, the foot of F3 was not lesioned. Further, re-examining more than 100 anatomical-clinical cases in the literature, P. Marie demonstrated that in no case did an isolated lesion in the foot of F3 give rise to Broca’s aphasia, and that in many cases a lesion of F3 had not provoked aphasic disorders. Therefore, P. Marie’s conclusions were very clear and simple: there is only one anatomical localisation of the lesions giving rise to aphasia and one aphasia under the clinical profile. This location coincides approximately with Wernicke’s area (posterior part of the first temporal convolution, supramarginal gyrus and angular gyrus). There are no important

dissociations between the various modalities inside this area, but the seriousness of the aphasia is proportional to the extent of the lesion striking Wernicke’s area.

Goldstein and the structure of the organism Although P. Marie’s conceptions, partly taken from Bergson’s criticisms of associationism, were not part of a general theoretical model of the functioning of the mind, Goldstein, on the contrary, countered theoretical model with theoretical model, bringing the concepts of Gestalt psychology to the study of aphasia. As is known, the theoretical conceptions of the Gestalt concerning the nature of cognitive processes differed radically from those of associationism. For the latter, knowledge derived from an association of elementary data (sensations) coming from the sense organs, whereas for Gestalt psychology perception could not be traced back to a simple sum or association of elementary sensory data. Perception responds above all to laws of internal organisation, which permit the forming of perceptual units (“figures”), that are stable and well differentiated from the surrounding “background”; These two characteristics: (1) identification of global units of knowledge, and (2) importance attributed to the processes of figure-background differentiation constitute the keystone of Goldstein’s interpretation of the behaviour of braindamaged patients. According to Goldstein, in fact, the significant unit the physician or psychologist must consider is the patient’s organism. In fact, the organism functions as a whole and cannot be explained on the basis of simple elements such as reflexes or feelings. Consequently, it would be wrong to think that cerebral lesions determine isolated disorganisations of particular functions, because they actually bring about modifications of the whole, involving the organism in its totality. On the other side, Goldstein recognised that the organism responds to every particular situation with a particular operation which constitutes the figure of the corresponding process, and the rest of the organism constitutes the background. In the same way, Goldstein conceded that different behavioural disorders arise from lesions in different parts of the

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cerebral cortex, but he interpreted this to be a consequence of the fact that in lesions of the “peripheral portions” of the cortex (motor and sensory areas, in direct relation with the external world) the loss of figure-background differentiation prevails in a sense or motor modality, in relation to the cerebral localisation of the lesion. On the contrary, in lesions of central portions o f the cortex (delegated to higher-order functions), the prevalent modification is more unitary and consists of a regression from the abstract attitude to a concrete one, with abandonment of operations requiring the use of abstract procedures and the tendency to seek refuge in short operations, based essentially on concrete procedures. Applied to the examination of aphasic patients, these general principles led Goldstein to distinguish: (a) forms in which disorders of the sensory functions predominate (due to poor figure-background differentiation); (b) forms in which motor disorders predominate (due to the inability to utter the appropriate sounds, detaching them like figures from the articulatory background); and (c) forms in which the deficit of abstract and categorical functions prevail. Typical of this is amnesic (or nominal) aphasia, in which the patient is unable to find the names of objects, even though he or she has no sensory and articulatory disorders. In fact, Goldstein held that as names are labels we use to outline classes or categories of objects, the categorical attitude towards the external world and the ability to use words to outline concepts are essentially the same thing. Therefore, a deficit in the categorical attitude usually implies a naming disorder. If we consider all of these statements critically, two general points emerge: • The first is that Goldstein actually ended up being much less unicistic than his theoretical conceptions would lead us to believe. Recognising the existence of a cortical “periphery”, anchored to sense and motor functions, Goldstein proposed a classification schemata of the aphasias that is very similar to the one proposed by the associationist authors. The major difference is the basic mechanism

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hypothesised (destruction of different types of images for the associationists, disorder of process of figure-background differentiation in different perceptual-motor areas for Goldstein), but, to a great extent, the clinical description overlaps. • The second is that, as prototypical expression of the disorganisation of the central processes of aphasia, Goldstein gave importance to word-finding disorders, independent from perturbations of the sense or motor functions, which are in first place in amnesic aphasia (anomia or nominal aphasia) and which were practically ignored by the associationist authors. These disorders, which constitute one of the most commonly observed clinical phenomena in aphasia, were interpreted by Goldstein in terms of deficit of abstract and categorical thought. The ambiguity of the term, or at least its polyvalence (as abstract and categorical are not synonyms, but refer back to different aspects of the higher cognitive functions), translates the difficulty of specifying the exact nature of the perturbations of the cognitive processes underlying disorders of naming activity in aphasics. Later, Bay (1962, 1964) examined the same problem, accepting the basic assumption that the inability to find names of objects is the essence of aphasic disintegration, and tried to interpret the nature of this disorder more precisely and on the basis of more controllable empirical data. His conclusion was that the naming disorders of aphasics depend on a more general defect in discriminating and actualising concepts (that is, in the ability to distinguish one concept from another that is correlated with it, and to intentionally evoke the verbal label corresponding to the concept in question). The affirmation that the naming disorders in aphasics are associated with a disorganisation of corresponding concepts is certainly drastic and debatable, but at least it has the advantage of being relatively simple and clear and, in any case, still today remains rather central to the debate on the nature of the cognitive deficit in aphasics (Gainotti, 1988; Vignolo, Chapter 13 this volume).

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EMPIRICAL CLASSIFICATIONS AND GESCHWIND’S NEO-ASSOCIATIONIST MODEL Towards the mid-1960s the unicistic schools of interpretation of aphasia had completely exhausted their initial innovative thrust. The basic theoretical model of Gestalt psychology showed its ambiguities and limits, data from clinical observation, although confirming the existence of a basic, essentially unitary nucleus of aphasic distintegration, also confirmed the existence of different clinical forms of aphasia; the intimate nature of the deficit underlying naming disorders was difficult to explain using the basic theoretical models available. Two tendencies emerged in the area of aphasiology, which were undoubtedly influential in successive years: • on one side, an effort was made to approach the problem of aphasia on a purely empirical basis, putting aside schemata and theoretical assumptions; • on the other side, Geschwind (1965) took another look at the associationist concepts and re-evaluated them, proposing a general theory of “disconnection syndromes”.

Empirical classifications A first attempt to point out objective investigation parameters able to differentiate between different subgroups of aphasic patients was made simultaneously by Howes and Geschwind (1964) and by Goodglass, Quadfasel, and Timberlake (1964). Howes and Geschwind (1964) proposed dividing aphasics into two groups, defined respectively “group A” and “group B” on the basis of verbal and extra-verbal criteria. Group A (approximately overlapping Broca’s aphasia) was characterised by: • a verbal utterance rate lower than the norm (100-175 words/minute); • more frequent verbal perseverations than controls;

• a tendency towards agrammatism; • a practically normal threshold of word perception; • a high incidence of hemiplegia (about 80%). Group B (approximately overlapping Wernicke’s aphasia), was characterised, instead, by: • • • • •

a verbal utterance rate equal to or higher than controls; paraphasias that, in most serious cases, reach jargon aphasia; a number of verbal perseverations equal to controls; a threshold of perception of words increased and, above all, variable from one moment to the next; a low incidence (about 20%) of hemiplegia.

Goodglass and colleagues (1964) and then Benson (1967) and others, instead, distinguished a “fluent” and a “nonfluent” form of aphasia, based only on the characteristics of verbal production of these two groups of patients. Among the characteristic parameters of nonfluent aphasia (overlapping Broca’s aphasia and Howes and Geschwind’s group A) these authors placed: • articulatory disorders; • disprody, that is, a disturbance in the rhythm and melody of language, which can give speech a “foreign accent”; • the effort, often important, shown at the beginning of every oral production; • the defect of incitation to speak; • the tendency to produce much shorter sentences than normal, mostly composed of nouns and verbs (that is, by the lexical units that are richest in semantic information); • the tendency to neglect grammatical particles (articles, prepositions, auxiliary verbs, etc.) and to not conjugate verbs; the latter are often used in the infinitive or in the past participle, giving an agrammatical quality to the verbal production of these patients. Among the parameters characterising fluent aphasia (overlapping Wernicke’s aphasia and

7 DEVELOPMENT OF THE CONCEPT OF APHASIA

Howes and Geschwind’s Group B), the same authors identified: • the absence of articulatory disorders and obvious effort at the beginning of verbal production; • the preservation of normal language melody; • the pressure to speak, which makes these patients verbose, and even logorrheic; • the tendency to produce sentences of the same length and syntactic complexity as the controls; • the high incidence of verbal and/or phonemic paraphasias and neologisms, making the verbal production of these patients scarcely understandable. Benson (1967) also showed that the dichotomisation of aphasia into fluent and nonfluent forms not only corresponds to characters intrinsic in the verbal production of aphasics, but also reflects a different localisation of the lesions within the left hemisphere. The lesions responsible for the fluent forms of aphasia tend to be concentrated in the posterior regions of the sylvian valleys, and those responsible for the nonfluent aphasias tend to be concentrated in the lower parts of the Rolandic fissure. These results agree with the anatomoclinical observations of the classical authors (Foix, 1928), who noted that the lesions responsible for Broca’s aphasia tend to encroach on the lower part of the rolandic region, and the lesions responsible for Wernicke’s aphasis are concentrated primarily along the posterior two-thirds of the sylvian fissure.

Geschwind’s neo-associationist conception When I presented Goldstein’s thought, I said that, from the clinical point of view, one of the most obvious limitations of the associationist conceptions was their difficulty in interpreting disorders in naming activity, one of the most important and ubiquitous components of aphasic disintegration. Geschwind, who made a great effort in the second half of the 1960s to repropose the associationist models, was aware of this limitation and took the anatomical bases of naming activity as the starting point for his theoretical model.

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He affirmed that one of the newest and most important characteristics of the human brain is the possibility of forming direct associations between somesthetic, auditory, and visual modalities of sensory processing. In fact, in all subhuman species the intermodal associations are made indirectly, through the limbic system, where the afferences of sensory modalities converge. Only in humans does the great development of the temporoparieto-occipital associative areas permit the flow of information relative to the various sensory attributes of objects into nonlimbic cortical areas. According to Geschwind, this polysensory convergence is the necessary prerequisite of naming activity for two main reasons: first, because it is at the basis of the formation of concepts, considered (analogously to the construct of “associated images” developed by associationist authors) as the organised set of perceptual attributes of objects; second, because the convergence of multimodal information permits association of concepts of objects with the corresponding verbal labels. In fact, Geschwind holds that naming ability depends above all on the possibility of “associating names heard to things seen”. This is why Geschwind identifies the region of the angular gyrus, considered “the associative area of the associative areas” the anatomical substrate of naming ability. Starting from these phylogenetic conceptions on the anatomical bases of naming activity, and from his own anatomical-clinical observations on the behaviour of patients stricken by anterior or posterior lesions of the corpus callosum (Geschwind & Fusillo, 1966; Geschwind & Kaplan, 1962) Geschwind looked again at the conceptions of the associationist authors, emphasizing, in particular, the mechanisms of disconnection both within language areas and in the relationships between these areas and other motor and sensory portions of the cortex. Here, I do not intend to go into Geschwind’s conceptions on the clinical forms of aphasia due to the destruction of pathways or nervous centres within language areas, as these conceptions are the same as those of the classicists; one exception is the description of a form of anomia due to a lesion of the angular gyrus, which naturally depends on the general conception

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I have insisted upon thus far in the relationships between angular gyrus and naming activity. Instead, I will briefly touch on his conceptions concerning extrinsic disconnection syndromes in language areas, in which the connections between the language area and other motor and sensory cortical areas are interrupted. According to Geschwind, the largest form of disconnection of this type is the s y n d r o m e o f is o la tio n o f la n g u a g e a r e a s , produced when the lesion, even though it leaves the connections between Broca’s and Wernicke’s area unimpaired, cuts all other association pathways linking the language area to the other cerebral structures (Geschwind, Quadfasel & Segarra, 1968). In these cases, the patients’ language is characterised by the absence of articulatory and repetition disorders, in the presence of serious deficits in comprehension, almost complete impossibility of naming objects, and a more or less marked tendency toward echolalic behaviours. If, instead, the disconnection is more limited and selectively involves the relationships between the language areas and areas of projection of a specific sensory modality, partial disconnection syndromes occur; essentially they involve the impossibility of translating the information coming from these specific sense pathways into linguistic terms. In this case, we might find: 1. T a c tile a n o m ia f o r o b je c ts p la c e d in th e le ft

h a n d , in the syndromes of anterior disconnection, where there is an interruption of the fibres linking the somesthetic areas of the right hemisphere with the language centres of the left hemisphere, passing through the anterior part of the corpus callosum. 2. Pure alexia and anomia fo r colours in the posterior disconnection syndromes, in which there is a joint lesion of the left occipital lobe (with right homonymous lateral hemianopsia) and the splenium of the corpus callosum. In this case, in fact, the visual afferences may be processed only by the occipital areas of the right hemisphere where they receive a thorough nonverbal treatment) and may not reach the language areas of the left hemisphere, because the commissural pathways relative to visual

information pass through the splenium of the corpus callosum. Therefore, tactile anomia and pure alexia and anomia for colours are due to the impossibility of processing the information contained in a given sensory modality in linguistic terms, because of an interruption in the pathways linking the areas of sensory projection of the right hemisphere with the language centres of the left hemisphere.

LURIA AND THE CONCEPT OF FUNCTIONAL SYSTEMS During the years in which, in the West, research on aphasia tried to overcome the impasse in which the “unicistic” approach found itself, in the East, the personality and interpretative system of Luria (1966, 1970) dominated. Luria repudiated both the rigidly localising conceptions of the associationist authors and the nonlocalising theses of the unicistic authors, countering them with the concept of “functional system”, introduced and developed by Anochin (1935) in the area of reflexological theory. According to this concept, a complex function, such as the execution of a linguistic task, cannot be localised in a circumscribed portion of the cerebral cortex, because it requires the joint work of more elementary functions, situated in different areas of the cortex, which collaborate in the processing of the function, each making a specific contribution. In part taking up Pavlov’s theses, but primarily based on Vygotsky’s (1962) notions concerning the relationships between thought and language, Luria considered language as the basic organiser of the human mind. In fact, language not only distances humans enormously from the other animals at the level of interpersonal communication, but it also permits them to organise their own thought activities and to intentionally regulate their behaviour. On the other side, this basic organiser of the human mind, this regulator and mediator of the higher nervous functions, is processed just like every other form of nervous activity, starting from the work carried out by basic

7. DEVELOPMENT OF THE CONCEPT OF APHASIA

sensorimotor functions at a relatively elementary level. Therefore, according to Luria, it is the diminished specific contribution the damaged cortical zone brings to the processing of verbal behaviour that determines the various clinical forms of aphasia. In identifying these contributions and their specificity, Luria made reference both to the theory of cortical analysers (with regard to the functional organisation of the cortex) and the linguistic conceptions of his time concerning the intrinsic organisation of linguistic codes. Luria isolated six clinical forms of aphasia: 1. A k in e s th e tic m o t o r a p h a s ia , in which the basic disorder is difficulty in pronouncing single sounds of the language, called “articulemes”. 2. A k in e t ic m o t o r a p h a s ia , in which the articulemes are intact, but the patient is unable to correctly organise the sequence of movements necessary to pass fluidly from one articúleme to another, thus damaging the kinetic melody of the language. The first of these forms of motor aphasia is due to a lesion of the post-rolandic cortex and depends on an impairment of the afferent (proprioceptive) branch of the sensorimotor circuit of articulation. The second is due to a lesion in the pre-rolandic cortex corresponds to Broca’s classical aphasia and is based on a more purely motor deficit. 3. A s e n s o ry a p h a s ia , due to a lesion of the “cortical nucleus of the acoustic analyser” situated in the first temporal convolution of the left hemisphere (corresponding to Wernicke’s area) which provokes a deficit in acoustic analysis and synthesis of phonemes, resulting in disorganisation of both phonemic structure and semantic-lexical organisation of the languages. 4. An a c o u s tic -a m n e s ic a p h a s ia , due to a lesion in the middle regions of the temporal lobe, which do not directly belong to the cortical nucleus of the acoustic analyser and in which the deficit would have more to do with memory retention of the auditory-verbal traces than with the difficulty in grasping the acoustic structure of the word.

5.

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A s e m a n tic a p h a s ia , due to lesions

in the parietal lobe, in which the basic deficit is not the inability to understand the meaning of isolated words, but the inability to understand complex grammatical constructions requiring a simultaneous operation of analysis and synthesis, in which a spatial component often intervenes. 6. A d y n a m ic a p h a s ia , due to frontal lesions, in which linguistic codes are preserved but cannot be used because of a deficit in the dynamic components of cognitive processes. In this form of aphasia there is also a loss of the language ability to guide and regulate action and a more general disorganisation of the ability to process, develop and control the execution of complex motor programs, both in the verbal and extraverbal area. Two basic points seem to emerge from this attempt at a very rapid synthesis of Luria’s extremely complex, original and articulated conceptual system: on one side, the effort made by Luria to formulate many of his ideas in linguistic terms and to look for models in linguistics which would allow him to interpret data acquired from his very rich clinical observation activity; on the other side, the importance that, in spite of this, conceptions of a neurophysiological order continued to play in his interpretative system. It is, in fact, true that Luria adopted Trubetskoy’s conceptions (1933) regarding the organisation of the phonological aspects of language and the relevance of the distinctive traits of phonemes as a means for differentiating the meaning of words. It is also true that he adopted the ideas of Jakobson (1956b) on the distinction between the paradigmatic and syntagmatic aspects of language (see the next section) to characterise the “motor” and “sensory” aphasias in linguistically pertinent terms. However, it must be acknowledged that the Pavlovian doctrine of cortical analysers always remained in the background, as the basic interpretative schemata, to which the single parts of the taxonomy proposed by Luria made constant reference. Thus, it seems that we can conclude by stating that theories and linguistic models are introduced by Luria above all to analyse and

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explain particular aspects of a disorganisation that finds its basic reference system at the neurophysiological level.

LINGUISTIC INTERPRETATIONS OF APHASIA This final section will deal with the conceptions that have attributed a much more important role to linguistics in the study of aphasic disintegration than Luria did. Thus, we will be concerned with interpretations or with authors who, considering aphasia as a real pathology of language, have looked for the cleavage planes of its pathological disorganisation in the organisational principles of normal language, without resorting to notions or to disciplines outside linguistics, such as neuroanatomy or neurophysiology. The first author who tried to interpret aphasic disintegration in this way was Jakobson, who emphasised the existence of two general processes at all levels of language processing: the selection process and the combination process (Jakobson & Halle, 1956). The selection process consists of choosing a linguistic unit from among all units belonging to a specific level of linguistic organisation (for example, choosing a phoneme from among all phonemes of the language or choosing a lexical unit from among those that form the vocabulary of a specific linguistic community). The combination process consists of combining the chosen unit with others belonging to the same level. Thus, the formation of a lexical unit results from a process of selection and combination of appropriate phonemes, and the formation of a phrase requires a selection of lexical units and their combination, following the grammatical rules of language. According to Jakobson and Halle (1956), all the perturbations in aphasics’ language are due to disorders in selection processes (disorders of similarity) and in combination processes (disorders of contiguity). The perturbations of similarity explain the semantic alterations of Wernicke’s aphasics (semantic paraphasias, tendency to substitute the correct word with a generic word) while perturbations in contiguity explain several

characteristics of Broca’s aphasia, such as agrammatism or several types of expressive disorders described by Luria, such as the inability to correctly organise the sequence of movements necessary to pass fluidly from one articúleme to another. This model of analysis of language functioning and dysfunctioning, although it allows for a linguistic interpretation of several of the main differences and basic characteristics of Broca’s and Wernicke’s aphasia, is actually too general to provide a thorough explanation of the complexity of the clinical aspects of aphasia. Therefore, Jakobson (1964) tried to give a more elaborate neuro-linguistic interpretation of the classification of the aphasias proposed by Luria, with the intervention of the “similarity disorders”/ “contiguity disorders” dichotomy as well as two other dichotomies. The first separates comprehension disorders from expression disorders, and the second opposes the aphasic symptoms due to an impairment in linguistic codes (“disintegration” aphasias) to those due to extralinguistic perturbations (“limitation” aphasias). The form of aphasia described by Luria under the name of “dynamic aphasia”, in which the patient is unable to use substantially unimpaired linguistic codes due to a deficit of the dynamic component of cognitive processes provides a good example of limitation aphasia. Besides the distinction proposed by Jakobson between selection and combination disorders (which are at the base of both Wernicke’s and Broca’s aphasia), another important contribution to the flowering of linguistic interpretations in aphasiology was provided by the distinction proposed by Chomsky (1957), in a much more general theoretical area, between linguistic competences and performances. First, we can consider competence as the linguistic knowledge of a subject, that is, as the implicit, intuitive knowledge (not necessarily reflexive) this subject has of the rules and processes of language. Instead, performance is the actual use the subject makes of linguistic competence in a concrete situation. As the concrete behaviour we observe is given by performance, competence cannot be observed directly, but can only be inferred starting from the total performances.

7.

Particularly important in aphasiology is the fact that a performance does not depend only on competence, but also depends on a whole series of other factors (perceptual, attentive, mnesic, emotional, etc.) that may interfere with competence in the execution of a performance. As a cerebral lesion can obviously impair one or more of these factors, the distinction between linguistic competence and performances induces us to pose the first problem, which can be formulated as follows: Do the perturbations we observe in aphasia depend only on an impairment of perceptual, motor, attentive, mnesic factors, etc. which make a linguistic performance possible, in spite of the substantial integrity of models of competence, as sustained, for example, by Weigl and Bierwisch (1970), or does aphasic disorganisation depend both on a perturbation of performance factors and on an impairment of models of competence? A second, equally important problem concerns the unitariness or multiplicity of models of competence. Thus, the problem is posed of evaluating whether the term “linguistic competence” denotes a unitary phenomenon or whether, instead, it is possible to distinguish different competences due to phonemic, semanticlexical, and syntactic-grammatical levels of linguistic articulation, as suggested, for example, by Lesser (1978). With regard to the first problem, all authors agree in recognising that many difficulties encountered by aphasics are due to motor, perceptual, mnesic, praxic, attentive, etc. disorders following a cerebral lesion and which can have repercussions at the level of linguistic performances. On the contrary, there is no agreement in also conceding a disintegration of models of competence as well as perturbation of performance factors. One of the most used methods for resolving this problem has been to study the correlations between different tests (for example, of comprehension and expression, or of comprehension in the auditory-verbal and written modality) that use different peripheral components, all requiring the intervention of the same models of competence (or the same central representations). If the model of competence is altered, its perturbation will be reflected in the performances obtained on all tests used. If, instead,

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the model of competence is unimpaired, and only several performance factors are impaired, then the performances obtained on the various tests will be remarkably heterogeneous, as only those that depend on impaired performance factors will be pathological. This research strategy was used, for example, to clarify the meaning of different types of expressive disorders observed in patients with different clinical forms of aphasia and which might suggest the possibility of a selective dissolution of different components of linguistic competence. For example, phonemic disorders at the expressive level are typically observed in the form of phonemic paraphasias, in conduction aphasia, in many cases of Wernicke’s aphasia, and in some cases of Broca’s aphasia. Analogously, lexical semantic disorders of the semantic paraphasia type can be observed primarily in transcortical sensory aphasia and in many cases of Wernicke’s aphasia, and also in several forms of nominal aphasia and Broca’s aphasia. Finally, morpho-syntactic expressive disorders can be typically observed in the agrammatism of Broca’s aphasics, but also in the paragrammatism of some Wernicke’s aphasics. Towards the end of the 1970s some authors posed the problem of evaluating whether the phonemic, lexical-semantics and morpho-syntactic disorders emerging in production tasks are due to impairment of peripheral factors, selectively involved in the selection, combination, and oral production of phonemes, in the selection, activation, and production of lexical-semantic units, and in the programming, holding in working memory, and production of phrasal units; or whether they are due to the disorganisation of central processors regarding phonology, the semantic-lexical system, or morpho-syntactic rules. Here, I do not intend to go into the details of research that has tackled this problem, as the results are thoroughly discussed in the chapters of this volume concerned with phonological, semanticlexical and morpho-syntactic disorders of aphasics. However, it seems important to briefly mention several of the general conclusions these results seem to suggest and the criticisms addressed to this research strategy.

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With regard to the phonological level of linguistic production, one of the first studies on the topic, conducted by Alajouanine, Lhermitte, Ledoux, Renaud, and Vignolo (1964) suggested the existence of a significant correlation between production of phonemic paraphasias on the expressive side and disorders of “phonemic hearing” on the receptive side. However, subsequent research, carried out in more controlled conditions by Gainotti, Caltagirone, and Ibba (1975), Blumstein, Cooper, Zurif, and Caramazza (1977a) and Miceli, Gainotti, Caltagirone, and Masullo (1980) showed that at the phonemic level disorders of production and comprehension are in large part independent. These data seem to indicate that the phonemic disorders in input or output are due more to a deficit in the processing of verbal sounds and respectively to a disorder in programming and articulatory production than to the perturbation of a central phonological processor. The situation regarding the lexical-semantic level seems different because, in almost all group studies conducted on the topic by Alajouanine and colleagues (1964), Gainotti and colleagues (1975), Gainotti, Miceli, Caltagirone, Silveri, and Masullo (1981), Butterworth, Howard, and McLaughlin (1984), and Gainotti, Silveri, Villa, and Miceli (1986), a highly significant simultaneous occurrence of disorders was documented at the level of naming and discrimination between units belonging to the same semantic field. Obviously, these results do not allow us to conclude that the presence of semantic paraphasias involves a central disorganisation of the semantic-lexical systems in every case. In fact, patients certainly exist who present semantic disorders limited to only one modality of linguistic production (for example see Caramazza & Hillis, 1990b and Hillis & Caramazza, 1995a for an illustration of patients presenting semantic paraphasias only in oral or written production); these cases are particularly important from the point of view of cognitive neuropsychology, because more thorough study of them may allow for better comprehension of the structure and functioning of the lexical-semantic system. However, the existence of rare cases of this type does not detract from the fact that in most patients the study of the associations and

dissociations between performances obtained in different modalities and linguistic tasks favours a central disorganisation of semantic systems. The situation seems rather similar when we consider the significance of the morpho-syntactic disorders observed at the expressive level in agrammatic patients. The majority of the group studies that have examined the ability of these patients to extract the morpho-syntactic information contained in sentences (Caramazza & Zurif, 1976; Heilman & Scholes, 1976; Schwartz, Saffran, & Marin, 1980a) have shown that agrammatic s are unable to extract the morphosyntactic indicators that denote the relations between the lexical constituents of sentences. Therefore, these authors postulated that agrammatism is due to the disorganisation of a central processor of morpho-syntactic information. However, in this case too the detailed study of single cases has shown that expressive agrammatical difficulties can also be observed in patients who do not present analogous difficulties in tasks of syntactic comprehension, and that dissociations can be observed in expressive agrammatical traits between reduction of syntactic complexity of utterances and omission of free grammatical morphemes (Bemdt, 1987; Miceli, Mazzucchi, Menn, & Goodglass, 1983). These data seem to indicate that, even if the expressive and receptive components of agrammatism usually tend to associate, they can do so according to different formulas and can, in some cases, present as clearly dissociated (see Miceli’s chapter for a more thorough examination of this problem). Passing from a synthetic presentation of the results obtained following this research strategy to the criticisms against it, we can say that the opposition between models of competence and performance factors (or between central processors and peripheral components) seems too rough and not explicit enough to increase our current state of knowledge. The much more articulated models offered by cognitive neuropsychology and the connectionist models still in the phase of development could make a more important contribution to a better understanding of the mechanisms responsible for aphasie disintegration.

8 The Neurological Foundations of Language Stefano F. Cappa and Luigi A. Vignolo

investigations, the data collected using the traditional anatomo-clinical approach will be presented in some detail in order to provide an adequate background for the comparison with new findings. The chapter is divided into four sections dealing with:

INTRODUCTION Until relatively recent years, the main source of information about the neurological basis of language was the anatomo-clinical study of aphasie patients. The quantitative and qualitative modifications of language behaviour, observed at the time of clinical evaluation, were correlated to the site of cerebral damage observed post-mortem. Following the introduction of computerised tomography (CT) in the early 1970s, and of magnetic resonance imaging (MRI) shortly afterwards, neuroradiological methods have provided the possibility of studying lesion site and size in vivo, at the same time as the clinical evaluation. A further development has been the introduction of functional imaging techniques, which allow the investigation of regional cerebral blood flow and metabolism in normal subjects and aphasie patients, both at rest and while engaged in linguistic tasks. This chapter will review some of the available evidence about the neurological foundations of language. While placing a particular emphasis on the results of recent functional imaging

• Lesion localisation in aphasic syndromes. • Anatomo-functional correlates of specific psycholinguistic aspects in aphasic patients. • Neurological correlates of aphasia in particular populations, such as acquired aphasia in childhood or aphasia in left-handers. • In vivo mapping of the cerebral organisation of language with functional imaging in normal subjects.

NEUROLOGICAL CORRELATES OF THE APHASIC SYNDROMES Aphasic syndromes are the consequence of left hemispheric lesions in right-handed subjects and in 155

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the majority of left-handers. The results of pharmacological deactivation studies (Wada test) indicate that the left hemisphere is language-dominant in about 70% of left-handers (Kimura, 1983). There is evidence for an anatomical counterpart of this functional dominance (see Perani & Cappa, Chapter 5 in this volume): the perisylvian areas of the left hemisphere are larger than the homologous region in the right hemisphere both macroscopically (Falzi, Perrone & Vignolo, 1982; Geschwind & Levitsky, 1968) and cytoarchitectonically (Eidelberg & Galaburda, 1984). Furthermore, the neurones in the left language areas are larger than on the contralateral side (Hayes & Lewis, 1993) and the dendritic synaptic morphology has features which suggest later ontogenic development (Jacobs, Batal, Lynch, Ojemann, Ojemann, & Scheibel, 1993; Simonds & Scheibel, 1989). The usefulness of the classification of aphasic syndromes following damage to the left hemisphere is controversial (for a discussion,see Caplan, 1987; Kohn & Smith, 1992). Traditional taxonomic labels, such as “Broca’s aphasia”, are of limited informative value, given the extensive variability in diagnostic criteria. Some cognitive neuropsychologists tend to deny the validity of the concept of “aphasic syndrome” itself (Marshall, 1986). Other authors advocate the usefulness of the concept of functional syndrome, due to the impairment of a specific component within an explicit model of the function under study (Vallar, this volume; see also Plaut & Shallice, 1993, for a discussion of the implications of connectionist modelling for the concept of functional syndrome). To what extent the traditional aphasic syndromes can be re-interpreted as functional syndromes is a matter of debate (Kohn & Smith, 1992). Taxonomic categories probably follow from the non-random localisation of cerebral vascular lesions within the brain (Foix, 1928; Poeck, 1983). In the following summary, we will refer to the traditional neurological classification (Goodglass & Kaplan, 1972; Vignolo, 1977). This choice is dictated by the wide diffusion of this taxonomy in clinical and rehabilitation settings. For a more detailed discussion of the clinical and linguistic aspects of the aphasic syndromes, see Chapter 9 by Basso and Cubelli.

One important factor that should be always given appropriate consideration when correlating the aphasic syndromes with the site of cerebral damage is the time elapsed between lesion onset and the moment of the examination. In the acute phase after a cerebral lesion, such as a stroke, perifocal oedema and other functional effects may contribute to the severity of the clinical picture, while compensation mechanisms are most likely to play a role in the chronic stage. It is thus a frequent observation that a patient may move from one taxonomic label to another with time post-onset. As a general rule, it must be underlined that the neuroimaging methods have different indications and specific limitations. Structural imaging techniques, such as CT and magnetic resonance imaging (MRI) require a localisation of the lesion according to a reference method (atlas, stereotactic localisation) (see Chapter 9, by Perani & Cappa). In the case of functional methods, such as positron emission tomography (PET) or single photon emission tomography (SPECT), the physiological data (regional blood flow and metabolism) must be correlated to the anatomical information (Fox & Woldroff, 1994; Roland & Zilles, 1994).

Broca’s aphasia Broca’s aphasia is characterised by nonfluent, often agrammatic speech with disorders of articulation. Repetition is impaired, while auditory comprehension is good or only moderately defective in most clinical tests. On the other hand, performance with syntactically complex material, such as reversible passive sentences (of the type “the boy is chased by the girl”) is typically impaired. The discussion about the site of lesions associated with Broca’s aphasia dates back to the beginning of the century, when the Broca’s “dogma” of a lesion in the posterior part of the left third frontal convolution (Déjerine, 1914), corresponding to Brodmann’s areas 44 and 45 (frontal operculum) (Fig. 8.1) was challenged by Pierre Marie (Marie, 1906). Marie denied any linguistic role for this area, claiming that the lesions associated with typical Broca’s aphasia always involve the posterior portion of the perisylvian language areas, plus the insulolenticular region (the “quadrilatère”: Fig. 8.2). A lesion limited to the insulo-lenticular region,

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FIGURE 8.1 The language areas of the left hemisphere according to Dejerine (1914).

FIGURE 8.2

Pierre Marie’s “quadrilatère”.

according to Marie, is associated only to an articulatory disorder, which he called “anarthria” (see later). CT studies (Alexander, Naeser, & Palumbo, 1990; Blunk, De Bleser, Willmes, & Zeumer, 1981; Mazzocchi & Vignolo, 1979; Mohr, Pessin, Finkelstein, Funkenstein, Duncan, & Davis, 1978) have, in general, supported, Dejerine’s position. The full syndrome of Broca’s aphasia is usually associated with a large anterior lesion involving, besides Broca’s area proper, the precentral gyrus, the anterior portion of the insula, the underlying white matter, and often reaching down to the basal ganglia. This is the vascular territory of the superior branches of the left middle cerebral artery. Smaller lesions are often observed in patients who show clinical components of the syndrome. Mohr et al. (1978) have described patients with lesions limited to Broca’s area proper: their language disorder was mild and transient. The rolandic region, with the underlying white matter, has been suggested to play a crucial role for articulation (Alexander, Naeser, & Palumbo, 1990; Lecours & Lhermitte, 1976; Tonkonogy & Goodglass, 1981; Mori, Yamadori, & Furumoto, 1989). If this region is spared by the lesion, a nonfluent aphasia without articulatory impairment and no associated hemiparesis is the rule (Tonkonogy & Goodglass, 1981; Masden &

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O’Hara, 1983; Henderson, 1985; Alexander, Naeser & Palumbo 1990). A transient Broca’s aphasia has been observed in a patient with a lesion limited to the insula (Shuren, 1993). Persistent alexia in Broca’s aphasia occurs in patients who have recovered from global aphasia, and hence harbour large lesions extending posteriorly (Boccardi, Bruzzone, & Vignolo, 1984). While these are the most frequent correlates, several “exceptions” have been reported in the literature, including entirely retrorolandic lesions (Basso, Lecours, Moraschini, & Vanier 1985; Willmes & Poeck, 1993). A possible hypothesis to account for these cases is that they represent instances of “atypical” cerebral dominance for language (Daffner, Schomer, Cosgrove, Rubin, & Mesulam, 1991; for a discussion of the concept of atypical dominance see Alexander, Fischette, & Fisher, 1989). A different prognosis may be associated with an atypical lesion location (Tramo, Baynes, & Volpe, 1988). The assessment of glucose metabolism in the resting state with 18 fluorodesoxyglucose (18FDG) and PET in patients with chronic Broca’s aphasia (Metter et al., 1987) has shown an extensive region of hypometabolism in the left hemisphere (frontal and parietal lobes, caudate, thalamus), which exceeded in extent the structural area of damage shown by CT. The metabolism was also severely depressed in the right cerebellar hemisphere. This “crossed cerebellar diaschisis” (Baron, Bousser, Comar, & Castaigne, 1981) was absent in other aphasic syndromes and was significantly correlated with the severity of both aphasia and motor impairment.

Wernicke’s aphasia The traditional correlation between a clinical picture characterised by fluent, paraphasic speech, disordered repetition, and impaired auditory comprehension, and a lesion that includes the posterior part of the left superior temporal gyrus (Wernicke’s area, area 22) has been confirmed by all CT studies (Kertesz, Harlock, & Coates, 1979; Mazzocchi & Vignolo, 1979; Naeser & Hayward, 1978). Exceptions to this anatomo-clinical correlation are rare (14% against the 43% of nonfluent aphasias in the series reported by Basso et al., 1985). Fluent aphasia with prerolandic lesions has been

found to be more frequent in old age (Basso, Bracchi, Capitani, Laiacona, & Zanobio, 1987). Embolism from the heart or the large vessels is a frequent pathogenetic mechanism of Wernicke’s aphasia (Knepper, Biller, Tranel, Adams, & Marsh, 1989). The linguistic characteristics of jargon seem to be related to lesion location: Kertesz (1983) found that in patients with neologistic jargon the lesion extended towards the parietal operculum, while cases with semantic jargon had lesions circumscribed to the temporal lobe. Patients with severe jargonagraphia have frequently multiple lesions (Cappa, Cavallotti, & Vignolo, 1987). The presence and severity of written language disorder is related to lesion site (Kirshner, Casey, Henson, & Heinrich, 1989). In patients who are more impaired in reading than in auditory comprehension the lesion usually spares part of the superior temporal gyrus and extends towards the parietal lobe, in particular to the angular gyrus. Lesions confined to the temporal lobe are associated with the reverse asymmetry in comprehension.

Global aphasia Global aphasia is the most severe aphasic syndrome, and is characterised by scarcely informative, nonfluent speech and severely impaired comprehension. The neuropathological substrate is compatible with the global features of the linguistic impairment: the responsible lesion in most cases destroys the entire vascular territory of the left middle cerebral artery, which includes most of the language areas of the left hemisphere. CT studies, while confirming this correlation, have brought to light several interesting exceptions. A persistent global aphasia has been observed in patients with prerolandic lesions, completely sparing Wernicke’s area, as well as in cases with posterior lesions or even in subcortical strokes (De Renzi, Colombo, & Scarpa, 1991; Vignolo, Boccardi, Caverni, & Frediani, 1986; Willmes & Poeck, 1993). The patients with unexpected lesion sites do not differ from “standard” global aphasics from the linguistic standpoint. Poeck, De Bleser, and Graf von Keiserlingk (1984) did not find any relationship between lesion characteristics and peculiar clinical aspects, such as the fluent production of syllabic stereotypies.

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Global aphasia without hemiparesis can be observed with two separate lesions of the anterior and posterior parts of the language areas (Legatt, Rubin, Kaplan, Healton, & Brust, 1987; Tranel, Biller, Damasio, Adams, & Cornell, 1987; Van Horn & Hawes, 1982). This clinical presentation is considered typical of embolic stroke, although exceptions are on record (Legatt et al., 1987).

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account for at least some features of the syndrome (Poncet, Habib, & Robillard, 1987; Tanabe, Sawada, Inone, Ogawa, Kuriyama, & Shirashi, 1987).

Transcortical aphasias The distinguishing feature of all transcortical aphasias is the preserved ability to repeat. Three different clinical forms can be observed.

Conduction aphasia This syndrome is characterised by fluent speech, with phonemic paraphasias, and by a disproportionate impairment of repetition in comparison with a relatively preserved auditory comprehension. The lesion damages the posterior sylvian region, usually involving the parietal operculum (supramarginal gyrus) and the underlying white matter. The latter includes the arcuate fasciculus, which connects temporal and frontal associative cortical areas (Benson et al., 1973). An involvement of the arcuate fasciculus has traditionally been considered responsible for conduction aphasia: this lesion is compatible with the traditional account of the syndrome. The interruption of a pathway connecting anterior and posterior language areas was supposed to explain the defective repetition, due to the impaired transmission between a “decoding” and an “encoding” centre. The results of a PET study with 18-FDG do not support the “disconnection” hypothesis, as the reduction of metabolism in the temporo-parietal areas was not constantly associated with frontal hypometabolism (Kempler et al., 1988). A more serious problem for the traditional hypothesis is that many patients have lesions involving Wernicke’s area only (Benson et al., 1973). CT studies have confirmed that both lesion sites can be observed (Kertesz et al., 1979; Mazzocchi & Vignolo, 1979). In some patients the lesion involves the insular region and underlying white matter (i.e. other association fibres linking the anterior and posterior language areas), or the angular gyrus and underlying white matter (Damasio & Damasio, 1980; Palumbo, Alexander, & Naeser, 1992). Mild conduction aphasia has also been observed in patients with small lesions limited to the white matter, suggesting that an isolated involvement of the connection pathways can

Transcortical motor aphasia is characterised by reduced, nonfluent, sometimes agrammatic speech; confrontation naming is usually preserved and auditory comprehension unimpaired. The different lesion locations that have been reported in association with this syndrome share the characteristic of interrupting the connections between the dorsolateral prefrontal cortex and the anterior portion of the language area. These include damage to the white matter anterolateral to the frontal horn of the left lateral ventricle (Damasio, 1981; Freedman, Alexander, & Naeser, 1984), or bilateral lesions of the centrum semiovale (Mazzocchi & Vignolo, 1979). When the damage involves the medial surface of the frontal lobe, as in strokes in the territory of the anterior cerebral artery, the supplementary motor area is destroyed. These cases are characterised by the severe reduction of spontaneous speech, without the other aspects of linguistic impairment (Bogousslavsky, Assal, & Regli, 1987; Masdeu & O’Hara, 1978; Tijssen, Tany, Hekster, Bots, & Endtz, 1984). An ataxic hemiparesis, with severe involvement of the leg, is frequently associated (Iragui, 1990). In “variant” forms (Freedman et al., 1984), the presence of articulatory disorders is related to lesion extension towards the white matter underlying the motor strip for the face in the precentral gyrus. A mild auditory comprehension impairment can be observed with lesions involving the capsulo-lenticular region (see later for a discussion of transcortical motor aphasia in subcortical strokes). Transcortical sensory aphasia is characterised by fluent speech with profuse verbal and semantic paraphasias and severely impaired auditory comprehension. This clinical syndrome has frequently been observed in the advanced stages of

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Alzheimer’s disease (Coslett, Roeltgen, GonzalezRothi, & Heilman, 1987; Whitaker, 1976); when it is due to vascular lesions, the temporo-parietooccipital junction, between the vascular territories of the middle and posterior cerebral artery, is usually involved (Heilman, Rothi, McFarling, & Rothmann, 1981). These lesions are usually due to a hemodynamic mechanism, such as severe hypotension (Howard, Trend, & Ross-Russel, 1987). In the series reported by Kertesz, Sheppard, and MacKenzie (1982) some patients had more posterior lesions, in the territory of the posterior cerebral artery. Similar cases have been reported by Damasio (1981) and Vignolo (1984). Alexander, Hiltbrunner and Fisher (1989), who reviewed the literature and described 12 new cases, suggest that a crucial role is played by damage to the left posterior paraventricular white matter. This is an area of convergence of fibres originating from visual associative areas and the thalamus, directed towards the temporal associative cortex and the temporo-parieto-occipital junction, which could be related to semantic processing.

1990) or the pharmacological deactivation of the right hemisphere with amobarbital (Berthier et al., 1991) abolished the preserved repetition abilities.

Mixed transcortical aphasia, or isolation of the language area, is characterised by nonfluent speech, severely impaired comprehension and echolalia; it is due to extensive cortical lesions, sparing the immediately perisylvian cortex (Geschwind, Quadfasel, & Segarra, 1968; Assal, Regli, Thuillard, Steck, Deruaz, & Perentes, 1983). It has also been observed in association with two separate lesions: an embolic stroke, involving the frontal cortex anterior to Broca’s area, and a watershed lesion in the borderzone between the territory of the middle and posterior cerebral artery (Bogousslavsky, Regli, & Assal, 1988). According to these authors, this combined lesion is typically associated to internal carotid artery occlusion. In the case of transcortical aphasias, unexpected lesions involving the perisylvian language areas have been reported (Berthier et al., 1991; Grossi et al., 1991; Rapcsak, Krupp, Rubens, & Reim, 1990). It has been suggested that in these unusual cases repetition may be subserved by the right hemisphere, possibly through a nonlexical route. This hypothesis is supported by the observations that a second, right-sided stroke (Rapcsak et al.,

Alexia with agraphia

Anomic aphasia Anomic aphasia has been considered for a long time as due to “diffuse” cerebral damage, as it is frequently observed in patients with Alzheimer’s disease, head trauma, or intracranial hypertension (Benson, 1979). Although an impairment of confrontation naming is present in most, if not all, aphasic patients, it is particularly severe when the lesions involve the left parieto-temporal cortex (Benson, 1977) or the left temporal lobe (Coughlan & Warrington, 1978; Newcombe, Oldfield, Ratcliff, & Wingfield, 1971). The label of anomic aphasia is reserved for patients in whom a severe disorder of word finding (amnesia nominum) is observed in the context of fluent speech, good repetition, and preserved comprehension. This clinical picture is infrequent, and is observed in patients with temporal lesions sparing Wernicke’s area proper (Fig. 8.3) (Miozzo, Soardi, & Cappa, 1994).

A selective impairment of written language was associated by Dejerine (1892) to lesions restricted to the left angular gyrus. Cases without any impairment of oral language (usually a mild fluent aphasia or anomia is associated) are extremely rare (Benson, 1979). Kawahata, Nagata, and Shishido (1988) have described three remarkably “pure” cases in Japanese patients: the lesion was localised with TC and PET to the left temporal lobe.

Pure forms The rare instances of selective disorders of one modality of language performance are called “pure forms”. Recent reports have by and large confirmed the traditional localisations associated with these unusual disorders (Geschwind, 1965). Anarthria (also called pure motor aphasia or cortical dysarthria) is characterised by a severe articulation disorder, in the absence of any other linguistic impairment. The responsible lesion involves the left precentral gyrus and the underlying white matter (Lecours & Lhermitte, 1976), and destroys the

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FIGURE 8.3 Coronal MRI sections showing a left temporal hemorrhage (due to the rupture of an arteriovenous malformation) associated with anomic aphasia.

motor area of the face (Bay, 1964). The opercular part of the inferior frontal gyrus is sometimes involved by the lesion (Pellat et al., 1991; Schiff, Alexander, Naeser, & Galaburda, 1983). A PET study has shown a similar localisation in a patient with a negative CT scan (Kushner et al., 1987). Partial lesions of the precentral gyrus may be associated with the “foreign accent” syndrome (Takayama, Sugishita, Kido, Ogawa, & Akiguchi, 1993). If the anarthria-producing lesion is associated with a mirror lesion in the right hemisphere, speech is completely suppressed (Cappa, Guidotti, Papagno, & Vignolo, 1987; Groswasser, Korn, Groswasser-Reider, & Solzi, 1988; Villa & Caltagirone, 1984). This clinical picture (the biopercular syndrome or Chavany-Foix-Marie syndrome) must be differentiated from mutism (Cummings, Benson, Houlihan, & Gosenfeld, 1983; David & Bone, 1984), which is due to a wide range of different conditions, from lesions in the anterior cerebral artery territory involving area 24 (Damasio & Damasio, 1989) to psychiatric

disorders, and is characterised by the total absence of vocalisation. Pure word deafness: Patients with pure word deafness are unable to understand what is said to them, while speech, reading, and writing are normal or only mildly impaired. The traditional neurological interpretation of this condition is that it is due to a lesion which disconnects both acoustic areas of Heschl from Wernicke’s area. Most patients have had two small strokes: typically, the disorder appears suddenly, after a left or right temporal lesion, in a patient with a previous lesion in a similar location in the opposite hemisphere (for a recent review, see Vignolo, 1995). In exceptional cases a single subcortical lesion in the left temporal lobe seems to be sufficient to produce pure word deafness (Gazzaniga, Glass, Sarno, & Posner, 1973). In several patients with CT or MRI documented lesions (Auerbach, Allard, Naeser, Alexander & Albert, 1982; Coslett, Brashear, & Heilman, 1984; Tanaka, Yamadori, & Mori, 1987), both Heschl’s primary acoustic areas and acoustic

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radiations were bilaterally involved by the lesions, with a prevalent right-sided extension. Two subcortical lesions, involving the medial geniculate body on the left and the internal capsule on the right, were shown by CT and MRI in a case with transient pure word deafness, but persistent auditory agnosia (Motomura, Yamadori, Mori, & Tamaru, 1986). Pure agraphia has been described with superior parietal lobule lesions (Basso, Taborelli, & Vignolo, 1978; Mazzocchi & Vignolo, 1979): an unilateral optic ataxia was associated in another case (Auerbach & Alexander, 1981). This is probably a form of apraxia relatively specific for writing movements (Alexander, Fischer, & Friedman, 1992). A selective disorder of writing has also been reported in association with a lesion in the left temporal lobe (Rosati & De Bastiani, 1979). Alexia without agraphia has been considered a typical disconnection syndrome, due to the interruption of the connections between visual cortex and the language areas of the left hemisphere, i.e. to a “visuo-verbal disconnection” (Dejerine, 1892). The responsible lesion is usually an ischemic stroke in the territory of the left posterior cerebral artery (De Renzi, Zambolin, & Crisi, 1987), or a hematoma (Greenblatt, 1983; Henderson,

Friedman, Teng, & Weiner, 1985) or a tumour (Turgman, Goldhammer, & Braham, 1979) involving the same areas. Typical lesions damage the calcarine fissure, the lingual gyrus, and the white matter around the occipital horn of the lateral ventricle (Fig. 8.4): this results in a right homonymous hemianopia and in an interruption of the fibres coming from the visual areas of the right hemisphere (Damasio & Damasio, 1983; De Renzi et al., 1987; Vignolo, 1983). Colour anomia is frequently associated, and indicates lesion extension towards the temporo-occipital areas (Damasio & Damasio, 1983). De Renzi etal. (1987) have shown that the visual naming disorder also extends, although with lesser severity, to other categories. The presence of verbal memory defects is due to the damage to the left hippocampal region (Damasio & Damasio, 1983; De Renzi etal., 1987). Pure alexia can also be observed in the absence of hemianopia. In these cases the visuo-verbal disconnection could be due to the interruption of the white matter pathways located immediately beneath the angular gyrus (Greenblatt, 1973); or at the occipito-temporal junction, at the level of the fusiform gyrus (Henderson et al., 1985; Weisberg & Wall, 1987). If the lesion extends towards the lingual gyrus, but spares the calcarine fissure and the optic radiations, hemichromatopsia can be observed instead of hemianopia (Damasio & Damasio, 1983).

FIGURE 8.4

Schematic drawing of the medial surface of the posterior part of the cerebral hemisphere, showing the main sulci and gyri.

8. NEUROLOGICAL FOUNDATIONS OF LANGUAGE

Subcortical aphasias The notion that aphasia can be observed in patients with subcortical lesions, sparing the cortical language areas, is not new (Henschen, 1922). These cases were often considered as instances of disconnection between cortical areas, due to the interruption of fibre pathways (see earlier), while the role of damage to grey nuclei, such as the thalamus and basal ganglia, was discounted (Nielsen 1946). The introduction of CT in clinical practice has resulted in increasing recognition of cases of subcortical aphasia. This renewed interest has led several authors to speculate about the possible linguistic function of subcortical structures (for an extensive review, see Cappa & Vallar, 1992). The studies of unselected samples of patients with subcortical stroke, identified with CT, have clearly indicated that only some patients with subcortical lesions present with a persisting aphasia (Vignolo, Macario, & Cappa, 1992). In the case of lesions involving the thalamus, a fairly typical clinical syndrome, similar to transcortical aphasia, has frequently been observed (Cappa & Vignolo, 1979; Puel et al., 1986). These patients usually have a reduced verbal output, with low vocal volume and frequent verbal paraphasias; repetition is preserved, and the impairment of auditory comprehension is usually moderate. Attempts at lesion localisation within the thalamic complex have indicated that in most patients with lesions of limited extent the anterior nuclei bear the brunt of damage (Bogousslavsky, Regli, & Assal, 1986; Davous et al., 1984; Graff-Radford, Damasio, Yamada, Eslinger, & Damasio, 1985). Patients with posterior thalamic lesions are frequently not aphasic (Cappa, Papagno, Vallar, & Vignolo, 1986), although some cases of aphasia due to pulvinar damage are on record (see, for example, the pathologically verified case of Crosson, Parker, Kim, Warren, Kepes, & Tully, 1986). These cases may be characterised by more fluent speech (Alexander & Loverme, 1980). The correlations are more muddled in the case of lesions involving the basal ganglia. Most clinical series (Basso, Della Sala, & Farabola, 1987; Cappa, Cavallotti, Guidotti, Papagno, & Vignolo, 1983;

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Puel et al., 1984) have failed to identify specific correlates of lesion site with the type, or even the presence of aphasia. Both “classical” and “atypical”, unclassifiable aphasic syndromes have been described in these patients (Damasio, Damasio, Rizzo, Varney, & Gersh, 1982; Puel et al., 1984) . A “core” syndrome of selective lexical impairment, in particular in controlled association tasks, has been suggested to be typical of capsulostriatal lesions (Mega & Alexander, 1994). Similar disorders are typical of transcortical motor aphasia, which has frequently been observed in patients with ischemic lesions in the territory of the anterior choroidal artery (pallidum, posterior limb of the internal capsule; Cappa & Sterzi, 1990; Decroix, Graveleau, Masson, & Cambier, 1986; Wallesch, 1985) . Subcortical aphasias are usually, but not invariably, associated with a fast recovery rate (Vallar et al., 1988), in particular if the lesion is of limited size and speech production is fluent (D’Esposito & Alexander, 1995; Mega & Alexander, 1994); residual lexical-semantic disorders are often present in the chronic stage (Kennedy & Murdoch, 1993). The physiopathological mechanisms underlying subcortical aphasia have been a focus of debate. PET and SPECT imaging studies of cortical metabolism and blood flow in patients with subcortical stroke and aphasia have shown a functional depression in the structually unaffected ipsilateral cortex, which is more severe and extensive in aphasic than in nonaphasic patients (Baron et al., 1986; Perani, Vallar, Cappa, Messa, & Fazio, 1987; Skyhoj Olsen, Bruhn, & Oeberg, 1986) . These effects have been interpreted by some authors as “diaschisis”, i.e. afunctional depression remote from a cerebral lesion. According to this interpretation, the reduction of neural activity is due to the interruption of synaptic connectivity from the area affected by the structural lesion (Feeney & Baron, 1986; Powers & Raichle, 1985). Weiller et al., (1993) suggested that in the cases associated with a reversible occlusion of the middle cerebral artery, a selective cortical neuronal loss may be due to an incomplete infarction. It must be underlined that sometimes patients with lesions limited to subcortical areas on CT are shown to have cortical

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damage on MRI (Godefroy, Rousseaux, Pruvo, Cabaret, & Leys, 1994). Lesion size appears to play a crucial role for the presence of aphasia (Perani et al., 1987; Skyhoy Olsen etal., 1986;Takanoetal., 1985; WeilleretaL, 1993). Lesion site is however also important. In cases with damage limited to the white matter, aphasia is infrequent (Perani et al., 1987; Skyhoy Olsen et al., 1986). This finding is in contradiction to the results of the study by Alexander, Naeser, and Palumbo (1987), where lesions limited to the putamen and caudate were associated only with mild anomia, while the site and extent of the white matter damage was related to specific aspects of linguistic impairment. The limited spatial resolution of CT, as well as heterogeneity in patients’ characteristics, may be responsible for the disagreements among reports. It is possible that MRI will be helpful to clarify these differences. In conclusion, the available data are compatible with a three-dimensional view of the language areas, which comprise multiple cortico-subcortical functional systems, related to specific aspects of linguistic processing. Some aspects of linguistic impairment in patients with subcortical lesions, such as articulatory disorders, may be related to damage to white matter pathways; however, lesion data support a participation of the thalamus in the neural substrates of lexical-semantic processing, together with the temporal and prefrontal cortex. The role of the basal ganglia remains unclear, and deserves further investigation.

NEUROLOGICAL CORRELATES OF APHASIC SYMPTOMS The previous section has summarised what can be called the traditional neurological approach, i.e. the correlation of aphasic syndromes with lesion site. Another possible method of investigation in clinical studies is the correlation of specific aspects of linguistic impairment, such as the individual symptoms that cluster in the aphasic syndromes, to lesion site. The introduction of psycholinguistic models to the study of aphasia (for an introduction, see Caplan, 1992) has been influential in this type

of approach, leading to a better definition of the aspects of linguistic impairment. These studies have been conducted both in clinical series and in individual patients. While group studies have usually addressed broadly defined clinical symptoms, such as disorders of naming or impairments in syntactic aspects of auditory comprehension, single case studies have tried to look for the neurological correlates of selective dysfunctions of a discrete component within a model of normal processing (for example, the inability to read non words). The first approach has been more successful: it is generally based on the comparison of a group of patients with a severe, or persistent, defect, with another sample of patients where the symptoms have been mild or transient. In the case of speech production, it has already been remarked that case studies suggest a crucial role of the precentral gyrus for articulation (Lecours & Lhermitte, 1976; Sugishita, Konno, Kabe, Yunoki Togashi, & Kawamura 1987). In a prospective study of 54 patients, this area was consistently involved in patients with persistent nonfluency at six months post-onset (Knopman, Seines, Niccum, Rubens, Yock, & Larson, 1983). Lesion extension towards the basal ganglia region (Ludlow, Rosenberg, Fair, Buck, Schesselman, & Salazar, 1986), and in particular the mesial frontal white matter (Naeser, Palumbo, Helm-Eastabrooks, Stiassny-Eder, & Albert, 1989) predicts poor recovery of fluency. Extensive involvement of deep fronto-parietal white matter seems to be associated with automatism in speech (syllabic, verbal, and phrasal stereotypies: Haas, Blanken, Mezger, & Wallesch, 1988). A recent study has reported a close association between articulatory impairment (“apraxia of speech”) and damage to the anterior part of the insula (Dronkers, 1996). A disorder of naming is observed in almost every patient in the acute phase. At six months it is persistent only in patients with extensive lesions, or damage to two critical regions: posterosuperior temporal-inferior parietal or insulo-lenticular (Knopman, Seines, Niccum, & Rubens, 1984). In the first instance the prevalent error type was semantic paraphasia, whereas phonological errors were conspicuous with the insulo-lenticular localisation. In a study devoted only to fluent

8. NEUROLOGICAL FOUNDATIONS OF LANGUAGE

aphasics, it was found that phonological errors in naming were associated with damage to the posterior perisylvian region, whereas semantic paraphasias were associated with lesions involving posterior temporo-parietal cortex (Cappa, Cavallotti, & Vignolo, 1981) (Fig. 8.5). In this study, patients with perisylvian involvement had a severe repetition impairment. Seines, Knopman, Niccum, and Rubens (1985) have shown that the disorder of repetition was persistent in fluent aphasics with lesions involving Wernicke’s area. A selective naming disorder can be observed with anterior temporal lesions, sparing Wernicke’s area (BA 20 and 21): these patients frequently show a grammatical category effect, with action naming superior to object naming (Damasio, 1992; Miozzo, Soardi, & Cappa, 1994); the opposite dissociation has been reported in patients with frontal lesions (see Daniele, Giustolisi, Silveri, Colosimo, & Gainotti, 1994, for a review). Damasio, Grabowski, Tranel, Hichwa, and Damasio (1996) have reported differential temporal lobe involvement in a large group of patients with category-specific lexical retrieval impairment. Proper name anomia was associated with lesions involving the left temporal pole, while animal naming was abnormal in patients with damage to anterior inferior temporal cortex (IT) damage; a disorder in retrieval of words for tools correlated with damage in posterolateral IT. The correlation for proper names was not supported by a meta-analysis of single case reports (Semenza, Mondini, &Zettin, 1995). On the receptive side, a group study of the identification and discrimination of consonants indicated inferior performance in patients with extensive damage to the white matter of both

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hemispheres, without a particular influence of left temporal lesions (Yeni-Komshian, Ludlov, Rosenberg, Fair, & Salazar, 1986). This finding is compatible with the results of a study of discrimination of synthetic consonants differing in sonority (Basso, Casati, & Vignolo, 1977), in which defective performance was not related to the fluency/nonflueney dimension. A recent investigation, using a more refined method (MRI morphometry) has found that involvement of a parietal region, centred on the left posterior supramarginal gyrus, was associated with defective phonemic discrimination and identification (Caplan, Gow, & Makris, 1995). A clinicoradiological investigation has indicated an important role of Wernicke’s area in vowel perception (Lund, Spliid, Andersen, & Moeller, 1986). Hart and Gordon (1990) have shown that lesions involving the posterior temporal-inferior parietal region are associated with severe single-word comprehension impairments. In unselected samples, a similar disorder is frequently present in the acute stage, but persists at six months only in patients with extensive cortical damage (Seines, Niccum, Knopman, & Rubens, 1984). Defective performance on sentence comprehension, as assessed with the Token test, is associated with lesions of Wernicke’s area and of the inferior parietal cortex (Seines, Knopman, Niccum & Rubens, 1983; Vignolo, 1979); these results have been confirmed by Naeser, Helm-Estabrooks, Haas, Auerbach, and Srinivasan (1987). In the latter study, lesion extent in the temporal, but not in the parietal, lobe correlated with the severity and persistence of the disorder. A conflicting finding has been reported

FIGURE 8.5

Schematic drawing of lesion overlap (mapped according to the method described by Mazzocchi & Vignolo) in patients with predominantly phonological (A) or lexical (B) errors in a picture naming task.

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by Kertesz, Lau, and Polk (1993), who found that only lack of damage to the inferior parietal region (supramarginal and angular gyri) predicted good comprehension recovery. Global aphasics show superior recovery of auditory comprehension if the lesion involves the temporal isthmus, rather than Wernicke’s area (Naeser, Gaddie, Palumbo, & Stiassny-Eder, 1990). No specific correlation emerged for the impairment on the test of syntactic comprehension (Caplan, Baker, & Dehaut, 1985), neither from the point of view of lesion location nor of lesion size within the left perisylvian language area (Caplan, Hildebrandt, & Makris, 1996). In the cases reported by Nadeau (1988) a relatively selective disorder of syntactic comprehension was associated with large frontal lesions. In a long-term follow-up study of veterans who had a nonfluent aphasia due to a cerebral wound 15 years before, a persistent syntactic impairment in production and in comprehension tests, both oral and written, was associated with posterior extension of the lesions towards Wernicke’s area (Ludlow et al., 1986). According to Naeser et al. (1987) Wernicke’s area involvement is associated with a qualitatively similar, but more severe impairment of syntactic comprehension, in comparison to other perisylvian locations of damage. In the area of written language, a psycholinguistic approach has largely superseded the anatomo-clinical classification, with which, however, it partially overlaps. The basic distinction is between disorders of the lexical route, which is required for irregular word reading, and disorders of the nonlexical mechanism, which performs grapheme-to-phoneme conversions and is necessary for reading unknown or nonexistent words (Coltheart, Patterson, & Marshall, 1980; Patterson, Marshall, & Coltheart, 1985). There have been some efforts to relate selective, or relatively selective, disorders of one of the two reading pathways to lesion location, which have met with limited success (Black & Behrmann, 1994; Roeltgen, 1994). In the case of deep dyslexia (in which a damage to the nonlexical route is associated with the production of semantic paralexias), the lesions are usually large, involving most of the left hemisphere language areas. This has led some

authors to postulate that the residual reading abilities of these patients may be mediated by the intact right hemisphere (Coltheart, 1980). Contrary to this hypothesis, in a case described by Roeltgen (1987), residual reading was totally abolished by a second, left hemispheric lesion. In surface dyslexia, where the lexical reading route is impaired, the lesion is usually smaller, and often circumscribed to the left temporal lobe (Vanier & Caplan 1987). Writing disorders compatible with the selective involvement of the different routes have also been observed. Phonological agraphia, characterised by poor nonword writing, has been observed with posterior perisylvian lesions (Alexander, Friedman, Loverso, & Fisher, 1992; Bolla-Wilson, Speedie, & Robinson, 1985; Roeltgen, Sevush, & Heilman, 1983), while the converse picture of lexical agraphia (poor irregular word writing) has been associated with different lesion sites, sparing the perisylvian region (Rapcsak, Arthur & Rubens, 1988; Roeltgen & Heilman, 1984).

APHASIA IN SPECIAL POPULATIONS Acquired aphasia in children The effects of damage to the left hemisphere have different consequences in children and adults, leading to a greater potential for plasticity and to better recovery in childhood aphasia (Lenneberg, 1967). The exact timing of brain damage is probably a crucial factor. Prenatal and early perinatal focal damage to the right or left hemisphere is associated only with mild delays in language acquisition (Bates et al., in press). A recent study of children evaluated for epilepsy surgery, in which the method of electrical stimulation through chronically implanted subdural electrodes was used to assess cerebral language representation (Dichowny et al., 1996) reported some unexpected results. No displacement to the right hemisphere was found in the case of developmental lesions, while lesions acquired before the age of 5, extensively damaging the language cortex, were associated with right hemispheric language dominance. The situation is different in the case of focal lesions occurring after language acquisition.

8. NEUROLOGICAL FOUNDATIONS OF LANGUAGE

Right-handed children then develop aphasia after left, but not right, hemispheric lesions (Cranberg, Filley, Hart, & Alexander, 1987; Woods & Teuber, 1978). Aphasia in children has been suggested to differ clinically from adult aphasia, because of the nonfluent production, independently from lesions site. This observation is in disagreement with reports of Wernicke’s (Van Dongen, Loonen, & Van Dongen, 1985), transcortical sensory (Cranberg et al., 1987), and anomic aphasia (Hynd, et al., 1995) in children. Similar clinical pictures seem to be associated with comparable lesion sites in children and adults (Aram, Rose, Rekate, & Whitaker, 1983; Van Dongen et al., 1985; Cranberg et al., 1987). It has been suggested that the high prevalence of subcortical lesions in children may account for some of the features considered typical of childhood aphasia, such as mutism and nonfluency (Martins & Ferro, 1993). This evidence suggests that the potentialities for language of the right hemisphere may be more limited in time than it was originally thought.

Aphasia in left-handers Naeser and Borod ( 1986) have shown that, when the site and extent of the cerebral lesion are matched, the clinical picture in right- and left-handers is comparable. Aphasia followed left hemispheric damage in 22 out of 31 left-handers. The patients who became aphasie after a right-sided stroke had atypical clinical features, such as good auditory comprehension in a case with extensive damage to Wernicke’s area. In these patients the pattern of cerebral hemispheric asymmetry shown by CT was characterised by a longer occipital lobe, suggesting left hemispheric dominance for some aspects of linguistic function. Lack of significant differences with right-handers has also been reported by Basso, Farabola, Grassi, Laiacona, and Zanobio (1990): in most cases the type and severity of aphasia, as well as the prevalence of associated symptoms, were comparable for similar lesion size and site in leftand right-handers. Moreover, recovery was not faster in a group of 15 left-handers, who were compared to a matched sample of right-handed aphasies participating to the same rehabilitation programme.

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Taken together, these findings confirm that only a minority of left-handers have a right hemispheric language representation, which appears to involve areas homotypical with those of the left hemisphere in right-handers.

Crossed aphasia The term “crossed aphasia” was first used by Bramwell in 1899 to designate, in a much broader sense than nowadays, both aphasia with right hemiplegia in a left-handed individual (Bramwell’s own case) and, by analogy, aphasia with left hemiplegia in a right-hander (which he stated he had never seen). Since the 1920s, however, the term has been restricted to purely right hemispheric lesions in an unmistakably right-handed individual. The syndrome, so defined, is comparatively rare (1 or 2% of right-handed aphasics), as the exacting demands of exclusively right hand preference, absence of left-handedness in the family, and intactness of the left hemisphere were seldom met in the older case reports. In a review of the literature from 1880 to 1988, Faglia and Vignolo (1989) found that only 26 out of the 87 published cases were satisfactorily documented. The review did not support the claim that the language disorder is qualitatively different from that due to left hemispheric damage; type and severity of aphasia and lesion size and site are similar to patients with comparable left hemispheric damage (Basso, Capitani, & Laiacona, 1985; Henderson, 1983). Similarly, the review failed to support the hypothesis that deep hemispheric lesions are particularly frequent in crossed aphasia (Habib, Joannette, Ali-Cherif, & Poncet, 1983), although several case reports of “subcortical” crossed aphasia are on record (see, for example, Perani, Papagno, Cappa, Gerundini, & Fazio, 1988). A clinical and metabolic follow-up study with PET in two crossed aphasics with subcortical lesions (Cappa, Perani, Bressi, Paulesu, Franceschi, & Fazio, 1993) has shown the presence of massive diaschisis in the ipsi- and contralateral cortex. Regression of these remote effects paralleled clinical recovery (Fig. 8.6). These findings indicate that the cerebral language areas in these patients mirror those usually present in the left hemisphere. If this is so, the

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FIGURE 8.6 Regional cerebral metabolic rate for glucose measured with PET and 18F-FDG in a patient with crossed aphasia due to a subcortical stroke. (A) Acute stage: widespread cortical metabolic depression, including both ipsilateral (right) and contralateral (left) cortex. (B) After clinical recovery: partial regression of the metabolic depression, in particular in the left hemisphere.

question of the division of competences arises. Some authors maintain that in these individuals, before stroke, there was a complete reversal of the normal representation of functions (language to the left hemisphere, spatial abilities to the right), while others argue that the right hemisphere has acquired language without losing its relative dominance for certain spatial skills. The presence of visuospatial neglect and the qualitative features of constructional apraxia in several cases (see Faglia, Rottoli, &

Vignolo, 1990; Faglia &Vignolo, 1990) favour the second possibility. Further thorough case studies are required.

Aphasia in deaf signers Sign-language aphasia has been reported after left hemispheric lesions in right-handers. In two lefthanded patients the lesion was left hemispheric in one, right in the other (Kimura, 1986). Clinical correlations have been reported in three right-

8. NEUROLOGICAL FOUNDATIONS OF LANGUAGE

handed aphasic signers in whom lesion localisation had been assessed with CT (Poizner et al., 1984). A lesion of the supramarginal gyrus was associated with a severe impairment in repeating linguistic gestures, suggesting a diagnosis of conduction aphasia. A nonfluent aphasia was observed in the patient with anterior cerebral damage, while the fluent patient had a subcortical lesion. A picture similar to Broca’s aphasia was observed in a signer with a left frontal opercular lesion (Hickok, Kritchevsky, Bellugi, & Klima, 1996). A striking dissociation between sign language aphasia and preserved nonverbal gestural communication has been observed in a deaf signer with a left hemispheric lesion (Corina et al., 1992). In a group study, comparing 13 left hemisphere-damaged signers to 10 signers with right hemispheric lesions, patients with left lesions had a significantly inferior performance on all linguistic tasks, and were unimpaired on visuospatial tests; the reverse dissociation was found in patients with right hemispheric lesions (Hickok, Bellugi, & Klima, 1996). These results indicate that sign language has a similar cerebral organisation as spoken language, and that hemispheric dominance is linked to language per se, rather than to processing mechanisms related to specific input-output modalities.

Aphasia in polyglots Many different variables, such as age at acquisition, level of proficiency, and affective resonance have been suggested to influence the clinical characteristics of aphasia in polyglots (Lambert & Fillenbaum, 1959). Several different patterns of impairment have been described in bilinguals who become aphasic. There are remarkable exceptions to the rule that the severity of impairment in each language should be proportional to the premorbid degree of mastery: for instance, selective aphasia for one of the languages, differential recovery, or even mixtures of the two languages, and different symptoms in each (see Paradis, 1995, for a review). An important role of subcortical structures in the cerebral organisation of the most frequently used language has been suggested on the basis of clinical evidence (Aglioti & Fabbro, 1993).

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Aphasia in speakers of non-indoeuropean languages The hypothesis of a different cerebral organisation of language in speakers of non-indoeuropean languages has been suggested on the basis of clinical observations. Crossed aphasia has been reported to be particularly prevalent in Chinese right-handers (15.5% in the study by Yu-huan, Ying-Guan, & Gui-quing, 1990). However, this does not seem to be the case in Japanese, in which crossed aphasia has a prevalence of about 1% (Sakurai et al., 1992). One of the factors that has been suggested to determine a difference in cerebral localisation for non-indoeuropean languages is the presence of an ideographic writing system (kanji). While dissociations between kanji and kana reading and writing are well documented in individual patients (Iwata, 1984), recent PET studies have indicated left hemispheric processing for both types of written language (Sakurai et al., 1992; see later, PET studies in normal subjects). The selective impairment of kanji, with preserved kana, is the characteristic feature of a syndrome known as Gogi aphasia in Japanese. This syndrome, which is similar to transcortical sensory aphasia and reminiscent of the pattern of linguistic impairment in the degenerative condition of semantic dementia (Hodges, Patterson, Oxbury, & Funnell, 1992), is associated with lesions of the postero-inferior part of the left temporal lobe (Jibiki & Yamaguchi, 1993).

FUNCTIONAL MAPPING OF THE CEREBRAL ORGANISATION OF LANGUAGE IN NORMAL SUBJECTS The possibility of investigating the cerebral organisation of language in normal subjects is relatively recent, and follows from the availability of methods that allow the in vivo measurement of parameters of cerebral function, such as regional blood flow, while subjects are engaged in linguistic processing tasks. The functional imaging era starts with the studies of regional cerebral blood flow, with the 133Xe method of the Scandinavian school. Ingvar and Schwartz (1974) and Larsen, Skinhoj,

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and Lassen (1978) were the first to show that automatic language (such as counting, or reciting the days of the week) activates multiple cerebral areas, in both hemispheres. The increase in blood flow was particularly large in the supplementary motor areas, anterior prefrontal cortex, sensorimotor area for the mouth, and auditory cortex. Listening to words (Nishizawa, Skyhoj Olsen, Larsen, & Lassen, 1982) was associated with a prevalent left hemispheric activation, in particular in the superior temporal lobe and in the prefrontal and orbitofrontal areas. Knopman, Rubens, Klassen, and Meyer (1982) confirmed the presence of a prevalent left hemispheric activation in the posterior sylvian region when the subjects were engaged in phonological tasks, such as rhyming judgements, but also in nonverbal auditory discrimination tasks. A left frontal activation was shown with lexical retrieval tasks, such as verbal fluency (Risberg, 1986). Object naming activated a wide network of cerebral areas, including the left temporo-parieto-occipital and frontal regions and the right parieto-occipital area (Demeurisse & Capon, 1987). Further progress came with the introduction of tomographic methods, such as single photon emission tomography (SPECT) with 133Xe, for activation studies. Using this method, Wallesch, Henriksen, Kornhuber, and Paulson (1985) have shown that verbal production increases blood flow in the left frontal and thalamo-pallidal region, while a bilateral activation is present in the caudate and retrorolandic cortex. The introduction of positron emission tomography (PET) marks the most important advancement for the investigation of language activation in normal subjects (see chapter by Perani & Cappa for a discussion of the technical aspects). It must be underlined that this field of investigation has been characterised by a continuous interaction with the theoretical developments in neuropsychology: more refined language activation paradigms have provided an ideal match for the hitherto unthinkable possibilities offered by PET. The inaugural study of this new era of research is the PET study of single word processing by the St. Louis group (Petersen, Fox, Posner, Mintun, & Raichle, 1988, 1989). This study will be reviewed

in some detail, as many of the methodological discussions related to this field of endeavour (Démonet, Wise, & Frackowiak, 1993; Perani, Gilardi, Cappa, & Fazio, 1992; Petersen & Fiez, 1993; Sergent, Zuck, Lévesque, & MacDonald, 1992) have made reference to this pioneering investigation (Fig. 8.7). The study provides a clear example of the application of the classical “subtractive” methodology to a lexical processing model (Posner & Raichle, 1994). It includes a control condition, in which cerebral perfusion was assessed while the subjects fixated a cross in the centre of a computer screen. The first “activation” step, according to the internal logic of the paradigm, was the auditory or visual presentation of words. The subjects had no task to perform during the presentation: they were simply asked to watch the screen where the words were presented. A further step was the condition in which the subjects had to read or repeat aloud the words. Finally, the subjects were required to produce a verb associated with the word presented on the screen (for example, “eat” for “cake”). Regional cerebral perfusion was measured with PET during each of these phases. The paradigm clearly entails the hypothesis of sequential stages in lexical processing. Subtraction of the scans collected during the control condition from those assocated with passive word presentation should then elucidate the areas involved in the perceptual analysis (including access to the word form). Subtraction of passive presentation from reading aloud or repetition should isolate the areas involved in encoding and articulatory programming. Finally, subtraction of the scans collected during the latter condition from verb generation should individuate the correlates of semantic processing. The results of the first two subtractions gave apparently uncontroversial results: modality-specific areas were activated by passive presentation (extrastriate cortex for visual words, superior temporal, more extensive in the left temporoparietal areas, for auditory words), while oral production was associated with frontal activation (precentral gyrus, supplementary motor area, Broca’s area). The third subtraction (generation minus reading or repetition) gave an unexpected result: semantic processing was associated not with left hemispheric temporal or

8. NEUROLOGICAL FOUNDATIONS OF LANGUAGE

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FIGURE 8.7 The Petersen et al. (1988) single word processing PET activation experiment. The sensory stage corresponds to simple stimulus (word) presentation. The production stage is word reading or repetition. The associative stage is the retrieval of a verb which was semantically related to the stimulus word.

parietal activation, as predicted by neuropsychological investigations, but with the anterior cingulate area and the dorsolateral prefrontal cortex. The explicit and implicit assumptions of this paradigm have been the focus of an intensive debate. The “task decomposition”, which is mandatory for the application of the subtractive methodology, requires a strictly serial information processing model of the task under scrutiny. In the case of visual presentation, for example, the model assumes that when the subject is shown a word without instruction, the visual word form is accessed, without significant further processing of the meaning or activation of an output lexical representation. This is clearly implausible (Sergent, Zuck, Lévesque, & MacDonald, 1992). Even if serial, modular models might be internally coherent at the cognitive level, a further problem is that it is highly unlikely that they apply to neural processing, which is typically parallel and non linear (Friston et al., 1996; see chapter by Perani & Cappa for a

further discussion of cognitive subtraction). However, these and other criticisms directed to this study do not detract from its value in opening a new avenue of investigation. Any effort to provide an exhaustive review of what has been happening in the field of language activation studies since the paper just discussed is nowadays fatally doomed to rapid obsolescence. The following summary attempts to provide a selective review of the work that we consider most fruitful for future research approaches.

Acoustic-phonological processing Passive listening to linguistic material, both meaningful and nonmeaningful, in comparison to rest, results in a bilateral superior temporal activation (Wise, Chollet, Hadar, Friston, Hoffner, & Frackowiak, 1991). A linear increase in blood flow was observed in this area, including Heschl’s gyri, with increased rate of stimulus presentation. Only Wernicke’s area was insensitive to rate,

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showing a flat profile of activation which could be related to a categorical, stimulus-independent analysis of auditory input (Price et al., 1992; see Buechel, Wise, Mummery, Poline, & Friston, 1996, for nonlinear parametric analyses). A recent study with a non-subtractive methodology (Paus, Perry, Zatorre, Worsley, & Evans, 1996) has reported that a linear increase in superior temporal cortex blood flow could be observed also increasing the rate of silent syllable production by the subjects (whispering), suggesting a modulation of the auditory cortex by motor-tosensory (corollary) discharges. If the task requires the phonological analysis of acoustic material, a more extensive pattern of activation has been observed. Zatorre, Evans, Meyer, and Gjedde (1992) have reported an experiment in which the control condition was not rest, but the presentation of acoustic stimuli sharing the same physical characteristics of linguistic material. The activation measured during this condition was subtracted from the scans collected during phonetic discrimination (syllables ending with the same or a different consonant) and tonal discrimination (ascending or descending syllables). The main results of the subtraction were the activation of Broca’s area and the left superior parietal lobule for phonetic discrimination, while tonal discrimination was associated with a right prefrontal activation. A more difficult phonological discrimination task has been studied by Demonet et al. (1992). The subjects had to respond to the presence of the phoneme /b/ in nonwords only when it was preceeded by /d/. The comparison task was a tonal one (respond to ascending pure tones). The activated areas were not only posterior (the left superior temporal gyrus and, to a lesser degree, the homologous area on the right), but also frontal (left Ba 44 and 45). In a continuation of this study, Demonet, Price, Wise, and Frackowiak (1994) have further analysed the effect of sequential order and phonetic ambiguity, manipulating the stimuli used in the phonological discrimination task. In the nonsequential, unambiguous condition, the subject had to respond to nonwords beginning with /b/, which were intermixed with nonwords beginning with a phoneme that differed in more than one distinctive feature (i.e. to /bituval/, but not to /laritun/). The

nonsequential, ambiguous condition required a response to nonwords that contained a /b/, intermixed with words that contained a phoneme that was different for only one distinctive feature (i.e. to /livboki/, but not to /rokpamul/). The sequential, unambiguous required a response to ib/ only in nonwords if it was preceeded by /d/; the distractors were different in more than one distinctive feature (i.e. to /daboki/, but not to /donifal/ or /rinuban/). Finally, the sequential, ambiguous condition was based on nonwords where /b/ was preceeded by /d/; the distractors differed only for one distinctive feature (/odalubik/ but not /rotabig/ or /pidupan/). The main result was that the fusiform gyrus was activated only in the conditions with perceptual ambiguity (nonsequential tasks), while the Broca’s area activation was specific for the sequential conditions. The former activation was attributed to the need of orthographic encoding as a supplementary resource to disambiguate the stimuli, while articulatory rehearsal seems to be a plausible interpretation for Broca’s area activation. Fiez et al. (1995) reported activation of left frontal opercular areas when the phonological task required consonant detection, but not with vowels or with passive listening. Price et al. (1996) found that activation was greater with slower presentation rates, with a peak in Ba 45. Broca’s area has also been consistently activated in tasks requiring the phonological recoding of visual material. Sergent et al. (1992), using a rhyme judgement task for pairs of letters presented visually (i.e. T-B versus T-L) found an activation of Ba 45 and 46 and of the orbitofrontal cortex. Paulesu, Frith, and Frackowiak (1993) have confirmed the activation of Ba 44 during phonological recoding of visual material.

Lexical-semantic processing The first study of the visual processing of words and nonwords was reported by Petersen, Fox, Snyde, and Raichle (1990). The control task was central fixation, while the activation conditions were: visual presentation of sequences of abstract symbols similar to letters; unpronounceable strings of real letters, violating English orthographic rules; pronounceable non words; real words. The extrastriate occipital areas were activated by all four

8. NEUROLOGICAL FOUNDATIONS OF LANGUAGE

classes of stimuli. However, only real words and pronounceable (“legal”) nonwords activated a left medial extrastriate area, which was proposed as the substrate of the orthographic lexicon. The lack of difference between words and pseudowords is surprising, considering that real words might be expected to engage lexical-semantic processing. Price, Wise, and Frackowiak (1996) have shown that even if subjects are asked to perform a nonlinguistic task, such as visual feature detection, on words and nonwords, an extensive activation can be observed not only in extrastriate cortex bilaterally, but in all left hemispheric language areas. The activation is actually greater for nonwords than words, suggesting that all level of linguistic processing can be engaged by unfamiliar, but “language-like” stimuli. A fractionation between the different levels of linguistic processing must then be sought with more complex designs. For example, Howard et al. (1992) set out to investigate the cerebral correlates of the visual and auditory input lexicon. Two main subtractions were studied. In the first, the scans collected while the subjects listened to nonwords, while repeating (“shadowing”) continuously the same word (“crime”), were subtracted from a condition in which the subjects repeated real words. The second subtraction was the visual analogue: the scans obtained from the condition in which the subjects read non words while repeating continuously “crime” were subtracted from a condition in which they read aloud real words. The basic assmption underlying this complex design is that real-word processing is associated with automatic activation of all levels of lexical analysis, including access to word meaning, while the nonword and “shadowing” tasks engaged only the stages of perceptual analysis and production. The comparison of the results of the two subtractions should then allow the individuation of the areas associated with the phonological lexicon and the orthographic lexicon. The results were the following: the first subtraction (repetition) resulted in an area of activation which involved the middle part of the left superior and middle temporal gyri. The result of the second subtraction (reading) was unexpected, as the activation was centred on the posterior part of the

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left middle temporal gyrus. Also unexpected was the lack of any overlapping area of activation, which could be interpreted as the cerebral correlate of semantic access. The obvious discrepancy in the anatomical correlate of the visual input lexicon between this study and the results of Petersen et al. (1990) has prompted a further investigation (Price, Wise, Watson, Patterson, Howard, & Frackowiak, 1994), which tested the hypothesis that experimental parameters, such as the time of exposure of the stimuli and the type of task, may influence the pattern of cerebral activation during reading. The results indicate that these variables have clear effects not only on the intensity, but also on the topographic location of the response. A strict control of all the experimental variables is thus necessary to allow reproducibility and comparison of studies from different centres. If these factors are kept in appropriate consideration, the inter-centre agreement has been shown to be high (see, for example, Poline, Vandenberghe, Holmes, Friston, & Frackowiak, 1996). The difficulty of individuating activations related to semantic access has been attributed to the “distributed” nature of the semantic system, or to its automatic involvement in any aspect of linguistic processing. A possible role of the left prefrontal cortex was suggested by the results of Petersen et al. (1988). In a further study by the same group, the subjects were asked to respond to the names of dangerous animals, from a visually presented word list: the control condition was again “passive” presentation (Posner, Petersen, Fox, & Raichle, 1989). Here too the activation was localised to the anterior cingulus and left prefrontal cortex. Wise et al. (1991) suggested that semantic activation is present for all word-processing tasks (as suggested by Price et al., 1996), thus cancelling out in any subtraction condition, and that the left frontal activation is actually related to lexical retrieval. In their study, a semantic task requiring the matching of superordinate to subordinate nouns, and of actions with objects, showed only a bilateral superior temporal activation, identical to passive listening to nonwords, when compared to rest. Demonet et al. (1992) used a more attentional demanding semantic task, i.e. the monitoring of the names of small animals associated with positive

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adjectives (i.e. the subjects had to respond to “pretty mouse”, but not to “nasty mouse” or “gentle elephant”), compared to tone monitoring. An extensive area of activation related to semantic processing was observed in the left temporal lobe, fusiform gyrus, supramarginal gyrus, and Ba 39 and 40. Frontal activation was limited to Ba 47. A direct comparison between this task and the phonological monitoring condition described earlier, and vice versa, showed the areas of differential activation: the semantic task activated the left angular gyrus (Ba 39), the superior prefrontal cortex (Ba 8), the posterior cingulate cortex, and the middle temporal gyrus; only the angular gyrus was activated on the right. These results have been replicated, with different paradigms, by Vandenberghe, Price, Wise, Josephs, and Frackowiak (1996) and by Cappa et al. (in press) (see Fig. 8.8). Conversely, the phonological task was associated with left supramarginal activation (Ba 40) as well as with a small area of increased activity in the motor strip (Demonet, Price, & Frackowiak, 1994).

Word retrieval has been investigated with repetition (externally generated) and fluency (internally generated) tasks. Repetition is associated with greater activation of Broca’s area in comparison to passive listening, and the location of the peak is posterior, in Ba 44 proper (Price et al., 1996). There are many studies of word generation, starting from the Petersen et al. (1988) study, which required generation of verbs associated with nouns, and reported anterior cingulate and left dorsolateral frontal cortex activation. Wise et al. (1991), using the same task, found a more extensive pattern of activation, including left posterior temporal activation. In a replication of the same experiment, Raichle et al. (1994) confirmed the presence of a left posterior temporal activation. The difference with the results reported in the 1988 paper could be related to the different rate of presentation of the nouns, to which the subject had to associate an action (every second in 1988; every 1.5 seconds in 1994). A remarkable result of this second series of experiments was that the pattern of cerebral

FIGURE 8.8

Areas activated by lexical-semantic access (answering to questions about the referents of words, compared with pseudoword reading). After Cappa et al. (in press).

8. NEUROLOGICAL FOUNDATIONS OF LANGUAGE

activation was different according to the subjects’ practice with the task. The activation in the anterior cingulate, left prefrontal and posterior temporal cortex, and right cerebellar hemisphere, which was conspicuous in naive subjects, was substantially reduced if the subject had been trained on the task. In the latter subjects there was a bilateral activation of the sylvian-insular cortex, and of medial occipital extrastriate areas. This modification of the pattern of cerebral activation could be related to the learning of the task, which was executed in a more automatic fashion. A further systematic study of word generation tasks has indicated that temporo-parietal activation can be observed only in comparison with a resting state. The comparison with any other word processing task cancels the temporal activation (Warburton et al., 1996). This finding explains the observations of Frith and co-workers (Frith, Friston, Liddle, & Frackowiak, 1991a, b; Friston, Frith, Liddle, & Frackowiak, 1991) who, by directly comparing word generation (letter fluency) with word or letter repetition, confirmed the dorsolateral frontal cortex and anterior cingulate activation, which seems to be specific for task requiring spontaneous, intentional (willed) action, detached from the demands of the external environment, but consistently reported deactivations in the left temporal region. The comparison between letter and semantic fluency tasks has indicated significant differences. Mummery, Patterson, Hodges, & Wise (1996), with PET, found a selective left inferolateral and anteromedial temporal activation with category fluency, while the reverse comparison showed a peak in left Ba 44 and 6. Differential activations were observed in a similar study with fMR (Paulesu et al., 1997).

Sentence processing The studies reported earlier have mainly addressed single word processing tasks: sentence processing has been less investigated with functional imaging. Mazoyer et al. (1993) have studied the pattern of cerebral activation while the subjects listened to stories in an unknown language, to lists of words in their mother tongue, to meaningful stories, and to distorted stories. The main result of this study was that meaningful stories activated all the areas

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implicated in single word processing tasks, plus the middle temporal gyrus, an extensive portion of the left prefrontal cortex and the temporal poles bilaterally. The distortions, which mantained an unaltered syntax and prosody, but made the story unintelligible, abolished all these activations, with the exception of the temporal poles. A related paradigm was applied to study a group of Italian subjects with a fair knowledge of English: stories were presented in Italian, English, and Japanese (Perani et al., 1996): the Italian condition was associated with a similar pattern of extensive cerebral activation, included the temporal poles. A surprising result was the much more restricted pattern of cerebral activation not only with the Japanese stories, which the subjects did not understand, but also with the English ones, which were adequately understood (Fig. 8.9). Stroms wold, Caplan, Alpert, and Rauch (1996) have studied the cerebral correlates of acceptability judgement of sentences of different syntactic complexity which could contain semantic violations. An activation of Broca’s area was observed in the comparison of more complex (centre-embedded) with less complex (right-branching) relative sentences. Different results have been reported in a fMR study, where the subjects had to answer to questions of increasing syntactic complexity (Just, Carpenter, Keller, Eddy, & Thulborn, 1996): in this case, the volume of activated tissue increased with syntactic complexity not only in Broca’s, but also in Wernicke’s area and in their homologous right hemispheric areas. Extensive right hemispheric activation was observed in a study that examined the metaphorical interpretation of sentences (Bottini et al., 1994). The activation also included a superior frontal area (Ba 8), which has been shown to be engaged when subjects listened to stories requiring inferences about other people’s mental states (Fletcher et al., 1995).

Kana and Kanji Some PET studies have investigated the pattern of activation in Japanese subjects engaged in ideographic (kanji) or syllabographic (kana) reading. Kanji reading (Sakurai et al., 1992), when compared to fixation, activated bilaterally, with a

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FIGURE 8.9 .

Activations related to the processing of Italian language (mother tongue), the second language (English) and the unknown language (Japanese) in a group of Italian/English bilinguals with low proficiency for the second language (English). The figure shows cerebral areas activated by listening to a story in the maternal language (first row), in the second language (second row) and in the unknown language (third row), when compared with the attentive silence condition (baseline). The bottom row shows the activations related to listening to Japanese backwards when compared with the baseline condition. Zscores are displayed according to a linear colour scale (Zscore > 2.7; p run must be considered as the substitution of the inflection -s with the “zero” inflection. Myerson and Goodglass (1972) and Marin, Saffran, & Schwartz (1976) observed that agrammatic patients experience problems with verbs not only when producing inflections, but also when producing roots, as shown by the occurrence of verb omissions and nominalisations in spontaneous speech. Recent studies confirmed these observations and provided quantitative measures of the deficits (Kolk et al., 1985; Menn, & Obler, 1990; Miceli et al., 1989; Nespoulous et al., 1988; Saffran, Bemdt, & Schwartz, 1989). Another deficit reported in analyses of agrammatic speech is the difficulty with word order and, specifically, the inversion of thematic roles. This difficulty was described by Saffran et al.

12. GRAMMATICAL DEFICITS IN APHASIA

(1980), who observed the production of sentences like Man chasing woman in response to the picture of a woman chasing a man. These analyses allowed the formulation of a more complete description of agrammatic speech errors, but also underscored some relevant problems. First, with the single exception of the difficulties with grammatical morphemes, none of the symptoms considered as typical of agrammatism is observed in all the subjects classified as agrammatic (but see Note 3). One such symptom, the simplification of syntactic structures, is observed in most subjects, but some agrammatic speakers manage to produce fairly complex structures. The variability of this parameter is exemplified in Table 12.2, which reports sentences produced by three Italianspeaking agrammatic subjects. The first contains many subordinate clauses; the second consists of independent clauses linked by coordinate

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conjunctions; and the third results in a series of holophrastic utterances. Another classical symptom of agrammatism is reduced phrase length. However, analysis of the spontaneous speech of 20 Italian-speaking agrammatic subjects (Miceli et al., 1989) showed the average length of syntactic structures to range in various subjects from 3.1 to 10.5 words (the latter value does not differ from the average length observed in 10 cognitively unimpaired subjects). Yet another typical agrammatic disorder, difficulties with main verbs, may severely disrupt speech in some subjects, but may be completely absent in other cases (among the 20 subjects studied by Miceli, A.A. omitted 36.7% main verbs, whereas G.F. did not omit any). As a final example, the occurrence of word order problems is also extremely variable: it was found to be high in the subjects studied by Saffran et al. (1980), low in M.L. (Caramazza & Hillis, 1990), and was never observed by Miceli et al. (1989),

TABLE 12.2 Samples of spontaneous speech collected from three agrammatic speakers. a) Subject G.F.

Prendere [V ] anticoagulante e poi cambiare [le] cure e poi venire [il] nervoso perché io dice, dire sempre [che] morire, morire, morire, sempre impressionare che morire. To take [the] anticoagulant and then to change [the] medications and then to come [the] nervous because I says, to say always [that] to die, to die, to die, always to be scared that to die. Take anticoagulant and then change medications and then go berserk because I says, always to say die, die, die, always be scared that die.

b) Subject C.S.

Mi alzo ... lavo prima tutto quanto ... alla mattina metto [la] gonna ... poi dopo [faccio il] bagno ... poi dopo [mi] lavo ... quindi [faccio] gli esercizi, sempre ... e poi dopo mia figlia si va a scuola ... e poi dopo si fa tornare ... poi mangiamo ... e poi dopo si mette a dormire. I get up ... I wash first everything ... at the morning I put on [the] sk irt... then [I take the] bath ... then [myself] wash ... then [I do] the exercises, always ... and then my daughter goes herself to school... and then she makes herself come back ... then we e a t... and then one puts herself to sleep (target: then I/we go to sleep). I get up ... first I wash everything ... in the morning wear sk irt... then bath ... then wash ... then gymnastics, always ... and then my daughter goes herself to school... and then makes herself come back ... then we eat ... and then puts herself to sleep.

c) Subject G.D.C.

... il medico ... ospedale ... cervello ... ginnastica ... morto ... le m an i... niente. ... the doctor ... hospital... brain ... gymnastics ... dead ... the hands ... nothing

For each sample, the transcription of the subject’s output is reported first (omissions are in square parentheses; errors are underlined). It is followed by a verbatim English translation, and by an attempt at rendering what the transcript would sound like in English (only the subject’s output and the verbatim English translation are reported for subject G.D.C., who only produced holophrastic utterances).

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who found only one questionable instance of thematic role reversal in the speech of their 20 subjects. Second, pathological behaviours present in agrammatic patients may result from very different deficits, which sometimes do not involve grammar. Difficulties with main verbs and with word order can clarify this issue. Recent studies (McCarthy & Warrington, 1985, 1988; Miceli et al., 1984; Zingeser & Bemdt, 1988, 1990) demonstrate that difficulties in producing verbs may be observed not only in connected speech, but also in tasks like naming, reading aloud, and writing, that require the production of verbs as isolated words. In naming, agrammatic subjects tend to nominalise verbs (to pray —►the prayer), and sometimes are unable to provide any response to a pictured action. Selectively poor performance in spoken and in written naming of verbs may be observed in the absence of a comparable deficit with nouns (Caramazza & Hillis, 1990). Consideration of these results forces us to consider the possibility that difficulties with verbs in spontaneous speech derive, at least in part, from a lexical-semantic deficit, independent of disorders in the production of syntactic structures or grammatical morphemes. The interpretation of errors resulting in incorrect word order, and especially in apparent thematic role reversals, is even more problematic. As agrammatic speech is characterised by difficulties with grammatical morphemes (and sometimes with main verbs), errors that appear to be thematic role reversals may have different causes. Let us consider as an example the sentence Man chase woman, in response to the drawing of a woman chasing a man. The error may result from a genuine inversion of thematic roles in the presence of a difficulty with grammatical morphemes (the subjects tries to produce the sentence The man chases the woman, which contains a role reversal and, in addition, omits articles and produces the infinitive form of the verb). However, it may also derive entirely from a difficulty with grammatical morphemes (the subject attempts the production of The man is chased by the woman but fails in producing the morphology of the passive voice) or from difficulties with both grammatical morphemes and main verbs (the patient means to produce the

sentence The man precedes the woman, but has problems with grammatical morphemes and produces a substitution in lexicalising the verb— chase —► precede). Therefore, an error that surfaces as an inversion of thematic roles may result from very different deficits that may not even concern the grammatical level, such as a difficulty in verb lexicalisation or in thematic role assignment (see also sections later).

PARAGRAMMATIC PRODUCTION Paragrammatic speech has received far less attention than agrammatic speech. Nevertheless, even the results of the few studies on paragrammatism leave us with many puzzling questions. Kleist (1914) used the term paragrammatism to indicate a disorder, usually secondary to left temporal lesions, clinically characterised by errors in selecting and ordering words and grammatical forms. According to Kleist, this constellation of behaviours offers a sharp contrast with agrammatism, which is characterised by the impoverishment of syntactic structure, omissions of grammatical words and “telegraphic” style. The distinction between agrammatism and paragrammatism has remained in the literature, and is still accepted. However, the efforts to clearly define the phenomena distinguishing these two deficits have been less than successful. Goodglass and Mayer (1958) observed that omissions and substitutions of grammatical morphemes occur more frequently in agrammatic than in paragrammatic speech, but also underlined a large overlap between subjects of the two types. In an analysis of the grammatical structures produced by aphasic subjects, Goodglass and Hunt (1958) found that the agrammatic patients’ tendency to produce very short sentences is the only parameter that distinguishes these subjects from paragrammatic aphasics (and from subjects affected by other clinical forms of aphasia without grammatical errors). More recently, Butterworth and Howard (1987) analysed the spontaneous speech of control subjects and of five brain-damaged subjects,

12. GRAMMATICAL DEFICITS IN APHASIA

classified as paragrammatic because they produced grammatical errors in the context of fluent and neologistic speech. They analysed the production of content words, grammatical words, and inflections, as well as the production of syntactic structures. The errors observed in paragrammatic subjects were identical to (but more frequent than) those observed in normal controls, and all the errors typical of agrammatism were also found in paragrammatic speakers. Butterworth and Howard concluded that the errors observed in paragrammatic speech do not result from a grammatical disorder (as is the case of those produced by agrammatic speakers), but from damage to control mechanisms operating in the speech output system. Nevertheless, they admitted that it is not possible to clearly distinguish agrammatic from paragrammatic speakers based on the characteristics of spontaneous speech, and concluded that agrammatic and paragrammatic phenomena usually co-occur in the same subject. Their conclusion is very similar to that of Kleist (1934), who initially proposed a distinction between the two types of grammatical deficits, but after an analysis of his data came to the conclusion that the same subject usually produces agrammatic and paragrammatic sentences. To sum up, efforts to substantiate the claims advocating clear-cut empirical and theoretical differences between agrammatism and paragrammatism have largely failed to support the proposed distinctions.

PROBLEMS WITH RESEARCH ON CLINICALLY DEFINED GRAMMATICAL DISORDERS Hopes that detailed analyses of agrammatic (or paragrammatic) speech would allow a better definition of these disorders, and subsequently the development of articulated theories, were not fulfilled. Such analyses improved the description of grammatical disorders of production, but did not clarify their interpretation. This is very clear in the case of agrammatism. The analyses of agrammatic speech briefly reviewed so far, conducted on subjects classified

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on the basis of clinical criteria, yielded problematic results. First of all, none of the deficits considered to be typical of agrammatic speech was observed in all agrammatic speakers, with the exception of omissions of grammatical morphemes (but, as has already been said, the systematic occurrence of this phenomenon is only obvious, as the omission of function words is the criterion used to classify a subject as agrammatic). Second, all the phenomena that define agrammatic speech demonstrated great across-subject variability. Third, some of the phenomena reported in agrammatic speech result from true grammatical deficits (morphological or syntactic), but others can result also from phonological, lexical, or semantic disorders. Finally, the same, apparently grammatical, error may result from distinct impairments in different subjects. These results raise the possibility that agrammatic speakers are a heterogeneous group (Caramazza & Berndt, 1985; Goodglass & Menn, 1985), and that the difficulties in accounting for their speech disorder depend not only on inadequate theories, but also on methodological and metatheoretical problems resulting from the approach selected to analyse these deficits (Caramazza, 1986, 1988). Consideration of these issues has led different authors to take contrasting positions. Badecker and Caramazza (1985, 1986) underlined that in studies on agrammatism the neuropsychological deficit had been clinically defined, based on a small set of a priori criteria (the omission of grammatical morphemes, the simplification of syntactic structures, and the reduction of phrase length). These criteria, however, do not allow the identification of subjects affected by the same cognitive deficit. Consequently, the groups of agrammatic speakers selected on this basis include subjects with different cognitive lesions, whose average behaviour in a specific task results from impairments that differ across subjects. Therefore, the results of studies that use this methodology lead to uninterpretable results, and do not allow conclusions that are relevant for a theory of the cognitive processes involved in sentence production. Moreover, this approach does not permit one to deal in a principled way with the issue of across-subject variability of

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grammatical speech errors. In fact, the presupposition that a set of a priori criteria leads to the identification of cognitively homogeneous subjects amounts to the assumption that variations across subjects classified as agrammatic based on those criteria are random, and therefore theoretically irrelevant. According to Badecker and Caramazza, difficulties in the study of agrammatism result from these metatheoretical and methodological flaws. Efforts to define the disorder, based on empirical analyses, did not succeed; enlarging the database by collecting large speech corpora from subjects who were premorbidly speakers of a wide range of languages only confirmed the impossibility of providing an objective definition, and even identifying in a theoretically defensible way the types of empirical observations that were relevant for a correct interpretation. To overcome these problems, Badecker and Caramazza propose a different approach. Analyses of agrammatic speech should not be aimed primarily at an increasingly detailed description of the pathology of the linguistic system, or at formulating theories of agrammatism and paragrammatism. On the contrary, their main purpose should be to propose hypotheses about the structure of the normal cognitive system. Consequently, their starting point cannot be a clinical category identified a priori, but explicit hypotheses on the cognitive mechanisms that allow grammatically correct speech in normal subjects. Such hypotheses are necessary to identify the cognitive lesion responsible for the deviant speech observed in each subject. Due to the complexity of speech production mechanisms, the deficits that may result from damage to one or more components of these processes are so varied that they cannot be identified a priori. Therefore, the functional lesion responsible for agrammatic behaviour must be identified a posteriori, through theory-driven, detailed analyses of deviant linguistic behaviour. In addition, as the complexity of the system and the subsequent variety of possible deficits make it quite unlikely that groups of cognitively homogeneous subjects (i.e. of subjects affected by the same cognitive impairment) can be found, the most adequate strategy for the

investigation of agrammatic production (or of any other cognitive deficit, for that matter) is the study of single cases. Other authors (e.g. Caplan, 1986; Grodzinsky, 1987,1990,1991) took different positions. Caplan (1986) agrees with Badecker and Caramazza’s critique of the use of clinical categories. He, too, believes that empirical criteria and pretheoretical intuitions cannot lead to relevant conclusions about a theory of the organisation of normal language. However, Caplan does not consider these problems, nor the objections to the traditional approach, to be sufficient to abandon the use of a priori identified clinical categories in neuropsychological studies of the cognitive system. If the criterion selected for categorisation is based on a valid theory, clinical categories can still be used in research. In the case of grammatical disorders of production and comprehension, the use of the clinical category “agrammatism” is admissible, provided that this category is defined on the basis of a theory formulated independently from agrammatism. Caplan’s proposal starts from linguistic theory, which considers grammatical morphemes as a class of words distinct from the other words of a language. Because, on this account, grammatical morphemes constitute an autonomous category, selecting function word omissions as the criterion to classify a subject as agrammatic allows one to identify cognitively homogeneous subjects. According to Caplan, the term agrammatism should be used only to denote omissions of grammatical morphemes in spontaneous production; the other disorders often reported in agrammatic speech (syntactic simplification, reduced phrase length, difficulty with main verbs) should be disregarded. If the basic assumptions of this theory were correct, the study of groups of subjects classified as agrammatic based on the proposed criterion should yield results relevant for theories of the cognitive system. In order to evaluate these two positions based on empirical data, Miceli et al. (1989) analysed the spontaneous speech of 20 patients classified as agrammatic because they omitted grammatical morphemes (i.e. based on the criterion proposed by Caplan, 1986). They studied the errors of omission and substitution in the production of five free-

12. GRAMMATICAL DEFICITS IN APHASIA

standing grammatical morphemes (definite and indefinite articles, prepositions, clitics, and auxiliary verbs) and of three bound grammatical morphemes (nominal, adjectival, and verbal inflections). When all grammatical morphemes were lumped together, a large across-subject variability was observed for total errors, and for omissions and substitutions considered separately; in addition, the incidence of omission and substitution errors was not related (there were subjects with a comparable occurrence of omissions, but who presented with a very different occurrence of substitutions, and subjects with the reverse pattern). An even greater variability was observed when each of the five types of freestanding grammatical morphemes was considered separately (Table 12.3): both in the analysis of overall errors, and in the separate analyses of omissions and substitutions, the same morpheme may be the most spared in one subject and the most damaged in another. Moreover, the same patient

may present with only omissions in the production of a morpheme, and with omissions and substitutions in the production of another. The comparison of errors on free-standing and on bound grammatical morphemes also demonstrated a substantial across-subject variability: subjects with comparable numbers of errors on free-standing morphemes presented with very different numbers of errors on bound morphemes, and vice versa. Also the difficulties with nominal, adjectival, and verbal agreement were not homogeneous (Table 12.4): some subjects had problems with all types of agreement, whereas others only had problems with verb agreement (a similar observation is reported by Grodzinsky, 1990). Moreover, an analysis of verb agreement showed that errors almost always resulted in the citation form of the verb (infinitive and past participle) in some subjects, and in a finite but incorrect verb form in others. Thus, the results of this study are more consistent with the position taken by Badecker and

TABLE 12.3 Percent occurrence of omissions and substitutions in each category of free-standing grammatical morphemes. A rtic le s P rep o sitio n s

D e fin ite

Subject

Om

Subst

Om

A.A. F.A. F.B. C.D. F.D. C.D.A. G.D.C. E.D.U. G.F. T.F. F.G. G.G. M.L. A.M. M.M. B.P. C.S. F.S. L.S. M.U.

66.7 28.1 13.8 7.4 22.3 27.1 83.3 7.3 38.5 18.6 8.3 18.5 2.7 38.9 27.6 43.3

14.3 6.2 1.5 3.4 10.8 12.9

30.7 14.3 20.0

24.0 7.1 20.0

10.7 8.3 3.5 6.0 20.7 24.8 25.0 5.5 58.5 64.0 5.9 32.7 15.2 50.0 6.0 24.1 12.1 11.2 22.6 14.3

3.6 5.8 1.7 8.3 2.7 1.7 10.0

Subst

A rtic le s In d e fin ite Om

Subst

C litic s Om

46.7 1.5 5.4 5.0 8.9 7.3 2.0 1.9 3.0 6.8 5.0 3.4 3.3 24.5 16.1 2.0

257

12.5 33.3 25.0 33.3 33.3 37.5

12.5 9.5 33.3 5.3 7.1

33.3

10.0

7.0 16.1 53.8 22.2 10.0 36.4 100.0 14.3 15.4 8.3 80.0 14.3

15.0 50.0

50.0 20.0 33.3

A u x ilia rie s

Subst

Om

75.0

25.0 33.3 23.1 8.7 27.3 3.1 100.0 21.0 72.2 63.3

18.2 9.7 8.1 7.7 44.4 15.0

9.4 8.3 42.9 18.7 13.3 11.1

5.0 28.6 33.3 25.0 6.2 80.0 37.5

Subst

7.7 8.7 2.3 3.1 31.6 10.0 50.0 3.6 22.2 37.5 16.7 12.5

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TABLE 12.4 Occurrence and distribution of the violation of agreement phenomena (article-noun, noun-adjective and subject-verb). Subject

N

A.A. F.A. F.B. C.D. F.D. C.D.A. G.D.C. E.D.U. G.F. T.F. F.G. G.G. M.L. A.M. M.M. B.P. C.S. F.S. L.S. M.U.

25 71 63 ill

67 95 70 99 18 18 73 65 34 18 110 43 20 138 32 61

A r tic le -N o u n % V io la tio n s

8.0 5.6 0.8 1.5 4.2 5.7 2.0 5.6 1.4 2.9 11.1 4.5 9.3 14.5 12.5 3.3

Caramazza (1985) than with the hypothesis favoured by Caplan (1986) and Grodzinsky (1990). In fact, even though the items under analysis belong to the linguistically homogeneous category of grammatical morphemes, huge variations and dissociations are observed, both across subjects and in the same subject, in contrast with Caplan’s hypothesis.4

GRAMMATICAL PRODUCTION DEFICITS Analyses of the spontaneous speech of subjects classified as exemplars of two traditionally opposed clinical entities (agrammatism and paragrammatism) demonstrated more commonalities than differences—variability within category is at least as large as between categories (Badecker & Caramazza, 1985; Miceli et al., 1989). Therefore, it is not surprising that an approach based on the a priori classification of subjects cannot result in an objective and precise definition of the two deficits.

N

8 45 9 57 78 9 32 28 56 32 26 25 20 26 26 10 50 7 12

N o u n -A d je c tiv e % V io la tio n s

11.1 11.1 7.0 14.1 38 22.2 6.2 3.1 3.8 4.0 3.8 20.0 28.6 8.3

N

S u b je c t-V e rb % V io la tio n s

23 81 86 194 193 100 46 152 100 101 114 54 52 85 61 46 33 88 51 63

\

43.5 29.6 3.5 6.7 11.9 16.0 43.5 18.4 55.0 64.4 4.4 18.5 3.9 15.3 14.7 52.2 9.1 47.7 19.6 12.7

These facts have direct implications for the study of grammatical disorders in aphasia. The cognitive damage responsible for agrammatic production can be identified only a posteriori, because only explicit hypotheses on the functioning of normal processes allow the definition of the range of observations necessary to identify the cognitive lesion responsible for the observed behaviour, and to rule out all alternative accounts (Caramazza, 1986; Caramazza & McCloskey, 1988). Thus, the starting point of the analysis of aphasic speech must be a theory of the normal production system. In the scientific literature some production models, based on the analysis of speech errors produced by normal subjects during spontaneous conversation, have been presented (e.g. Bock, 1982; Dell, 1986; Garrett, 1980,1982,1984,1992; Lapointe & Dell, 1989; Stemberger, 1985): these models have begun to offer explicit hypotheses on the levels of representation involved in language production and on the mechanisms used to process these representations.

12. GRAMMATICAL DEFICITS IN APHASIA

Distinction among levels of representation in sentence production One of the best known production models is that proposed by Garrett in several papers (1980,1982, 1984, 1992). According to this author, sentence production requires several independent stages, corresponding to independent levels of representation. At the message level, which is sensitive to linguistic and extralinguistic factors, a conceptual syntax constructs complex utterances starting from a basic (but not small) repertoire of easy concepts. At this level, the message to be conveyed is decided (for example, that a woman is putting a bag on a chair). The message-level representation controls the phrasal processes that lead to the next level of representation: the functional level. This second level is based on the conceptual relationships specified at the message level. At the functional level, the lexical representations that will be used to communicate the content of the message are selected; the predicate-argument structure is organised and the thematic roles are assigned to the different arguments of the verb. Lexical representations are defined at this level only by their semantic and syntactic features, and do not have phonological or orthographic content. At the next stage, the positional-level representation is constructed, that involves three different processes. The first process consists of the organisation of a phrasal structure that includes the syntactic features needed to specify free-standing and bound grammatical words. The second process consists of the selection of the phonological forms corresponding to the major-class lexical items specified at the functional level and of their placement in the slot assigned by phrasal structure. The third process consists of assigning a phonological value to all the grammatical morphemes specified in the phrasal structure. Therefore, the representation created at the positional level consists of a string of phonologically specified elements, and is used in the following stages of production. A fundamental aspect of Garrett’s theory is the hypothesis that words are divided in two classes (open-class words and closed-class words), which are processed by distinct mechanisms. Open-class

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words are processed both at the functional level (where the semantic information generated at the message level activates lexical representations defined by their syntactic and semantic properties) and at the positional level (where a phonological value is assigned to the lexical representations activated at the functional level). By contrast, closed-class words are processed only at the positional level, where a phonological value is assigned to each grammatical morpheme on the basis of the information contained in phrasal structure, which is also constructed at this level.

Damage to morphosyntactic mechanisms as the cause of disorders in the production of grammatical morphemes The procedural distinction between open-class and closed-class words allows one to predict that a positional level deficit should selectively disrupt the production of grammatical morphemes in sentence production, but not as isolated words. Moreover, as the positional level is involved only in production, a deficit at this level should not affect comprehension. Two aphasie subjects, whose neuropsychological profile is consistent with positional-level damage have been described by Caramazza and Hillis (1989) and by Nespoulous et al. (1988). Both subjects presented with normal comprehension, in the presence of a severe deficit in the production of grammatical morphemes in a phrasal context. Their spontaneous output (both oral and written) was characterised by frequent omissions (and by infrequent substitutions) of freestanding grammatical morphemes, and by the production of the citation form of the verb (infinitive and participle) instead of the correctly inflected form. A narrative collected from M.L. (Caramazza & Hillis, 1989) contained 173 obligatory contexts for free-standing grammatical morphemes, 79 for bound grammatical morphemes, and 207 for open-class words. M.L. demonstrated substantial difficulties in the production of free-standing grammatical morphemes (62.4% omissions and 2.3% substitutions in obligatory contexts) and of bound grammatical morphemes (“omissions” of 18.5% of total inflections—remember that this subject is an

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English speaker), but very few problems with openclass words (major-class lexical items were omitted in 3.8% obligatory contexts, and word substitution errors never occurred on these items). Similar results were observed in other sentence production tasks (writing to dictation, reading aloud, repetition, sentence anagram). By stark contrast with performance in sentence production, M.L. flawlessly read aloud, repeated, and wrote to dictation morphologically complex words when these were presented in isolation. The performance reported for Mr Clermont (Nespoulous et al., 1988) is very similar to that reported for M.L. Mr Clermont flawlessly read all the words presented in isolation, irrespective of grammatical class and morphological structure, but made many morphological errors (omissions and substitutions of grammatical words) when reading sentences. An anecdote on this patient’s reading behaviour nicely exemplifies his contrasting behaviour when reading words as opposed to sentences. In a covert sentence reading task, words were presented each on a different page, but their sequence constituted a sentence. Mr Clermont read the first few words correctly, but as soon as he realised that they formed a sentence, he started to make errors on grammatical words, just as when reading sentences. That the production of grammatical morphemes can be spared at the single-word level, but selectively disrupted at the sentence level, is consistent with damage to the morphosyntactic mechanisms that, according to Garrett (1980,1982, 1984), act at the positional level5, by inserting grammatical morphemes in the slots specified by the phrasal structure. Garrett’s model argues that the positional-level representation is specified phonologically, but does not clarify its role in the different production tasks. In particular, it does not specify whether the same positional-level representation is shared by all production tasks, or distinct, modality-specific positional-level representations exist for speaking and for spelling. The performance reported for M.L. and for Mr Clermont, characterised by similar errors on grammatical words in both oral and written production, is compatible with the hypothesis of a modality-independent representation, used for both speech and writing. Other

observations, however, are more consistent with the alternative hypothesis that distinct positional-level representations are used for oral and written production. For example, subject P.B.S. (Rapp & Caramazza, 1997) had disorders of both oral and written output, but when asked to describe the same picture in speech or in writing he presented with very different behaviours. In speech, grammatical words were produced accurately, whereas attempts at producing content words resulted in many neologisms; in writing, grammatical words were often omitted, whereas content words were produced correctly. For example, when describing the drawing of a boy washing a car, RB.S. said “the/wVd/are rVzd/ the /md^/ with flWd/ and /tVv/ in a /rodld/” and wrote BOY WASHED CAR immediately afterwards. A related behaviour was observed in Case 1 (Miceli et al., 1983), who presented with agrammatic speech and grammatically correct writing. The results reported for these four subjects suggest that a production deficit may selectively preserve grammatical words in an output modality, while selectively disrupting them in the other. This pattern can be explained only by assuming that in the course of sentence production distinct positional-level representations are realised for speech and for writing6.

Damage to lexical morphology as the cause of difficulty in producing grammatical morphemes The cases discussed so far demonstrate that a positional-level deficit may result in a difficulty in producing grammatical morphemes in sentences. However, as other components of the output system are also involved in processing these morphemes, errors may result from damage other than to morphosyntactic processes. For example, difficulty with grammatical words may result from damage to the lexical-semantic system. Such a deficit may cause grammatical production errors, because morphological structure is one of the dimensions along which the lexical-semantic system is organised. The hypothesis that morphological structure plays a central role in language organisation has been repeatedly proposed in linguistic and neuropsychological studies of single-word

12. GRAMMATICAL DEFICITS IN APHASIA

processing and of sentence production (e.g. Anderson, 1982; Aronoff, 1976; Bock, 1982; Garrett, 1984; Mohanan, 1985; Scalise, 1984; Selkirk, 1982; Taft, 1985). Relevant neuropsychological evidence for the role of morphology in lexical organisation was collected, among others, from subject F.S. (Miceli & Caramazza, 1988). Just like the subjects described by Nespoulous et al. (1988) and by Caramazza and Hillis (1989), F.S. presented with grammatical difficulties in spontaneous speech, as shown by the frequent occurrence of errors in the production of freestanding and bound grammatical morphemes. F.S. made errors on 102/242 obligatory contexts for free-standing grammatical markers (42.1%, of which 22.3% were omissions and 19.8% were substitutions), and on 70/275 (25.5%) obligatory contexts for bound grammatical morphemes (19/138 for article-noun agreement, 13.8 %; 11/55 for noun-adjective agreement, 20%; and, 45/82 for subject-verb agreement, 54.9%). However, in contrast with the other two subjects, he also made very many errors in the production of morphologically complex nouns, adjectives, and verbs (which in Italian are virtually always inflected and sometimes derived) presented in isolation. In repetition tasks, 636/659 incorrect word responses (96.5%) could be classified as inflectional errors (chiamava, he was calling —► chiamare, to call) and 23/659 (3.5%) as derivational errors (passando, passing —► passaggio, passage). The dissociation between inflectional and derivational errors was also observed when the occurrence of the two error types was separately analysed in the repetition of words containing only a root and an inflection (fior/, flowers; cattiv-e, bad, f.pl.; sentiv-a, he was hearing) and of words consisting of a root, one or more derivational suffixes, and an inflection (parlatore, speaker; dolorosi, painful, m.pl.; utilizzazioni; utilisations). Of 511 morphological errors made in repeating words consisting of root + inflection, 492 (96.3%) were inflectional, 5(1%) were derivational, and 14 (2.7%) were ambiguous — e.g. the response ballo to the stimulus ballava may be interpreted both as an inflectional error (iballo, 1st sg. present indicative form of the verb ballare, to dance) and as a derivational error (ballo,

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noun, the dance). Of 109 morphological errors produced in the repetition of stimuli containing one or more derivations, 90 (82.6%) were inflectional, 12 (11%) were derivational, and 7 (6.4%) were ambiguous. In F.S.’s incorrect responses, therefore, a categorical dissociation was observed: errors to stimuli that did not contain derivational affixes only resulted in inflectional errors; and only errors to stimuli that contained one or more derivational affixes resulted in some derivational errors (in addition to many inflectional errors, of course). The analysis of the inflectional errors in the repetition of adjectival forms unambiguously demonstrated a deficit of lexical morphology (Table 12.5). In repeating four-ending adjectives, the masculine singular form was repeated more accurately than any other form, and was most frequently produced in the event of an inflectional error; in the repetition of two-ending adjectives, the singular form was produced much more accurately than the plural. Moreover, with four-ending adjectives most inflectional errors resulted in the production of the masculine singular form, even for those adjectives in which the male singular form is the least frequent in the language. That F.S. produced a very high number of morphological errors in repeating words presented in isolation (that is, out of a phrasal context) shows that morphological processes take place in the lexicon, and that morphology is one of the dimensions of lexical-semantic organisation. The dissociation between inflectional processes (severely damaged) and derivational processes (largely spared) also suggests that the two types of morphological processes take place in separate components of the lexicon. This separation is supported by both theoretical and empirical observations. Regarding the first, the distinction between inflectional and derivational processes is an important part of some linguistic theories (for review, see Bybee, 1985; Scalise, 1984). Moreover, a procedural distinction between inflectional and derivational processes is explicit in some psycholinguistic models of production. For example, according to Garrett, the base form of a derived word is inserted in the phrasal structure at the functional level, based on semantic information (like any other open-class word), whereas its

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TABLE 12.5 Stimulus-response relationships of the inflectional errors produced by F.S. in repeating four-way ending and two-way ending adjectives (percentages are in parentheses). (a)

4-way ending adjectives R esponse

Stim ulus

m.sg.

m .pl.

fs g -

fp l.

Total

m.sg. m.pl. f.sg. f.pl.

149 40 43 34

(94.9) (52.6) (48.9) (61.8)

8 (5.1) 26(34.2) 1 (1-1) 2 (3.6)

5 (6.6) 35 (39.8) 5 (9.1)

5 (6.6) 9 (10.2) 14 (25.5)

157 76 88 55

Total

266 (70.7)

37 (9.8)

45 (12.0)

28

376

-

-

(7.4)

(b) 2-way ending adjectives Response Stim ulus

sg-

pi

Total

pi-

sg-

56 (81.2) 36 (65.5)

13 19

(18.8) (34.5)

69 55

Total

92 (74.2)

32

(25.8)

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inflection is selected at the positional level, based on phrasal structure information. Further empirical support to the hypothesis of a processing distinction between derivations and inflections comes from available transcripts of agrammatic speech: subjects demonstrate marked difficulty with inflectional, but not with derivational morphology. For example, M.L. (Caramazza & Hillis, 1989), who presented with a morphosyntactic deficit (but not with a morpholexical deficit), made errors on 18.5% inflectional suffixes, but never on derivational suffixes7. The contrasting behaviour observed in F.S., Mr Clermont, and M.L. is worth stressing. While the last two subjects had problems with grammatical morphemes only in a phrasal context, F.S. made morphological errors both when producing isolated words and when producing sentences. Therefore, it is likely that a morphosyntactic deficit was responsible for the performance observed in Mr Clermont and in M.L., whereas a morpholexical deficit was responsible for at least part of the errors on grammatical morphemes observed in F.S. In the case of this last subject, it would be desirable to unequivocally assign each error on grammatical morphemes in sentence production to a

morphosyntactic or to a morpholexical deficit. If this were feasible, an analysis of F.S.’s morphological errors across tasks could lead to a better understanding of the relative contribution of lexical and syntactic mechanisms to the processing of inflectional morphology in sentence production. However, a clear-cut conclusion cannot be drawn, for the time being. As neither linguistic theory nor available computational models of sentence production are sufficiently detailed with respect to the role of morpholexical and morphosyntactic mechanisms in language output, the relevant analyses cannot be decided. These uncertainties notwithstanding, the performance of F.S. clarifies at least one relevant aspect of the language output system: inflectional morphology is represented in the lexicon, and the correct production of inflections implies the ability to access the lexicalsemantic system both from semantic-lexical information (in the production of isolated words) and from syntactic representations (in sentence production). This hypothesis allows one to account for inflectional errors in sentence production both as the result of a lexical deficit (as in F.S., at least partially) and as a result of a syntactic deficit (as in Mr Clermont and M.L.).

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The independence of morphosyntactic mechanisms from the mechanisms that assign thematic roles In sentence production, information processed at the message level is used to assign thematic roles (agent, theme, beneficiary, etc.) to the lexical representations selected on the basis of conceptual information. Subsequently, grammatical roles are assigned on the basis of thematic roles. For example, for the sentence The mother gives the doll to the girl, the roles of subject, and direct and indirect object are assigned to the agent noun (mother), to the theme noun (doll), and to the beneficiary noun (girl). Neuropsychological observations show that a cerebral lesion may selectively disrupt thematic role assignment, sparing the production of grammatical morphemes. In a picture description task that required the oral or written production of simple declarative, semantically reversible sentences in the active or passive form, subject E.B. (Caramazza & Miceli, 1991) produced only seven errors (0.02%) out of 3600 contexts that offered the opportunity for morphological errors (omissions and substitutions of grammatical morphemes), but inverted thematic roles in 40/240 (16.7%) sentences (to the picture of a dog chased by a horse he said The dog chases the horse; to that of a boy kissing a woman he responded The boy is kissed by the woman). It is worth stressing that grammatical morphemes were produced accurately in essentially all the sentences that contained thematic role reversals. The errors produced by E.B. are not easily interpreted. The assignment of thematic roles is the final result of complex cognitive operations, and may take place correctly even in the presence of a severe semantic deficit (Saffran & Schwartz, 1994). It involves semantic-lexical mechanisms (knowledge of the object-verb structure, in order to establish which thematic roles are assigned by each verb) and syntactic mechanisms (in order to map syntactic roles like subject, direct object, dative object onto thematic roles like agent, theme, beneficiary). As the mechanisms involved in these operations are very complex, errors of thematic role assignment may result from various impairments. In the case of semantic-lexical damage, if conceptual information about the verb is spared but

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the argument-verb structure is unavailable, the mechanisms subservient to thematic role assignment, even though unimpaired, may assign roles inappropriately. In the case of syntactic impairment, information on single words (including the argument-verb structure) may be spared, but damage to the mechanisms that assign thematic roles will result in thematic role reversal errors. Irrespective of the specific cause (semanticlexical or syntactic) of their disorder, E.B. and other subjects with similar performance (Caramazza & Bemdt, 1985; Martin & BlossomStach, 1986) suggest two kinds of considerations. Their deficit (difficulty in thematic role assignment, without noticeable problems in the production of grammatical morphemes) is complementary to that observed in subjects like Mr Clermont (Nespoulous etal., 1988), Case 1 (Miceli et al., 1983), and P.B.S. (Rapp & Caramazza, 1997), who present with difficulties in the production of grammatical morphemes, but not in the assignment of thematic roles. This double dissociation supports the notion that in sentence production, morphosyntactic mechanisms are independent of the mechanisms that assign thematic roles. In the light of these results, the frequent co-occurrence of errors on grammatical words and of incorrect thematic role assignment in the same subject (Byng, 1988; Caramazza & Hillis, 1989; Saffran et al., 1980) cannot be interpreted as the result of one and the same deficit, and is better accounted for by assuming cognitive lesions involving distinct components of the production process. Furthermore, even if it is not possible to unequivocally establish the origin of the errors, the very fact that at least two alternative hypotheses can be entertained to explain thematic role assignment disorders suggests the possibility that the apparently homogeneous group of subjects who make errors in assigning thematic roles also comprises aphasies with very different cognitive disorders. Recent neuropsychological studies have resulted in relevant progress of our understanding of the disorders that underlie agrammatic production. Nevertheless, many problems raised by available empirical observations are as yet

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unsolved. Reliable answers to these problems will depend on the development of detailed cognitive models of language production. To mention but one example, current models cannot account for the dissociation between free-standing and bound grammatical morphemes (e.g. Caramazza & Hillis, 1989; Miceli et al., 1989), nor among different types of morphemes within each subset of items (Miceli et al., 1989) that are frequently observed in the same agrammatic speaker. Neither can they account for the modality-specific occurrence of agrammatic output disorders (Rapp & Caramazza, 1997). Unfortunately, in the absence of sufficiently explicit theories of language production, the experimental analyses necessary to evaluate the theoretical relevance or the irrelevance of these observations simply cannot be identified. Despite contingent limitations, however, the continuous interplay between theories of normal language and theory-based, experimental analyses of aphasic language disorders promises to lead to more detailed hypotheses of representations and procedures involved in speech production.

GRAMMATICAL COMPREHENSION DEFICITS Many of the studies mentioned in this section were conducted on groups of subjects, and set out to propose a unitary account of agrammatic comprehension. Therefore, for the reasons discussed earlier, they are difficult to interpret. By relative contrast with production studies, investigations of the disorders of grammatical comprehension helped to describe some general features of the comprehension processes, but did not result in sufficiently explicit models. Thus, the neuropsychological observations that follow are not presented in order to propose a coherent interpretation based on a specific theory, but rather to draw the reader’s attention to issues that are potentially relevant for normal comprehension processes. Difficulties of comprehension of grammatical structures have been hypothesised to result from phonological short-term memory deficits (Shallice, 1988; Vallar & Baddeley, 1984). This hypothesis

is based on the assumption that sentence understanding requires the construction of a veridical phonological representation, which is maintained active by a working memory component. The phonological string stored in this short-term memory system is processed by the syntactic parser, in order to build the syntactic representation needed for the subsequent stages of comprehension. On this account, normal phonological memory is necessary to construct a complete syntactic representation. When shortterm phonological memory is damaged, the parser can only work on shorter-than-normal phonological strings, which may at times result in poor comprehension. This interpretation of agrammatic comprehension is controversial (for a collection of different viewpoints, see Shallice & Vallar, 1990). It was suggested not on the basis of explicit theoretical models, but based on the empirical observation that in early descriptions of subjects with agrammatic comprehension, poor understanding of sentences co-occurred with poor performance on verbal span tasks. Thus, it cannot be ruled out that other, non-phonological memory systems play a role in sentence comprehension (for example, it would not be unreasonable to hypothesise that the syntactic parser works on information that, although abstract, is not phonologically coded; and, that this information is stored in a non-phonological short-term memory system). As a matter of fact, Martin (1987) and Waters, Caplan, and Hildebrandt (1991) showed that subjects with severe disorders of phonological short-term memory (as shown by major deficits in span tests) demonstrate a surprising ability in understanding complex syntactic structures. This result does not support the hypothesis of a causal relationship between damage to phonological short-term memory and asyntactic comprehension. Consequently, if the assumption that asyntactic comprehension results from a memory deficit is to be maintained, it must be assumed that the damaged short-term memory system is not one that stores veridical, phonologically coded strings, but a memory system that stores abstract representations of some other type. If a difficulty in the comprehension of grammatical structures may indeed result from a

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memory disorder (phonological or otherwise), it is also obvious that asyntactic comprehension may derive from a true syntactic deficit. Goodglass, Blumstein, Gleason, Hyde, Green, and Statlender (1979) presented a group of agrammatic subjects with a comprehension task that included two sets of stimuli, similar in length, but different in grammatical complexity. The first set consisted of two coordinate clauses (The man is greeted by the wife and is smoking the pipe), the second of a main clause and a subordinate clause (The man greeted by the wife is smoking the pipe). Agrammatic subjects performed much more accurately on the first type of sentence than on the second. Among the studies that tried to account for agrammatic comprehension in terms of the consequence of a specific inability to process syntactic structures, those by Caplan and Hildebrandt (Caplan & Hildebrandt, 1988; Hildebrandt, Caplan, & Evans, 1987) and by Grodzinsky (1987,1990) are of great interest. These studies reflect a strictly linguistic approach to the study of grammatical comprehension deficits, based on the theory of government and binding (Chomsky, 1981). The assumption of these papers is that poor grammatical comprehension results from the inability to process traces, i.e. the elements of a sentence that are not phonologically realised, but are present in the deep structure of the sentence8. Also relevant to the understanding of mechanisms that may disrupt sentence comprehension are the observations reported on by Linebarger, Schwartz & Saffran (1983), who submitted subjects with grammatical comprehension deficits to grammaticality judgement tasks that included structurally complex sentences. Some of these subjects, who in a previous study (Schwartz et al., 1980) had demonstrated very poor understanding of simple active declarative sentences presented auditorially, were reliably (even though not flawlessly) able to judge if a much more complex sentence presented in the same modality was grammatically correct or incorrect. Similar results were obtained also when the stimulus sentences were presented after completely eliminating prosody (Bemdt, Salasoo, Mitchum, & Blumstein, 1988). These observations show that in subjects with agrammatic comprehension, very

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poor comprehension may be associated to spared ability to judge the grammaticality of a sentence. Linebarger et al. (1985) interpreted this dissociation as support for the hypothesis that agrammatic comprehension does not result from a syntactic deficit, but from a difficulty in mapping grammatical roles onto semantic roles (Schwartz et al., 1980). Contrasting performance on grammaticality judgement and on sentence comprehension tasks may be accounted for by assuming that knowledge of syntax, enough spared as to allow judgement of whether grammatical rules are correctly applied, cannot be used to construct a sentence representation sufficiently accurate for comprehension. In Linebarger’s study, the sentences that proved to be the most difficult for agrammatic subjects were those in which the violation involved two words that appeared at very distant positions in the sentence. For example, subjects found it very difficult to judge the grammaticality of tag questions, which contain a long-distance noun-pronoun agreement (The little boy fell down, didn’t he?). These results raise the possibility that agrammatic patients are unable to build a global syntactic representation of the sentence, even though they still manage to build local syntactic representations. Consistent with this hypothesis, Blumstein, Goodglass, Statlender, and Biber (1979) reported that agrammatic subjects understand pronominal reference better when the pronoun and its referent are near (The boy watched the chef bandage himself) than when they are distant (The boy watching the chef bandaged himself). Results consistent with this hypothesis were reported in subject D.E. by Tyler (Tyler, 1985, 1989; Tyler & Warren, 1987). Poor comprehension may also result from the inability to process information carried by grammatical morphemes. The reasons for poor comprehension in this case are quite obvious. Utterances like The horse is chased by the cow, or My cousins nephew can be understood correctly only if grammatical morphemes are adequately processed. Problems with grammatical morphemes in comprehension have been repeatedly observed in subjects with asyntactic comprehension (Bradley et al., 1980; Caramazza & Zurif, 1976; Goodenough et al., 1977; Heilman & Scholes,

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1976; Zurif et al., 1972), and can affect various grammatical morphemes to a very different extent. For example, the same preposition may or may not be used by the same subject in comprehension tasks, as a function of the role it plays in a sentence (Friederici, 1982, 1985). In these studies, subjects with agrammatic comprehension had fewer problems in processing prepositions that are semantically loaded (in the sentence The book is under the box, the relationship between book and box is entirely expressed by the preposition under) than in processing semantically “empty” prepositions (as the preposition on in The vase fell on the floor). The possibility that an impairment of the ability to process grammatical morphemes results in asyntactic comprehension receives support from the results obtained by subject D.E. (Tyler & Cobb, 1988). In a task that required the ability to process auditorily presented words, this subject performed normally with derived words, but demonstrated severe difficulties on inflected words (note that these results duplicate, in an auditory input processing task, the dissociation between inflectional and derivational morphology reported in production by Miceli & Caramazza, 1988). Further observations relevant to the interpretation of grammatical comprehension disorders were gathered from studies focused on the comprehension of reversible sentences. Schwartz et al. (1980) demonstrated that agrammatic subjects present with a severe difficulty in comprehending active and passive reversible sentences, and attributed it to the inability to map grammatical roles onto thematic roles. Poor grammatical comprehension associated to difficulties in assigning thematic roles has been reported on repeatedly (e.g. Byng, 1988; Caplan & Futter, 1986; Caramazza & Berndt, 1985; Caramazza & Miceli, 1991; Martin & Blossom-Stach, 1986; Martin, Wetzel, Blossom-Stach, & Feher, 1991; Mitchum, Haendiges, & Berndt, 1995; Weinrich, McCall, & Weber, 1995). Understanding a sentence like The man is kissing the woman requires that the thematic roles of agent and theme be assigned to man and woman, respectively, starting from the grammatical roles of subject and direct object. A difficulty in establishing this correspondence

(resulting in the incorrect assignment of the role of theme to woman, and of that of agent to man) may result in poor comprehension. Schwartz et al.’s hypothesis is supported by the observation that subjects with agrammatic comprehension perform normally on grammaticality judgement tasks, even though they make many errors in understanding reversible sentences (Berndt et al., 1988; Linebarger et al., 1983). Possible problems for the account proposed by Schwartz et al. come from the fact that their subjects, in addition to being poor at thematic role assignment, suffered from other disorders that might result in asyntactic comprehension. For example, they presented with difficulties on grammatical morphemes; therefore, poor comprehension in some of these subjects may have resulted from inaccurate processing of grammatical words, and not from problems with thematic roles (in The man is chased by the woman, grammatical morphemes signal the passive voice, and are instrumental in establishing that the first noun is the theme and not the agent of the sentence). However, this possibility can be safely ruled out in other cases. Subject E.B. (Caramazza & Miceli, 1991; see also subjects in Martin & Blossom-Stach, 1986) correctly used grammatical morphemes in all comprehension and production tasks, and performed normally on grammaticality judgement tasks, but he made many errors in the comprehension of reversible sentences. When asked to match an auditorially or visually presented sentence (The men are chasing the women) to one of two pictures, E.B. almost systematically selected the correct picture when it was paired with a morphological foil (e.g. men chasing a woman) or a semantic foil (e.g. men pushing women), but frequently selected the inappropriate picture (40% incorrect responses out of 240 stimuli) when it represented an inversion of thematic roles (e.g., women chasing men). In this subject, agrammatic comprehension could not be attributed to a disorder of phonological short-term memory (E.B. repeated all sentences correctly, even those to which he produced an incorrect response), nor to difficulties with grammatical morphemes (E.B. demonstrated normal comprehension of nominal, adjectival, and verbal inflections). Therefore, it is reasonable to

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assume that his errors resulted from difficulties in thematic role assignment. As already discussed (see previous section), the nature of E.B.’s errors is not unambiguous. The assignment of thematic roles during sentence comprehension requires the integrity of semanticlexical mechanisms (which establish the thematic roles assigned by the verb, such as agent, theme, beneficiary, goal, instrument, etc.) and syntactic mechanisms (which parse the sentence into its grammatical constituents, assigning the correct thematic role to each). Thus, the errors in sentence comprehension reported for E.B. might result both from a semantic-lexical deficit and from a syntactic deficit. The first account is based on the fact that lexical verbs are characterised both by conceptual information (to kill means to cause someone’s death), and by a predicate-argument structure, which specifies the thematic roles assigned by the verb (to kill assigns the roles of agent, theme, and instrument). Thus, E.B.’s errors might be explained by assuming selective damage to verbs as a grammatical class in the semantic-lexical system9. As E.B. shows normal preservation of both nouns and verbs in word-picture matching tasks, he may still be able to correctly process conceptual information on all the words in the sentence, taken one by one. However, damage to the predicate-argument structure might prevent the correct assignment of thematic roles, even if the mechanism that assigns thematic roles to grammatical constituents is spared, thus resulting in poor comprehension of reversible sentences. As an alternative, it might be assumed that the deficit in E.B. is syntactic, and involves the mechanisms that map grammatical roles onto thematic roles. In a sentence like The lion is killed by the tiger, these mechanisms assign the roles of agent and theme to the nouns that occupy the grammatical roles of subject and agent (lion and tiger, respectively). In this case, even though conceptual information about individual words is preserved, and the predicate-argument structure is unimpaired, asyntactic comprehension may result from a deficit of the syntactic mechanisms that assign thematic roles. A firm decision between these alternative interpretations is not possible. As already stated in the section on production disorders, the very fact

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that thematic role assignment errors in comprehension admit to more than one account strongly suggests the possibility that subjects who have difficulty assigning thematic roles in comprehension are cognitively heterogeneous. This short survey of grammatical comprehension disorders in aphasia helps to make at least one important (albeit controversial) point. Despite many efforts, a unitary characterisation of asyntactic comprehension cannot be proposed. Traditionally, disorders of grammatical comprehension were attributed to an impairment of grammatical morpheme processing. It is obvious at this point that such a deficit is only one of many possible causes of asyntactic comprehension. For several subjects, flawless ability to process the surface structure of a sentence, in the presence of asyntactic comprehension due to poor thematic role assignment, was reported. In these cases, poor performance in comprehension tasks may result from distinct cognitive lesions (damage to the semantic representation of the main verb, to the predicate-argument structure of the verb, or to the mechanisms assigning thematic roles). In addition, even if very debated, the possibility that asyntactic comprehension results from short-term memory deficits must also be considered. Even though current research still does not allow us to draw a coherent picture of grammatical disorders of comprehension, at the very least the studies briefly reviewed here make it clear that many problems will ultimately be solved only when more detailed theoretical models are available. A typical example of a yet unsolved problem, often raised in this area of research, concerns the relationship between grammatical deficits of production and of comprehension. Available reports clearly demonstrate that the co-occurrence of the two deficits in the same subject, although statistically very likely, is by no means necessary— some subjects only present with a comprehension deficit, others only with a production deficit, yet others with an impairment of both production and comprehension. In the presence of the repeatedly reported double dissociation between asyntactic production and comprehension, the interpretation of the frequent co-occurrence of the two disorders relies on the hypotheses one is willing to entertain on the mech-

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anisms involved in sentence comprehension and production. On the account that these mechanisms do not overlap at all, the co-occurrence of agrammatic speech and comprehension in the same subject results from damage to distinct mechanisms (one or more involved only in production, one or more involved only in comprehension). Alternatively, it might be assumed that some mechanisms are shared by comprehension and production, whereas others are dedicated to one or to the other process. On this account, the co-occurrence of disorders of grammatical comprehension and production might result from damage to one or more components shared by comprehension and production; from damage to independent components, some involved only in comprehension and some only in production; or from damage to some shared mechanisms and to some dedicated mechanisms. Obviously, only a model that explicitly specifies which mechanisms are involved only in production or only in comprehension, and which mechanisms are shared by both processes, will allow us to carry out the relevant experimental analyses and to correctly evaluate the alternative hypotheses10. Also in research on sentence comprehension, the combination of theoretical developments and of theorydriven experimental analyses is necessary in order to improve our understanding of the mechanisms underlying grammatical disorders.

ANATOMO-CLINICAL CORRELATES OF GRAMMATICAL DISORDERS In the first half of the twentieth century, detailed reports of the lesions in some agrammatic subjects were reported. Two patients studied by Bonhoeffer (1902) presented with agrammatism and motor aphasia following surgery “in the vicinity of Broca’s area”. According to Pick (1913), the frontal areas of the left hemisphere are most frequently damaged in subjects with agrammatism (and especially in subjects affected by the so-called pseudoagrammatism, usually found in association with motor aphasia) and damage to the left temporal structures is responsible for “true” agrammatism. Also Kleist (1934) stressed the role

played by damage to the foot of the third frontal circumvolution in the pathogenesis of agrammatic speech, and that played by the impairment of the temporal structures (in particular of Brodmann’s area 22) in agrammatic comprehension. More recently, noninvasive imaging techniques have allowed the extenson of the analysis of the anatomo-clinical correlates of agrammatism to large numbers of subjects. Some studies (e.g. Benson, 1967; Kertesz, Harlock, & Coates, 1979; Naeser & Hayward, 1978) demonstrated a correlation between Broca’s aphasia with agrammatism and lesions located in the foot of the third frontal circumvolution of the left hemisphere. These results duplicate the historical report published by Broca (1861), and are the not unexpected result of the clinical observation that agrammatism is frequently observed in the context of Broca’s (nonfluent) aphasia. However, other investigations failed to demonstrate such a close correspondence between agrammatism or agrammatic Broca’s aphasia and Broca’s area. In a study of 18 subjects, Mohr, Pessin, Finkelnstein, Funkenstein, Duncan, and Davis (1978) concluded that permanent Broca’s aphasia with agrammatism is observed only following lesions that involve, in addition to Broca’s area, postrolandic and perisylvian structures as well. From the analysis of two subjects, Levine and Mohr (1979) concluded that a lesion restricted to Broca’s area, even if bilateral, is not sufficient to result in Broca’s aphasia with agrammatism. More recently, Lecours, Basso, Moraschini, and Vanier (1985) showed that as many as 13/52 patients affected by completely prerolandic lesions involving Broca’s area (25%) did not present with a clinical Broca’s aphasia, and that 8/82 subjects affected by completely postrolandic lesions (9.8%) could be classified as having Broca’s aphasia. Also when agrammatism was considered perse, and not merely as a symptom of Broca’s aphasia, very heterogeneous anatomo-clinical correlates emerged. In an analysis of 26 subjects, classified as agrammatic solely on the basis of their speech disorder (i.e. irrespective of other symptoms of Broca’s aphasia), who were premorbidly speakers of different languages (Vanier & Caplan, 1990), the structure most frequently lesioned was not Broca’s area but the insula—a region that usually

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is not included among the structures involved in language processing. Another study (Miceli et al., 1989), that included subjects selected on the basis of the linguistic criteria proposed by Caplan (1986) failed to identify more reliable anatomo-clinical correlates of agrammatic speech. Of 18 subjects with focal lesions of the left hemisphere, verified by CT-scan, classified as agrammatic because they omitted grammatical morphemes in spontaneous speech, 3 (16.7%) suffered from an entirely postrolandic lesion. Thus, investigations dealing with the anatomoclinical correlates of agrammatic disorders have led to very heterogeneous results. From these studies, it emerges that in right-handed subjects the left hemisphere structures that receive blood from the middle cerebral artery play a crucial role in processing the grammatical aspects of language and that, among these, prerolandic areas seem to play a more relevant role than postrolandic structures. Nevertheless, precise correlations are not yet possible, and the available reports demonstrate that grammatical disorders occur in subjects affected by disparate lesions. These contrasting results are not surprising. A survey of the studies focused on the anatomo-clinical correlates of agrammatism reveals that the criteria used to group subjects were inconsistent or unreliable. In some cases, Broca’s aphasia (and not agrammatism) was the target category. In other cases, subjects were classified as agrammatic on the basis of features of their spontaneous speech (omissions of grammatical morphemes and production of sentences with a pathologically simple structure) that allegedly do not allow the selection of cognitively homogeneous subjects. If “agrammatism” does not denote damage to one and the same component of the cognitive system, but rather a heterogeneous group of symptoms, it is not surprising that the anatomo-clinical correlations obtained from the study of subjects presenting with these symptoms and classified on this basis as agrammatic are also diverse. More detailed correlations between the neural substrate and the cognitive mechanisms that control the processing of grammatical production and comprehension will be forthcoming when more explicit hypotheses on the cognitive/linguistic mechanisms involved in

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sentence comprehension and production allow subjects with agrammatic disorders to be studied in detail at the level of both the cognitive deficit and the cerebral lesion (Caramazza, 1987; Miceli, 1989).

CONCLUSIONS The recent metatheoretical, methodological, and theoretical developments of neuropsychological research have profoundly changed the approach to the study of the deficits observed in brain-damaged subjects. Analyses of the grammatical disorders of production and comprehension briefly considered in this chapter have also been influenced. As in all the areas of the neuropsychology of language, the study of grammatical deficits was initially based on clinical categories, on the implicit assumption that a limited number of intuitively predefined criteria would allow the identification of cognitively homogeneous subjects. Driven by these assumptions, researchers clinically classified subjects as agrammatic or paragrammatic, and tried to understand and analyse their deficits. However, studies based on these presuppositions led to contrasting conclusions: agrammatism has been considered as a selective production deficit, or as the deficit of a “central” component (involved in both comprehension and production); the cognitive lesion responsible for agrammatism has been located at the phonological, at the lexical-semantic, and at the syntactic level; agrammatic production has been considered as the direct consequence of a cognitive disorder, but sometimes also as the result of a compensation mechanism. As metatheoretical considerations and empirical data suggested that use of the clinical category agrammatism (and paragrammatism) results in the inclusion of very heterogeneous subjects in the same experimental group, various attempts were made to remedy this situation. It was proposed to keep using a priori categories, based not on clinical intuitions but on a linguistic theory, but this approach does not allow the identification of cognitively homogeneous subjects either—briefly stated, the study of grammatical deficits cannot be based on a priori categories (whatever the theory used to

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define these categories), but must rely on explicit hypotheses of the mechanisms responsible for the production and the comprehension of the grammatical aspects of language. The cognitive neuropsychological approach has already provided encouraging results, resulting from detailed analyses of the behaviour of individual aphasic subjects. It is reasonable to expect that this approach will improve our knowledge in the relevant areas of research, which include the mechanisms involved in language production and comprehension, knowledge of the relationships between these mechanisms and the anatomical substrate, the correct interpretation of language deficits in aphasia, and their rehabilitation.

ACKNOWLEDGEMENTS Preparation of this chapter was supported in part by grants from MURST and from CNR. This support is gratefully acknowledged.

NOTES 1. The two vocabulary classes have been given several other names, which stress various features that distinguish items belonging to the two groups. Major-class lexical items (nouns, adjectives, verbs) have also been called “content words”, to stress the fact that they convey most of the meaning of the sentence, and “open-class words”, to indicate that they are part of a vocabulary that allows the inclusion of new entries (consider terms like “Internet”, “fax”, etc.). Grammatical morphemes have also been called “function words”, because they specify the relationships among the content words that comprise a sentence and the role these play in the grammatical sentence structure, or “closed-class words”, because they form a subset of the vocabulary, to which new items are not added. This vocabulary class distinction reflects much more than a terminological detail. It results from the assumption, proposed by several authors (e.g. Bradley, Garrett & Zurif, 1980; Garrett, 1980), that there is a computational distinction between words belonging to the two classes; i.e. that words of the two

types are processed by distinct mechanisms. In the present chapter, the labels “major-class lexical items”, “content words” and “open-class items”, and the labels “grammatical morphemes”, “grammatical words”, “function words”, and “closed-class items” will be used as synonyms. 2. In the transcripts of agrammatic speech reported in this chapter, the following notations are used: substitutions of grammatical morphemes are underlined, and omissions of grammatical morphemes and of major-class lexical items are marked by square parentheses [ ]. Omitted items are reported in parentheses when the available narrative allows an unequivocal guess; otherwise, the omitted word is reported as [...]. Long pauses in the speech flow are indicated by ... A full stop indicates a short pause, or the end of an utterance (in this case, the following word starts with a capital letter). 3. Note that this is hardly surprising. As omission of grammatical words is the criterion for the clinical diagnosis of agrammatism, it is obvious that all agrammatic subjects will present with this deficit. 4. The study by Miceli et al. (1989) has been criticised by Bates, Applebaum, & Allard (1991) and by Grodzinsky (1991). Bates et al. objected that the reported differences across subjects can be fully accounted for by statistical variability, associated to the effect of other cognitive, linguistic, and neurological variables. On this account, the results reported by Miceli et al. could be explained by assuming random variation in a population of subjects in whom the cognitive system suffers from a high level of noise and/or a reduced processing capacity, which render the production of grammatical words particularly difficult (Bates et al., 1987). Because on this view across-subject variability results from variables independent from a grammatical deficit, agrammatism can be legitimately studied by using clinically identified groups of subjects (a similar position has been taken by Miyake, Carpenter, & Just, 1994). Grodzinsky (1991) objected that the results reported by Miceli et al. are not relevant because, however large, the quantitative differences observed in a group of subjects who suffer from a deficit that can be defined on a linguistic parameter do not license the conclusion that those subjects are heterogeneous. Therefore, agrammatism can be legitimately studied on the assumption that agrammatic speakers constitute a homogeneous group, and that across-subject variations are theoretically irrelevant, and as such can be legitimately neglected.

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In response to these objections, it should be stressed that Miceli et al. never argued that each and every discrepancy in grammatical morpheme production observed in their sample (either across or within subjects) results from theoretically relevant distinctions. They merely argued that, even when a linguistically defensible criterion is chosen, variability and dissociations across subjects are so evident as to make the idea that a p r io r i criteria (be they clinical or linguistic) allow one to identify cognitively homogeneous patients rather implausible. It is obvious that firm conclusions on the theoretical relevance (or irrelevance) of a particular dissociation cannot be based merely on an error distribution analysis (but again, that position was never taken by Miceli et al.); however, it is just as obvious that similar conclusions cannot be drawn on the basis of a statistical analysis (Bates et al., 1991) or of a linguistic hypothesis (Grodzinsky, 1991). Only investigations based on an explicit model of speech production will ultimately lead to motivated conclusions on the pathological mechanisms that result in agrammatic speech in each subject. 5. In addition, the dissociation that complements that observed in M.L. and in Mr Clermont (i.e. preservation of function words in the presence of damage to content words) has been reported several times, in at least two contexts. Subjects with the so-called “pure anomia” syndrome make normal use of grammatical morphemes in spontaneous speech, but demonstrate severe difficulty with open-class words (e.g, Kay & Ellis, 1987; Miceli, Giustolisi, & Caramazza, 1991). In addition, analyses of the spontaneous speech in neologistic jargonaphasia have repeatedly demonstrated the occurrence of pseudowords consisting of a neologistic root paired with a real suffix (e.g. Caplan, Kellar, & Locke, 1972; Semenza, Butterworth, Panzeri, & Ferreri, 1990). For example, spared agreement phenomena in the presence of damage to major-class lexical items were observed in the subject described by Caplan et al. (1972), who produced utterances like B ecause I ’m ju s t persessing to o n e ..., in which persess- is not a real root, but -in g is an inflection, used appropriately in the target sentence frame. These observations provide further support for the procedural distinction between closed-class and open-class words proposed by Garrett. 6. With reference to the problems discussed in the previous section, it seems unlikely that the four agrammatic subjects just described are affected by the same cognitive deficit, and that the observed discrepancy in performance can be accounted for by random

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(Bates et al., 1991) or theoretically irrelevant (Grodzinsky, 1990) across-subject variation. Subject M.L. and Mr Clermont present with agrammatic production both in speaking and in spelling; Case 1 in Miceli et al. (1983) shows agrammatic speech but not writing, and subject P.B.S. suffers from agrammatism in writing but not in speech. These contrasts are very difficult to interpret in the context of linguistic theories, which try to account for agrammatic output in terms of damage to a modality-independent level of representation, without considering the computational demands of each output task (e.g. Caplan, 1986; Grodzinsky, 1987, 1990, 1991). These theories cannot accommodate the observation that in the same subject production may be agrammatic in speech, but not in writing, or agrammatic in writing and neologistic in speech. Also theories that consider agrammatic output as the result of reduced capacity of the cognitive system or of noise (Bates et al., 1987, 1991; Miyake et al., 1994) have a hard time accounting for such diverse patterns of output disorders. Leaving aside that notions like “reduced capability” or “noise” have no explanatory value unless they are qualified in at least some detail, it is not clear how reduced capability or noise could selectively disrupt the ability to produce grammatical words in one modality while sparing the other (Case 1), or the ability to produce grammatical words in one modality, and that to produce content words in another (P.B.S.). Also theories that consider agrammatic production to be the result of an adaptive strategy (e.g. Kolk & Heeschen, 1990) can hardly explain these dissociations, as the same adaptive strategy would have to result in neologistic speech and in agrammatic writing. The dissociations reported in the subjects we have just discussed can be adequately interpreted only in the context of theories that include explicit hypotheses about computational demands, processes, and representations involved in each cognitive task. 7. The results reported for F. S. also speak to another relevant aspect of the organisation of the cognitive system. In particular, they converge with those obtained from Italian-speaking normal subjects (e.g. Burani & Caramazza, 1987; Caramazza, Laudanna, & Romani, 1987; Laudanna, Badecker, & Caramazza, 1992) and from other Italian-speaking aphasics (e.g. Job & Sartori, 1984; Caramazza, Miceli, Silveri, & Laudanna, 1985; Semenza, Butterworth, Panzeri, & Ferreri, 1990), in supporting the hypothesis that morphologically complex words are represented in the lexicon in a morphologically decomposed form. The

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hypothesis here is that roots (in Italian, items like do lo r-, sol-, gioc- for the words dolore; solo, giocare— pain, high, to play, respectively) and base forms (in Italian, items like d o lo ro s -, s o litu d in , g io c - for the words doloroso, solitudine, giocatore—painful, loneliness, player, respectively) are represented in a lexical component distinct from that in which inflections are represented. Contrary to this hypothesis, Taft has argued in several papers (e.g. 1985) that morphological decomposition plays a role during access to lexical representations, but that the latter are not themselves morphologically decomposed. For a more extensive discussion on the issue of the morphological organisation of the lexicon, the reader is referred to Chapter 11 in this handbook, where subjects who make morphological errors in strictly lexical tasks (e.g. Badecker & Caramazza, 1987; Badecker, Hillis, & Caramazza, 1991; Patterson, 1980) are discussed. 8. There is not enough room for an extensive discussion of Chomsky’s theory and of all the investigations it has inspired. Nonetheless, it is important to stress that, even though these studies are extremely stimulating, the same objections apply that were raised earlier to studies of asyntactic comprehension based on the analysis of subject groups and to investigations of agrammatism that have sought a unitary account of the disorder. It is entirely possible that in some subjects agrammatic comprehension results from a difficulty in processing traces (or from whatever deficit is appropriately described in linguistic terms). However, even if this turned out to be true in some

subjects, it cannot be argued from these observations that in all subjects with poor grammatical comprehension the deficit results from an impaired processing of traces. And in fact, the study of sentence comprehension abilities in F.M. (Badecker, Nathan, & Caramazza, 1991), E.B. (Caramazza & Miceli, 1991) and in the subjects studied by Martin et al. (1991) shows that poor grammatical comprehension may result from different disorders, and cannot be due (at least in these cases) to the deficit proposed by Grodzinsky (1991). 9. Selective disorders of verb comprehension have been already described (Miceli et al., 1988), and the possibility that these disorders cause difficulty in comprehending semantically reversible sentences has been demonstrated by McCarthy and Warrington (1985) in a subject whose deficit involves the conceptual representations of verbs. 10. This problem is exemplified by disorders of thematic role assignment. All the subjects who present with this disorder make errors both in comprehension and in production. When such errors are qualitatively and quantitatively comparable in comprehension and production tasks, in the oral and in the written modality, the simplest explanation is that they result from damage to a single, “central” component, shared by all the tasks administered to the subject. Nonetheless, such a conclusion is not justified, due to the lack of explicit hypotheses about modality-independent and modality-specific mechanisms involved in thematic role assignment (Caramazza & Miceli, 1991; Mitchum et al., 1995; Weinrich et al., 1995).

13 Disorders of Conceptual Thinking in Aphasia Luigi Amedeo Vignolo

ongoing debates about the inner structure of the semantic system and the category specificity in semantic loss (see Saffran & Schwartz, 1992, for an update on this problem). Several widely overlapping terms have been employed through the years to denote the impaired ability, and they are often used loosely as synonymous. Their different shades of meaning are briefly recalled here. Concept may be tentatively defined as a representation formed in the mind by generalising from particulars, and conceptual thinking as the process of performing the operations required to form and handle concepts. Abstraction is used here in two ways, first, as the process by which a concept is obtained, and second, as a general idea, considered apart from the particulars perceived by the senses. Abstract thinking is opposed to concrete thinking, while abstract attitude underlines the intentionality of the conceptual operation. Categorical (or “categoreal”) thinking belongs to the wider sphere of conceptual thinking, stressing, however, the classificatory activity. Finally, symbol is used here in its broadest meaning, including both one thing representing another and, improperly, an arbitrary

INTRODUCTION The neurological and neuropsychological literature of the past 150 years provides evidence that the language disturbances due to focal lesions of the brain are sometimes associated with disorders of conceptual thought. This fact is interesting as it can perhaps shed some light on the relationships between language, conceptual thinking, and the brain. The purpose of this chapter is to review both the older studies based on clinical observation alone and the subsequent ones based on the systematic administration of nonverbal standardised tests. The data discussed here are relevant to other areas of neuropsychology, such as the associative agnosias (see De Renzi, Chapter 16) and the semantic-lexical aspects of aphasia (see Semenza, Chapter 11). They may also be viewed in an historical perspective as the contribution of the lesion studies, from classical to contemporary aphasiology, to our knowledge of the semantic memory impairment following circumscribed cerebrovascular damage of the left hemisphere, although they provide no useful evidence for the 273

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sign such as a word. Symbols thus defined constitute an essential instrument of conceptual thinking. It is important to stress that all such terms designate only some aspects of the broader notions of “general intelligence” and “cognition”, and, in particular, they do not include the purely spatial organisational abilities. Among the reviews of disorders of general intelligence and cognition in aphasia are the earlier works of Isserlin (1936), Weisenburg and McBride (1935), Ombredane (1951), and Ajuriaguerra and Hecaen (1959), and the more recent studies by Hamsher (1981) and Gainotti (1988). The present review, like a previous one (Vignolo, 1989), focuses on the nonverbal, nonspatial conceptual impairment in post-stroke aphasia.

HISTORY Early clinical observations As early as 1869 the pioneer Broca recognised some sort of intellectual defect in aphasia, and since the late nineteenth century a number of clinicians have studied it. The evidence used in these studies, based as it was mostly on either one or a few case-reports and heavily loaded with theoretical assumptions, was of questionable worth, and only a few examples need to be mentioned here. Trousseau (1864,1865) stressed the fact that reading, writing, and sometimes the imitation of gestures were as impaired as oral expression, and on this fragile basis he argued that aphasic patients suffer from a partial, but significant, loss of intelligence. Finkelnburg (1870) noticing an inability to recognise pantomimed actions and various conventional symbols (such as coins and military signs of rank) in aphasics, suggested the comprehensive concept of “asymbolia” i.e. impairment of the symbolic function, to encompass both these nonverbal disorders and those of oral and written language. On the basis of two post-mortem cases, he indicated that the lesion was in the left insula and neighbouring temporal and parietal lobes. Jackson (1878) is credited with being the first in the English literature to suggest that aphasia involves an intellectual

element. He observed that pantomime may be impaired and stated that aphasics are “lame in thinking”, in as much as “speech is a part of thought” and that they often suffer from a “loss or defect in symbolizing relations of things in any way”. These now oft-quoted statements were virtually ignored until Head revived Jackson’s work in 1915 and developed it in his comprehensive book of 1926. Head observed that patients were often unable to carry out a number of partially nonverbal tasks, such as pointing to their eye and ear both on command and on imitation, setting the hands of a clock, performing simple arithmetical calculations, assessing the comparative value of coins, and executing what would now be called “constructional” tasks. He concluded that aphasia is a defect of “symbolic formulation and expression”, which to some extent transcends the linguistic sphere— a definition that enjoyed great success until the mid 1960s, especially among Anglo-saxon researchers. The Continental counterparts of the Jackson-Head line of thought were Marie’s views in France and Goldstein’s and Bay’s in Germany. Marie (1906, 1926), based on his clinical observation of about 100 cases, undertook in 1906 an epoch-making “revision of the question of aphasia”, and he emphatically concluded that “true aphasia” is an intellectual impairment. By “true” aphasia he meant Wernicke’s aphasia (including, in a unified way, all forms that are nowadays subsumed under the heading of “fluent” aphasia), while Broca’s aphasia (corresponding to all “nonfluent aphasia” forms, including global aphasia) also had an essential intellectual element in it, being merely a combination of “true aphasia” and an articulatory defect (“anarthria”). Marie maintained that the intellectual impairment of aphasics, unlike that of demented patients, is confined to “didactically acquired procedures”. It is both general (affecting the association of ideas, memory, professional knowledge, and conventional and descriptive mimicry) and specific to language (affecting the comprehension of oral and written language, reading, and writing). A well known example of what Marie regarded as an intellectual deficit is

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the description of the striking errors made by an aphasic patient, a cook by profession, in the simple tasks of frying an egg—a grossly defective behaviour which would now be diagnosed as a severe ideational apraxia. The idea that the aphasic’s disorder of thinking may reflect a specific conceptual impairment did not arise until the work of Goldstein, whose often intricate arguments leading to this conclusion are found in a number of papers spanning several decades (e.g. Goldstein, 1919, 1927, 1942, 1948). This author’s distinction between a concrete and abstract (categorical, conceptual) attitude is central to our topic, and it is clearly stated in his book of 1942 (p.89): We can distinguish normally two different kinds of attitudes toward the world: a concrete and an abstract one. In the concrete attitude we are given over and bound to the immediate experience of a given thing or situation in its uniqueness. Our thinking and acting are directed by the immediate claims that one particular aspect of the object or situation in the environment makes. [...] We respond unreflectively to these claims. In the abstract attitude we transcend the immediately given, or sense impression; we abstract from particular properties. We are oriented in our actions by a conceptual point of view, be it the conception of a category, a class, or a general meaning under which the particular object before us falls. Our actions are determined not so much by the objects before us as by what we think about them. We detach ourselves from the immediate impression, and the individual thing becomes an accidental example or representative of a category. Therefore, we also call this attitude the categorical or conceptual attitude. According to Goldstein, the loss of abstract attitude is not only an accompaniment but a basic ingredient of aphasia, which entails (a) language disruption, particularly in amnesic aphasia (Goldstein, 1924), and (b) inability to perform nonverbal tasks requiring the patient to pick out (in

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Gestalt terms) the essential in a field, to hold the figure clearly against the ground and, if necessary, to shift intentionally from a concept-directed classification to another (Goldstein & Scheerer, 1941). Two such tasks are, for example, Weigl’s (1927) Colour-Form Sorting Test, in which the patient classifies different cuts of wood according to colour and form, and Gottschaldt’s (1926, 1929) Hidden Figures Test, which evaluates the ability to disengage a geometrical figure from a distracting background which has been constructed using known field factors to produce maximal concealment. Bay’s theory (1962, 1963, 1964, 1974) incorporated both Marie’s view of the true aphasia and Goldstein’s contention of the primary role played by categorical impairment in the disruption of language. He stressed that the intellectual defect in aphasia can be traced back to a specific disorder of “concept formation” and actualisation. As nonverbal evidence of such a disorder, he described the remarkable errors made by some aphasics when requested to shape a plastic substance into threedimensional models of common animals or objects. For example, when asked to reproduce a giraffe, a patient modelled an animal with a short neck but a very long tail, thereby showing that he was unable to form the exact concept of the giraffe, although he still had a vague idea that a salient feature of this animal was a long body part attached at one extremity of the trunk. Likewise, a tea-cup became, in the patient’s reproduction, a much wider and flatter container, endowed, however, with a handle. Unfortunately, Bay provided no norms for such tasks, nor did he rule out the possibility that his patient’s errors were due to constructional apraxia — a disorder that cannot be considered a good marker of defective “concept formation”. The same criticism applies to similar tasks, such as spontaneous drawing and drawing to command. Most of these authors not only believed that aphasia entails an intellectual defect, they further maintained that the language disorder is merely one component of a more comprehensive and basic cognitive disorder of thinking. The opposite view was upheld by other workers, such as Wernicke (1874), Kleist (1934),

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Ajuriaguerra and Hecaen (1959), and Geschwind (1974) among others, all of whom minimised the importance of the cognitive impairment and maintained that disruption of the language mechanisms is an independent disorder. Wernicke, for example (1874, p.33), though well aware that aphasics did in fact sometimes show some intellectual deficits, explicitly warned that “nothing could be worse for the study of aphasia than to consider the intellectual disturbance associated with aphasia as an essential part of the disease picture”. This lengthy controversy, sometimes referred to, in the French literature, as the “noeticians vs. antinoeticians” debate, was inconclusive and indeed, as Benton (1985) rightly observed, proved to be “a rather fruitless exercise”. Nevertheless, it is both interesting and relevant for the present state of knowledge, because it contains some issues that are revived in more cautious terms in current hypotheses about the role of the conceptual impairment in aphasia.

First experimental studies 1930-1960 The main drawbacks of the research reviewed so far were the lack of a clear differentiation between verbal and nonverbal performances, the undue generalisation from single cases, and the absence of normative values for the tests employed to assess cognitive impairment. Substantial progress in this respect was made by Weisenburg and McBride (1935), who were the first to administer a standard battery, including nonverbal as well as verbal tasks, to representative samples of aphasics, nonaphasic brain-damaged patients, and “normal” controls. They found that not only the verbal but also the nonverbal tests were performed more poorly by aphasics as a group than by the controls. Unfortunately their nonverbal battery included form-boards, mosaics, picture completion, and drawing tests, which involved first and foremost a visual constructional element, and this is spatial rather than conceptual in nature. As Zangwill (1964) rightly observed, estimates of intelligence in aphasic patients should be based on performance tests only ¿/constructional apraxia has been satisfactorily excluded—which does not apply to Weisenburg and McBride’s study.

Further experimental research was carried out by Teuber and Weinstein (1956), who, setting out to investigate perceptual selectivity in brain-damaged patients, did in fact contribute to our knowledge of the abstraction deficit in aphasics. They gave Gottschaldt’s Hidden Figures Test to controls and brain-damaged patients who had suffered penetrating missile wounds about 10 years before the testing. Brain-damaged patients were found to perform consistently worse than controls. Within the brain-damaged sample, aphasics as a group, irrespective of presence or absence of visual field defects and/or somatosensory symptoms, were significantly more defective than the other patients. This difference also persisted when the influence of “general intelligence” (expressed by the Army General Classification Test score) on Gottschaldt’s scores was ruled out by covariance. These findings led Teuber and Weinstein to conclude that the disorder disclosed by Gottschaldt’s test was intellectual rather than sensory-specific in nature, but could not be identified sic et simpliciter with general intellectual deterioration: it was rather, a disorder of abstraction, conceived in its original meaning of mentally “isolating from” (abstraite re). Dissenting evidence came from the work of Meyers (1948) and Bauer and Beck (1954), who found no significant inferiority in aphasics as compared to controls. Zangwill (1964), stressing the importance of these negative contributions, added quasi-anecdotal evidence of his own that pointed to the poor correspondence between severity of aphasia and number of errors in the Progressive Matrices Test (Raven, 1962) and concluded by taking a sceptical stand on the alleged cooccurrence of abstract thinking impairment and aphasia. It should be noted, however, that the Progressive Matrices were subsequently shown to be performed significantly worse by aphasics (although not selectively so) in carefully controlled experimental studies (see review in Gainotti, 1986). The intrinsic difficulty of the topic, the too often contrasting results, and the admixture of empirical evidence with theoretical dogmas brought about a certain disaffection for the problem (cf. Zangwill, 1969,1975).

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REVIVAL OF RESEARCH IN THE 1960s Nonverbal association tasks Indirect (and unexpected) evidence of a nonverbal conceptual disorder in aphasia came from a number of quantitative studies in the 1960s and early 1970s, most of which were originally aimed at investigating the possible concomitance of aphasia and the hemispheric side of the lesion with the classical agnosias, i.e. the nonverbal recognition defects. The mechanism of the agnosias, like that of the apraxias, is an obscure problem in clinical neurology, and it is not surprising, therefore, that this line of research was started off experimentally by the Milan group of neuropsychology, which at the time was entirely made up of neurologists. Nonverbal recognition in various modalities (such as audition and vision of different types of stimulus) was assessed by means of ad hoc quantitative tests, administered to large unselected samples of right-handed patients, either without cerebral lesions (“controls”) or with stabilised lesions confined to one hemisphere. The latter were further subdivided according to presence/absence of aphasia, as assessed by standard language batteries, and often also by the presence/absence of a visual field defect (VFD), which was considered evidence of postrolandic extensions of the lesion. Auditory verbal comprehension scores were usually chosen as a measure of the severity of language disruption in the broader sense, as oral expression measures could be biased by concomitant articulatory difficulties. The control group scores were used to establish norms, i.e. to determine to what extent the imperfect performance of any given hemisphere-damaged patient could still be considered to fall within normal limits, or had to be defined as “abnormal”. In spite of variations in recognition modality, test construction, and scoring criteria, the common and crucial aspect of such nonverbal tasks is that they involved the association or matching of meaningful items (e.g. braying noise with donkey, red colour with cherry, etc.). Results were often compared with those of another type of tasks, entailing the perceptual discrimination of meaningless items (e.g. nondescript noises, different shades of the same colour etc.). It was

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observed from the beginning of these studies that the association tasks were selectively impaired in aphasics, even in the presence of good perceptual discrimination, and this led to the hypothesis that failure on these tasks betrayed a “high-level” disorder of recognition of meaning rather than of formal differentiation of perceptual characteristics. This possibility fuelled new interest in the problem of conceptual impairment in aphasia. The main pertinent studies will be discussed in some detail. Sound-to-picture association In an investigation of auditory agnosia, Spinnler and Vignolo (1966) examined three samples of patients with unilateral hemispheric damage (aphasic, nonaphasic left-brain-damaged, right-braindamaged, and “normal” controls) by means of a sound-recognition test requiring the identification of meaningful sounds or noises. The subjects were asked to indicate which of four pictures shown to them represented the natural source of the sound they had just heard. The picture corresponding to a given sound (e.g. the song of a canary) represented respectively (1) the correct natural source of the song (e.g. a canary singing); (2) the natural source of a sound acoustically very similar to the presented sound (e.g. a boy whistling); (3) a sound-producing event or object belonging to the same semantic category of the natural source of the presented sound, but producing a sound completely different from the presented one from an acoustic standpoint (e.g. a cock crowing); and (4) a sound-producing event or object unrelated to the presented sound either acoustically or semantically (e.g. a train in motion). Thus, three types of error were possible; acoustic errors, when the patient pointed to picture 2; semantic errors when he or she pointed to picture 3; odd errors, when he or she pointed to picture 4. About one fourth of aphasics (26%) fell below the normal cut-off score, while left nonaphasic and right brain-damaged patients performed virtually the same as normal controls. Moreover, aphasics made significantly more semantic than acoustic errors, while the reverse trend occurred in the remaining groups. These results were confirmed by Faglioni et al. (1969), employing two ad hoc tests,

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one similar to that used in the preceding study and intended to test the ability to identify the exact meaning of sounds, and the other intended to test the ability to accurately discriminate the acoustic patterns of sounds: the patients heard two successive nondescript noises and had to say whether they were the same or different. Aphasics, while specifically failing on the first test, were unimpaired on the second, which, by contrast, was particularly vulnerable to lesions of the right hemisphere. This double dissociation was later confirmed by Vignolo (1982), who checked the hemispheric side of the lesion by means of a CT scan, while Varney and Damasio (1986) showed that the associative defect may be concomitant with several lesion sites within the left hemisphere. The aphasics’ inability to match meaningful sounds and noises with their meaning is now well established (see also Doehringetal., 1967; Strohneretal., 1978; Varney, 1980, 1982a). The percentage of aphasics selectively impaired varies according to the testing techniques and experimental design from 26% (Spinnler & Vignolo, 1966) to 45% (Faglioni et al., 1969; Varney, 1980) and 43% (Varney, 1982a). On the whole, global and Wernicke’s aphasia patients do worse than the other aphasics. All these findings are rather consistent and show that the impaired sound recognition, which is found in aphasics, is due mainly to the inability to associate the perceived sound with its correct meaning, rather than to a defect of acoustic discrimination. Colour-to-picture association In a study of colour agnosia, De Renzi and Spinnler (1967) found that aphasics, in contrast with other groups of brain-damaged patients and controls, were specifically impaired on a test requiring the subject to choose the typical colour of a given object. The patient was given a set of coloured pencils and a sheet of paper with a number of black-and-white line drawings of common objects having a typical colour (such as a banana, a cherry, a cigar, etc.) and was asked to colour each drawing with a few strokes, choosing the appropriate pencil. On the other hand, Scotti and Spinnler (1970) found that aphasics had no difficulty in carrying out

tasks such as Farnsworth’s (1943) 100 Hues Test, requiring subtle chromatic perception and discrimination. Failure on this test was specific for the right brain-damaged patients with posterior lesions. These data were confirmed by De Renzi et al. (1972a), who concluded that the aphasics’ poor performance in the colour-to-picture tasks may be, at least in part, contingent upon a more general disorder of cognition, associated with, but not directly dependent on, the language derangement. This defect, which, whenever reported, was found in about one-third of the aphasic samples under study, has been confirmed by a number of investigations (Assal & Buttet, 1976; Basso et al., 1976, 1985; Cohen & Kelter, 1979; Varney, 1982b). It should be also noted, however, that colour-to-picture impairment in the absence of a major aphasic syndrome (though associated with colour anomia and alexia) has been described in single case reports by Stengel (1948), Kinsboume and Warrington (1964), and Varney and Digre (1983). Object-to-picture association A study of visual agnosia, carried out by De Renzi et al. (1969), showed that aphasics, in contrast to other samples of brain-damaged patients and controls, were selectively impaired in tasks requiring the subject to match a picture with the corresponding object. The test was so designed that the picture was not an exact copy of the corresponding real object, but belonged to a different type of the same category. For example, the real key was a small, flat, whitemetal car key, while the pictured one was a big, thick, black iron, old-fashioned gate key. As a consequence, a correct matching could rely very little (or, most often, not at all) on the mere perceptual features of the two items, while it implied a categorisation of the matched objects, leading to the awareness that both the real and the depicted object were subsumed under the same concept, e.g. the concept “key”. The poor performances of aphasics in this associative test (later confirmed by Della Sala, 1987) contrasted with their good performance on perceptual tasks such as the Overlapping

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Figures Test (Poppelreuter, 1917) and a Face Recognition Test, which were specifically vulnerable in patients with right posterior hemispheric lesions. Object-to-gesture and gesture-to-picture association In a study of so-called “agnosia of use” (Morlaas, 1928) or “apraxia of use”, which belongs to the wider category of ideational apraxia (De Renzi et al., 1968), the patient was given, successively, a number of objects frequently employed in everyday life, such as a hammer, and was asked to take the object into his or her hands and show how he or she would use it. This simple task was performed well by all experimental groups, except 34% of aphasics, and the deficit tended to be both more frequent and more conspicuous in global (80%) and severe Wernicke’s aphasia (50% affected). Comparison with the scores obtained on a parallel test of imitation of gestures ruled out the possibility that the poor performances were due to ideomotor apraxia, and indicated that the low scores resulted from inability to choose the gesture normally associated with the appropriate use o f the object. Here again, the basic disturbance of aphasic patients was associative rather than psychomotor, and it could be tentatively described as the failure to synthesise two different aspects of the same concept —a definition reminiscent of Bay’s (1964) view of impaired concept formation. Conversely, when gestures were demonstrated for the patients, rather than requested of them, the results were quite similar. The association of seen gestures with the correct picture presented in a multiple-choice array was significantly impaired in aphasics, from 41% (Varney, 1982a) to 62% (Gainotti & Lemmo, 1976) of the examined sample, but not in nonaphasic brain-damaged patients (see also Duffy & Duffy, 1981; Duffy & Watkins, 1984; Daniloff et al., 1982 and reviews by Peterson & Kirshner, 1981, and by Christopoulou & Bonvillian, 1985). When the type of mismatch was specifically investigated (Varney & Benton, 1982), semantic errors were found to be predominant, representing 80-100% of the total errors of aphasics, parallel to what had been observed with the identification of meaningful sounds.

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Tactile object-to-object association It is appropriate to insert here the results of research carried out several years later, in order to verify the possibility of isolating an associativesemantic aspect of recognition, as distinct from an apperceptual-discriminative one, even in the field of somesthetic (tactile) recognition. Bottini et al. (1995) gave two somesthetic tests to groups of aphasic, left hemisphere-damaged nonaphasic, right hemisphere-damaged and control patients. In the first test the patient had to tactually explore, with the hand ipsilateral to the lesion and blindfolded, a small stimulus object (e.g. a ring) and identify it tactually among four foils. These consisted, for example, of a ring of a different type from that of the stimulus ring (correct response), an earring, a brooch (semantic responses), and a rubber band (unrelated response). In the second test, which was identical to the first as far as structure and procedure were concerned, small three dimensional meaningless shapes were used, and the patient had to tactually discriminate among them. The aphasic group significantly failed on the first (associative or semantic) task, but not on the second (apperceptual or discriminative); performance on the latter was specifically impaired in right braindamaged patients. When individual patients with a severe deficit strictly confined to one test were singled out, it was found that all the three patients specifically impaired on the associative test were left brain-damaged (and one of them was aphasic), while all the three patients specifically impaired on the apperceptual test were right brain-damaged. This double dissociation confirmed the results of a preceding study of tactile-visual matching (Bottini et al., 1991) and extended to the purely haptic recognition the notion of a semantic-conceptual disorder, linked to left hemisphere damage and, to a certain extent, to aphasia. This evidence clearly indicates a preferential concomitance of aphasia in general with failure on nonverbal association tasks. This constitutes the socalled associative-semantic level of agnosia (consisting of faulty identification of the meaning of percepts), as opposed to the purely perceptualdiscriminative level (consisting of impaired

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discrimination of the form of percepts) (Vignolo, 1972). This isolation of the semantic-conceptual level of the nonverbal recognition disorder can be traced back to earlier theories. Finkelnburg’s (1870) view that defective pantomime recognition reflected a higher, symbolic disorder has already been mentioned. Lissauer (1890) isolated an “associative” form of visual object agnosia, to be distinguished from an “apperceptual” form. Lewandowski (1907) described a specific inability to connect the appropriate colour with the corresponding line drawings. Kleist (1928) discussed agnosia for nonverbal noises by contrasting the “deafness for the meaning of noises” (Gerauschsinntaubheit) with other types of deafness, such as that for isolated sounds or noises (perceptive Gerauschtaubheit) and for sequences of noises (Gerauschfolgetaubheit) The experimental findings reviewed so far add to the theoretical autonomy of these “higher-level” nonverbal disorders the important qualification that they are specifically associated with lefthemisphere lesions and aphasia. Why should these matching defects be considered conceptual in nature? The main argument is that, in spite of their seeming differences, they all require basically similar conceptual operations, as they all essentially test the ability to grasp and handle the meaning of the presented stimuli. To correctly match stimuli that are perceptually very different, such as a miaowing sound and the picture of a cat, a blue pencil and a line drawing of waves, a realistic picture of a big, old-fashioned black iron key and a small, whitemetal flat car key, etc., one must realise that the members of each pair signify the same thing. In other words, one must recognise them, beyond the appearances, as representative of the same concept and thus associate them. Likewise, as the gesture of hammering is a constituent element of the concept of hammer (as are the object itself, its typical shape, the sound of the blows, etc.), it is difficult not to see in the so-called “apraxia of use” still another instance of the same conceptual disorder. This analogy also applies to the whole series of tasks requiring gesture-to-figure matching, investigated on the receptive rather than the expressive side. Therefore, it is not surprising that even pantomime

recognition, like all association tasks, is specifically impaired in aphasic patients.

Weigl’s test The conceptual disorder revealed by the failure of a sizeable proportion of aphasic patients on nonverbal association tasks can be examined more directly by means of a classic test of categoreal thinking, such as the Colour-Form Sorting Test, devised by Weigl in 1927 and included in Goldstein’s battery (Goldstein, 1948). In the modified version adopted by De Renzi et al. (1966) the patient was given 12 pieces of wood which, although all different from one another, could be sorted according to five discrete categories, i.e. colour, form, suit (symbol), thickness, and size. The patient was then asked to group them by putting together all the blocks that had “something in common”. The ability to sort out, one at a time, each single feature of the blocks (e.g. form), leaving aside the other features implied an ability akin to that involved in the matching tests, as, in order to sort and group together all round blocks, for example, it is necessary to realise that they all belong to the same concept, the concept of circle. Results indicated that impairment on Weigl’s test is specifically associated with lesions that also produce aphasia, and not merely with lesions anywhere in the left hemisphere, as maintained by McFie and Piercy (1952). In addition, they failed to establish a poorer performance by amnesic aphasics (contrary to Goldstein, 1924), probably because the authors chose only patients with very pure, hence rather mild, amnesic aphasia. Not all nonverbal tasks proposed by Goldstein (1948) as specific tests of abstract thinking proved to be equally adequate to the intended purpose, probably because they also involve nonconceptual abilities. This is the case with Holmgren’s (1877) Skein Test and Gottschaldt’s (1926, 1929) Hidden Figures Test, among others. The former requires primarily the capacity to perform subtle perceptual discriminations (as pointed out by De Renzi et al., 1972b) while the latter is heavily loaded with a visuospatial component (as stressed by Russo & Vignolo, 1967). Finally, mention should be made of the studies performed on hemisphere-damaged patients (but

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not specifically on aphasics) with the Wisconsin Card Sorting Test (WCST), a “Weigl-type test” developed in 1948 by Grant and Berg. This test assesses not only abstract reasoning but several other cognitive abilities as well, such as working memory and the ability to shift conceptual sets according to changing feed-back. Therefore, the evidence gathered with the WCST lesion studies and pointing mainly to frontal lobe damage, with a dubious prevalence of the left hemisphere (see Mountain & Snow, 1993, for a recent review), adds little to the present discussion. In summary, the isolation of the associative or semantic level of agnosia alerted the investigators to the possibility of a nonverbal conceptual impairment in aphasia, and this hypothesis was confirmed by the use of Weigl’s Test. Whenever other intellectual tests, implying subtle perceptual discrimination or visuospatial analysis, were employed, right-brain-damaged patients also performed poorly.

TENTATIVE HYPOTHESES AND RECENT RESEARCH The evidence reviewed so far indicates that disorders of nonverbal conceptual thinking were more severe and more frequent in aphasics, as a group, than in left and right nonaphasic braindamaged patients and controls. However, closer scrutiny of the findings pointed to the need for further clarification of two problems, i.e. (a) the unity or multiplicity of the nonverbal conceptual impairment, and (b) its relationship to the language defect. Are we dealing here with one single basic Grundstôrungl This is the more economical

interpretation of the data, but it requires that the performances of aphasics as a group on these tasks should correlate with one another to a highly significant degree. This, however, is not the case. Vignolo (1972) computed the correlations between sound-to-picture, colour-to-picture, and object-topicture matching in 99 focal brain-damaged patients who had been administered the three tests together, and found that, while correlations were indeed significant only among the 57 left brain-damaged patients (virtually all of whom were aphasics), the degree of such correlations was not sufficiently high to point to one single underlying disorder (see Table 13.1). The unitary nature of the conceptual impairment was also questioned by Varney (1982a) who failed to find a close correlation between sound-to-picture and gesture-to-picture matching. Inquiry into the relationship of the nonverbal conceptual defect and the language disorder immediately meets with a perplexing finding: conceptual thinking was impaired only in a fraction of the aphasic groups, ranging approximately from one-third to two-thirds, according to different samplings, tasks, and experimental designs. Some severe aphasics did not show the defect, which, in contrast, was occasionally present, though to a less severe degree, in a few left-brain-damaged patients without aphasia. Moreover, the attempt to quantify the correlation is hampered by the difficulty in finding an adequate behavioural parameter of the severity of aphasia. As previously mentioned, auditory verbal comprehension scores were chosen as the least inadequate measure of the overall degree of language impairment, as in all aphasics except the so-called “word-deaf’ this modality is relatively independent of the lower-level sensorimotor mechanisms involved in communication. The correlations between the conceptual defect and comprehension of words and sentences were not as

TABLE 13.1 Correlation among matching tasks in 57 aphasic patients.

Sound to picture Colour to picture

C o lo u r to p ic tu re

P ic tu re to o b ject

0.48 PcO.OOl -

0.36 Pmammillo-thalamic tract—►anterior thalamus—►cingulate gyrus (Fig. 15.6). According to Papez’s original view, this circuit was concerned with emotion, rather than with memory. The afferent and efferent connections of the medial temporal region, shown in Fig. 15.7, are more complex, however. The present chapter takes into consideration data from human amnesia (reviews of animal studies may be found in Aggleton & Sahgal, 1993; Squire, 1992b; ZolaMorgan & Squire, 1993). Medial temporal region and hippocampus Even though early observations date back to the beginning of the twentieth century (von Bechterew, 1900, reviews in Angelergues, 1969; Victor & Agamanolis, 1990), the association between lesions of the hippocampal formation and amnesia was definitely established in the 1950s in epileptic patients, such as the noted case HM, who underwent a bilateral medial temporal lobectomy, that removed the amygdaloid nucleus, the uncus, the anterior two-thirds of the hippocampus, and the hippocampal gyrus (Fig. 15.8). Removals confined to the uncus or the amygdala did not bring about persistent memory deficits, which were related to the extent of the hippocampal damage (Scoville, 1954; Scoville & Milner, 1957; Terzian & Dalle Ore, 1955). These observations were complemented by the finding of transient memory deficits after bilateral temporal lobectomies sparing the hippocampal region (Petit-Dutaillis, Christophe, Pertuiset et al., 1954). A recent MRI study in patient HM showed a bilateral medial temporal lobe lesion including most of the amygdaloid complex, the entorhinal cortex, and the anterior part of the hippocampal formation, with partial damage to the parahippocampal gyrus (Corkin, Amaral, González et al., 1997). Unilateral and bilateral lesions of the amygdaloid complex do not disrupt verbal acquisition (Andersen, 1978; Jurko & Andy, 1977), but deficits of visual learning have been reported (Tranel & Hyman, 1990). The amygdaloid complex

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FIGURE 15.6

Papez’s (1937) circuit (a) A medial view of the right cerebral hemisphere, showing the hippocampal formation, and its connections with the mammillary bodies through the fornix, the mammillo-thalamic tract, which projects to the anterior thalamic nuclei, and the cingulate gyrus; cc: corpus callosum, eg: cingulate gyrus, cp: posterior part of the cingulate gyrus (retro-splenial cortex), f: fornix, a: anterior thalamic nucleus, mt: mammillo-thalamic tract, m: mammillary nucleus, u: uncus, h: hippocampus, d: dentate gyrus, hg: hippocampal gyrus, (b) A schematic representation of the circuit.

FIGURE 15.7

Hippocampal formation (hippocampus or Ammon’s horn, subicular complex, dentate gyrus, entorhinal cortex). A schematic representation of the main connections; the dashed lines indicate connections with subcortical structures (source: Amaral & Insausti, 1990; Squire, 1992).

may however participate in the emotional aspects of learning (Babinsky, Calabrese, Durwen et al., 1993; LeDoux, 1992). Bilateral extensive medial temporal lesions, including the hippocampal formation and the amygdaloid complex, do not disrupt the implicit acquisition of emotional material (Tranel & Damasio, 1993). The seminal observation of Scoville and Milner (1957) was confirmed by successive reports of amnesia associated with bilateral infarctions (DeJong et al., 1969; Victor, Angevine, Mancall et al., 1961; Woods et al., 1982) and anoxic atrophy

(Cummings, Tomiyasu, Read et al., 1984; Duyckaerts, Derouesne, Signoret et al., 1985; Muramoto, Kuru, Sugishita et al., 1979) of the hippocampal formation. In some of these patients the amygdaloid complex and the uncus were preserved. MRI studies have revealed a 50% reduction of the volume of the hippocampal formation in amnesic patients, compared with control subjects (Press, Amaral, & Squire, 1989; Squire, Amaral, & Press, 1990). The patient of Kartsounis et al. (1995), with a severe anterograde and retrograde amnesia, had a MRI-assessed

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FIGURE 15.8 Bilateral medial temporal lobectomy in patient HM (redrawn from Scovilie & Milner, 1957). A recent MRI study suggests a minor rostrocaudal (5cm) and lateral extent of the lesion (Corkin, Amaral, González et al., 1997).

ischaemic bilateral damage confined to fields CA1 and CA2 of the hippocampus. A number of post-mortem examinations have provided additional and more precise evidence for a crucial role of the hippocampal formation. In the patient of Cummings et al. (1984) the bilateral lesions were confined to the hippocampus, in which the number of pyramidal cells was dramatically reduced; the subicular complex, the dentate gyrus, the parahippocampal gyrus and the adjacent white

matter were preserved. In the patient of Duyckaerts et al. (1985) a complete neuronal loss in fields CA2 and CA3 was found. Also in the patient of Victor and Agamanolis (1990) the lesion was confined to the hippocampus with a virtually complete loss of the pyramidal cells (fields CA1-CA4). In patient RB the loss of pyramidal cells was confined to field CAI (Zola-Morgan et al., 1986). Patient RB has been described as a relatively mild amnesic, compared, for instance to patient HM; his

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retrograde deficit was minor, confined to a few years before the onset of the disease. The hypothesis that structures other than the hippocampal formation play a relevant role in amnesia (the temporal stem, which includes bidirectional connections of the temporal cortex and the amygdaloid complex, but not of the hippocampal formation: Horel, 1978) is not supported by these findings. The memory deficit of patients such as RB may be comparatively mild, as some temporal structures, such as the entorhinal, perirhinal, and parahippocampal cortices were spared. Damage to the entorhinal cortex may disrupt bidirectional connections between the hippocampal formation and other areas of the brain (Hyman, Van Hoesen, Damasio et al., 1984; Hyman, Van Hoesen, Kromer et al., 1986). In a recent neuropathological study Rempel-Clower et al. (1996) found damage confined to the CA1 field of the hippocampal formation in a patient with anterograde amnesia but no retrograde amnesia for autobiographical events; by contrast, two patients, with more extensive damage to the CA1, CA2, CA3 fields, the dentate gyrus and the entorhinal cortex, exhibited both anterograde and temporally graded retrograde amnesia. Diencephalon It has long been known that lesions of midline structures, such as tumours near the third ventricle may be associated with amnesia (Brierley, 1977, for review; Ignelzi & Squire, 1976; Kahn & Crosby,

1972; McEntee et al., 1976; Williams & Pennybacker, 1954). Some grey nuclei and white matter fibre tracts play a relevant role in memory processes: the mammillary nuclei, the mammillo-thalamic tracts, and the anterior and dorso-medial thalamic nuclei. The main connections between the anterior thalamus, the cingulate gyrus, and the hippocampal formation are shown in Fig. 15.9. Mammillary nuclei. Bilateral lesions of these structures have been described in patients with alcoholic Korsakoff’s syndrome (Barbizet, 1963; Delay & Brion, 1954; Delay, Brion, & Elissalde, 1958a; Delay, Brion, & Elissalde, 1958b; Malamud & Skillicorn, 1956; Remy, 1942). In four such patients, in whom the memory deficit had been documented through quantitative tests, a pathological examination showed neuronal loss in the mammillary nuclei, and gliosis in a region localised between the third ventricle and the dorsomedial thalamic nucleus (Mair et al., 1979; Mayes, Meudell, Mann et al., 1988). In some patients, however, the mammillary nuclei were spared: three out of 70 patients in the series of Malamud and Skillicorn (1956), and in case VIII of Delay et al. (1956); in these early studies the pathological examination may have failed to detect minor abnormalities, revealed by the more recent assessments. Mammillo-thalamic tracts, dorso-medial and anterior thalamic nuclei. The dorso-medial

FIGURE 15.9

Hippocampal formation, anterior thalamic nuclei, and the cingulate gyrus. A schematic representation of the main connections; the thicker lines denote the quantitatively more relevant projections (source: Aggleton & Sahgal, 1993).

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thalamic nucleus, which is not a component part of the circuit described by Papez (1937), is frequently damaged in amnesic patients. This nucleus was damaged in 53% of the 70 patients with alcoholic Korsakoff’s syndrome reported by Malamud and Skillikorn (1956). Victor et al. (1971) described five patients without amnesia, who showed lesions of the dorso-medial thalamic nuclei, but not of the mammillary nuclei; by contrast, in amnesic patients both nuclei were damaged. On the basis of these findings they concluded that damage to the dorso-medial nuclei was a main correlate of amnesia (see also Victor, 1976, pp.264-66). In the patient of McEntee et al. (1976) a postmortem examination showed a bilateral neoplastic lesion of the dorso-medial thalamic nuclei, while the mammillary nuclei, the mammillo-thalamic tracts, and the anterior thalamus were spared. Other structures such as the septum pellucidum (see section Fronto-basal region) were damaged, however. Other single case studies have confirmed the association between amnesia and CT-assessed bilateral lesions of the dorso-medial thalamic nuclei (Schott et al., 1980; Winocur et al., 1984). Von Cramon et al. (1985) localised the CTassessed intra-thalamic vascular lesions of a number of patients with and without amnesia. They suggested an association between amnesia and lesions of the mammillo-thalamic tracts and of the internal medullary lamina, a white matter fibre tract which includes connections between the thalamus and the amygdaloid complex, and between the dorso-medial thalamic nucleus and the cortex. In line with this view, in the two patients without amnesia (#5 and #6) the lesions were confined to the dorso-medial and ventro-oral nuclei. In line with von Cramon et al.’s (1985) conclusions, in other patients not just the dorsomedial thalamic nuclei, but also the mammillothalamic tracts were damaged. In the patient of Nichelli et al. (1988) the CT-assessed bilateral lesion involved the internal medullary lamina, and the dorso-medial thalamic nucleus; also the right mammillo-thalamic tract was damaged. In the patient of Barbizet et al. (1981) the CT-assessed bilateral damage involved the mammillo-thalamic tracts, with a relative sparing of the dorso-medial

thalamic nuclei. In the series of eight patients with bilateral thalamic infarctions described by Gentilini et al. (1987), only patient #3 exhibited a severe and persistent amnesia: the lesion was confined to the mammillo-thalamic tracts, while both the dorsomedial nucleus and the internal medullary lamina were preserved. In the patient of Hankey and Stewart-Wynne (1988) post-mortem examination revealed a haemorrhagic lesion of the left anterior thalamic nucleus at the termination of the mammillo-thalamic tract. In the series of GraffRadford et al. (1990) the two patients (cases #1 and #2) with severe global amnesia had bilateral lesions involving the mammillo-thalamic tracts and the anterior nuclei. Two patients (cases #3 and #4) had a milder deficit, revealed by psychometric testing: in patient #3 the mammillo-thalamic tracts were spared, while the bilateral lesion involved the dorso-medial thalamic nuclei; in patient #4 the lesions were small and involved fibres from the inferior thalamic peduncle. Also the amnesic patient of Malamut et al. (1992) had bilateral MRIassessed lesions of the mammillo-thalamic tracts, while the dorso-medial nucleus was spared. In patient #2 of Kritchewski et al. (1987), who did not show amnesia, a pattern complementary to that of the patients of Barbizet et al. (1981), and Malamut et al. (1992) was found: two small bilateral MRI-assessed lesions of the dorso-medial thalamic nuclei, with preserved mammillary nuclei, and mammillo-thalamic tracts. It remains possible, however, that these lesions, which involved about 10% of the dorso-medial nuclei, were too small to bring about memory deficits. To summarise, the observations discussed here suggest that a lesion of the mammillo-thalamic tracts plays a relevant role, disconnecting the thalamus from the hippocampal formation. Furthermore, the baso-lateral limbic circuit (dorso-medial thalamic nucleus, subcallosal area, amygdaloid complex) may be a component of the neural basis of LTM processes (discussion in von Cramon, 1992). The empirical observations that support this view come from patients with small infarctions of the left internal capsule, assessed by CT (Kooistra & Heilman, 1988, posterior limb) and MRI (Markowitsch, von Cramon, Hofmann et al., 1990, genu), who had deficits concerning mainly

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verbal memory. The lesions, involving the inferior thalamic peduncle, may disconnect the dorsomedial thalamic nucleus from the subcallosal area and the amygdaloid complex (through a lesion of the ventral amygdalofugal fibres). Lesions of the amygdaloid complex do not produce relevant memory deficits, however. Cingulate gyrus In psychiatric patients, Whitty and Lewin (1960) reported that bilateral anterior cingulectomy produced a transient confusional state and a memory disorder, characterised by a defective temporal localisation of events. This clinical observation, however, was not confirmed by a study of Long et al. (1978). Using an extensive neuropsychological battery in a series of 19 psychiatric patients they were unable to detect memory deficits both before the surgical operation and 3 to 12 months later. Valenstein et al. (1987) described a patient with amnesia associated with a left-sided lesion of the splenium of the corpus callosum, of the posterior part of the cingulate gyrus, posterior to the splenium, and possibly of the fornix and of the hippocampal commissure. The patient, TR, suffered a severe amnesia: for instance at noon he did not remember what he had done in the morning, even though the psychometric assessment showed an anterograde deficit involving mainly verbal memory, and a retrograde amnesia for about four years. Valenstein et al. (1987) ascribed this retrosplenial amnesia to a disconnection between the anterior thalamus and the hippocampal formation, as the retrosplenial cortex is a component part of a pathway, different from Papez’s (1937) circuit, which connects these two brain regions. In patient TR a PET study showed hypometabolism in the ipsilesional left thalamus, and increased metabolic activity in the left frontal cortex (Heilman, Bowers, Watson et al., 1990). Also in patients suffering from tumours of the splenium of the corpus callosum, the memory deficit may be attributed to damage of the posterior part of the cingulate gyrus (retro-splenial cortex), and of the fornix (Rudge & Warrington, 1991). The different effects of anterior vs. posterior lesions of the cingulate cortex (minor vs. severe

memory deficits) may reflect major damage to the connections between the anterior thalamus and the hippocampal formation, produced by a lesion of the retrosplenial cortex (Aggleton & Sahgal, 1993). Fornix Clinical observations in epileptic patients who underwent a surgical section of the fornix suggest that this white matter tract does not play a main role in LTM processes (review in Garcia-Bengochea & Friedman, 1987). Woosley and Nelson (1975) did not detect clinically relevant memory deficits in a patient with bilateral severe neoplastic damage to the fornix, and preserved hippocampal formation and dorso-medial thalamic nuclei. In other patients, however, damage to the fornix was associated to memory deficits. The patient of Brion et al. (1969) had anterograde and retrograde amnesia, and a bilateral ischaemic lesion of the fornix, with secondary atrophy of the mammillary nuclei. In the patient of Heilman and Sypert (1977) the surgical ablation of a tumour involving the posterior part of the fornix brought about an anterograde deficit, assessed through psychometric testing, and a clinically relevant retrograde amnesia. During the Vietnam war, the patient of Grafman et al. (1985) suffered a bilateral traumatic lesion of the fornix, and of other cortical and subcortical structures, including the anterior thalamic nuclei. The patient had a mild learning deficit for both verbal and spatial material, without retrograde amnesia, was able to live on his own, to work in a clerical position, and was aware of the memory impairment. Patient KW, who had a neoplastic lesion of the left fornix, exhibited a verbal memory deficit (Tucker, Roeltgen, Tully et al., 1988). Hodges and Carpenter (1991) reported two patients, with fornix damage after the removal of third ventricle colloid cysts, who had an anterograde deficit and a mild retrograde amnesia (less than one year) (Gaffan & Gaffan, 1991, for review; Gaffan, Gaffan, & Hodges, 1991). Also the patient of D’Esposito et al. (1995b) showed no retrograde deficits. To summarise, at least in some patients, there is evidence that damage to the fornix may produce an anterograde deficit, with a relative sparing of memory for past events.

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Fronto-basal region The rupture or surgical repair of aneurysms of the anterior communicating artery may produce severe memory deficits, associated with personality changes, anosognosia, and confabulation (Alexander & Freedman, 1984; Damasio, GraffRadford, Eslinger et al., 1985; Irle, Wowra, Kunert et al., 1992; Lindqvist & Norlen, 1966; Phillips, Sangalang, & Sterns, 1987; Talland et al., 1967; Vilkki, 1985; Volpe & Hirst, 1983). The damage associated with amnesia involves the median and para-median basal forebrain. This region, whose boundaries are not precisely defined, includes the septal area, the substantia innominata, and parts of the amygdaloid complex. The septal nuclei have bi-directional connections with the hippocampal formation, mainly through the fornix (Goldberg, 1984; Phillips etal., 1987;Taren, 1965). In one patient the removal of a tumour of the septum pellucidum produced amnesia (Berti, Arienta, & Papagno, 1990). In two other patients the memory deficit has been attributed to a lesion of the septal nuclei (von Cramon, Markowitsch, & Schuri, 1993), and to a septo-hippocampal disconnection, produced by damage to a dorsal septo-hippocampal pathway, different from the fornix (von Cramon & Schuri, 1992). From structures to circuits The anatomo-clinical correlation studies discussed in the previous sections suggest that damage to a number of connected cerebral areas may produce amnesia. Seen in this perspective, amnesia may be considered as a disconnection syndrome, in which the deficit is produced not only by the focal lesion, but also by the dysfunction of a circuit of which the damaged area is a component part (von Cramon, 1992; Warrington & Weiskrantz, 1982; Weiskrantz, 1985). In line with this view, in 11 patients with mixed aetiology (alcoholic Korsakoff’s syndrome, anoxia, cerebrovascular attacks, aneurysms of the anterior communicating artery) with diencephalic (thalamus, mammillary nuclei), or no detectable damage, as assessed by MRI, Fazio et al. (1992) showed through PET a bilateral reduction of metabolic activity in the fronto-basal and medial temporal regions, in the thalamus and in the cingulate cortex. In a patient with a predominantly

verbal memory deficit and a left thalamic infarction (anterior nuclei, mammillo-thalamic tracts, internal medullary lamina) PET showed hypometabolism not only in the anterior thalamus, but also in the posterior part of the ipsilateral cingulate gyrus (Clarke, Assal, Bogousslavsky et a l., 1994). In the patient of Markowitsch et al. (1997), who become amnesic after a heart attack, MRI showed no focal damage, while PET revealed bilateral general hypometabolism, more pronounced in the thalamus and in the mesial and polar temporal regions. In patients with alcoholic Korsakoff’s syndrome Paller et al. (1997) found hypometabolism in the middle and inferior frontal cortex, and in the cingulate gyrus. In the thalamic and hippocampal regions, however, glucose metabolism was comparable to that of the alcoholic control group (but see the different findings of Fazio et al., 1992), and no significant correlation was found between delayed memory performance and metabolism in these structures. The few published studies assessing regional metabolism in amnesic patients concur in suggesting that the cerebral dysfunction may involve a number of connected regions, in addition to the areas in which structural damage is present. However, the pattern of dysfunction may differ according to the aetiology of amnesia, and, perhaps, to the site of the lesion. The neural correlates o f implicit memory The investigation of the performance of braindamaged patients with lesions different from those of amnesics has provided relevant data concerning the neural correlates of implicit memory. Patients with Huntington’s disease, a disorder producing a progressive degeneration of the caudate nucleus, exhibited defective learning of a number of visuo-motor and visuo-perceptual tasks (pursuitrotor, reading mirror-reversed text) and did not show the adaptation-level effect. Stem-completion, by contrast, was preserved. Patients with senile dementia of the Alzheimer type showed an opposite pattern of impairment (Heindel, Butters, & Salmon, 1988; Heindel, Salmon & Butters, 1991; Heindel, Salmon, Shults et al., 1989; Martone et al., 1984; Shimamura et al., 1987). Patients with Huntington’s disease are also impaired in problem-

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solving tasks, such as the Tower of Hanoi puzzle (Butters et al., 1985). Visual repetition priming for words and nonwords is disrupted by temporo-occipital lesions, in the vascular territory of the posterior cerebral artery (Carlesimo, Fadda, Sabbadini et al., 1994; Swick & Knight, 1995). In a patient with bilateral occipital damage visuoperceptual, but not conceptual (meaning-based), priming was defective, visual recognition (explicit) memory being preserved; a patient with bilateral medial-temporal lesions (HM) showed the opposite dissociation (Keane, Gabrieli, Mapstone et al., 1995). Habit learning (the formation of associations in which a neutral stimulus comes to elicit a certain response as a function of repeated reinforcement) is defective in patients with Parkinson’s disease (a degenerative disorder producing atrophy of the substantia nigra and a consequent major reduction of the dopaminergic projection to the basal ganglia) but preserved in amnesic patients. The two groups showed an opposite pattern for declarative memory for facts about the testing episode, which was preserved in patients with Parkinson’s disease, and defective in amnesics (Knowlton, Mangels, & Squire, 1996). These results provide evidence to the effect that the neural correlates of implicit memory are different from those of the explicit systems, impaired in amnesia, and include structures such as the basal ganglia, the cerebellum, and the sensory and motor cortices (reviews in Salmon & Butters, 1995; Ungerleider, 1995). Activation studies In the last few years the neural correlates of memory function have been extensively explored in normal subjects by functional neuroimaging methods. The present section summarises the main findings, with the cautionary note that this is a rapidly developing field. A general pattern emerging from these studies is the association between specific tasks and the activation of sets of discrete cerebral regions. These neurocognitive networks, which overlap in part across different tasks, may be currently conceived as the neural bases of mental activities. A number of studies have investigated the neural structures active during encoding and

retrieval processes in LTM. In the experiment by Shallice et al. (1994), who used a verbal learning task, encoding was associated with activation in the left pre-frontal and retro-splenial cortices, retrieval with activation in the right pre-frontal cortex, and in the precuneus, on both sides. This hemispheric asymmetry has been found also by Tulving, Kapur, and their co-workers (review in Tulving, Kapur, Craik et al., 1994a). A “deep” encoding (a “living/nonliving” decision about a word) produced a higher recognition performance, compared to a “shallow” encoding (deciding whether or not a word included the letter “a”), and was associated to activation in the left inferior prefrontal cortex (Kapur, Craik, Tulving et al., 1994). Retrieval of verbal material activated the right dorso-lateral prefrontal cortex, the parietal cortex on both sides, and the anterior part of the left cingulate gyrus (Tulving, Kapur, Markowitsch et al., 1994b). This left (encoding and retrieval from semantic memory: Cabeza & Nyberg, 1997, for review) vs. right (retrieval) hemispheric asymmetry has been confirmed by a number of studies (Buckner, Petersen, Ojemann et al., 1995; Demb, Desmond, Wagner et al., 1995; Nyberg, McIntosh, Cabeza et al., 1996a). The role of the prefrontal cortex, with the right/left asymmetry mentioned earlier, appears to be related more to retrieval attempt or mode than to the actual successful recovery (ecphory) of stored material (Kapur, Craik, Jones et al., 1995; Nyberg, Tulving, Habib et al., 1995; Rugg, Fletcher, Frith et al., 1996). In the study by Nyberg et al. (1995) successful retrieval was associated with activation of a large set of frontal, temporal, and subcortical regions. Finally, an association between autobiographical memory and activation in the temporal, insular, and posterior cingulate regions of the right hemisphere has been reported (Fink, Markowitsch, Reinkemeier et al., 1996). The lack of hippocampal activation in the encoding and retrieval stages is remarkable, in the light of the well known association between medial temporal damage and amnesia (discussion in Haxby, 1996). Some recent studies have however provided evidence for a role of the medial temporal region in conscious recollection. In a task requiring the recall of supraspan lists of words, Grasby et al. (1993a) found a correlation between performance

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level in the central part of the list (which is based on LTM processes) and rCBF in the hippocampal region, more on the left side; recall of within-span lists showed no correlation with hippocampal activation (but see Grasby, Frith, Friston et al., 1993b). Nyberg et al. (1996b) showed a correlation between performance level in an episodic memory task (proportion of recognised auditory words) and rCBF in the left medial temporal lobe. Schacter et al. (1996) found activation of the right hippocampal region during successful recall of visually presented words. Activation of the hippocampal formation during object recognition has also been reported (Schacter, Reiman, Uecker et al., 1995).Owen et al. (1996) found activation of the right parahippocampal gyrus in the retrieval of object location. In a recent fMRI study Gabrieli et al. (1997) showed activation of discrete medial temporal lobe regions during retrieval (subiculum) and encoding (parahippocampal cortex) of meaningful material (line drawings). The hippocampal region, furthermore, seems to be also involved in other and more general aspects of stimulus processing, such as novelty detection (Stern, Corkin, González et al., 1996; Tulving, Markowitsch, Kapur et al., 1994c). The neural correlates of the facilitation effects of visual priming (stem completion) include a reduction of activation in the visual and temporal cortices, mainly in the right hemisphere (Buckner et al., 1995; Schacter et al., 1996; Squire, Ojemann, Miezin et al., 1992). In line with these findings Marsolek et al. (1992) found in normal subjects a left visual half-field (right hemisphere) superiority in stem completion. Finally, a number of studies have explored the neural correlates of working memory, a complex system involved in the temporary retention of verbal or nonverbal material, prior to and during the application of procedures, strategies, and analyses (see Baddeley, 1992, 1996). The concurrent performance of two tasks (D’Esposito, Detre, Alsop et al., 1995a), self-ordered and conditional memory tasks (Petrides, Alivisatos, Evans et al., 1993a; Petrides, Alivisatos, Meyer et al., 1993b) activate the dorso-lateral prefrontal cortex (review in Fiez, Raife, Balota et al., 1996).

Unilateral lesions o f Papezs circuit and o f related areas Unilateral lesions and global amnesia. Global amnesia is typically associated with bilateral diencephalic or medial temporal damage. Unilateral lesions do not usually produce amnesia, and, if this is the case, the damage more frequently involves the left hemisphere. In a series of 90 patients who underwent unilateral mesial temporal lobectomies, Penfield and Milner (1958) found a global memory disorder, concerning both verbal and nonverbal material, only in two cases, with a left-sided ablation of the amygdala, the uncus, and the hippocampal formation. On the basis of EEG recordings, they suggested however that the global amnesia was produced by the presence of additional contralateral damage. In one of these patients a post-mortem exam confirmed this hypothesis, showing atrophy of the right hippocampal formation (Penfield & Mathieson, 1974). Also in the patient of Dimsdale et al. (1964), who had a global and persistent amnesia produced by a right-sided medial temporal lobectomy, a sclerosis of the contralateral left hippocampal formation was subsequently found (Warrington & Duchen, 1992). In the patient of Mohr etal. (1971), who had a persistent and severe memory deficit, the post-mortem exam showed an ischaemic lesion confined to the left hippocampal formation, and a small right thalamic infarction. Left thalamic lesions may also produce an amnesic syndrome (Speedie & Heilman, 1982; Teuber et al., 1968, patient NA; von Cramon et al., 1985, patient #4). In these patients the retrograde deficit was mild (NA, the patient of Speedie & Heilman) or absent (the patient of von Cramon et al.). In the patient of Speedie and Heilman (1982) the anterograde deficit was more severe for verbal material. In patient NA, MRI showed a lesion of the left thalamus (internal medullary lamina, intralaminar, dorso-medial, ventral-anterior, and lateral nuclei), the mammillo-thalamic tract, and the post-commissural fornix; the mammillary nuclei were damaged on both sides (Squire et al., 1989a). To summarise, in some patients with global amnesia and unilateral lesions, a contralateral

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damage has subsequently been shown (Penfield & Mathieson, 1974; Squire et al., 1989a; Warrington & Duchen, 1992). In the PET study of Fazio et al. (1992) patients #10 and #11 had unilateral right-sided lesions (thalamus, fronto-basal region), but the reduction of regional metabolism was bilateral. To summarise, severe and persistent global amnesia is associated in many patients with bilateral damage or dysfunction. Minor memory deficits associated with unilateral damage. Even though unilateral cerebral lesions may, as noted earlier, produce a global amnesia, this is not the most frequent pattern of impairment. More frequently, unilateral damage brings about mild memory deficits, which may be revealed through psychometric testing. Unilateral temporal lobectomies in the hemisphere dominant for language (the left in the majority of patients) selectively disrupt learning and retention of verbal material, sparing nonverbal stimuli, such as spatial positions, faces, melodies, or meaningless patterns. Temporal lobectomies in the right, non-dominant, hemisphere produce an opposite pattern of impairment (Iversen, 1977; Milner, 1967, 1971, 1972; Paivio & te Linde, 1982). The relevant role of the left medial temporal regions has been confirmed by the finding that verbal LTM is defective in patients with ischaemic lesions in the vascular territory of the left posterior cerebral artery, which frequently involve the hippocampal formation (De Renzi, Zambolin, & Crisi, 1987b; Vallar, Papagno, & Cappa, 1988). In the series of patients with pure alexia of Damasio and Damasio (1983), the two patients with defective verbal LTM (cases #5 and #6) had vascular lesions involving the mesial temporal region (hippocampal formation, parahippocampal gyrus). Von Cramon et al. (1988) reported a series of 30 patients with ischaemic lesions in the vascular territory of the left posterior cerebral artery. In all patients auditory-verbal span was normal. The 12 patients with defective learning and retention had lesions involving the posterior parahippocampal gyrus and its afferent and efferent connections in the collateral isthmus (related discussion in Squire, 1992b); in three such patients the hippocampal formation was also damaged. By contrast, both left-sided lesions

sparing these areas and right-sided lesions did not affect verbal LTM. Unilateral thalamic lesions may also produce a similar pattern of impairment. In a patient with ischaemic damage to the right dorso-medial thalamic nucleus, learning of visuospatial material was defective, while memory for verbal material and past events was preserved; perceptual processes were also affected, however (Speedie & Heilman, 1983). Conversely, left dorso-medial thalamic lesions may selectively affect verbal LTM, sparing verbal STM and learning of nonverbal material (Michel, Laurent, Foyatier et al., 1982; Mori, Yamadori & Mitani, 1986). A clinical exam may be unable to detect these mild deficits of long-term learning and retention. Patients with posterior lesions of the right hemisphere, however, in addition to a defective performance in visuospatial learning tasks (e.g. a maze) may show anterograde and retrograde topographical amnesia. The cardinal feature of the disorder is the patients’ defective spatial orientation in both unfamiliar (e.g., the hospital’s wards) and familiar environments (De Renzi, 1982; De Renzi, Faglioni, & Villa, 1977b). Selective retrograde amnesia In some patients, electrophysiological and neuroimaging assessments (e.g. EEG, CT, MRI, PET) did not show any definite structural lesions or functional disorder (Andrews et al., 1982; De Renzi et al., 1995; Stracciari et al., 1994). In other patients CT or MRI did not show structural lesions, but EEG suggested a left temporal dysfunction (Damasio et al., 1983; Kapur et al., 1986; Kapur et al., 1989; Roman-Campos et al., 1980). In two such patients the initial memory deficit was a transient amnesia, global (RomanCampos et al., 1980) and epileptic (Kapur, 1993b). Patient JV (Stuss & Guzman, 1988), who exhibited a severe retrograde deficit (mainly autobiographical, but also for public events), and a mild anterograde deficit, had a left anterior temporal dysfunction, assessed by MRI and PET. In patient MM (Lucchelli et al., 1995) PET showed a bilateral reduction of metabolic activity in the posterior part of the cingulate gyrus. In the patient of Mattioli et al. (1996) PET revealed bilateral hypometabolism

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in the temporal regions, including the hippocampal formation. Other patients had focal structural lesions. In the case of Goldberg et al. (1981) CT showed bilateral post-traumatic temporal lesions and a mesencephalic damage (median and left paramedian zones, ventral tegmental area). In patient LD (Eslinger et al., 1993; O’Connor et al., 1992) MRI showed extensive post-encephalitic lesions in the right hemisphere (temporal pole, lateral and medial temporal regions, infero-medial frontal lobe, insula, inferior parietal lobule), and very limited damage to the left hemisphere (region of the collateral sulcus, insula, posterior ventromedial frontal cortex). In the patient of Markowitsch et al. (1993a,b) the post-traumatic lesion (more extensive on the right side) involved the temporal poles, the fronto-basal cortex, the right basal and lateral temporal areas, and the left temporo-parietal regions; the hippocampal formation was spared. In the post-encephalitic patient Felicia (De Renzi & Lucchelli, 1994) MRI showed bilateral temporal lesions, including both the temporal pole and the hippocampal region, more extensive on the left side. These three patients, however, had also mildto-moderate anterograde deficits, reported as less severe than retrograde amnesia. LD (O’Connor et al., 1992) had additional severe visuo-perceptual and constructional deficits, and Felicia (De Renzi & Lucchelli, 1994) had a category-specific semantic disorder. In patient LT (Kapur et al., 1992) the MRI-assessed post-traumatic bilateral lesion involved the anterior part of the temporal lobes, while the hippocampal formation was spared. A patient described by Calabrese et al. (1996) had right-sided inferior lateral prefrontal and temporal lesions, also involving the amygdalohippocampal region; minor left-sided frontotemporal damage was also present. To summarise, the available anatomical data suggest an association between bilateral temporal lesions and retrograde amnesia, with minor, or absent, anterograde deficits (see also the recent cases of Kroll, Markowitsch, Knight et al., 1997). The study of Barr et al. (1990) suggests a more prominent role of the left hemisphere: left, but not right, temporal lobectomies produced retrograde amnesia for public (verbal identification of famous

faces, knowledge of TV programmes) and autobiographical events, even though the latter deficit was less severe. The lesions were extensive, involving the hippocampal formation, part of the lateral temporal cortex, the amygdaloid complex and the uncus. The left and the right hemisphere may contribute to different aspects of memory for past events. Suggestions have been made that visuospatial processes and the right hemisphere may play a relevant, though not exclusive, role in recalling autobiographical episodic events (Markowitsch, 1995; O’Connor et al., 1992; Ogden, 1993, patient MH with autobiographical amnesia). The left hemisphere, by contrast may be more specifically involved in memory for semantic facts and public events (De Renzi et al., 1987a; Grossi et al., 1988; Markowitsch, 1995).

DEFICITS OF SHORT-TERM MEMORY Since the late 1960s patients have been described with selective, material-specific, STM impairments, concerning auditory-verbal or visuospatial material. The anatomical correlates of these disorders are focal cortical lesions.

Deficits of visual and spatial STM In brain damaged patients with focal lesions Warrington and Rabin (1971) assessed immediate memory for sequences of five stimuli (digits, letters, lines) simultaneously presented through a tachistoscope. Left brain-damaged patients had a level of performance lower than that of right braindamaged patients, who, in turn, were comparable to normal subjects. Patients with left posterior (parietal, occipital, temporo-parietal) damage were most severely impaired. These patients had also a disproportionately low auditory-verbal span, but its correlation with visual span and with performance on the Vocabulary subtest of the Wechsler Adult Intelligence Scale was low. This makes unlikely an interpretation of the visual memory deficit in terms of a co-occurring aphasic disorder. Similarly, a visual half-field deficit cannot account for this impairment: a

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comparable proportion of right brain-damaged patients with posterior lesions had eontralesional hemianopia, with no impairment of visual immediate memory. Finally the memory disorder cannot be attributed to a perceptual deficit. In a comparable series, left brain-damaged patients were not disproportionately impaired in dot detection and letter recognition tasks (Warrington & Rabin, 1970), and had a normal performance in a number estimation task (Warrington & James, 1967), in which, conversely, right brain-damaged patients were defective. The visual memory deficit of left brain-damaged patients with posterior lesions may reflect therefore the impairment of a visual STS. The patients’ preserved ability to make numerosity judgements makes unlikely an interpretation in terms of defective iconic memory. De Renzi and Nichelli (1975) investigated visuospatial memory using the block-tapping test devised by R Corsi (quoted by Milner, 1971). In this task the subject is presented with nine cubes, arranged in nonsymmetric positions on a board, and receives instructions to reproduce the sequence of blocks touched by the examiner. Using sequences of increasing length, a measure of visuospatial STM may be obtained. Right brain-damaged patients with left visual half-field deficits, and presumably posterior lesions, were disproportionately impaired, compared to both control subjects and left braindamaged patients without hemianopia. Patients with left hemisphere lesions and hemianopia scored worse than control subjects, but did not differ from the other patient groups. Finally, the auditory-verbal span of patients with right-sided lesions and hemianopia was normal. These results suggest that the posterior regions of the cerebral hemispheres, with a more relevant role of the right side, are involved in the short-term retention of visuospatial material. All patients were able to reach single cubes touched by the examiner, using the ipsilesional hand. Perceptual or motor impairments cannot therefore account for the span deficit, which may be interpreted in terms of defective visuospatial STS. The pattern of impairment of some patients may be explained in the light of a two-component view of memory processes. In the series of De Renzi and Nichelli (1975) two right brain-damaged patients with left visual half-field deficits had a low

visuospatial span, without visuo-perceptual deficits and hemineglect. These patients were able to learn the path of a visual maze, and showed no evidence of topographical amnesia. Another right braindamaged patient exhibited the opposite dissociation: Preserved visuospatial span, topographical amnesia, and defective maze learning. These results support the distinction between STM and LTM processes, but are not compatible with a serial organisation of the system, such as that shown in Fig. 15.1, suggesting instead a parallel architecture. A serial organisation does not predict selective STM deficits, because they would also produce a LTM impairment. By contrast, a parallel architecture, in which, after perceptual analysis, the signal independently gains access to short-term and long-term storage systems, is compatible with the existence of selective deficits of either component (discussion in Shallice, 1970). The early observations of De Renzi and Nichelli (1975) have been confirmed by Hanley et al. (1991). Their right brain-damaged patient ELD had a low visuospatial span and her immediate memory for unknown faces was defective. ELD’s performance was also defective in a task requiring the recall of sentences of increasing length, which described the spatial position of a sequence of digits, in a 4 x 4 matrix. Auditory-verbal span was normal, and the presence of the effects of phonological similarity suggests that the phonological STS-rehearsal system (Fig. 15.2) was preserved. Visuo-verbal span was normal also during articulatory suppression (the continuous uttering of an irrelevant speech sound). Under these conditions, visuo-verbal material does not enter the phonological STS, and may be held in a visual STS, different from the visuospatial system damaged in the patient. Finally, ELD’s performance was also defective in tasks requiring spatial operations on mental images, such as rotation, while access to visual nonspatial representations stored in LTM (the prototypical colour of an object, size judgements) was preserved. Recognition of other nonverbal materials (unfamiliar faces, objects, and voices) was also defective (Hanley, Pearson, & Young, 1990). The deficit of patient LH (Farah, Hammond, Levine et al., 1988) was opposite to that of ELD.

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This patient was able to perform spatial operations on mental images (rotation of shapes and letters, memory for matrices), but generation of visual images was defective. LH’s bilateral lesions involved the temporo-occipital areas and the right inferior frontal region. To summarise, the observations of De Renzi & Nichelli (1975) and Hanley et al. (1990, 1991) on the one hand, and those of Warrington and Rabin (1971) and Farah et al. (1988) on the other, provide evidence for a distinction between visuospatial and visual short-term retention systems. Other short-term components may exist. Davidoff and Ostergaard (1984) suggested a STS for colours, participating in the activation of a specific lexicon in naming tasks. The main deficit of their patient, who had a left temporo-occipital lesion, was colour anomia, while pointing to colours named by the examiner was preserved. The deficit was specific for colours, as immediate memory for meaningless shapes was normal.

Deficits of auditory-verbal STM It has long been known that aphasic patients with lesions in the left hemisphere have a pathologically low auditory-verbal repetition span (Zangwill, 1946). Selective deficits were reported only in the late 1960s, however, Luria et al. (1967) described two patients (B and K) who had suffered a traumatic lesion of the temporal lobe and showed a defective immediate repetition of sequences of phonemes, words, and digits. Luria et al. (1967) suggested a selective deficit of auditory-verbal memory traces. Warrington and Shallice (1969) reported in left brain-damaged patient KF a selective deficit of auditory-verbal span, which they interpreted in terms of the impairment of auditory-verbal STM. In the following years, a number of patients with a similar pattern of impairment have been described. The deficit has three main features: (1) auditory-verbal span for sequences of verbal material (digits, letters, words) is selectively impaired; (2) the patients’ level of performance is higher with visual presentation of the stimuli; (3) the impairment cannot be attributed to deficits of acoustic-phonological analysis or of processes involved in the production of a verbal

response (Shallice & Vallar, 1990; Vallar & Papagno, 1995). The latter characteristics of the deficit indicate that the pathological reduction of span is due to a memory impairment. In many patients repetition of individual stimuli was errorless. In addition, some patients had a normal performance in tasks requiring phonological analysis, but posing a minimal memory load (e.g. same-different judgements on consonant-vowel pairs differing in a single distinctive feature, phonemic categorisation: review in Vallar & Papagno, 1995). In this type of patient the memory deficit is primary, being produced by the pathologically reduced capacity of the auditory-verbal STS, and cannot be attributed to perceptual deficits. Other patients show associated deficits of phonological analysis. In these cases, the memory deficit is secondary, being produced, wholly or in part, by a perceptual disorder (Vallar, Basso, & Bottini, 1990; Vallar & Papagno, 1995). The span performance of some patients did not improve when a nonverbal response, such as recognition by pointing, was used (e.g. patients PV and KF: Basso, Spinnler, Vallar et al., 1982; Vallar, Corno, & Basso, 1992, for a group study; Warrington & Shallice, 1969). This rules out the hypothesis that the repetition deficit is produced by the impairment of output processes, involved in speech production, According to the traditional taxonomy of language disorders, these patients may be classified as conduction aphasics, because they show a disproportionate impairment of repetition. In the early 1970s a number of alternative interpretations have been proposed, in the context of the WemickeLichtheim model of aphasia, Kinsboume (1972) suggested a disconnection between processes involved in the analysis of the stimulus and processes participating in response production, with a reduced capacity of the transmission pathway; and Tzortis and Albert (1974) a specific deficit of memory for sequences; and Strub and Gardner (1974) and Allport (1984a, 1984b) a central phonological deficit. The hypothesis of a reduced capacity of the connection between input and output processes does not explain the patients’ defective

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performance in conditions in which the memory load was minimal (a single letter), such as the Brown-Peterson task (patients PV and KF: Basso et al., 1982; Warrington & Shallice, 1972), or when the patient was required to communicate whether or not a stimulus had been presented in the sequence (patients MC and KF: Caramazza, Basili, Koller et al., 1981; Shallice, 1970). In this probing task no signal had to be transmitted to output processes. The hypothesis of a defective memory for sequences does not explain the patients’ impairment in the recency part of the free recall curve (Vallar & Papagno, 1986; Warrington, Logue, & Pratt, 1971), and in the Brown-Peterson task. In these conditions no serial recall was required. The hypothesis of a central phonological deficit does not account for the selectivity of the span disorder, which may occur in the absence of phonological impairments of both stimulus analysis and response production. To summarise, the selective deficit of auditoryverbal span cannot be readily interpreted in the light of the traditional anatomo-clinical model of aphasia. The clinical syndrome of conduction aphasia, in which repetition is disproportionately impaired, fractionates into discrete disorders: 1. Defective auditory-verbal STS: the patients’ immediate memory of sequences of auditoryverbal stimuli is defective, while repetition of individual words and spontaneous speech are preserved. 2. Defective phonological processes involved in speech production (Dubois, Hecaen, Angelergues et al., 1973; Kohn, 1992): repetition of individual words is defective— and the deficit is more severe with polysyllabic and low frequency items—while span for highfrequency stimuli such as digits may be relatively preserved (Damasio & Damasio, 1980). In one patient the impairment has been explained in terms of defective rehearsal (see section The fractionation o f auditory-verbal STM, and Vallar, Di Betta, & Silveri, 1997). 3. Disconnection between phonological processes involved in language perception and production: repetition is defective, more than spontaneous speech (Green & Howes, 1977;

Kinsbourne, 1972; McCarthy & Warrington, 1984). Auditory-verbal STM: A selective deficit Most patients with a selective deficit of auditoryverbal span have a higher level of performance when the stimuli are presented visually (Shallice & Vallar, 1990; Vallar & Papagno, 1995). Normal subjects, by contrast, show a better serial and free recall of the final positions of the list when presentation is auditory (modality effect: Crowder, 1976; Watkins & Watkins, 1980). This auditory/visual dissociation indicates that the affected STM system is not supramodal (Atkinson & Shiffrin, 1971; Waugh & Norman, 1965), fractionating instead into an auditory-verbal (phonological) STS and a visual-verbal STS (see Fig. 15.2 and Deficits of visual and spatial STM). Coding in the latter store may be in terms of shape. Warrington and Shallice (1972) showed that patient KF made visual errors (confusions among visually similar letters, such as O vs. Q, P vs. R) in a visual span task. Normal subjects, by contrast, also make phonological errors when the stimuli are presented visually; this indicates retention in the phonological STS, after phonological recoding. Fig. 15.10 shows the auditory/visual dissociation in the recency part of the free recall curve of patient PV: the deficit of recency was confined to the auditory modality, suggesting a selective deficit of the auditory-verbal STS (Vallar & Papagno, 1986). The auditory-verbal STS is specific for verbal material. The performance of patients KF and JB (Shallice & Warrington, 1974) in the short-term recall of sequences of three familiar sounds was comparable to that of control patients, who were engaged in a concurrent articulatory suppression task (i.e. the continuous uttering of an irrelevant speech sound, such as blah, blah, blah). This prevents the operation of the rehearsal process, which is not utilised by patients with a defective auditory-verbal span (see later). In the three patients of Tzortis & Albert (1974) recall of nonverbal sequences (meaningful sounds and rhythms) was defective. Their performance, however, was not compared to that of normal subjects during articulatory suppression. The putative impairment of Tzortis and Albert’s (1974) patients could

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FIGURE 15.10

Deficits of auditory-verbal STM. Immediate free recall of 12 word lists by patient PV and 16 normal control subjects. The patient’s performance in the recency part of the list was defective with auditory (a), but not with visual (b), presentation of the stimuli (redrawn from Vallar & Papagno, 1986).

therefore be due to the availability to normal controls of the process of rehearsal, rather than to a deficit of auditory nonverbal memory. The view that retention of auditory nonverbal material makes use of a component different from the auditoryverbal STS is also supported by the finding that patient EA was able to monitor sequences of tones presented at a rate higher than two stimuli per second, which did not allow the utilisation of rehearsal (Friedrich, Glenn, & Marin, 1984). To summarise, the observation that some patients with a defective auditory-verbal span show a preserved immediate retention of auditory nonverbal material (meaningful sounds, tones) suggests the existence of an auditory nonverbal STS, independent of the auditory-verbal component. The locus o f the auditory-verbal STS: Perception or production ? Many multicomponential models of memory proposed in the early 1970s include a STM component. According to some of them the verbal STS is acoustic in nature, with an input locus (e.g. Sperling & Speelman, 1970). In others models the verbal STS is articulatory, with an output locus

(Baddeley, Thomson, & Buchanan, 1975; Ellis, 1979; Morton, 1970) The two types of models also differ in the relationships between verbal STM and linguistic processes. The input STS may participate in the process of language comprehension, while the output STS may be involved in speech production. Neuropsychological evidence concurs to suggest an input locus of the verbal STS. Patient JB had a normal spontaneous speech, as assessed through a quantitative analysis of pauses and speech errors (Shallice & Butterworth, 1977). In patient PV spontaneous speech was normal at a clinical assessment and articulation rate was within the normal range (Vallar & Baddeley, 1984a). The hypothesis of an output locus of the verbal STS predicts, by contrast, an abnormal speech output, with increased pauses and phonemic errors. An additional case for an input locus of the store is provided by the auditory/visual dissociation discussed earlier. A functional architecture including two input STSs (auditory-verbal and visual, see Fig. 15.2) readily accounts for the visual advantage in immediate memory, as the latter store is preserved. An output locus of the store does not

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explain this modality difference, unless a further distinction is drawn between two output stores, one for auditory and one for visual material. The articulatory nature of the output store, and its role in language production, make this hypothesis unlikely, however. The fractionation of auditory-verbal STM Studies in normal subjects suggest a fractionation of auditory-verbal STM into a phonological STS, the main storage component of the system, and an articulatory rehearsal process. Auditory-verbal material has a direct access to the phonological STS, which has an input locus. The rehearsal process prevents the decay of the phonological trace, and conveys written material to the phonological STS, after phonological receding (Baddeley, 1992; Sperling, 1967; Vallar & Baddeley, 1984a; Vallar & Cappa, 1987). The fractionation of verbal STM is suggested by the effects of two phonological factors on immediate serial span, and by their interactions with articulatory suppression (Baddeley, Lewis, & Vallar, 1984), which prevents the operation of the rehearsal process. Normal subjects have a higher memory span with phonologically dissimilar stimuli, compared to similar (e.g. K, F, Z, vs. B, C, T: phonological similarity effect). Articulatory suppression abolishes the effect of phonological similarity with visual, but not with auditory presentation of the stimuli. This modality difference suggests that auditory material has a direct access to a nonarticulatory phonological STS. Visual stimuli, conversely, require the additional operation of rehearsal, which is disrupted by articulatory suppression (Baddeley et al., 1984; Levy, 1971). The articulation of irrelevant speech abolishes also the effect effect of item length, a phenomenon whereby span is higher for short letter strings (e.g. dog) than for long ones (e.g. hippopotamus), Suppression wipes out the item length effect with both input modalities, suggesting an articulatory nature of the phenomenon. In this respect the rehearsal process may be metaphorically described as a tape with a finite length, which carries more short letter strings than long ones, and where the temporal duration of the stimuli is the relevant variable (Baddeley et al.,

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1975, 1984; Baddeley & Andrade, 1994; Caplan, Rochon, & Waters, 1992, for an alternative view). These effects have been studied in a number of patients with a selective deficit of auditory-verbal span. Most patients showed the effect of phonological similarity with auditory, but not with visual presentation, while the effect of item length was absent in both input modalities. This pattern, which is similar to the behaviour of normal subjects during articulatory suppression, suggests an account of the span deficit in terms of a selective impairment of the rehearsal process. This interpretation is implausible, however. In addition to the arguments discussed in the previous section, which suggest an input locus of the disorder, articulatory suppression produces in normal subjects a minor, albeit significant, reduction of auditory digit span (from 7.96 to 5.79 in Baddeley & Lewis, 1984). By contrast the patients' span is much lower (2.3 digits, according to the metaanalysis of Vallar & Papagno, 1995). Furthermore, in immediate free recall of auditory lists of words these patients show a defective recency effect, to which the rehearsal process provides a minor contribution (discussion in Vallar & Papagno, 1986). Finally, patient PV had a normal performance in phonological tasks (rhyme judgement, stress assignment) that involve the process of rehearsal (Vallar & Baddeley, 1984b). In sum a selective deficit of rehearsal does not account for the complete pattern of impaired and preserved performances of patients with a defective auditory-verbal span. The more plausible interpretation is in terms of a pathologically reduced capacity of the phonological STS. Vallar and Baddeley (1984a), who assumed that the process of rehearsal makes use of components participating in the production of speech, suggested that patient PV did not make use of rehearsal due to a strategic choice. There may be little advantage in conveying visual-verbal material to a defective phonological STS, or rehearsing traces held in this damaged system (see Fig. 15.2). This hypothesis predicts that articulatory suppression, (which impairs the performance of normal subjects) should not affect the patients' defective visual-verbal span; they would hold visual-verbal material in the preserved visual-verbal STS, rather than in the

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damaged phonological STS, and, therefore, would not use the process of rehearsal. The lack of disruptive effects of articulatory suppression on the visual-verbal span of patients PV (Vallar & Baddeley, 1984a) and RR (Bisiacchi, Cipolotti, & Denes, 1989) confirms this interpretation. The phonological output buffer (or phonological assembly system, see Fig. 15.2) component of the rehearsal process is preserved, however. This accounts for the normal speech production of some patients with a defective auditory-verbal span (Shallice & Butterworth, 1977, patient JB; Vallar & Baddeley, 1984a, patient PV). The operation of the process of rehearsal has also been investigated in anarthric patients, who, due to brainstem or cortical damage, were unable to utter any speech sound. Auditory digit span was within the normal range, even though in some patients the response was very slow and effortful, due to the severity of the motor deficit. In some of them, normal effects of phonological similarity and item length have been found (Baddeley & Wilson, 1985; Cubelli & Nichelli, 1992; Vallar & Cappa, 1987; Vallar & Papagno, 1995, for review). Furthermore, children with congenital anarthria had a normal span and showed the standard effects of phonological similarity and item length (Bishop & Robson, 1989). This indicates that the process of rehearsal does not require to be implemented at the level of the peripheral musculature, involving instead a more central stage, such as premotor programming of speech output (the phonological output buffer or assembly system of Fig. 15.2). Vallar et al. (1997) have recently investigated a patient with a major impairment of the process of articulatory rehearsal, with little, if any, damage to the phonological STS. This patient, who had nonfluent spontaneous speech, showed a reduced auditory-verbal span, which improved when a nonverbal response (recognition by pointing among alternatives) was used (related evidence in Kinsboume, 1972; Romani, 1992). The patient was also impaired in phonological tasks (rhyme and initial sound judgements), which involve the operation of rehearsal (see also Caplan & Waters, 1995), but showed a

relatively preserved recency effect, suggesting that some capacity of the phonological STS was available. Finally, the process of phonological recoding may be selectively impaired, with sparing of both articulatory rehearsal and the phonological STS. Two patients have been described: MDC (Vallar & Cappa, 1987) and FC (Cubelli & Nichelli, 1992), who had a normal auditoryverbal span, and bilateral and left-sided damage to the prerolandic frontal regions. The effects of phonological similarity and item length were present with auditory presentation, but absent when input was visual. This dissociation suggests that written material could not enter a preserved rehearsal process, due to a defective phonological recoding. This interpretation is supported by the finding that MDC’s ability to make phonological judgements on written material was defective. STS and long-term learning Phonological STS. Patients with damage to auditory-verbal (phonological) STM may have a preserved performance in a number of tasks that assess long-term acquisition and retention of verbal material: learning of word lists and of a short story, paired-associate learning (review in Vallar & Papagno, 1995). In the immediate free recall of lists of auditory words, the level of performance in the earlier positions, which is mainly based on LTM processes, was preserved, but the patients showed a reduced or absent recency effect, which represents the output of the phonological STS (see Fig. 15.10). The ability of these patients to learn visuospatial sequences may be also preserved (patient PV: Basso et al., 1982). This dissociation between defective verbal STM and preserved verbal LTM is however confined to real words, which have pre-existing lexicalsemantic representations. The acquisition of novel words, by contrast, is also based on STM processes. Patient PV was unable to learn novel words (Russian words transliterated into Italian) in a paired-associate paradigm, while learning of Italian words was normal (Baddeley, Papagno, & Vallar, 1988, see Fig. 15.11). A 22-year-old man, SR, who had a defective auditory-verbal span compared to

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controls matched for age and educational level, exhibited a similar pattern of impairment (Baddeley & Wilson, 1993). Unlike patient PV, subject SR did not suffer a brain disease in adult age, but his deficit was likely to be congenital. These observations suggest that phonological memory participates in the acquisition of vocabulary. Studies in normal subjects and children have provided converging evidence. Phonological similarity, item length, and articulatory suppression, which reduce verbal span, interfering with the operation of the articulatory rehearsal-phonological STS system, disrupted learning of nonwords, but did not affect the acquisition of real words (Papagno, Valentine, & Baddeley, 1991; Papagno & Vallar, 1992). In children, the level of performance in tasks that assess phonological memory, such as nonword repetition, was highly correlated with the successive acquisition of vocabulary, both in the native (Gathercole & Baddeley, 1989) and in a foreign language (Service, 1992; Service & Kohonen, 1995). The correlation of vocabulary acquisition with other abilities

(reasoning, syntactic and semantic skills, copying nonwords) was comparatively minor. In line with these results, polyglot subjects had a higher auditory-verbal span and a superior learning of non words, compared to matched nonpolyglot subjects; the two groups had a similar level of performance in tasks assessing visuospatial memory, reasoning, and word learning (Papagno & Vallar, 1995). Finally, FF, a 23-year-old woman, suffering from Down’s syndrome, with defective intelligence, episodic memory, and visuospatial processes, was able to learn three languages (Italian, English, French). FF’s phonological STM was preserved and she was able to learn novel words (Fig. 15.11), with an acquisition rate similar to that of normal subjects (Vallar & Papagno, 1993). This observation, which complements patient PV’s pattern of impairment, suggests a relevant role of phonological STM in vocabulary acquisition, which may take place also in the presence of severe cognitive deficits. These findings have been replicated in a 20-year-old

FIGURE 15.11

Phonological STM and vocabulary acquisition. Paired-associate learning of (a) Italian word pairs and (b) Italian word-nonword pairs (Russian words transliterated into Italian). Patients: PV, a left brain-damaged patient, suffering from a selective deficit of phonological STM; FF, suffering from Down’s syndrome. PV, but not FF, was able to learn Italian words with a rate similar to that of normal subjects. FF, but not PV, was able to learn nonwords (redrawn from Baddeley, Papagno, & Vallar, 1988; Vallar & Papagno, 1993).

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woman, CS, suffering from Williams’ syndrome (Barisnikov, Van der Linden, & Poncelet, 1996). Visuospatial STS. Patient ELD (Hanley et al., 1990; Hanley et al., 1991), who had a defective visuospatial span (see earlier) was also unable to learn novel material, such as faces and objects. Her memory for familiar material was, by contrast, preserved. Her defective recognition of faces was confined to individuals who became famous after the onset of her disease (1985). These experimental findings confirm the patient’s report: defective orientation in houses where she had never been before, defective recognition of faces of people met after the onset of her illness. This pattern of LTM impairment is similar to PV’s defective learning of nonwords (Baddeley et al., 1988). Taken together, these findings suggest that the acquisition of unfamiliar verbal and nonverbal material (nonwords or new faces) requires temporary retention in specifically committed STS systems. The studies concerned with vocabulary acquisition mentioned earlier indicate that the building up of stable phonological entries may be supported by the temporary availability of such representations, provided by the phonological STSrehearsal system. By contrast, the acquisition of lists of real words does not involve novel phonological representations, being supported instead by preexisting lexical and semantic knowledge. The findings of Baddeley et al. (1988), Vallar and Papagno (1993), and Hanley et al. (1990,1991) support therefore the traditional serial architecture of memory processes (see Fig. 15.1), whereby the stable acquisition and retention of novel material (e.g., novel words or faces) requires temporary storage in the specifically committed STS (phonological, visuospatial). Some results in patients with defective visuospatial STM suggest however a parallel, independent architecture of STM and LTM systems, in which some types of material may be acquired in the presence of defective STM. The two patients of De Renzi and Nichelli (1975) showed a disproportionately low visuospatial span (2.5 positions), without deficits of spatial orientation, and were able to learn the pathway of an unfamiliar visual maze.

Neural correlates Phonological STM The main anatomical correlate of defective auditory-verbal span is a lesion in the left inferior parietal lobule (supramarginal gyrus). These observations are based on a variety of anatomical data (neurosurgery, post-mortem exam, brain scan, CT) (reviews in Shallice & Vallar, 1990; Vallar & Papagno, 1995). In line with these findings, Risse et al. (1984) showed in a series of 20 left braindamaged patients an association between defective auditory-verbal span and posterior lesions (inferior parietal lobule), while damage to the frontal regions or the basal ganglia did not impair the patients’ immediate memory. The PET study of Perani et al. (1993) in 18 patients suffering from dementia of Alzheimer type showed a correlation between auditory-verbal span and metabolic activity in a number of regions in the left hemisphere (associative and basal frontal areas, posterior parietal, and superior temporal regions). Converging evidence has been more recently provided by functional neuroimaging activation studies. In normal subjects Paulesu et al. (1993) measured by PET rCBF during immediate memory for letter sequences, a task that engages both the phonological STS and the rehearsal process, and a rhyme judgement task, specific for the latter component of phonological STM. A comparison between the patterns of activation during these two tasks suggested that the inferior parietal lobule (supramarginal gyrus) is the neural correlate of the phonological STS, a left premotor frontal region (Broca’s area 44) of the process of rehearsal. Successive activation studies in normal and dyslexic subjects have confirmed and extended these results, showing that the neural correlates of rehearsal include a number of regions in the left hemisphere (premotor areas 44 and 6, and the insula, Fiez et al., 1996, for review of recent PET activation studies; Paulesu, Frith, Snowling et al., 1996; Schumacher, Lauber, Awh et al., 1996, for related evidence). This localisation is compatible with the view that the process of rehearsal makes use of systems that participate in the articulatory programming of speech production (see Shallice & Vallar, 1990; Vallar & Baddeley, 1984a).

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This anatomical dissociation of the neural correlates of the phonological STS and the process of rehearsal has recently been confirmed in two patients (LA and TO) with selective deficits of these components of phonological STM (Vallar et al., 1997). In patient LA, who had a disproportionately reduced capacity of the phonological STS, the left inferior parietal lobule and the superior and middle temporal gyri were damaged, in line with previous observations (Vallar & Papagno, 1995). Patient TO, in whom rehearsal was defective, had a subcortical frontal lesion, involving the left premotor and rolandic regions, the frontal paraventricular area, and the anterior part of the insula. Visual and spatial STM In the 1960s Kimura (1963) and Warrington & James (1967) found that right brain-damaged patients were disproportionately impaired in number estimation, a task that is likely to involve both perceptual and STM processes. In addition, in the series of Warrington and James (1967) patients with parietal damage had the more defective performance, in both the contralesional and the ipsilesional half-field. Right brain-damaged patients, however, were also impaired in a dot detection task; this suggests the existence of a perceptual deficit, which might account, at least in part, for the memory disorder. De Renzi and his co-workers used Corsi’s block tapping test (De Renzi, Faglioni, & Previdi, 1977a; De Renzi & Nichelli, 1975). Both left and right brain-damaged patients with visual half-field deficits had a disproportionately low visuospatial span, but damage to the right hemisphere appeared to be more relevant. This hemispheric asymmetry was confirmed by single-case studies of patients with a defective visuospatial span. De Renzi and Nichelli (1975) reported two patients whose only neurological deficit was a left homonymous hemianopia: one had undergone a right occipital lobectomy and coagulation of the right amygdaloid complex and the right fornix, the other had suffered a cerebrovascular attack in the right hemisphere. Patient ELD (Hanley et al., 1990, 1991) had an extensive fronto-temporal infarction, due to the rupture of an aneurysm of the right middle cerebral artery.

Also PET studies suggest a main role of the right hemisphere. Perani et al. (1993) in patients with dementia of the Alzheimer type found a correlation between the patients’ performance in the block tapping test and metabolic activity in the right fronto-parietal association cortex. Jonides (1993) compared rCBF in two conditions in normal subjects: deciding whether or not an outline circle encircled a dot (perceptual task), or the position where a dot had been presented three seconds before (STM task). In the latter condition a number of right hemisphere regions were activated: visual association cortex (area 19), inferior parietal lobule (area 40), prefrontal cortex (area 47). According to Jonides et al. (1993) these regions may be involved in different aspects of short-term retention of visuospatial information: the occipital regions in image generation (related evidence in Kosslyn, Alpert, Thompson et al., 1993), the parietal cortex in the computation of the coordinates of the stimulus, the prefrontal cortex in storage and retention. Kinsboume and Warrington (1962) described four patients who were able to recognise individual visual stimuli (letters, numbers, geometric figures). If two stimuli were simultaneously presented, however, one of them was not identified (defective simultaneous form perception). The deficit was independent of the spatial position of the stimuli (horizontal, vertical), and, therefore, was not a manifestation of spatial hemineglect. Number estimation (see Warrington & James, 1967) was also preserved. This deficit was interpreted in terms of the reduced capacity of a visual STS (see McCarthy & Warrington, 1990, pp.280-285). All four patients had lesions in the left hemisphere. In one patient a post-mortem examination showed left occipital damage, with a minor involvement of the superior temporal region (Kinsbourne & Warrington, 1963). Finally, left parieto-occipital lesions disrupt the patients’ ability to reproduce sequences of visual-verbal and nonverbal stimuli, immediately after presentation (Warrington & Rabin, 1971). Recent PET activation studies by Smith et al. (1995) provide evidence for an anatomical dissociation between spatial (position) and object visual short-term memory. The spatial task, as

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discussed previously, activated primarily right hemisphere regions (occipital, posterior parietal, premotor, and prefrontal), and a comparable object recognition task activated left hemisphere regions (inferior temporal, posterior parietal) (review in Smith & Jonides, 1995). In line with these findings, McCarthy et al. (1994) found by fMRI a right-sided prefrontal activation in a task requiring the shortterm retention of spatial locations. To summarise, a distinction can be drawn between two visual STS systems with discrete anatomical correlates: (1) a visuospatial STS in the right posterior-inferior parietal and frontal cortices; (2) a visual STS in the left occipito-parietal association cortex. The former system is involved in the retention of information concerning the spatial position of a stimulus (a “where” system, see Wilson, O’Scalaidhe, & Goldman-Rakic, 1993). The specific role of the frontal component may concern a representation of spatial position in terms of motor programmes towards relevant targets. The latter system is concerned with the retention of visual stimuli, coded in terms of shape.

NOTES 1. Since the end of the 19th century up to the 1950s, unitary models of memory have been the leading view. The early and seminal studies by Ebbinghaus (1885), Bartlett’s (1932) original approach, and the great deal of experimental studies that investigated the learning processes in the context of the theory of associative interference, very influential between the 1930s and the 1950s (discussion in Baddeley, 1976), were concerned with problems different from the fractionation of memory systems. 2. The pairs of terms STM/LTM and primary/secondary memory (James, 1895; Waugh & Norman, 1965)

may be considered largely equivalent. In this chapter the terms STM and LTM are preferred, as they are widely used in the neuropsychological literature. According to Atkinson and Shiffrin (1968) STM and LTM denote the experimental paradigms. A typical STM task involves the immediate recall of a limited amount of material. A LTM task, by contrast, requires the acquisition of a larger amount of material, which is recalled or recognised after a longer retention interval. The term “Store” (STS, LTS) denotes the components that subserve the retention process (theoretical construct). 3. Immediate memory span is the longest sequence of letters, digits, words, or other stimuli (e.g. spatial positions), that a subject is able to repeat or reproduce in the presentation order (Jacobs, 1887). According to a popular view immediate memory span is 7 ± 2 stimuli (Miller, 1956). 4. According to Atkinson and Shiffrin (1971, p.88) short-term forgetting is due to a displacement mechanism: as the capacity of the STS is limited, new items displace the old ones. According to Waugh and Norman (1965), the decay of the memory trace also contributes to forgetting, as material that is not rehearsed may be lost, in the absence of displacement. 5. In the early 1980s, the term procedural memory denoted systems different from declarative memory (Cohen & Squire, 1980). Procedural memory, however, referred mainly to the progressive acquisition of specific skills (e.g. visuo-perceptual abilities), and did not include the whole variety of nonconscious LTM processes. The more neutral term nondeclarative memory is therefore used. The term propositional memory (Tulving, 1983,1984) refers to declarative memory systems. 6. In memory experiments (e.g. the Brown-Peterson task), the term proactive interference refers to the negative effect of preceding stimuli on the recall of subsequently presented material. The interference effect is revealed by a progressive decrement of performance level.

Part IV

Recognition Disorders

Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

16 Agnosia Ennio De Renzi

The concept of agnosia is defined in both positive and negative terms. It refers to patients who show recognition deficits in one sensory modality, which are not accounted for by elementary sensory or oculomotor disorders, attentional impairment, disruption of language mechanisms, and severe mental deterioration. These constraints do not imply that these functions must be wholly intact, but that the degree of their impairment is not proportionate to the recognition impairment, as shown by the absence of agnosia in patients with comparable deficits and the fact that the breakdown occurs at definite levels of the perceptual process. Although agnosia is an uncommon symptom (there are around 100 published cases of visual agnosia, Farah, 1991, and those of tactile agnosia are much rarer), its contribution to our understanding the brain organisation of recognition is of paramount importance. Before dealing with recognition disorders, we will briefly outline the anatomo-functional organisation of the visual cortex and the more elementary perceptual symptoms that can result from its damage.

ANATOMO-FUNCTIONAL ORGANISATION OF THE VISUAL CORTEX Traditionally, visual functions were attributed to the calcarine cortex (area 17) and to the surrounding associative areas (area 18 and 19). Actually, a much larger number of visual areas have been identified in the monkey, some localised outside the occipital lobe. Eleven have a prevalent or exclusive visual function, four are polyfunctional, and five have a probable visual characterisation (Van Essen, 1985). In agreement with this multiple cortical representation, vision is currently conceived of as a process that involves successive stages and assigns the analysis of the stimulus perceptual features to discrete centres (DeYoe & Van Essen, 1988; Livingstone and Hubei, 1988). A functional specialisation of visual input is already apparent at the level of the retina, where two types of ganglion cells, with opposite properties, have been identified both in the cat (where they are called Y and X cells) and in the monkey (where they are called A and B cells). The former respond steadily to the presence of the 371

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stimulus, have small receptive fields and slow conducting axons. The latter respond transiently to the presence of the stimulus, have large receptive fields and fast conducting axons. These cells give rise to two discrete efferent systems, which maintain their independent course throughout the brain, well beyond the primary visual areas, and have distinct functions. One is called the magno system and corresponds to the efferents from retinal A cells to the two ventral magnocellular layers of the lateral geniculate nucleus, from where it projects to area V 1, first making connection with the cells of the sublayer 4Calpha and then with those of the sublayer 4B. The magno system terminates in area MT, located on the lateral surface of the posterior temporal lobe at the border of the occipital lobe. The projections from 4B to MT are either direct or indirect, via a preliminary synapse in a region of area V2, where cells stained with cytochrome ossidase appear grouped in thick stripes. This system is devoted to the processing of information related to movement direction and stereoscopic vision. The cells of the thick stripes also project to area V3 and V3A, where there are neurones sensitive to line orientation and possibly engaged in the processing of form information. The other system is called parvo and corresponds to the projections of retinal B cells to the four dorsal layers of the geniculate body. Its output is to the cells of the sublayer 4Cbeta of VI, from which two discrete pathways can be traced. One projects first to spots or “blobs” of cells that are located in layers 2 and 3 of V 1 and are stained by cytochrome oxidase, then to the thin stripes of V2 and finally reaches area V4. This subdivision is thought to be dedicated to colour detection. The other subdivision projects to the “interblob” cells of area V 1 (not stained by cytochrome oxidase) and then to the pale stripes of area V2, whose output is to V4 and to the visual area TEO of the temporal lobe. It would be specialised for the processing of information concerned with line orientation and shape. The main conclusion to be drawn from these findings is that different areas of the brain are dedicated to the processing of different features of the visual stimulus. Movement and stereopsis

pertain to the competence of the magno system and are encoded by MT. Colour is analysed by the subdivision of the parvo system that has its terminal station in V4. Cells sensitive to line direction and shape are found in several areas, but particularly in V2, V3, V4, and TEO. The further processing of visual data is thought to occur in the inferior temporal and the parietal cortex, linked to the lower centres by a ventral and a dorsal pathway, respectively (Mishkin et al., 1983). The ventral pathway consists of multisynaptic connections that follow the route of the inferior longitudinal fasciculus and connect the occipital areas with the inferior temporal areas (areas TEO and TE in the monkey), where the identification of “what” the stimulus represents occurs. The dorsal pathway, which consists of multisynaptic connections that follow the route of the superior longitudinal fasciculus, links the striate and peristriate areas with the inferior parietal lobule, which analyses “where” the stimulus is located. This strict segregation of functions, proposed by Livingstone and Hubei (1988), has been partially attenuated and modified by recent studies. They have shown that blobs and interblobs also receive input from the magno system (Nealey & Maunsell, 1994), that within area V4 there are anatomical subdivisions, which correspond to discrete input and output projections with presumably different functional characteristics (DeYoe et al., 1994) and that an important contribution to the dorsal channel is also made by collicular projections, probably via the medial pulvinar (Gross, 1991).

PERCEPTUAL DEFICITS Cortical blindness A bilateral lesion of the calcarine fissure or of the optic radiations causes blindness, characterised by: 1. Loss of vision, which in some cases may not be total, permitting light and movement perception. 2. Preservation of the light reflex. 3. Substitution of the dominant alpha rhythm with a slow posterior dominant rhythm of reduced voltage, unresponsive to eye opening. Visual

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evoked potentials are of limited value in the evaluation of cortical blindness (Aldrich et al., 1987). 4. Anosognosia for blindness and an amnesicconfabulatory syndrome, which are, however, present in few patients only. By far the most common aetiology is vascular, caused by emboli to the posterior cerebral arteries, which occur either spontaneously or following medical procedures (heart surgery, vertebral angiography, etc.). The onset of blindness is usually sudden, though in some cases it is preceded by unilateral hemianopia, the disease progressing in two successive strokes that involve first one occipital lobe and then the other (Bogousslavsky et al., 1983). In the course of a spontaneous or eclamptic hypertensive crisis, cortical blindness can also result from a rapidly developing brain oedema, which compresses the posterior cerebral arteries against the tentorium and produces bilateral occipital ischaemia. The literature (see Symond & McKenzie, 1957, for a review of old cases) has pointed out great variability in the evolution of the deficit, which ranges from complete blindness — in no more than 10% of cases, according to Aldrich et al. (1987) — to complete recovery (Gloning et al., 1968). Brindley and Janota (1975) reported on a patient who, 11 years after the stroke, was still unable to distinguish darkness from light. Yet in a similar patient (Perenin et al., 1980), it was possible to demonstrate with the forced choice method that he could detect moving stimuli and estimate by pointing the position of flickering lights. These residual capacities, similar to the phenomenon of “blind sight”, observed in hemianopic patients, were attributed to the transmission of visual information by extrastriate (collicular-pulvinar) pathways. If no improvement occurs within the first week, visual function is likely to remain severely impaired (Aldrich et al., 1987) and some of these patients pass on to the stage of apperceptive agnosia. Denial of blindness, or lack of concern for the loss of sight, was the first instance of anosognosia reported in the literature (Anton, 1898). Its manifestation is often astonishing. The patient reported by Dejerine and Vialet (summarised by

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Symonds & McKenzie, 1957) denied being blind, gave confabulated names to the objects presented by the examiner and, if his responses were questioned, apologised for his mistake by saying that a tear in his eye had prevented him from seeing clearly. It has been argued (Goldenberg, 1995; Redlich & Bonvicini, 1907) that the patients’ claim to be able to perceive and describe the visual features of stimuli they do not actually see is contingent on the translation of acoustic or tactile images into visual images and on the confusion between visual images and visual perceptions. Denial of blindness tends to be associated with amnesia, temporal disorientation, and mental confusion, a symptom complex the French authors call Dide and Botcazo’s syndrome and that is consequent to the extension of the lesion to the medial temporal lobes. It must be stressed, however, that the frequency of denial of blindness is rarer than thought by the early literature and that it is a transient phenomenon (Gloning et al., 1968 ).

Disorders of movement perception Loss of movement perception, or akinetopsia (Shipp et al., 1994) is often found in the context of a severe disorder of form perception (Goldstein & Gelb, 1918; Milner et al., 1991; Poetzl & Redlich, 1911). A case has, however, been reported (Zihl et al., 1983), in whom akinetopsia appeared in the absence of deficits of depth and space perception, colour and form discrimination, and object and face recognition. The deficit remained substantially unmodified for 13 years after the stroke (Zihl et al., 1991) and has been the subject of repeated investigations (Baker etal., 1991; Hess etal., 1989; Paulus & Zihl, 1989; Shipp et al., 1994; Zihl et al., 1991) that have clarified its nature. The patient complained of seeing a person or an object first in one place and then in another, but of not being able to see them moving between the two places. She could not cross a road, because of her inability to judge the speed of a car. “When I am looking at the car first, it seems far away. But then, when I want to cross the road, suddenly the car is very near” (Zihl et al., 1983). She was unable to pour tea or coffee into a cup, because the liquid appeared to be frozen, like a glacier and she could not estimate its rise in the cup. A series of experiments showed that

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akinetopsia was not absolute, but varied as a function of the spatial and physical features of the movement. The perception of moving stimuli was completely lost when they occurred in depth, was limited to the discrimination between a steady and a moving stimulus at the periphery of the visual field, and was relatively preserved for slow movements at the centre of the visual field. Movement velocity was also an important variable. Only stimuli moving at a velocity between 0.1° and 10° degrees per second were perceived as moving, but their direction was often not discriminated. The movement of auditory and tactile stimuli was correctly appreciated. The lesion was located by MRI (Zihl et al., 1991) and PET (Shipp et al., 1994) on the lateral surface of the hemispheres, where it involved bilaterally areas 39 and 19 and the underlying white matter, at the border between the temporal and the occipital lobe. In primates this region corresponds to area V5 or MT, which is located in the posterior bank of the superior temporal sulcus and is thought to be specialised in movement perception. PET studies carried out in normals have confirmed the activation of an area at the confluence of the occipital, temporal, and parietal lobe on the hemisphere convexity, (corresponding to V5) ,when subjects looked at a moving random square pattern (Zeki et al., 1991) and of the left inferior parietal lobe, when they attended to changes of stimulus velocity (Corbetta et al., 1990). Interestingly, an area located 2cm in front of V5 was activated when subjects looked at object drawings and had to generate the name of an associated action (Martin et al., 1995). Disorders o f depth perception The reader is referred to Chapter 20 for a discussion of the psychophysiological basis of depth perception. Here we will limit ourselves to a reminder that a severe impairment of depth perception has occasionally been reported in patients with bilateral parieto-occipital damage (Gloning, 1965; Holmes & Horrax, 1919; Michel et al., 1965; Valkenburg, 1908), often associated with Balint’s syndrome. This was confirmed by Rizzo and Damasio (1985), who, on the basis of CT scan and MRI data, localised the lesion at the

parieto-occipital junction of both hemispheres. The deficit is usually reported by the patients themselves. Gloning et al.’s (1965) patient complained of seeing a flattened world, “like in a picture or photograph” and Holmes and Horrax’s (1919) patient was unable to say which of two persons or objects was closer or farther away. As the deficit did not change by closing one eye, it could not be attributed to loss of stereopsis alone. Milder deficits, which escape clinical observation, are brought out in a much larger number of patients, when they are systematically investigated with sensitive tests. Carmon and Bechtold (1969) used Julesz’ stereograms and found a selective impairment in right brain-damaged patients. This hemispheric asymmetry has been confirmed by Benton and Hécaen (1970) and Hamsher (1978), even in the absence of deficits in conventional tests that measure local stereopsis, such as the Titmus or the Keystone test. Danta et al. (1978), who used the “doppling bead” and the “haploscopic” method, also had data pointing to a greater contribution of the right brain to stereopsis, but cautioned that the asymmetry might be contingent on an uncontrolled matching of the locus of lesion across the hemispheric samples, especially with respect to parieto-occipital damage. Also the infero-temporal cortex is likely to contribute to global stereopsis, which was found impaired after its bilateral ablation in monkeys (Cowey, 1985) and after unilateral temporal lobectomy of either side in humans (Ptito et al., 1991). Disorders of colour perception Impairment of colour perception (a- or dyschromatopsia) will be treated later, under the heading of colour recognition disturbances.

VISUAL AGNOSIA Brain damage does not necessarily impair the recognition of all visual stimuli, but can selectively affect certain categories of percepts (objects, faces, written words, or colours), leaving others intact, in agreement with evidence from neurophysiological and neuroimaging studies that discrete cerebral

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areas are dedicated to their perceptual processing and storage. In this view, the autonomy of visual agnosias is the consequence of the anatomical separation of the corresponding neuronal substrates. Farah (1990, 1991) took exception to this assumption and claimed that what plays a crucial role in determining which kind of stimuli are impaired by the lesion is not the category to which they belong, but the way they are perceptually processed. Some stimuli (faces) are coded as a whole, while others (words) are broken up into their constituent elements (letters) and still others (objects) share one or both apperceptive modes, depending on their features.

Object agnosia In 1890 Lissauer, then a 27-year-old German neurologist of Breslau, published a paper that had a lasting influence on the way subsequent authors were to deal with the problem of visual agnosia and which for the first time clearly distinguished a perceptual from an associative form. Just a year before, Freund (1889), who worked in the same institute, had reported a case of visual recognition disorders that he interpreted as consequent to the disconnection of visual areas from language areas and named optic aphasia. These three syndromes—apperceptive agnosia, associative agnosia, and optic aphasia— still represent the building blocks of the current conceptualisation of visual recognition disorders. [The reader who is not familiar with the German language is referred to the English translation of Lissauer’s and Freund’s articles, published in Cognitive Neuropsychology, 5, 153-192, 1988 and 8, 21-38, 1991, respectively.] Apperceptive agnosia corresponds to the breakdown at the stage where the sensory features of the stimulus are processed and its structural description is achieved. Associative agnosia is believed to result from the failure of the structured perception to activate the network of stored knowledge about the functional, contextual, and categorical properties of objects that permit their identification. Optic aphasia, in turn, defines the inability to name a visually presented object that has been correctly recognised.

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Apperceptive agnosia By apperception Lissauer (1890) intended “the conscious awareness of a sensory impression” and by apperceptive agnosia, the deficits of recognition that are due to the disruption of perceptual processing in a patient who has no major deficit of elementary visual functions. The latter qualification is important to establish the autonomy of apperceptive agnosia, all the more so because several of these patients were cortically blind at the beginning of disease, and agnosia was diagnosed when elementary visual functions had partially recovered, thus raising the question of whether their residual impairment contributed to the perceptual impairment. The evidence adduced to rule out this hypothesis is that visual acuity, visual fields, movement perception, and colour discrimination are intact or at least not more impaired than in patients who can perceive objects (Adler, 1944, 1950; Benson & Greenberg, 1969; Goldstein & Gelb, 1918; Landis et al., 1982; Milner et al., 1991; Shelton et al., 1994). Benson and Greenberg’s patient (see also Efron, 1968) was able to discriminate small differences in luminance and hue, to report if an object was moving, and to decide which was the larger of two objects. Yet he failed to recognise any object, face, and letter, to match identical figures, to copy simple drawings, to isolate an object from the background (unless it was moved), to trace the contours of a curved line, or even of an object the examiner was holding. He also made many errors in discriminating a square from a rectangle of the same area (Fig. 16.1). It was concluded that the patient was unable to perceive the form of a stimulus. A few of these patients (Goldstein & Gelb, 1918; Landis etal., 1982) show an amazing ability to compensate for the visual deficit, by tracing the contours of letters and objects with minimal movements of their fingers or head. The concept of apperceptive agnosia has been subjected to attacks from two fronts; one more radical, which claims that the perceptual impairment is entirely accounted for by sensory deficits, the other, more articulated, which contrasts impaired form discrimination with the inability to construct a three-dimensional structural description of the stimulus and reserves the name of agnosia to the latter form. Bay (1953) was the strongest

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proponent of the former theory. He argued that if agnosic patients were examined with appropriate methods, they would invariably show much more severe sensory deficits than those ascertained with routine procedures. More precisely, he underscored the need to test each sector of the visual field with a dynamic procedure, based on local adaptation, i.e. on the time necessary to detect the appearance or disappearance of the stimulus. Using this procedure, it would be possible to show that stimuli presented in apparently normal areas of the field fade away much more rapidly in agnosic than in normal subjects and leave the patients with tubular vision, unsuitable for face perception. Bay’s methodology was rather crude and his claim was not supported by the findings of a much more rigorous study, in which Ettlinger (1956) investigated 30 brain-damaged patients on a wide range of elementary visual tasks (brightness discrimination, flicker fusion, acuity for small objects, tachistoscopic acuity, local adaptation, apparent movement perception). He confirmed that a certain number of patients, especially those with visual field defects, do show an impaired discrimination in perimetrically intact sectors of the field, but did not find a reliable association between sensory impairment and the presence of higher perceptual disorders. In particular, a patient with a face recognition deficit, though performing poorly, was less impaired than three patients who did not show agnosia. The same also held in an object agnosic patient reported in another paper (Ettlinger & Wyke, 1961) and in three patients with agnosia for faces and objects, recently studied with the same procedures (De Haan et al., 1995). It is unfortunate that neither Bay (1953) nor Ettlinger (1956) made a distinction between apperceptive and associative agnosia, as only in the former is the bearing of the sensory deficit upon perception crucial. For instance, the relative sparing of elementary functions manifested by the case reported by Ettlinger and Wyke (1961) may not be decisive, because the patient likely suffered from an associative form. Using a “fine-grained” static perimetry, Campion and Latto (1985) were able to show that the visual fields of their patient with apperceptive agnosia were peppered with scotomata that had gone undetected by Goldman perimetry. The authors argued that they may have

exerted a masking effect on perception. It is clear that the question of probing sensory deficits with more sensitive methods remains, but even if they were found to be invariably present, this would not necessarily imply that they are a sufficient cause of apperceptive agnosia. Let us not forget that Ettlinger (1956) reported patients who had severe sensory deficits and yet could recognise objects. Levine (1978), who found in his patient an impairment of the threshold of tachistoscopic perception and of flicker fusion, thought that sensory deficits may be necessary, but are not sufficient to cause apperceptive agnosia. A different kind of criticism of the traditional conceptualisation of apperceptive agnosia was raised by Warrington and her colleagues (Warrington, 1985; Warrington & Rudge, 1995). She emphasised that a prerequisite for differentiating these patients from those who are impaired at early stages of perception is the evidence that they are able to trace and isolate the form of the stimulus from the background. Practically all of the patients classified under the heading of apperceptive agnosia in the literature did not meet this requirement and thus should be called “pseudo-agnosie”. On the contrary, the term apperceptive agnosia should be reserved for patients who fail on perceptual categorisation, namely, the stage at which a common perceptual category is assigned to an object, whatever its condition of orientation, distance, illumination, etc. The differentiation between the two syndromes hinges on the outcome of two sets of tests. To qualify for the diagnosis of apperceptive agnosia, patients must, on the one hand, pass tests of shape discrimination and detection, such as the Efron test, in which a square must be differentiated from an oblong, matched in terms of total flux (Fig. 16.1) and a test in which a fragmented shape must be distinguished from a fragmented background (Fig. 16.2). On the other hand, they must fail a series of tests that manipulate the perceptual dimensions of the stimulus by degrading it or obscuring its salient features, such as recognising figures taken from an unusual perspective, incomplete figures, overlapping figures, foreshortened silhouettes, and shadow image projections. These tasks would implicate the ability

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FIGURE 16.1

An example of Efron’s test. The subject must say whether the two pairs of figures are the same or different.

to categorise complex visual stimuli, making reference to a stored canonical representation. This ability would be the province of the right parietooccipital cortex. This claim was based on studies in which patients with right posterior damage were found to be impaired by comparison with controls and left posterior patients in matching photographs of the same objects, taken from different views (Warrington & Taylor, 1973, 1978) and it found support in the right parieto-occipital location of lesion in three patients, who were considered typical cases of apperceptive agnosia (Warrington & James, 1988; Warrington & Rudge, 1995).

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Warrington’s position is not wholly convincing. While there is robust evidence that right hemisphere damage impairs tasks requiring subtle perceptual discrimination more than left brain damage (De Renzi & Spinnler, 1966b; De Renzi et al., 1969; Warrington & James, 1967c; Warrington & Taylor, 1973), the attribution of the deficit to a failure of perceptual categorisation rests on more flimsy data, as the hemispheric asymmetry found in matching objects photographed from different views has not been replicated by subsequent studies (Bulla Hellwig et al., 1992; Mulder et al., 1995). Moreover, it must be remarked that none of the three cases reported by Warrington and James (1988) as examples of apperceptive agnosia could be properly defined as agnosic, as they performed in the normal range when requested to recognise canonical views of objects. The same was true for patient BRA (Warrington, 1986), who failed the Efron test and did not show a deficit of object recognition. To use the label agnosia for patients who are not impaired in standard tests of object recognition is questionable and does not help us to clarify the issue. We prefer not to dwell on nominalistic discussions and to focus on the level at which the processing of perceptual information is disrupted in patients who do not have major

FIGURE 16.2

An example of Warrington and Taylor’s figure-ground discrimination test. The subject must say whether the fragmented letter superimposed upon the fragment of background is an 0 o ra n X .

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TABLE 16.1 Measures of basic visual functions and visuo-perceptual skills. Sensory tests

Visual field perimetry Visual acuity Sinusoidal gratings of different frequencies Visual evoked potentials Critical fusion frequency Hue and lightness discrimination Stereoscopic depth Movement perception P e rc e p tu a l tasks

Tracing the contours of a shape Same-different judgements of figures differing for minor details Efron test Figure-ground discrimination test Overlapping and incomplete figure identification Copying figures Perceptual categorisation

sensory deficits. Table 16.1 summarises the tasks suitable to assess sensory and perceptual functions. Shape agnosia is the inability to organise the sensory input into a coherent shape perception by discriminating the boundaries of the stimulus from the background and other contiguous or overlapping shapes. The patient is unable to: trace the contours of the stimulus; match identical shapes and distinguish those that differ for minor details; perform the Efron test and the figure-ground discrimination test; copy a figure (see Table 16.1). Recognition of drawings or photographs taken from a prototypical view is usually poorer than recognition of the corresponding objects. It is worth stressing that some of these patients maintain the ability to process the visual information that guides limb and hand movements during reaching, in spite of being unable to make simple discrimination judgements on shape and orientation. The patient with severe apperceptive agnosia reported by Milner and co-workers (Goodale et al., 1991; Milner et al., 1991; Milner & Goodale, 1995) was unable to report the orientation of a slot cut into a vertical disk or that of solid rectangular blocks, but

she oriented her hand correctly when requested to insert it into the slot or to grasp the blocks. Likewise, she failed to indicate the width of a block using her forefinger and thumb to make a perceptual judgement, but made accurate calibration of the finger-thumb separation when she had to pick up blocks of different sizes. This dissociation suggested to the authors that V 1 cells responsive to line orientation were intact, but disconnected from higher centres of the ventral streams, while maintaining connections with those of the dorsal stream. The disruption of form perception is not an all or nothing phenomenon that can be univocally assessed on the basis of the Efron test and the figure-ground discrimination test, as originally suggested by Warrington (1985), as the two performances can dissociate. Kartsounis and Warrington’s patient (1991) passed the former, but failed to identify overlapping, incomplete or poorly differentiated figures, while Davidoff and Warrington’s patient (1993) presented the opposite pattern, i.e. poor identification of simple forms and preserved discrimination of a shape from the background. Even more striking was the

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dissociation exhibited by De Renzi and Lucchelli’s patient (1993), who was able to: perform the Efron test; match an object with its pair, presented with three distractors; distinguish figures differing for minor details; and copy complex drawings in a nonslavish way. Yet she failed the figure-ground discrimination test, Ghent’s overlapping figure test, and a possible-impossible figure decision test (impossible figures are those containing subtle surface and edge violations that make their existence in space impossible). It is clear that apperceptive agnosia covers a spectrum of disorders that only a detailed analysis can bring out. A distinct form of apperceptive agnosia was identified by Riddoch and Humphreys (1987; see also Humphreys & Riddoch, 1987 and Boucart & Humphreys, 1992) under the name of integrative agnosia. Patients are able to trace the contour of a figure, to match objects for their physical appearance, and to copy a drawing they do not recognise, though the reproduction is slavish and carried out with a piecemeal approach. They fail, however, to segment elements of a complex display and to bind them together. Patients suffering from this deficit (Butter & Trobe, 1994; Graillet et al., 1990; Riddoch & Humphreys, 1987; Thaiss & De Bleser, 1992) can identify single details, which they rely on to interpret the figure, but are unable to integrate the information gleaned from these elements into a general shape and so do not attain an integrated form description. Their performance

improves when silhouettes with reduced internal details instead of drawings are used for discrimination but deteriorates when overlapping figures must be identified (Butter & Trobe, 1994; Riddoch & Humphreys, 1987) or when the exposure time is shortened. Impairment o f internal representations. The recognition process involves comparing the structured description of the object with its representation, stored in presemantic memory. In none of the reported cases was agnosia exclusively due to the inability to access stored representations or to their disruption. However, their impairment has been thought to contribute to featuring the disorders, exhibited by the patients reported by Ratcliff and Newcombe (1982), Sartori and Job (1988), Grailet et al. (1990), De Renzi and Lucchelli (1993), and Rumiati et al. (1994). The integrity of visual representations is assessed with bottom-up visual tasks or top-down verbal tasks (Table 16.2) and from their comparison it is possible to establish whether the representation is degraded or intact, but cannot be activated via a given route. Bottom-up visual assessment is based on object decision tests, requiring the patient to decide whether a stimulus corresponds to a real object or not. They range from nonsense shapes, which show a high approximation to real shapes (Kroll & Potter, 1984) to drawings that combine parts of different figures (Fig. 16.3), e.g. the head of an animal with

TABLE 16.2 Tasks to assess the internal representation. Visual s tim u la tio n

Object-nonobject decision (Kroll and Potter’s drawings; Riddoch and Humphreys’ drawings) Identifying the missing part of a drawing V erb a l stim u la tio n

Drawing from memory Verbal description of an object shape Difference between two similar objects Capital and small print letter configuration Tail and ear test Clock test

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FIGURE 16.3 Examples of the object decision test. The subject must say whether the figures correspond to a real animal or object (figures kindly provided by G. Sartori).

the body of another or the handle of an object with the body of another (Riddoch & Humphreys, 1987). Alternatively, patients can be presented with a figure missing a detail that must be identified and found among distractors. Note that none of these tasks demands the recognition of the stimulus, but simply to decide whether its configuration corresponds to a representation stored in presemantic memory. Top-down verbal tasks call for the generation of visual images, in response to the verbal requests made by the examiner. These images are thought (Farah, 1984; Goldenberg, 1993) to be retrieved from the long-term store of structured representations and to be kept in a short-term memory buffer for the time needed for their analysis. Several tasks have been devised to assess this ability: 1. Drawing from memory. Drawing skills differ from subject to subject, but what suffices here is that the basic features of the object are represented and correctly arranged in space. The possible bearing on the performance of constructional disability can be checked by copying tasks. 2. Verbal description of the shape of the stimulus. 3. Explaining the difference in shape between two perceptually similar objects, e.g. a needle and a pin, the blade of a knife and the blade of a saw, a lizard and a snake, etc. (see a list of these pairs in De Renzi & Lucchelli, 1994). 4. Judging whether a capital letter contains curved lines (D) or straight lines (M) and whether a

small print letter contains segments that extend above (t) or below (p) its main body. 5. Evoking the perceptual features of animal body parts, e.g. whether its tail is long or short and its ears are round or pointed. 6. The clock test (Grossi et al., 1989), in which the patient is asked to judge which of two orally given times (e.g. 7.15 or 7.45) has a larger angle subtended by the two hands of the clock. Occasionally dissociations among these performances are noted (Trojano & Grossi, 1992). Apperceptive agnosia may leave mental representations unimpaired, as was shown by the patient reported by Servos et al. (1995), who recognised only 11% of the line drawings of common objects and only 15% of letters, but was nevertheless able to make size discrimination, when given the name of two similar-sized objects or animals, to scan a mental image in search of particular features, and to draw lower and upper case letters from memory. Also the patient reported by Behrman et al. (1992), showed imaging integrity on verbal tasks, in the face of a severe integrative agnosia (Moscovitch et al., 1994). A likely interpretation of this dissociation is that the long-term store was accessible from higher centres, but not visual information. When the patient fails both bottom-up and top-down tasks, (De Renzi & Lucchelli, 1993), there is evidence that the long-term memory store is degraded Associative agnosia The diagnosis of associative agnosia must be envisaged when the patients fail to recognise a

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meaningful visual stimulus, whose perceptual structure has been adequately encoded. The term adequately does not mean that some minor deficit cannot be detected, as emphasised by Farah (1990), but simply that it is not sufficient to account for the recognition failure, because a comparable degree of perceptual impairment can also be found in patients who are not agnosic. Apart from the possibility that the lesion responsible for associative agnosia can impinge upon neighbouring perceptual areas, it must be pointed out that Lissauer (1890) himself had explicity warned that an associative impairment is bound to be associated with a certain degree of perceptual deficit in the fine-grained discrimination of complex stimuli, because top-down information is helpful in focusing attention on significant details. He consequently anticipated that no case of pure associative agnosia would ever be found but, at most, patients with a predominantly associative agnosia. Nevertheless, he maintained that the gist of the syndrome had to be identified in the defective arousal of associations by the visual percept. Evidence that the patient has not grasped the meaning of the stimulus must be sought in the failure on the following tasks. 1. Visual naming. The inability to name a visual stimulus in patients whose perceptual functions are adequate and whose spontaneous speech is apparently normal must raise the suspicion of agnosia and prompt testing of their naming skills in other modalities (e.g. naming on verbal definition). Some features of patients’ verbal behaviour are suggestive of the semantic nature of their deficit. Unlike aphasic anomies, they do not resort to circumlocutions in the attempt to define what the object is for. Errors are rarely based on the perceptual resemblance between the stimulus and the response, and tend to be semantic (e.g. fork for spoon) or totally unrelated to the stimulus (e.g. hammer for horse) or consist in the mere identification of the superordinate (animal for dog). Unlike apperceptive agnosia, naming drawings is not much more impaired than naming objects. Performance on verbo-visual matching tasks, i.e. pointing to a figure named by the examiner,

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is also impaired, albeit less than naming, especially when the foils are semantically related to the target. Interestingly enough, the performance can improve, if, instead of object naming, the description of a complex scene is required, possibly because recognition is helped by contextual cues (Hecaen et al., 1974). Unless the patient is prosopagnosic, familiar faces are recognised (Benke, 1988; Rubens & Benson, 1971), but named with difficulty. Naming is not the only way to show that an object has been identified and it is important to check whether the patients are also unable to demonstrate their knowledge nonverbally. 2. Miming the use o f objects. An identifying attribute of an object is the way it is used (this method is indeed frequently adopted by aphasics) and thus miming is useful in verifying whether there is a recognition deficit underlying the naming failure. The test can be given in two variants that mimic naming and comprehension, respectively. Either the patient must mime the action corresponding to a visually presented object or the examiner pretends to use an object and the patient has to select it from among foils. These performances are to be compared with miming in response to a verbal command, namely a condition that does not involve the processing of visual information. The assumption that miming represents a reliable alternative to naming as a means of proving recognition has been questioned by Ratcliff & Newcombe (1982), who argued that it lacks sufficient specificity and the use of an object can be suggested by its physical structure. There are in fact case reports of patients who produce correct mimes when shown various objects, but who fail not only to name them, but also to classify them on a semantic basis (Riddoch & Humphreys, 1987b; Schwartz et al. 1979). Particularly impressive was the dissociation shown by the patient of Sirigu et al., (1991), who could verbally describe and mime the manipulation of objects, whose function he could not identify. As he frequently remarked, “I can tell you how to use it, but I have no idea what it is used for”. The authors argued that sensorimotor experience can provide a

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self-cueing kinaesthetic strategy that helps the retrieval of actions, without activating semantic representations. It would be hazardous to make sweeping generalisations from so few case reports, not least because it has been remarked that when the patient misnames an object, he often mimes its use in agreement with the wrong identification. Yet caution must be exercised when inferring recognition from correct gesturing. 3. Semantic categorisation and association tasks. Recognition can be assessed by categorisation or association tasks, which imply knowledge of the semantic properties of the stimulus. Categorisation tasks: a set of pictures is placed on the desk in front of the patient, who must group all those belonging to the same semantic class (e.g. fruits, vegetables, tools, transportation, etc.). Association tasks: the patient is presented with a target and a number of pictures and must select which of them is related to the target, either because they have a common superordinate (e.g. both are mammals), or because they are used within the same context (e.g. tennis-racket and tennis-ball). The task may be made more difficult, if all of the alternatives bear some relation to the target and the patient is asked to identify that with the closest link (e.g. the target is a thimble and the choice is among scissors, threaded needle, buttons, and reels of thread). 4. Knowledge o f the semantic attributes that are not present in the figure, but can be readily activated, if its meaning has been decoded. For instance, a patient can be given a black and white drawing of a frog and asked the following questions. 1. Is it an animal? 2. Is it dangerous? 3. Does it live in your country? 4. Is it heavier than a cat? 5. How does it move? 6. What colour is it? The finding that a patient who has completed perceptual processing up to the activation of mental shape representations fails in the foregoing tasks is evidence that the visual input cannot gain access to semantic memory, where the attributes of an object, which confer its meaning, are stored. This condition must be differentiated from two different patterns

of deficits, optic aphasia and semantic amnesia. In the former a visual stimulus is recognised, but cannot elicit naming, whereas in the latter the knowledge of objects and their verbal labels is inaccessible, regardless of how the input is conveyed. Optic aphasia The clinical profile of optic aphasia was outlined by Freund (1889) just a year before Lissauer published his seminal paper on visual agnosia. The relation between the two syndromes has been a matter of debate for many years and is still not completely clarified. In optic aphasia there is no impairment of visual recognition, but merely an inability to name objects presented in the visual modality. It was Freund’s (1889) contention that such impairment resulted from the concurrent presence of two deficits, a lesion of the left optic pathways, which would hinder the processing of visual information by the left occipital lobe and the interruption of the pathways that connect the intact visual areas of the right occipital lobe with the speech centres, located in the left temporal lobe. The patient he reported in more detail also showed anomia in spontaneous speech, but could name objects placed in his hands, reject wrong names proposed for a visually presented object, and had no difficulty in name comprehension. Thus his language deficit did not conform to any classical aphasic syndrome. More problematic was the assumption that recognition was intact. It rested on his rare successful attempts to convey the meaning of the missing name by circumlocutions and on the claim that he knew the use of objects he could not name, but it is unclear how this was tested, as miming was not reported. Categorisation tasks were not given. In the subsequent literature, the lack of reliable criteria for distinguishing optic aphasia from visual agnosia was criticised and led to the syndrome eventually sinking into oblivion as did the fact that Freund had preceded Dejerine (1907) in introducing a disconnection paradigm to account for visuo-verbal matching deficits. Spreen et al. (1966) must be credited for having rekindled interest in optic aphasia, by reporting a patient with a left parietal tumour, whose visual naming was remarkably impaired relative to tactile

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naming and naming on definition and who was able to define the use of objects he could not name and to point to them, when their name was given. At about the same time, Geschwind (1965) proposed an interpretation of visual agnosia, associated with left occipital damage, which was practically identical to that advanced by Freund (1889) for optic aphasia, although no reference was made to his work. The main reason Geschwind gave in support of the theory that visual agnosia did not represent a recognition disorder, but rather a visuoverbal disconnection was that agnosic patients never mistake objects in real life, as would be expected if they had indeed misidentified them. This statement is too sweeping by far and was disproven by case reports of patients who did make these mistakes (Hecaen & Ajuriaguerra, 1956; Hecaen et al., 1974; McCarthy & Warrington, 1986; Rubens & Benson, 1971). Moreover, a mere reduction of visual agnosia to optic aphasia would not account for patients’ poor performance on tasks that do not involve verbal skills, such as miming and semantic categorisation. It is, however, true that in most agnosic patients there is a disproportion between the few errors they make in everyday life and the much more severe impairment shown on naming tasks, if the latter were entirely due to a recognition deficit. Although this discrepancy may in part be due to the fact that contextual cues and tactile information provided by handling the object make recognition easier, it does suggest that a disconnection component contributes to the poor naming performance even in associative agnosics. In recent decades the number of reported cases of associative agnosia and optic aphasia has increased quite considerably (for a review, see Iorio et al., 1992 and Davidoff & De Bleser, 1993, to which the case reports of Hillis & Caramazza, 1995, Campbell & Manning, 1996, and De Renzi & Saetti, 1997, must be added), thus providing a sufficient body of information for a balanced discussion of the relation between the two syndromes. An important, preliminary remark is that the two forms may be associated with the same locus of lesion, a finding not easily reconcilable with the assumption that they are subserved by discrete mechanisms. Contrary to apperceptive agnosia,

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which is usually caused by bilateral damage, a large number of patients with associative agnosia have a lesion confined to the left medial occipitotemporal areas (most cases have an infarct of the left posterior cerebral artery), as do patients with optic aphasia. This coincidence cautions against too rigid a differentiation between the two syndromes and invites to close inspection of whether the criteria used to contrast them are reliable. As already mentioned, patients with associative agnosia are expected to fail and patients with optic aphasia to pass the following tests: 1. Verbo-visual matching in name comprehension tasks. 2. Ability to circumvent anomia on visual confrontation tasks by providing information on the function and other nonperceptual features of the stimulus. When naming errors occur in optic aphasia, they should be predominantly semantic, indicating that some information on the nature of the stimulus has reached the left hemisphere. 3. Miming the use of objects. 4. Grouping stimuli on the basis of their categories and matching stimuli on the basis of their semantic association. As a matter of fact only a minority of patients labelled optic aphasics have been exhaustively tested and very few of them (Coslett & Saffran, 1992; Gil et al., 1985; Manning & Campbell, 1992) comply with all of the requirements set forth to validate the integrity of recognition. Moreover, their semantic knowledge was not perfect (Gil et al., 1985; Manning & Campbell, 1992, see also Campbell & Manning, 1996) and the tests proposed were not demanding enough. For instance, both Hillis and Caramazza (1995) and De Renzi and Saetti (1997) have shown that patients who perform well on association tests fail when the foils bear a semantic relation to the target as well, albeit not such a close relationship as the correct answer. These findings suggest that it is exceptional for patients labelled optic aphasics to give evidence of intact access to the complete semantic entry of the stimulus. On the other hand, a closer inspection of the cases of associative agnosia consequent to left

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brain damage (for a review, see De Renzi & Saetti, 1997) reveals that patients classified in this way were able to pass some tasks requiring the identification of the meaning of the stimulus. It seems, therefore, that patients with optic aphasia and associative agnosia differ quantitatively more than qualitatively and lie in a continuum of progressively more severe semantic deficits, whose opposite ends may be instantiated by Lhermitte and Beauvois’ (1973) patient, who apparently had only a naming problem, and Lhermitte et al.’s (1973) patient, who failed all tests of nonverbal recognition (despite passing a semantic association test with unrelated foils). In agreement with this account, are reported cases (Bauer & Rubens, 1985; De Renzi et al., 1987) whose clinical pattern has evolved from associative agnosia to optic aphasia, possibly thanks to the improved exploitation of the semantic potential of the right hemisphere. So, the question of interest is what factor accounts for the different semantic impairment of these patients? Coslett and Saffran (1989, 1992) agreed with Freund’s interpretation of optic aphasia as a disconnection between the right hemisphere and the left hemisphere, but added that the former uses structured descriptions to activate its own semantic store, which would be as capable as that of the left hemisphere to mediate nonverbal semantic knowledge, except for the inability to access the phonological output lexicon, as it is located on the left side. This account incurs two difficulties. First, if the semantic potential of the right hemisphere is adequate for object recognition, why does it not work in those agnosic patients who have the same lesional pattern as optic aphasics? Second, there is evidence from group studies (De Renzi et al., 1969; Warrington & Taylor, 1978) that the level of nonverbal semantic competence of the right hemisphere is not as effective as that of the left hemisphere, an asymmetry in agreement with the less than perfect performance shown by almost all optic aphasics on demanding semantic tests. So, Coslett and Saffran’s hypothesis requires two further specifications: first, the right hemisphere is usually less proficient at decoding the meaning of visual stimuli than the left hemisphere and, second, its semantic competence may show remarkable variation from subject to subject. It is this

premorbid individual feature that determines the degree to which the right hemisphere can compensate for the left side’s lack of contribution to visual semantic processing and whether the clinical profile of the patient is more skewed towards optic aphasia or visual agnosia. The issue of individual differences tends to be neglected by the neuropsychological literature, mainly because they cannot be ascertained in the healthy subject and are only inferred post-hoc, on the basis of different patterns of impairment associated with the same pathological findings (De Renzi et al., 1987,1994). Hopefully, functional MRI studies carried out in normal subjects will provide empirical evidence that will help to solve this issue, if, instead of averaging across subjects, they focus on interindividual variations and assess how consistent they are. A marked variability in the size of the primary visual cortex has been documented by anatomical studies (Dobell & Mladejowsky, 1974; Stensaas et al., 1974) and in the functional representation of language by stimulation studies (Ojemann & Whitaker, 1978). This conceptual framework accounts for some of the features of optic aphasia. One of them is the superiority of comprehension over naming in a visuo-verbal matching paradigm. This discrepancy may be contingent on anatomical reasons, as the splenial lesion interrupts the transmission of visual information to the speech centres, while leaving the anteriorly located auditory callosal connections that transmit the output of Wernicke’s area to the right hemisphere undamaged (McCormick & Levine, 1983). Moreover, the investigation of epileptic patients who underwent callosal section (Zaidel, 1990) has shown that the right brain has lexical competence in name comprehension. It follows that, while the entity of the naming impairment is proportional to the severity of splenial disconnection, the ability to match a name with an object is a function of the right hemisphere lexical and semantic knowledge. As for miming, its performance depends on the extent of interhemispheric connections involved by the task. Miming on command is intact, as the semantic store for gestures is located in the same left hemisphere that decodes verbal information (De

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Renzi & Lucchelli, 1988). More problematic for a disconnection interpretation is the putative sparing of gesturing on visual presentation, as it involves the transmission of visual information from the right hemisphere to the gesture store, located on the left side. However, the preservation of miming in optic aphasia is much less consistent than traditionally assumed and a review of the literature (De Renzi & Saetti, 1997) has shown that it represents the exception rather than the rule (in the few patients who are able to mime it might be argued that the gesture store is represented bilaterally). There are still a few outstanding questions: 1. Granted that the right hemisphere has decoded the stimulus, why does it not succeed in transmitting its knowledge to the left hemisphere via the callosal pathways linking the tactile and auditory associative areas of the two sides? Geschwind (1965) addressed this question apropos of the absence of object naming errors in pure alexics, who also have damage in the left medial occipito-temporal region. He ventured that object naming is impaired when the splenial lesion extends forwards and impinges on the callosal fibres transmitting tactile information, but this conjecture has never received empirical support. Moreover, the claim that pure alexics are free of object naming errors is contradicted by the findings of a study in which their naming performance was systematically assessed (De Renzi et al., 1987). 2. One would expect that patients who are unable to retrieve the name of an object they have recognised either admit their inability or use circumlocutions to show their knowledge of the functional or contextual features of the stimulus. This behaviour is frequent in anomic aphasics, but rare in the majority of optic aphasics, who tend to give the same type of response as associative agnosics suffering from left hemisphere lesions, namely, identification of the superordinate, semantic paraphasias, paraphasias unrelated to the stimulus, and perseverations. Errors of the first two types suggest that a certain amount of information has

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reached the left hemisphere (through the more anterior callosal fibres ?), but that it is not able to control whether its verbal production tallies with visual data. In some patients (Gallois et al., 1987; Glenn et al., 1985) miming the use of an object that was wrongly named was appropriate to the semantic paraphasia, but not to the stimulus, as if the left hemisphere had gained control of behaviour, responding to its own cues and ignoring what the right hemisphere had transmitted to it. 3. By definition, naming errors should be limited to the visual modality, while, as underlined by Morin et al. (1984), they also occur in the tactile modality in a considerable number of patients with left brain damage, both among those diagnosed as associative agnosic (Benke, 1988; Caplan & Hedley-White, 1974; Feinberg et al., 1986; Hecaen & Ajuriaguerra, 1956; Rubens & Benson, 1971) and those diagnosed as optic aphasic (Assal & Regli, 1980; Glenn et al., 1985; Poeck, 1984; Rapcsak et al., 1987). In a consecutive series of 16 patients with an infarct of the left posterior cerebral artery De Renzi et al. (1987) found a deficit of visual naming in 11 and of tactile naming in 10. As the occipitalsplenial lesion alone cannot interrupt the connections between the right associative somaesthetic area and the left language area, an anatomical interpretation cannot account for the tactile naming deficit, which was attributed by De Renzi et al. (1987) to the mediation exerted by visual images in tactile recognition. This hypothesis is bolstered by reports of patients who showed apperceptive visual agnosia (Ratcliff & Newcombe, 1982; Shelton et al., 1994) and tactile recognition disorders. Unilateral visual agnosia In the literature there are a few case reports of visual recognition disorders confined to one visual field, i.e. involving stimuli that have been processed by the contralateral hemisphere. Mazzucchi et al. (1985) pointed out that, leaving aside the cases of splenial section, the majority of patients showed a deficit of colour discrimination and belonged, therefore, to the category of unilateral dyschromatopsia (see later). In two patients, however,

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the impairment extended to other classes of stimuli. One (Mazzucehi et al., 1985) had a haemorrhage in the right lateral occipito-temporal region, causing left superior quadrantopia. In the intact inferior quadrant of the same field, which was apparently intact at Goldman perimetry, he could not recognise objects, faces, letters, and colours, while they were correctly identified in the right field. In the patient ofCharnalletetal. (1988), CT scan showed a lesion of the left lingual and fusiform gyri, plus two small lesions, encroaching on the forceps major of both sides, without impairment of the visual fields. Letters, colours, geometrical figures, and objects were not recognised in the right field, while matching identical forms was better, but very slow and hesitant. A subtle deficit in form recognition was hypothesised. The actual frequency of these unilateral deficits is a matter of speculation, because unilateral recognition was seldom tested. Loss o f visual imagery The inability to retrieve mental images characterises a clinical pattern that bears some relation to visual agnosia and is relevant to the understanding of the processes underlying visual perception. Patients affected by this syndrome complain of no longer being able to visualise objects or other representations of the external world and this inability can be verified with tests demanding the presence in the mind’s eye of distinct mental representations, such as those listed earlier. The deficit may be restricted to certain categories of stimuli, e.g. living objects, faces, letters, colours, spatial maps (Goldenberg, 1993). Cessation of dreams and daydreams is often reported. First described by Charcot (Bernard, 1883), this condition was occasionally reported in the subsequent literature, but became the subject of detailed investigation only when a seminal paper by Farah (1984) drew attention to its theoretical potential and worked out a model, first proposed by Kosslyn (1980), aimed at identifying the components of the imagery process and their susceptibility to brain damage. The model assumes that the same mental representations underlie imagery and perceptual recognition and that their activation involves two storage systems (a longterm memory store and a short-term visual buffer)

and three discrete processes (generation, inspection, transformation). The information about the appearance of objects is stored in a subset of longterm memory, dedicated to the knowledge of the perceptual features of objects. Its conscious reproduction in the mind’s eye requires a generation process and the transfer of the image into a visual buffer, where it can be inspected and submitted to further mental operations (verbal description, drawing, spatial transformation, etc.). The same visual buffer also provides a temporary store for encoded structured descriptions, which, to be recognised, must be matched with the corresponding mental representations, stored in long-term memory. Depending on which component of the model is damaged, imagery and recognition can be concurrently or differentially impaired. When the lesion affects the mental representations stored in long-term memory, both abilities will be disrupted, leaving the patient unable to recognise objects and imagine their visual appearance. This association has indeed been found in a number (probably the majority) of properly investigated cases of agnosia (for a review of the relevant literature, see Trojano & Grossi, 1994) and, interestingly, it can be specific for certain classes of objects (e.g. living things, De Renzi & Lucchelli, 1994;Methaetal., 1992;Sartori & Job, 1988). Loss of mental images, with intact or at least much less impaired recognition (Basso et al., 1980; Brain, 1954;Delevaletal., 1983; Farah etal., 1988b; Goldenberg, 1992; Grossi et al., 1986; Riddoch, 1990) results from damage to the generation process. The opposite pattern, visual agnosia and preservation of mental imagery, has also been reported, and it can reflect the impairment of perceptual processing at two distinct levels. Either the structured descriptions have been so poorly encoded that they fail to activate mental representations (apperceptive agnosia, see the case reports of Behrman et al., 1992, Servos et al., 1993, Servos & Goodale, 1995) or they are adequate, but cannot reach the long-term store, which, though intact (and hence able to generate images), is disconnected from the visual buffer (associative agnosia). In these cases the integrity of the image generation mechanism is inferred from the good performance in drawing from memory (Ferro & Santos, 1984; Kawahata & Nagata, 1989; Levine,

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1978; Rubens & Benson, 1971), and/or from verbal operations carried out on mental images (Jankowiak et al., 1992; Morin et al., 1984). While this model provides a reasonable overview of the architecture of the imaging processes, to some extent it remains conjectural and is in need of further refinement, if it is to account for the whole range of clinical findings. For instance, it has been found that in agnosic patients with a loss of mental images, there may be a discrepancy between the severity of imagery and recognition greater than would be expected from the theory that both are consequent to the disruption of the same mental representations. Nor is it clear why the disruption of the generation mechanism may have different consequences on various image categories. Hopefully, these and other questions will be settled by studies encompassing larger numbers of patients with wider batteries of imagery tests. The issue of the relation of mental images to encoded perceptions has also involved their anatomical underpinnings. The debate has mainly revolved around the question of whether the same areas participating in perception, in particular those engaged in the early processing of visual information (areas 17 and 18), are also activated by imagery. According to this view, the top-down information, triggering mental representations, is projected back to early visual areas, recreating a condition similar to that of perception. The issue has been addressed by investigating which areas of the brain showed increased metabolism in comparison to a baseline condition, when the subject was engaged in imagery tasks. SPECT (Goldenberg et al., 1987, 1989), PET (Kosslyn et al., 1993; Roland & Gulyas, 1994), and functional MRI (Le Bihan et al., 1993) studies concurred in showing increased metabolism in temporooccipital and parieto-occipital areas, but the data on the involvement of the primary visual areas were less consistent, with some authors (Goldenberg, 1993; Kosslyn & Ochsner, 1994; Le Bihan et al., 1993) reporting positive findings and others (Roland & Gulyas, 1994) failing to confirm them. Variations in the experimental paradigms used to elicit imagery and individual differences may account for such conflicting results. In a recent experimental study (Kosslyn et al., 1995) the

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evidence upholding the primary visual cortex activation was particularly impressive, because the site of maximal activity was related to the difference in size at which images were formed, being located posteriorly with small images, anteriorly with large images, and in an intermediate position with medium size images, in agreement with the functional anatomy of the calcarine cortex. However, even the demonstration that under certain conditions the activation of the primary visual areas is a constant concomitant of imagery operations does not provide unequivocal evidence that it represents a crucial, necessary stage in image retrieval. As pointed out by Moscovitch et al. (1994), this is an issue that can hardly be settled by normal studies and badly needs the contribution of clinical findings. If medial occipital areas play a crucial role in the retrieval of mental images, then patients with occipital damage causing impairment or loss of perception should be impaired or unable to carry out tasks requiring imagery. Patients with agnosia and preserved mental images are problematic for this theory, but the crucial test is represented by patients affected by cortical blindness, following bilateral occipital damage, who should fail every imaging task. At variance with this prediction, Goldenberg et al.’s (1995) cortical blind patient was able to describe the shape of capital letters and scored within the lower range of the normal performance on a sentence verification test concerning the shape and the colour of objects. The authors were loath to draw firm conclusions from this case, as the destruction of the occipital cortex was incomplete and small islands of the intact visual cortex might have contributed to the imagery performance. This was not the case in at least one of the three cortically blind patients reported by Chatterjee and Southwood (1995), who passed a series of visual imagery tests, in spite of a total destruction of the primary visual areas. Furthermore, the case reports of achromatopsia with preserved colour imaging and ability to name visual imaged colours (Bartolomeo et al., 1997; Shuren et al., 1996) do not tally with the assumption that the activation of early perceptual areas is a prerequisite for triggering imaging processes. Another issue addressed by the investigation of the anatomical substrates of visual imagery is

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whether they are equally or asymmetrically represented in the two hemispheres. Early speculations that imaging is a right brain function were dismissed because of the lack of experimental support (Ehrlichman & Barrett, 1983) and were reversed by Farah (1984), who, after reviewing the clinical literature, claimed that patients with a specific deficit in visual image generation suffer from left brain damage. In Sergent’s (1990) view, this inference rested on flimsy evidence, but subsequent reports of patients with pure image generation were in keeping with Farah’s hypothesis (Trojano & Grossi, 1994). Further support was provided by a number of SPECT and event-related potential studies (summarised in Goldenberg at al., 1993 and Farah, 1995, respectively) and also by a clinical study (Stangalino et al., 1995), which showed a greater incidence of image generation deficit in a left than in a right brain-damaged group. However, PET investigation yielded inconsistent support for a left hemisphere ascendancy in imagery tasks, possibly due to individual variations and the nature of the images required by the task (Kosslyn et al., 1993). A tentative conclusion may be that the greater specialisation of the left hemisphere is a matter of degree and is not absolute, otherwise generation deficits would be encountered far more frequently. Acoustic aphasia The inability to name a meaningful sound, whose source has been recognised, was reported in just one case. Denes and Semenza’s (1975) patient was affected by verbal agnosia, that is, he did not understand oral language because he could not discriminate the phonemic features of words, but had normal speech (in particular visual and tactile naming). Presented with a meaningful sound and four drawings of objects, he was able to correctly match the sound with a picture in 17/20 trials, but in only four could he retrieve the name of the object. Whenever he failed, he claimed not to know what the source of the sound was and, if pressed, would provide bizarre answers, without any semantic or acoustic relation to the real source. No information on the locus of lesion was available, but clinical data suggest that it involved the left hemisphere and the authors speculated that it

disconnected the Wernicke’s area from both primary acoustic areas and prevented it from receiving the acoustic information that the intact right temporal lobe had decoded. What is amazing in this case, as well as in some of those with optic aphasia, is that, instead of simply saying that he could not retrieve the name of the object, the patient claimed not to know what it was. Semantic amnesia The recognition disorders considered so far are characterised by the selective impairment of information transmitted through one sensory channel. Even if the unimodal nature of the deficit is sometimes not as strict as the definition of agnosia would imply, it is still possible to demonstrate that the patient is able to recognise the stimulus, if an appropriate channel is used. On the contrary, in semantic amnesia, patients have lost their knowledge of objects, regardless of the way information related to their features is activated (De Renzi et al., 1987; Marin et al., 1983; Warrington, 1975; Taylor & Warrington, 1971; Schwartz et al., 1979; Warrington & Shallice, 1981). The encyclopedia storing the attributes of things (their names, sensory features, functional and conceptual properties, etc.) is either damaged or inaccessible. Patients are not demented, have no language deficits, apart from lexical impairment, have preserved spatial and praxic skills, and may not suffer from global amnesia. Thus the label semantic dementia, proposed to define this clinical pattern (Hodges et al., 1992; Snowden et al., 1989) appears questionable, even if some of these patients suffer from a slowly progressive disease that leads to dementia. A frequently reported aetiology is encephalitis and in these cases the semantic deficit may be restricted to certain categories, e.g., living things (Basso et al., 1988; De Renzi & Lucchelli, 1994; Pietrini et al., 1988; Sartori & Job, 1988; Silveri & Gainotti, 1988; Warrington & Shallice, 1984). Location of lesion and aetiology Apperceptive agnosia is almost always associated with bilateral damage of the visual areas, although the contribution of the right brain to perceptual processing is likely to prevail (De Renzi et al.,

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1969; Warrington & Taylor, 1973) and two cases of apperceptive agnosia (De Renzi & Lucchelli, 1993; Levine, 1978) were found to have a lesion apparently confined to the posterior areas of the right brain. The most common aetiology is CO poisoning (Adler, 1944, 1950; Benson & Greenberg, 1969; Campion & Latto, 1985; Milner et al., 1991), followed by trauma (De Renzi & Lucchelli, 1993; Goldstein & Gelb, 1918; Kertesz, 1979), bilateral infarcts (Grailet et al., 1990; Riddoch & Humphreys, 1987a; Shelton et al., 1994) and mercury intoxication (Landis et al., 1982). Also in associative visual agnosia cases with bilateral occipito-temporal damage have been reported (for a review, see Iorio et al., 1992). Some of them evolved from an early pattern of apperceptive agnosia. Their deficit was interpreted (Albert et al., 1979; Kawahata & Nagata, 1989) as secondary to the interruption of the inferior longitudinal fasciculus, which links the occipital areas, where the stimulus is perceptually processed, with the medial temporal cortex, where its visual memory is stored. However, in the majority of cases, Lissauer’s patient (Hahn, 1895) included, there is evidence from anatomical (Caplan & Headley-White, 1974; Scheller, 1966), surgical (Hecaen & Ajuriguerra, 1956; Hecaen et al., 1974) and, more recently, CT and MRI findings that the lesion can be confined to the left side. The most common aetiology is an infarct in the territory of the left posterior cerebral artery, encroaching on the lingual and fusiform gyri, the hippocampal gyrus and the inferior longitudinal fasciculus (Feinberg et al., 1994). Visual areas are disconnected from area TE, which in monkeys has been found to play a crucial role in object recognition (Ungerleider & Mishkin, 1982). Exception to this location of damage are represented by the patient reported by McCormick and Levine (1983), who had a parietooccipital tumour and that of Rapcsak et al. (1987), who had a haemorrhage in the infero-lateral posterior region of the temporal lobe. Schnider et al. (1994) ventured that the difference between associative agnosia and optic aphasia is contingent on the extent of splenial damage, which would be spared in the former and invariably destroyed in the latter. It would follow

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that in optic aphasia object recognition is carried out by the right hemisphere, which has the competence to do it, while in associative agnosia its performance is inhibited by the left hemisphere, which receives visual information but, being damaged, is unable to process it. However, the claim that the splenium is intact in associative agnosia was not confirmed by Feinberg et al. (1994), who found that it was extensively damaged in three of seven patients. There is, therefore, no convincing evidence that the two syndromes differ in terms of location of lesion.

Prosopagnosia The term prosopagnosia (from the Greek word prosopon, meaning face) has been proposed by Bodamer (1947) to refer to the inability to recognise familiar faces. The deficit is strictly confined to the the identification of physiognomic traits, as shown by the fact that voices are readily recognised and that the patient takes advantage of nonphysiognomic visual cues (a scar or a mole, a particular item of clothing, etc.). The symptom was first reported by Quaglino (1867), an Italian ophthalmologist, who described a patient suffering from left hemianopia, achromatopsia, and an inability to recognise familiar faces, after a cerebrovascular disease. As he was able to read words printed in small print, the bearing of elementary visual deficits on face recognition was ruled out and Quaglino attributed the patient’s impairment to brain damage. The paper went unnoticed, possibly because it was published in an ophthalmological journal, and, in spite of occasional mention of the disorder in the subsequent literature, prosopagnosia had to wait for Bodamer (1947) before becoming a focus of neurological interest. In the most severe cases patients cannot recognise their own face, when they look at themselves in the mirror, or that of closest relatives. A patient of mine addressed his wife by saying “I do realise that there is no other woman at home, but tell me: are you really my wife?” In milder forms, the deficit may be limited to friends and acquaintances, especially when they are met in an unusual context, and to famous people, or it may only concern faces that have been known after

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disease onset (Hecaen & Angelergues, 1962; Hanley et al., 1990; Shuttleworth et al., 1982; Takahashi et al., 1995). Patients know that a face is a face and are usually able to differentiate its sex, race, and age. Even emotional expressions are correctly identified and the report of the opposite dissociation— prosopo-affective agnosia without prosopagnosia (Kurucz & Felmar, 1979)—attests that independent substrates subserve the two abilities (see later). What the patient cannot do is recognise a face as “that” face. A few of them complain of seeing faces in a dim light or distorted, but the majority do not report visual difficulty. They are well aware of their predicament (for an exception, see Sergent & Villemure, 1989) and often feel ashamed of it, because such a circumscribed visual deficit sometimes leaves them and their relatives puzzled. In two patients of mine the ophthalmologist diagnosed a psychogenic disorder, as he could not understand how a subject, who had normal elementary visual functions, could just fail to recognise faces. Recognition o f known and unknown faces In 1962, a paper of Hecaen and Angelergues (1962) provided impetus for considering faces as a class of stimuli suitable for bringing out hemispheric differences in performance. A review of the literature, made by these authors, pointed out that prosopagnosia was frequently associated with left visual field defects and led them to submit that the right brain plays a prominent role in face recognition. This hypothesis gained support from group studies (Benton & van Allen, 1968; De Renzi et al., 1968; De Renzi & Spinnler, 1966; Milner, 1968; Tzavaras et al., 1970; Warrington & James, 1967a), which consistently showed that right brain-damaged patients performed worse than left brain-damaged patients on unknown face recognition tests. The hemispheric asymmetry was confirmed in normal subjects, when they were requested to make an old/new discrimination of photographs of unfamiliar faces, flashed to either lateral visual field. Both accuracy and speed of response were higher for faces projected to the left visual field than for those projected to the right visual field. While the outcome of these

studies was unequivocal in providing evidence for right hemisphere ascendancy in processing unfamiliar faces, its bearing on prosopagnosia, which consists in the inability to recognise familiar faces, was challenged by the report of prosopagnosics who performed normally on these tasks (Assal, 1969; Benton & Van Allen, 1972; Tzavaras et al., 1970)and by the lack of correlation between unfamiliar and familiar recognition scores found in right brain-damaged patients (Warrington & James, 1967). Benton (1980) inferred from these data that there are two independent deficits, produced by brain damage, one concerning the perceptual processing of face information and brought out by unfamiliar face tasks, the other involving an additional mnestic factor and brought out by familiar face tasks. Apperceptive and associative prosopagnosia The identification of a face is the end stage of a process in which visual information is analysed by discrete, hierarchically organised modules. According to the model, developed by Bruce and Young (1986), perceptual processing results in the structured encoding module with the construction of an object centred, tri-dimensional description of the face. If the face is known, its structured description activates an abstract representation of it, stored in recognition units, giving rise to a feeling of familiarity. Recognition obtains, when the information gains access to the identity nodes, a sector of semantic memory, containing knowledge about familiar persons’ biography, the relationship we have with them, the circumstances in which we met them, etc. A separate module is devoted to their names and can only be accessed from identity nodes. Its independent status is suggested by the frequent inability, experienced by normal subjects, to retrieve the proper name of an otherwise perfectly recognised person, and is confirmed by the specific anomia for proper names, shown by a few left brain-damaged patients. In the most common form, the deficit is apparent whatever the modality (visual, verbal, acoustic) through which the name is elicited, contrasts with the perfectly preserved semantic knowledge about the same persons, and may or may not extend to other categories of proper names (e.g. geographical). A

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case of anomia limited to the visual presentation of a face (Carney & Temple, 1993) has been reported and named prosopanomia. Depending on the level at which the functional lesion occurs, two types of prosopagnosia occur. When perceptual processing is disrupted, the inability to recognise familiar faces is but an aspect of an apperceptive disorder across the board, as found in the patients of Goldstein and Gelb (1918), Adler (1944,1950). Benson and Greenberg (1969), Landis et al. (1982), Bauer (case 2, 1986), Grailet et al. (1990), Milner et al. (1991), and Shelton et al. (1994). More problematic are patients whose nonfacial recognition deficit is limited to discriminating the exemplars of a category, which, like faces, show remarkable similarity, e.g. car makes, banknotes, playing cards, some types of fruit and animals (De Renzi, 1986; Macrae & Trolle, 1956; Shuttleworth et al., 1982). They also tend to score poorly on perceptually demanding tests, such as Ghent’s overlapping figures, Gollin and Street’s interrupted figures, photos of objects taken from noncanonical views, face matching tests (Benton & Van Allen, 1968), and face age discrimination tests (De Renzi et al., 1989), thus suggesting a mild to moderate perceptual impairment. Its bearing on prosopagnosia must, however, be evaluated with caution, as a poor performance on one or more of these tests can also be found in right brain-damaged patients, who do not present prosopagnosia (McNeil & Warrington, 1991). In an attempt to rest the classification of face recognition deficits on more solid grounds, De Renzi et al. (1991) gave two face perception tests (unknown face matching and age discrimination) and two face memory tests (familiarity and verbovisual matching) to 100 normal subjects, and computed the external and internal tolerance limits of the difference between the two sets of scores. These norms made it possible to identify braindamaged patients who were outliers either for an exceedingly poor performance on perceptual tests (apperceptive prosopagnosia) or for an exceedingly poor performance on mnestic tests (associative prosopagnosia). It remains to be seen whether these measures also discriminate prosopagnosics from right brain-damaged patients, who recognise familiar faces.

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An amnestic or associative form of prosopagnosia can be envisaged when the patient passes all perceptual tests (in particular those involving face identification) and fails the recognition of familiar faces, though showing intact semantic knowledge of the persons to whom they refer. The impairment may occur either at the level of recognition units or identity nodes. In principle, the former should cause the inability to perform familiarity tests (to identify among alternatives the one known face), while they are passed in the latter, and the failure occurs on recognition tests (to name a familiar face or to choose it among distractors belonging to the same semantic category, when its name is given). As a matter of fact, almost all reported cases of associative prosopagnosia fail on both types of tests. An exception is represented by the patient of De Haan et al. (1991), who showed preserved familiarity and impaired recognition. De Renzi and di Pellegrino (in press) reported a patient with an apparently paradoxical dissociation, poor scores on the familiarity test and a face naming test, but almost perfect responses (though given with delay and hesitation) on a visuo-verbal matching test. The key to understanding this behaviour was the patient’s good performance on a face imaging test, in which she was given a triplet of proper names corresponding to famous persons and was requested to identify the person, whose face was markedly different from the others. Thus she could compare the face images generated on name presentation with the output of structured encoding and come, after painstaking analysis, to a correct response in the visuo-verbal matching test. This top-down strategy could not be used in the familiarity and naming tests, where the only available information was perceptual Loss o f semantic knowledge fo r individual entities Prosopagnosia must be distinguished from the inability to retrieve from semantic memory any type of information related to an individual, his or her face, name, and voice. In Ellis et al.’s (1989) patient the deficit was not limited to persons, but also involved famous animals (e.g. Lassie, Moby Dick), buildings (e.g. the Kremlin), and old product names, while other aspects of semantic and

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autobiographic memory were fairly well preserved. In Hanley et al.’s (1989) patient, the knowledge of living things was also impaired. Also Kartsounis and Shallice’s patient (1996) showed a deficit in recognising famous contemporary people in both the verbal and the visual modality, while famous historical people and buildings were misidentified in the visual modality only. When assessed with photographs of relatives and friends, he did not manifest prosopagnosia. A progressive transition from a pure impairment of familiar face recognition to a loss of knowledge of every piece of information concerning the same persons was reported in a patient (Evans et al., 1995) with light temporal lobe atrophy. In this case unique exemplars from other categories (e.g. buildings) were well recognised. Unconscious recognition An interesting phenomenon, brought out in prosopagnosia, as well as in other cognitive domains, is unconscious recognition. It consists in the fact that, when confronted with famous faces that they deny recognising, prosopagnosic patients react differently from when they are presented with faces never seen before, thus showing that they have retained an implicit knowledge of them. This behaviour was first investigated by Bauer (1984), by adapting to the experimental situation the Guilty Knowledge Test, a criminological procedure in which suspects are presented with a stimulus relevant to the crime with the aim of assessing whether it elicits changes in their galvanic skin reaction. Bauer presented a prosopagnosic patient with the photograph of familiar, but not recognised persons that he had to match with one of five names. While correct matching only occurred in 22% of trials, i.e. at chance level, a positive electrodermal response was recorded in 61% (in two control subjects it was present in 100% and 80% of trials). This finding was confirmed in subsequent studies (Bauer, 1986; Tranel & Damasio, 1985), providing evidence for an implicit identification of familiar faces that the patient was unable to overtly recognise. Other neurophysiological techniques yielded the same results. Renault et al. (1989) reported an increase in the amplitude of the P300 component of the event-related brain

potential, associated with the presentation of familiar faces provided they occurred less frequently than unfamiliar faces and Rizzo et al. (1987) showed that the scanpaths made in inspecting a known face were different from those elicited by an unknown face. Psychological procedures are also effective in revealing covert recognition. Prosopagnosic patients showed improved learning and increased priming if the stimuli were photographs of familiar rather than unfamiliar people. For instance, they were better at learning to associate a familiar face with a proper name or a profession if the pair was true rather than untrue (Bruyer et al., 1983; De Haan et al., 1987a; Diamond et al., 1994; Sergent & Poncet, 1990). However, the effect disappeared, if the task became more demanding (Young & De Haan, 1988), for instance, if only the first name, instead of the full name was given, or if more specific information was required (not simply whether the face was of a politician, but to which political party the person belonged). Another suitable paradigm to demonstrate covert recognition is priming, that is, the improvement in performance that occurs in a proper name decision task following the previous presentation of a semantically related photograph. For instance, one patient was able to decide more quickly whether the name Paul Newman was famous, when it was preceded by the presentation of the face of Robert Redford as opposed to that of Margaret Thatcher, though neither of them were recognised (Young et al., 1988). Sergent and Poncet’s (1990) patients were able to match two photographs of the same famous person across a 30-year period much better than control subjects from a different country, who were unfamiliar with him, despite claiming not to know the faces. Even more amazing was the finding, reported by Sergent and Poncet (1990) and partially replicated by De Haan et al. (1991) and Diamond et al. (1994), of a patient who, when informed that the faces he had not recognised belonged to the same semantic category, succeeded first in identifying the category and then in retrieving the names of the faces. However, none of them was recognised, when, after a while, they were presented again, intermingled with unfamiliar faces.

16. AGNOSIA

It must be added that a residual knowledge about faces that the patient claims not to recognise has also been shown with tests that explicitly require overt recognition, provided a forced choice paradigm was used. When asked to choose the name matching a non-recognised face among distractors, some prosopagnosic patients responded above chance, though commenting that they were merely guessing (De Haan et al., 1991; Diamond et al., 1994; McNeil & Warrington, 1991; Sergent & Poncet, 1990) and, when requested to match different views of the same face, they gave quicker responses to familiar faces (De Haan et al., 1987b). Surprisingly, no advantage accrued from the use of the forced-choice paradigm, when a familiarity judgement was requested. The phenomenon of unconscious recognition is not, however, present in every prosopagnosic patient. Negative cases have been reported by Bauer (1986), Newcombe et al. (1989), Sergent and Villemure (1989), Young and Ellis (1989), De Haan and Campbell (1991), and De Haan et al. (1992) and interpreted as consequent to damage at the level of perceptual encoding or recognition units, which would hinder the transmission of information about the physical appearance of faces to higher levels (Newcombe et al., 1989). There are, however, both patients who do not show covert recognition in the absence of perceptual deficits (Etcoff et al., 1991; McNeil & Warrington, 1991; Schweinberger, 1991) and patients who present the reverse pattern (McNeil and Warrington, 1991). The dissociation between covert and overt recognition has been accounted for in terms of there being two routes transmitting the perceptual output to the semantic system, one directly projecting to identity nodes and the other bypassing them and making a connection either with the name system (De Haan et al., 1991; McNeil & Warrington, 1991) or with other structures. Bauer (1984) couched this interpretation in anatomical terms, making reference to the two pathways transmitting visual information to higher centres, one directed to the inferior temporal cortex, where the meaning of the stimulus is decoded, and the other projecting to the parietal cortex, where its spatial features are processed (Ungerleider & Mishkin, 1982). The former would be damaged,

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preventing conscious recognition, the latter would be spared and would mediate unconscious recognition, by virtue of its connections with the cingulate cortex. Neither of these hypotheses is able to account for all of the manifestations of covert recognition. Names played no role in the aforementioned experiment, in which the identification of the same face across a 30-year period was required (Sergent & Poncet, 1990) or in the superior ability to match different views of the same face, when it was familiar rather than unfamiliar (De Haan et al., 1987a). Neither is it clear why, in a forced choice paradigm, the alternative occipito-parietal cingulate route was able to mediate a face-name matching, but not a familiarity judgement. Perhaps the most straightforward interpretation is that the threshold for triggering conscious recognition is higher than that for unconscious recognition. According to this view, a complete lesion of recognition units would impair both mechanisms, whereas partial damage would render their output insufficient to activate conscious recognition, but not unconscious recognition. In normal subjects, it is possible to show a dissociation between covert and overt recognition, when the latter is made more difficult by delaying it over a six-month period (Wallace & Farah, 1992). It is also worth noting that the magnitude of the neurophysiological and neuropsychological responses that assess unconscious recognition tends to be smaller in prosopagnosic patients than in normal controls (Schweinberger et al., 1995), in agreement with the hypothesis that reduced information is transmitted both to the overt and the covert system, but that the latter is more reactive to it, having a lower threshold. Specificity o f the face deficit A recurrent issue throughout the history of prosopagnosia is whether the impairment is specific to faces, as suggested by Bodamer (1947), who conceived prosopagnosia as the disruption of a primary ability, already present in the early months of life and destined to play a crucial role in the development of social skills. This speculation finds some support in experimental studies showing that at just 4 days of age neonates manifest a preference

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for face-like stimuli and look longer at their mother’s face than at a stranger’s face (Bushnell et al., 1989; Pascalis et al., 1995), although only at 2-4 months do they recognise their mother’s face, even after the hairline is masked by a scarf (de Schonen & Mathivet, 1990). Moreover, a right hemisphere advantage in a mother’s face recognition test, given with the divided field presentation procedure, was apparent in 4-10 month-old infants (de Schonen & Mathivet, 1990). Other considerations that must be kept in mind are that the individuality of a face must be identified among alternatives that are perceptually very similar, and that the number of face exemplars that subjects store in their life is incomparably higher than that of any other category, probably around one thousand, including relatives, acquaintances, and famous persons. Yet the contention that prosopagnosia is an autonomous disorder, contingent on the disruption of a discrete cerebral mechanism, has been disputed by several authors, who remarked that these patients also run into difficulty in discriminating the members of other categories, e.g. a chair from an armchair (Faust, 1955), car makes (Lhermitte et al., 1972), mammals of similar shape (Lhermitte et al., 1972; Lhermitte & Pillon, 1975), and so forth. There have been reports of farmers, who had become unable to identify their own cows (Assal et al., 1984; Bornstein et al., 1969) and an ornithologist who could no longer discriminate birds of different species (Bornstein, 1963). These findings were taken as evidence (Humphreys & Riddoch, 1987) that prosopagnosia represents a mild form of visual agnosia, apparent in everyday life for faces, but actually detectable whenever the patient must discriminate similar shapes. Damasio et al. (1982) breathed new life into the hypothesis, first put forward by Lhermitte and Pillon (1975), that underlying prosopagnosia is a more general disorder, namely, the inability to identify an exemplar within a category. They rightly remarked that object and face recognition are tested in different ways, because for objects patients are requested to identify the category to which the stimulus belongs (is it a hammer, a horse, etc?), while for faces they must identify its individuality. Prosopagnosics are not asked whether a face is a face, but whether it is that particular face, the one

they have previously met in a definite spatiotemporal context. Damasio et al. (1982) claimed that if object recognition is assessed through the same kind of questions (e.g. asking not whether a book is a book, but whose book it is), patients with face recognition impairment will also be found to perform poorly with other classes of stimuli. The evidence they adduced in support of this contention was, however, not very pertinent, as it did not concern the recognition of the stimulus individuality, but the errors made among subclasses belonging to the same general superordinate, e.g. a cat was mistaken for a tiger or a panther, and the British pound sign for a musical notation. It would, therefore, appear that their patients’ impairment boiled down to a deficit in discriminating figures that were similar in shape. This is not, however, a constant feature of prosopagnosics and there is evidence that some of them can show an amazing ability to differentiate exemplars of the same category, when they are not faces. Sergent and Signoret’ s (1992) patient had made a hobby of collecting miniature cars and was, therefore, an expert on car makes and models. When he was presented with 210 photographs of cars, of 14 models from 15 makes, he identified 172 of them correctly and for the remainder he was able to report the company for 31 and the model for 22. McNeil and Warrington’s (1991) patient was a shepherd, who had become proficient at recognising sheep faces. Contrary to normal controls, he showed a greater ability to learn arbitrary associations between sheep faces and proper names than between human faces and proper names. A direct test of the hypothesis that prosopagnosics fail whenever they have to identify a familiar object among exemplars of the same class, was carried out by De Renzi (1986). His patient was requested to select a personal belonging (his own wallet, electric razor, necktie, glasses, etc.) from an array of objects of the same class, and to recognise his handwriting in a sentence written by him and by nine other persons. He showed no hesitation in making the correct choice. The finding was replicated in a second patient (De Renzi et al., 1991) and confirmed by Sergent and Signoret (1992). These authors, however, argued that this successful performance was contingent on the use

16. AGNOSIA

of a forced-choice paradigm, because it also permitted their patients to recognise their own face or that of a close relative among distractors, once their names were provided. Only a limited number of items were given (two in one patient and five in another) and, moreover, the same procedure failed when the patients had to identify a famous person, in agreement with the results reported by De Renzi (1986) in a familiarity test and a visuo-verbal matching test. Thus the findings of this experiment remain open to question and it is possible that correct face identification was due to unconscious recognition and was not related to the use of a forced-choice paradigm. In the literature there are examples of patients who do not recognise a face, despite knowing that it must belong to a given person. For instance, Lhermitte et al.’s (1972) patient, who suddenly became prosopagnosic, said to his physiotherapist, “Miss, what’s happening to me, I am no longer able to recognise you?” The idea that the inability to recognise familiar faces is specific has found experimental support in the different patterns of impairment shown by a prosopagnosic patient (Farah et al., 1995), when he was requested to make an old/new recognition judgement in front of faces and of different exemplars of the same object (e.g. similar-looking eyeglass frames). In comparison with normal controls, he found faces disproportionally more difficult to recognise. Why such specificity? Farah (1990) championed the view that it does not result from an intrinsic quality of the face class, but from the nature of the perceptual processing they undergo, which would be different from that used for words and objects. Specifically, faces are coded as a whole, while words are broken up into their constituent elements (letters), and objects share both apperceptive modes in various proportions, depending on their formal features. It follows that, depending on whether the global mode or the analytical mode or both are impaired, different patterns of deficit involving faces, words, and objects are to be expected, while some associations are highly unlikely. If it is mild, a deficit of global perception will result in face agnosia, whereas if it is severe it will extend to objects that are perceptually similar. Conversely, a mild deficit of analytical perception will cause alexia, while a more

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marked impairment will also involve object recognition. Finally, a disruption of both modes of perceptual processing will be associated with global agnosia, impairing all categories. There are, however, two patterns of deficit that are explicitly excluded by the theory: agnosia for faces and words with integrity of objects, and agnosia for objects without impairment of either faces or words. Farah (1991) sought support for her theory in a review of all of the published cases of agnosia and found that none of them invalidated its predictions. However, they did not stand the test of time. In the subsequent years both of them were disproven by the report of a patient with object agnosia without alexia and agnosia for faces (Rumiati et al., 1995) and two patients with alexia and agnosia for faces, but not object agnosia (Buxbaum et al., 1996; De Renzi & di Pellegrino, in press). It is likely that the patterns of association and dissociations emphasised by Farah (1991) were due to the hemispheric specialisation in processing different types of perceptual stimuli, with the left side specialised in word identification and the right side playing a more important role in face identification. The association of alexia and agnosia for faces can only appear when the lesion is bilateral, a pathological event that will frequently, but not necessarily, encroach on the areas involved in object recognition. Further evidence in support of the theory that faces are special comes from monkey studies, which have shown the existence in the inferior temporal cortex (area TE) and in the superior temporal sulcus (area STP) of cells that fire selectively, when the animal is presented with faces (for a review, see Perret et al., 1987 and Desimone, 1991). Some of them are sensitive to certain parts of the face (the eyes, mouth, or hair region), others to face orientations (front-view, profile, etc) and about 10% to personal identity, being triggered by familiar faces. The last cells are mainly represented in the inferior temporal cortex, i.e. in the region whose damage is associated with prosopagnosia, while neurones in the superior temporal sulcus are sensitive to emotional expressions and gaze direction (Perret et al., 1992). Both abilities are impaired in patients with lesions of the amygdala (Adolphs et al., 1994; Young et al., 1995), a structure that has strong connections with the

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superior temporal sulcus. In monkeys social communication relies heavily on gaze direction and it has been speculated that in these animals the role played by the amygdala-superior temporal sulcus circuit is to some extent analogous to that played in humans by the language network, located in the left temporal lobe (Desimone, 1991). In the monkey the different functional specialisation displayed by the inferior and the superior temporal lobe has a correspondence with the dissociation between face and emotion recognition, found in brain-damaged patients. Although prosopagnosic patients do not usually show any deficit in identifying the emotional expression of the faces they do not recognise, two patients without prosopagnosia (Rapcsak et al., 1989, 1993) have been reported, who manifested a selective impairment in naming face expressions and in pointing to them when the name was provided, though they understood their meaning. Both had a lesion located in the right middle temporal lobe, an area where in epileptic patients cells have been found (Ojemann et al., 1992) to discharge when the patient had to label facial expressions. Location o f lesion As already mentioned, the prevalence of a left field defect in patients with prosopagnosia led Hecaen and Angelergues (1962) to surmise that the disorder may be associated with right brain damage. Twelve years later, Meadows (1974b) made a new review of the literature and confirmed the disproportionate frequency with which the left visual field was affected, but cautioned against drawing inferences about the prominent role of right hemisphere damage, because in six of the eight cases with pathological documentation, the damage to the temporal-occipital area was bilateral and in the other two there was, in addition to the right temporal-occipital lesion, a gliosis of the left angular gyrus and a neoplastic involvement of the splenium up to the left ventricular wall, respectively. Bilateral occipital lesions were also present in subsequent autoptic cases (two reported by Cohn et al., 1977 and four reported by Nardelli et al., 1982). Particularly telling was a patient (Ettlin et al., 1992), who did not show a face recognition deficit following two right-sided

infarcts, one of which completely destroyed the temporo-occipital region, but became prosopagnosic when he incurred a haemorrhage in the left occipital lobe. Based on pathological evidence, Damasio et al. (1982) posited that bilateral damage is a constant and necessary correlate of prosopagnosia. This claim, which gained wide consensus, is too drastic. First of all, it must be observed that cases coming to autopsy may yield a biased sample, in which patients with bilateral infarcts, and hence more severely ill, tend to be over-represented. In this respect, the evidence provided by CT scan and MRI is more trustworthy, because it is available in practically every patient and is collected at the time they are tested. A scrutiny of cases with this documentation, plus those with surgical documentation, reveals a substantial number of exceptions to the rule of the bilaterality of damage. In 1994 De Renzi et al. managed to marshal as many as 31 patients with evidence of a lesion confined to the right hemisphere (in 7 there were also PET data), to which 4 new cases (Evans et al., 1995; Takahashi et al., 1995; Tohgi et al., 1994) can now be added. Moreover, two cases of prosopagnosia showing at autopsy lesion of the right hemisphere alone, have been recently published (Kawamura & Takahashi, 1995; Landis et al., 1988). It is, therefore, apparent that bilateral damage does not represent a sine qua non condition for the occurrence of prosopagnosia, which can result from a lesion confined to the right side alone, in agreement with its superiority in face processing indicated by normal and brain-damaged group studies. However, it would be hazardous to draw a parallel between right hemisphere dominance for face recognition and left hemisphere ascendancy for speech. Prosopagnosia is a rare symptom, which does not usually accompany the infarct of the occipito-temporal area produced by right posterior cerebral artery occlusion. I did not find it in 10 consecutive cases, explicitly investigated, while, for instance, alexia was present in 13 of 16 consecutive cases with left posterior cerebral artery infarct (De Renzi et al., 1987). A balanced conclusion on the hemispheric contribution to the treatment of face information is that in the majority of human subjects both occipitotemporal areas participate in its processing, though

16. AGNOSIA

with a prevalence of the right side. Interestingly, the recognition of familiar voices is also more impaired following right brain-damage, particularly when the parietal lobe is involved, whereas a deficit in samedifferent discrimination between pairs of unfamiliar voices is found in association with damage to either hemisphere (Van Lancker et al., 1989). We can summarise the issue of the hemispheric contribution to prosopagnosia by saying that usually damage to the right brain areas can be compensated by the healthy hemisphere. However, the degree of hemispheric asymmetry may differ remarkably from subject to subject and in a sizeable minority can be so marked that the right brain failure is no longer repairable. Gender may be an important factor in determining the extent to which face processing skills are unevenly represented in the hemispheres, as there is a substantial prevalence of prosopagnosia in males (Mazzucchi & Biber, 1983). The lesion responsible for prosopagnosia is located in the medial occipito-temporal region. In apperceptive forms, damage involves bilaterally the subcalcarine occipital cortex, in keeping with PET (Haxby et al., 1994; Sergent et al., 1992) and fMRI (Clark et al., 1996) studies, which have found an increased blood flow in the posterior part of the fusiform gyrus and adjacent occipito-temporal cortex, while the subject performed face discrimination tasks. From the same areas in epileptic patients Allison et al. (1994) recorded surface-negative potentials in response to the presentation of human faces. In associative forms, the lesion likely interrupts the inferior longitudinal fasciculus, which links the perceptual area with the infero-medial temporal lobe. Autopsy and neuroimaging data do not allow for the differentiation between the anatomical substrate of apperceptive and associative disorders but PET studies (Kapur et al., 1995; Sergent et al., 1992) suggest that tasks involving face memory specifically activate more anteriorly located inferior temporal cortices. The retrieval of familiar face names is associated with the bilateral activation of the temporal pole (Damasio et al., 1996). A hemispheric asymmetry was pointed out by Sergent et al. (1992), who found a more marked increase in cerebral blood flow in the right than in the left parahippocampal gyrus, and by two

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neurophysiological investigations. Uhl et al. (1990) reported a more prominent enhancement of the late negative event-related potential component from the right than the left occipital lead when familiar faces were presented, while, using depth electrodes, Seek et al. (1993, 1995) recorded a distinct pattern of neural responses to familiar faces from various sites of the temporal lobe, especially the amygdala, where they were confined to the right side. The amygdala plays an important role in the interpretation of emotional face expression. It is strongly linked with unimodal and polymodal sensory association areas and projects to motor, endocrine, and autonomic effector systems, located in the striatum, hypothalamus, and brain stem, thus providing a route for associating sensory information with emotional reaction (Tovee, 1995). Clinical evidence consistent with this assumption has been collected only recently. Adolphs et al.’s (1994) patient suffered from Urbach and Wiethe congenital disease, in which there is deposition of hyaline material in the amygdala. She showed preserved recognition of facial personal identity, but impaired recognition of fear and the blends of multiple emotions that a face can transmit. Although this finding was not replicated in two encephalitic patients with bilateral destruction of the amygdala and temporal lobe structures (Hamann et al., 1996), it is in keeping with PET measures of increased neuronal activity in the left amygdala, found in normal subjects, when they view fearful as opposed to happy facial expressions (Morris et al., 1996). In a patient submitted to partial bilateral amygdalotomy for the relief of intractable epilepsy, Young et al. (1995, 1996) documented difficulties in matching and identifying emotional facial expressions and in imagining facial expression of emotions. In addition, he was impaired in the recognition of faces learned postoperatively and in discriminating gaze direction, a function to which neurones in the superior temporal sulcus, strongly connected with those of the amygdala, are dedicated. Congenital and slowly progressive prosopagnosia In a few patients, prosopagnosia dates back to the early years of life, either without any detectable

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aetiology or as a consequence of brain disease. McConackie (1976) reported a congenital case in a 12-year-old girl, who was re-assessed by De Haan and Campbell (1991) 15 years later. She was an intelligent young woman, with a VIQ of 144 and a normal school curriculum. Her visual recognition deficit also extended to the recognition of emotional expressions and objects, and no unconscious face recognition could be demonstrated. The deficit was deemed to be apperceptive. The same was true for the patient reported by Ariel and Sadeh (1996), an 8-year-old girl with high verbal intelligence, who had severe problems in recognising not only face identity, but also their gender, age, and emotional expressions. She was poor on object drawings, particularly if they were presented from an unusual view or were partially masked. On the contrary the recognition deficit was restricted to faces in Temple’s (1991) patient and in that reported by Kracke (1994), a 19year-old man, who presented autistic features of the Asperger type. Interestingly, all of these patients (except Ariel & Sadeh’s) had a relative who experienced mild difficulty in face recognition. Yisuoperceptual disorders involving faces as well objects were also found in a boy who had encephalitis in infancy (Young & Ellis, 1989). In adults, the most common aetiology of prosopagnosia is stroke in the territory of the posterior cerebral artery. Among other aetiologies it is worth noting that the inability to recognise familiar faces can antedate other cognitive deficits in a few patients with progressive degenerative disease, mainly affecting the right temporal lobe (Evans et al., 1995; Tyrell et al., 1990b). In Alzheimer disease misidentification of familiar persons is detectable at clinical level in about 20% of patients (Della Sala et al., 1995; Mendez et al., 1992), while an impairment at psychometric level is present in about 50% of patients (Della Sala et al., 1995).

Colour agnosia Colours play an important role not only in enriching our emotional and aesthetic appreciation of the world, but also in discriminating an object from its background. They are processed by specific systems both at retina and brain level. In the retina

there are three types of receptors (cones), whose pigment has peak sensitivity to short-, middle-, and long-wavelength regions of the spectrum. They mediate the perception of blue, green, and red, respectively, while that of other colours of the spectrum results from the different grade of stimulation of these basic receptors by light. This information is transmitted by the parvocellular system (see earlier) and ends in area V4, which in humans seems to be located more medially than in the monkey, in a region encompassing the lingual and fusiform gyrus. Physiological studies have shown that in this area cells are clustered according to their peak sensitivity to light wavelength (especially for blue, green, purple, and red) and not to their relation to the topography of the visual field (Zeki, 1980, 1988). The following parameters define the perceptual features of a colour: 1. Hue, corresponding to the wavelength or the wavelength combination of the light reflected by the stimulus. It is equivalent to what we usually mean by colour. 2. Saturation, or purity, which reflects how much a hue has been diluted by greyness, depending on the the degree to which the cone mechanism is stimulated by both the object and the background. 3. Brightness, corresponding to light intensity. Hue and brightness information is transmitted by the same neurones up to the level of the visual cortex, where different subsets of neurones are dedicated to their analysis. Cortical lesions can selectively impair colour cognition either at a perceptual level or associative level, giving rise to a welter of disorders (Davidoff, 1991). Disorders o f colour perception (achromatopsia) Disorders of colour vision following a cerebral injury (acquired achromatopsia or dyschromatopsia) can occur in isolation; that is, without impairment of acuity, visual fields, form perception, or other cognitive deficits (Zeki, 1991). The first detailed description of complete achromatopsia was made by Samelsohn in 1881

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and of hemiachromatopsia by Verrey in 1888, who must also be credited with having pointed out that the anatomical basis of the deficit was a subcortical lesion of the lingual gyrus. In the most severe forms, the patient spontaneously complains of being unable to see colours and of the world appearing like a black and white film or in different shades of grey (Damasio et al., 1980; Green & Lessel, 1977; Meadows, 1974a; Pearlman et al., 1979). In milder cases, hues appear washed out or as if they were seen through a filter and sometimes a suffix is added to the end of a colour name (as in reddish, bluey) or two colours are combined (reddish-orange). Patients often rely on brightness to distinguish colours and can name the colours of brightly coloured objects (Green & Lessel, 1977). Rizzo et al. (1992) used psychophysiological techniques to study a patient suffering from dyschromatopsia and showed that a severe deficit in hue discrimination was associated with a preserved threshold for luminance detection, spatial contrast sensitivity, stereopsis, and movement vision. Visual field defects, which are frequent, but not necessary accompaniments, generally involve both or just one of the superior quadrants, suggesting a subcalcarine lesion. This localisation is upheld by a few autopsies (reviewed by Meadows, 1974) and, in a larger number of cases, by neuroimaging findings, which point to a lesion encompassing the lingual and the fusiform gyrus, mainly at their junction (Damasio et al., 1980; Green & Lessel, 1977; Heywood et al., 1991). Consistent with these findings, PET studies in normal subjects (Corbetta et al., 1990; Lueck et al., 1989), have demonstrated a cerebral flow increase in the same region, when the subject looks at coloured patterns, e.g. a Mondrian picture. Unilateral occipital damage, not causing hemianopia, can be associated with contralateral hemiachromatopsia with features analogous to those of total achromatopsia: hues are not discriminated and appear grey (Albert et al., 1975a) and are named with an “ish” suffix (Henderson, 1982). A few patients show quadrantopsia in the contralateral upper field and achromatopsia in the lower field (Damasio et al., 1980; Koelmel, 1988). In conclusion, there

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is converging evidence from animal, PET, and pathology studies that each hemisphere contains a centre devoted to processing chromatic information from the contralateral visual field. Bilateral damage produces bilateral achromatopsia, unilateral damage contralateral hemiachromatopsia. As already mentioned on page 387, achromatopsia is not necessarily associated with deficit of colour imagery. Dyschromatopsia associated with a non-occipital lesion Damage to extraoccipital areas not directly concerned with vision were found to cause impaired colour discrimination in unselected patients with right brain injury. They did not complain of any deficit, but their mean scores on colour perception tests (Ishihara, Farnsworth, etc.), presented in central vision, were lower than those of control and left brain-damaged patients (De Renzi & Spinnler, 1967; Scotti & Spinnler, 1970), pointing to a greater contribution of the right hemisphere to chromatic discrimination, in analogy with what is seen for other visuoperceptual tasks and in keeping with the better accuracy shown by normal subjects in recognising colours tachistoscopically projected to the left rather than the right field (Davidoff, 1976; Hannay, 1979; Pennal, 1977). Other authors (Lhermitte et al., 1969; Vola et al., 1973) focused on patients with left posterior damage and visual field defects and found a defective performance on the Farnsworth test, presented in central vision, in 50% of them. The deficit mainly concerned blue-green discrimination (Dubois-Poulsen, 1982), in agreement with what Scotti and Spinnler (1970) most often found in brain-damaged patients. Capitani et al. (1978) investigated patients submitted to the ablation of well defined cortico-subcortical areas for the relief of epilepsy and found that the performance was poorer following a right frontal removal (occipital patients were very rare in this study). Associative disorders Since the turn of the nineteenth century, there have been reports of patients who show a deficit in colour naming and/or colour-object associations

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that cannot be accounted for by aphasia or dyschromatopsia. They perceive colours on Ishihara and Farnsworth tests well, but are unable to name them; to retrieve their name when given the name of an object of a definite colour; to match a colour with an object; or to sort colours according to their hue. Some of them fail only when they must make a verbo-visual match, others whenever a colour must be retrieved from semantic memory. The disorder of the latter type has often been labelled colour agnosia (Kinsboume & Warrington, 1964; Poetzl, 1928; Sittig, 1921), but it is doubtful whether this term is appropriate, when applied to stimuli such as colours, which are processed in one modality (Bauer & Rubens, 1985) and do not have meaning on their own. I prefer to call the syndrome colour amnesia. Test methods A thorough examination of the patient’s knowledge of colours requires, in addition to perceptual tasks,

a broad set of tests (Davidoff, 1991; De Vreese, 1991). These are summarised in Table 16.3. It is preferable to use common colours only (from 8 to 10) in naming and pointing tasks, because people differ in their competence in colour name knowledge, mostly as a function of their educational level. Generating the names of colours is a verbal fluency task, whose performance should be compared with that for other categories. Generating the names of objects of a definite colour assesses visual imagery. In preparing lists of object-colour associations, care must be taken to distinguish those in which the chromatic attribute of the object represents an overlearned verbal association from those that require visual imaging. For instance, knowledge that blood is red comes into many verbal expressions (red blood cells, red-blooded people, to turn red, blood-red to designate a certain variety of red, etc.) and can be retrieved from verbal

TABLE 16.3 Colour cognition tests. V erb o -vis u al tests

Colour naming: What colour is this? Pointing to colours: Show me the green. C o lo u r-n a m e g e n e ra tio n

Generate the names of colours. Generate the names of objects of a particular colour (e.g. red). O b je c t-c o lo u r association

Name the colour of an object that has a typical colour: What colour is a frog? Name the colour of a personal belonging. Decide whether two objects are the same colour (e.g. banana and sunflower). Colouring in drawings of objects of a typical colour or deciding whether a drawing has been correctly coloured. Provide a metaphoric colour on verbal definition (e.g. white lie, blue-blooded, red herring). C o lo u r le a rn in g

Short-term memory for colours. Learning arbitrary colour-object associations. C o lo u r ca teg o ris atio n

Holmgren’s skein categorization test.

16. AGNOSIA

memory without implying the formation of a mental image, which is likely, on the contrary, to be necessary when we evoke a conventional association, such as the colour of a mail box. Generally speaking, verbal knowledge is the only determinant of metaphoric associations (to be green with envy). It also contributes greatly to the retrieval of the colour of certain natural objects, but has minimal or no role for objects of a conventional colour and for the colour of personal belongings (De Vreese, 1991). As stressed by Beauvois (1982), what is interesting about this distinction is that the performance of some patients may change, depending on whether the visual or the verbal strategy is favoured. Colouring tasks can be given to patients with language disorders, while rejection of wrongly coloured drawings is an easier task (Stengel, 1948) that has shown little discriminative power in a group study (Basso et al., 1976). Short-term memory tests and learning arbitrary colour-object associations can be presented both in the visual and verbal modality and may be useful to assess whether the impairment in dealing with colours extends to anterograde memory. In the Holmgren skein sorting task, patients are presented with woollen skeins of different hues and shades and requested to pick out all the skeins belonging to the same colour category (e.g. all the reds, greens, etc.). In former times it was viewed as a colour perception test, but Sittig (1921) and Gelb and Goldstein (1924) stressed its potential for assessing the patient’s ability to categorise colours and assigned it a paramount role in the evaluation of so-called colour agnosia (for a more recent reappraisal of the test, see De Renzi et al., 1972b). Unfortunately, for the most part, the patients reported by the literature have not been exhaustively investigated and cannot be readily classified. There is, however, sufficient evidence to distinguish two main categories of disorders, namely, those characterised by a visuo-verbal disconnection and those by a colour amnesia. Visuo-verbal disconnection (colour anomia or aphasia) These patients, who do not complain of disorders of colour perception, fail colour tasks in which verbal information must be matched with visual

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information—that is, naming a visually presented colour and pointing to a colour named by the examiner—whereas they pass tasks that are carried out in one modality, either verbal (what colour is a frog?) or visual (colouring in a drawing of a frog). The classical interpretation is couched in anatomical terms. The patients have a left occipital lesion that causes right hemianopia and, consequently, confines the perceptual processing of visual data to the right visual areas. While this information is readily utilisable in visual tasks (e.g. colouring drawings), which can be carried out by the same hemisphere, it is not available in naming tasks, because the lesion interrupts, at the level of either the splenium or the forceps major, the fibres connecting the right occipital lobe with the left language areas, where names of colours are stored. An exemplar of this condition is the patient exhaustively studied by Geschwind and Fusillo (1966), though quantitative data were not reported, and that of Gainotti et al. (1974), although pathological documentation was lacking. Other less thoroughly investigated cases were reported by Boucher et al. (1976), who did not test pointing, and by Oxbury et al. (1969, case 1), M ohret al. (1971), and Levin and Rose (1979), who did not provide information on colouring drawings. Naming is often more impaired than pointing, which was normal in a few patients of this group as well as of the successive one (Davidoff & Ostergaard, 1984; De Vreese, 1991; Sasanuma, 1974; Varney & Digre, 1983). Possibly, the performance was carried out entirely by the right hemisphere, which may also be endowed with verbal comprehension skills in right handers. In the patient reported by De Vreese (1991) the visuo-verbal disconnection hypothesis was apparently challenged by the finding that he too failed on a colour imaging task, carried out in the verbal modality (what colour is a frog?). However, the impairment only involved colour-object associations that are not aided by verbal mediation, such as objects that have an arbitrary, conventional colour, and personal objects. As the patient correctly performed the task of colouring in drawings, the deficit could not be attributed to a mental imagery impairment and was viewed as consequent to the inability to link the output of

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visual imagery with the lexicon, thus confirming the visuo-verbal disconnection hypothesis. Geschwind and Fusillo (1966) had not drawn a distinction between verbally and nonverbally coded colours, and De Vreese’s case stresses the need to keep their assessment separate. Colour anomia is usually associated with pure alexia, which stems from the same visuo-verbal disconnection mechanism (Dejerine, 1892). Only a few exceptions are on record (Davidoff & De Bleser, 1994; Mohr et al., 1971; Vincent et al., 1977). Colour anomia restricted to the left visual field was observed (Zihl & von Cramon (1980) in a patient with damage to the right occipito-temporal white matter and the splenium, and it was attributed to the disconnection of the right visual areas from the left language centres. Colour amnesia The disconnection hypothesis is inadequate to account for the performance of patients whose failure involves tasks that are carried out in one modality, either verbal (what colour is a frog?) or visual (colouring in a drawing of a frog). Lewandowsky (1908, see the partial English translation of his paper in Cognitive Neuropsychology, 1989, 6, 165-177) was the first to exhaustively investigate a patient showing this syndrome. Following a stroke likely affecting the left occipital lobe, a highly intelligent man with right hemisphere hemianopia, but no deficit of colour perception, was unable to name colours, to point to them when their name or the name of an object of a typical colour was given, to colour a drawing, and to decide whether a picture was coloured correctly or wrongly. The inability also involved black and white, while no difficulty emerged in answering questions concerning the lightness of an object (e.g. that the night is dark and the moon shines light). Incidentally, the loss of black and white names was not confirmed in other case reports (Kinsbourne & Warrington, 1964; Macrae & Trolle, 1956). Lewandowsky thought that the lesion impaired the ability to associate colour images with shape images and brightness. Unable to recall that red is the colour of blood and cherries, the patient would find red a meaningless colour and fail in naming. A different interpretation

was proposed by Sittig (1921) and Gelb and Goldstein (1924), who emphasised these patients’ failure on the Holmgren skein sorting test and attributed it to the inability to assume an abstract attitude towards colours and to consider them as representative of a given category (e.g. red). However, the value of the Holmgren test as means of measuring abstract thought is dubious (De Renzi et al., 1972b). The term colour agnosia, proposed by Sittig (1921) for this syndrome, fails to capture its essence, which consists in the defective access to or degradation of the sector of the semantic store dedicated to the knowledge of how objects are associated with colours. Colour agnosia was also used by Kinsbourne and Warrington (1964), though they clearly stated that the basic disorders resided in the inability to evoke old associations and to learn new ones. In principle, all the tasks listed in Table 16.3 should be performed poorly. There are, however, a few cases (Farah et al., 1988; Luzzatti & Davidoff, 1994; Schnider et al., 1992), in which naming and colour name comprehension was spared, though colour-object association knowledge was lost. This finding suggests that the output of colour processing is first organised into regions (categories) of hues (red, green, etc.), called by Davidoff (1991) the internal colour space, which are connected both with semantic memory and directly with the phonological output lexicon. In the foregoing cases, only the former connections were damaged and naming was obtained via the direct route. The patients’ behaviour towards their errors is variable: some of them are unaware of their mistakes, others try to correct themselves, and only few claim not to know the name of the colour. Beauvois and Saillant (1985) emphasised that errors on nonverbal tasks, such as colouring pictures or selecting the correctly coloured object from foils, may not occur as a result of a primary visual imagery deficit, but reflect the interference of the damaged verbal semantics in the performance. One of their patients showed a dramatic improvement in visual tests when they were constructed so as to prevent the use of a verbal strategy and this was further discouraged by placing a plaster over his mouth.

16. AGNOSIA

Patients with colour amnesia have either bilateral damage or damage confined to the left hemisphere. The ascendency of this side of the brain in colour knowledge finds support in group studies. Goldenberg and Artner (1991) found that patients with damage in the territory of the temporo-occipital branch of the left posterior cerebral artery were particularly impaired in answering high-imagery questions concerning object-colour associations. Other studies (Cohen & Kelter, 1979; De Renzi & Spinnler, 1967; De Renzi et al., 1972a) showed that poor scores in colouring drawings were associated with left brain damage causing aphasia. Although the colouring scores were correlated with language scores and global aphasies were particularly impaired, the defective performance could not be accounted for by the language disorder, as the deficit still held when colouring scores were covariated for colour name scores (Basso et al., 1976; see Chapter 13). The generation of words denoting colours selectively activates a region in the ventral temporal lobe, just anterior to the colour perception area and was stronger on the left side (Martin et al., 1995).

TACTILE AGNOSIA Tactile agnosia is the inability to recognise an object through palpation, in spite of preserved or minimally impaired somatosensory functions. Wernicke (1895), who first investigated this disorder, drew a distinction between primary identification and secondary identification deficits. The former refer to the loss of memory for the tactile qualities of the object (its roughness, hardness, weight, size, and shape), which Wernicke tentatively localised in the postcentral gyrus. In the latter, the sensory features of the stimulus are correctly appreciated (“it is long, hard, has an oblong shape,” etc.), but its meaning is not recognised, because the lesion disconnects the tactile image centre from the centres where other sensory images (visual, auditory) are stored. This two-stage classification was taken up by Delay (1935), who further elaborated it by introducing a distinction in primary identification disorders

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between failure to identify substance features (ahylognosia) and failure to recognise shape (amorphognosia). He called the secondary identification deficit tactile asymbolia. To what extent are these subdivisions of tactile agnosia clinically autonomous and independent of elementary sensory deficits? Delay himself doubted that anhylognosia could be reliably discriminated from cortical sensory deficits, as one of their main features, emphasised by Holmes (1927), is the impaired ability to discriminate intensity variations of the stimulus, even in the presence of an intact threshold. As hylognosis is based on fine-grained variations of intensity, the two deficits are also conceptually very similar. The autonomy of amorphognosia rests on more solid grounds. Semmes (1965) submitted patients with penetrating brain injuries to careful sensory examination to single out those who were free of elementary sensory deficits. Their performance on roughness, texture, and size tests was similar to that of control patients, but they were significantly impaired in matching to sample bidimensional and tridimensional shapes, thus showing amorphognosia. In the search for a factor accounting for the deficit, Semmes investigated the correlation between the shape scores and a number of other variables, and found that the only significant correlation was with the errors made on a visual spatial orientation test, which required the patient to follow a path through a set of nine circular spots on the floor, guided by the information provided by a visual map. She argued that the ability common to the two tasks was the appreciation of the spatial relations in which the elements composing a map and a shape are arranged. Consistent with this hypothesis was the outcome of a study (De Renzi & Scotti, 1969) in which patients with unilateral brain damage were asked to identify under a curtain the shape of a block, which they explored by running the outstretched forefinger of the hand ipsilateral to lesion (i.e. free of sensory deficits) along its raised sides. Right brain-damaged patients performed significantly less well than left brain-damaged patients, a finding highly suggestive of the influence of a spatial factor, given the greater contribution that the right hemisphere makes to

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spatial performances. It seems, therefore, legitimate to conclude that brain damage can cause amorphognosia in the absence of a somatosensory defect, and that it is underpinned by a supramodal deficit, identifiable in the faulty integration of spatial information. Does this assumption also hold for cases of tactile agnosia? Saetti, De Renzi and Camper (in preparation) studied a patient with intact somesthetic functions and hylognosis, who showed a bilateral impairment not only in tactile object recognition, but also in the tactile identification of meaningful and meaningless shapes. His ability to discriminate line orientation was profoundly impaired in both the bidimensional and tridimensional space and was thought to be the crucial factor determining the patient’s amorphognosia. The autonomy of secondary identification deficits (tactile agnosia) with respect to elementary sensory deficits, ahylognosia and amorphognosia has been challanged by several authors, among them Dejerine (1907), von Monakow (1914), and Bay (1944). The last author was adamant in stating that the cases reported in the literature (including his own four patients) were not in fact free of somatosensory impairment, provided care was taken to test their discriminative ability and lability of somatosensory threshold with repeated stimulation. This argument has often been debated in the history of agnosia (see earlier), but it cannot be accepted at face value, because it begs the question of the actual relevance of minor sensory deficit to recognition. Even granted that a sensory impairment is often or always detectable in agnosics, a causal relationship can hardly be entertained if a deficit of a similar or greater degree is also present in patients who are not agnosic. In a group study Caselli (1991) showed that the degree of basic somatosensory function impairment is not commensurate to the impairment of tactile recognition. It must be admitted, however, that the attempt to bring out a tactile recognition impairment in patients with brain damage has proved to be a thorny problem, unless the lesion encroached on the postcentral gyrus. Corkin et al. (1970) tested 60 epileptics with well circumscribed ablations and Roland (1976) tested 93 patients with surgically

verified lesions, and both reported a deficit only when the middle third of the contralateral, postcentral gyrus was involved. Caselli (1991) was more successful. Out of a series of 88 patients with damage to various levels of the nervous system, he found 7 patients with cortical disease (3 confined to the left hemisphere and 4 to the right hemisphere), who showed a recognition deficit with the hand contralateral to lesion, disproportionate with respect to the mildness of the somatosensory impairment. The injury involved the parieto-temporal cortex. Case reports of patients with a clear-cut deficit of tactile recognition are admittedly much rarer than those of visual agnosia. It is possible that the difference is more apparent than real, being contingent on the features of cortical vascularisation. The two posterior cerebral arteries, which provide most of the blood supply to the visual areas, have a common origin from the basilar artery, while the branches of the middle cerebral arteries, which supply the parietal lobe, take origin from the two distinct carotid systems. It follows that the former are more likely than the latter to be the seat of emboli coming from a common source, or of a bilateral infarct ensuing the occlusion of the tip of the basilar artery. The consequence of this vascularisation pattern is that tactile agnosia tends to be associated with a unilateral lesion and to be confined to the contralateral hand, while visual agnosia usually involves the whole field (for unilateral forms, see Unilateral visual agnosia). A unilateral impairment is likely to be less obtrusive upon the patient’s attention and to go unreported. In Caselli’s patients the deficits of tactile recognition were relatively modest and not spontaneously reported by them. There are, however, a few cases in which the impairment was severe and interfered with the daily activities. Those of the early literature have been reviewed in detail by Delay (1935), who added a well documented personal case. A 21-year-old girl had shot herself with a pistol in the right parietal region. The bullet was located in the left parieto-occipital region, from which it was removed. Two years later, her neurological deficit was limited to a mild left hemiparesis, which did not hinder palpatory movements, a mild increase of the two-point

16. AGNOSIA

discrimination threshold, and a few morphognosic errors of the left hand. They were quite out of proportion with respect to the severe left hand agnosia and did not prevent the patient from recognising the tactile qualities of the stimuli, as can be seen from the following examples; “pencil. it’s hard, smooth, long, cylindrical at one end and pointed at the other; scissors: it’s cold, it’s iron, there is a ring, then another ring... they are glasses”. Right hand recognition was flawless. The features of Hecaen and David’s (1945) patient—left frontoparietal missile wound with right hand agnosia— were similar; comb: it’s long, a bit thick, rough, with some points; ring: a round, hollow object. It is, therefore, apparent that, contrary to Caselli’s claim (1991), there was no need to “rediscover” tactile agnosia, whose reality had already been well established by the literature, but simply to investigate it in more detail with the modem techniques of testing. This was done in three recently reported cases. Patient E.C. (Reed et al., 1994, 1996) had a small left inferior parietal infarct and failed to recognise a remarkable proportion of stimuli (objects, geometrical shapes, letters) with her right hand. Basic and intermediate (weight, texture, and size) somatosensory functions as well as spatial skills were intact, but she made errors in naming or describing two-dimensional geometrical shapes and in making same-different comparisons between nonsense shapes. The deficit was attributed to the inability to derive a complex shape representation from tactile information and was thought to represent an instance of apperceptive agnosia. On the contrary, the patients of Endo et al. (1992, case 1) and of Platz (1996) were diagnosed as forms of associative agnosia. Endo et al.’s (1992) patient had bilateral infarcts and only the right hand was tested, because the left suffered from a sensory deficit and neglect. Somatosensory functions, hylognosia, and matching to sample two-dimensional shapes were normal and he was able to draw in a recognisable way three-dimensional figures and different kinds of spanners that had been palpated with the right hand. In contrast, tactile naming was correct for 5/24 of items (visual naming was 22/24 correct) and the failure to group objects in categories and to mime their use provided evidence that the deficit

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affected recognition. Platz’ (1996) patient, affected by a right-sided meningioma damaging the postcentral and particularly the supramarginal gyrus, also showed intact discriminative somaesthetic abilities and correct tactile matching of nonsense shapes. The 8 objects (out of 17) that he could not recognize with his left hand were readily matched to sample both when the search was carried out tactually and when it was carried out visually. In the latter case the patient was amazed not to have recognised the palpated object that he so readily identified among the visual distractors. Whereas Endo et al. (1992), in the wake of Wernicke (1895), interpreted the agnosia of their case as due to a disconnection of the pathways linking the somatosensory association cortex with a multimodal memory system, tentatively located in the middle and posterior parts of the inferior temporal lobe, Platz (1996) argued that the deficit resided in the inability to associate the tactile features identifying an entity with its meaning, an activity intrinsic to the tactile modality, which does not imply cross-modal connections. The locus of lesion of tactile agnosia involves the postero-inferior region of the parietal lobe, contralateral to the affected hand. The available evidence does not permit us to differentiate between apperceptive and associative forms. As mentioned earlier, a lesion confined to the left hemisphere can cause associative visual agnosia in both fields, possibly due to the greater semantic role played by this side of the brain. Does the same hold for tactile recognition, or is each hemisphere only competent for the semantic knowledge displayed by the contralateral hand? Before the First World War there were two reported cases (Goldstein, 1915; Oppenheim, 1906) of bilateral tactile agnosia, associated with a left-sided parietal lesion that was verified at surgery and at autopsy, respectively. Three further patients must be added from the more recent literature (Assal & Regli, 1980; Feinberg et al., 1986; Morin et al., 1984), who presented both visual and bilateral tactile agnosia, following left brain-damage. In a study (De Renzi et al., 1987), in which a cohort of 16 consecutive patients with left posterior cerebral artery infarct had to name the same set of objects on visual and tactile presentation (in the latter case

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the hand ipsilateral to lesion was used), 10 fell below the cut-off score in both conditions. There is, therefore, sparse evidence that also in the tactile modality the left hemisphere semantic store has greater competence and damage to it can interfere with tactile recognition in both hands. This view was bolstered by a recent study. Bottini et al. (1995) gave patients with unilateral brain lesion two tactile matching-to-sample tasks, one consisting of nonsense shapes and the other objects. In the latter the two to-be-matched stimuli had the same meaning, but different shapes (e.g. one was a wedding ring and the other a ring mounted with a precious stone) and two of the three distractors were semantically related to the target. Both tasks were carried out with the hand ipsilateral to lesion. The two hemispheric groups showed a double dissociation. Left brain-damaged patients were impaired on the object test and did not differ from normal controls on the nonsense shape test. Right brain-damaged patients showed the opposite pattern. Thus damage to the left brain caused an associative-semantic deficit that extended to the hand ruled by the healthy hemisphere.

Tactile aphasia Analogously to optic aphasia, the concept of tactile aphasia applies to patients who fail to name an object they are handling, but are able to demonstrate recognition, either by miming its use or by passing categorization or semantic association tests. Incidentally, this requirement was not met by the first case report of tactile aphasia (Raymond & Egger, 1906), whose differentiation from tactile agnosia remains, therefore, open to question. Subsequent studies showed that the deficit can be observed in two categories of patients, those with callosal resection and those with damage to the left parietal lobe. Callosal patients cannot name objects palpated with the left hand, as the tactile information processed by the right parietal lobe does not reach the left language area. This condition was already known to the early literature (Delay, 1935, quotes the case reports of Goldstein, Van Vleuten, von Stauffenburg, and Hoff), but interest has been rekindled by the introduction of surgical callosotomy for the relief of epilepsy (Trevarthen, 1990). A paradigmatic

case, consequent to a callosal infarct, has been investigated by Geschwind and Kaplan (1963). Three cases of bilateral tactile aphasia associated with a lesion of the left hemisphere are on record (Beauvois et al., 1978; Endo et al., 1992, 1996; Rapcsak et al., 1987). The patient of Beauvois et al. (1978) correctly named visually presented objects and meaningful sounds, but made errors (mostly semantic) in naming 71 of 100 objects handled with the right hand, and 64 handled with the left hand. When the examiner proposed a name for the object the patient was handling, he accepted all the correct names, but also 32% of the false names, especially if they bore a semantic relationship to the target. The diagnosis of tactile aphasia rested on the finding that, though making errors in verbally explaining what the use of the object was, he could mime it not only with the hand holding the object, but also with the other hand, provided verbalisation was prevented. Tactile categorisation and semantic association tasks were not given. Riddoch et al. (1988) criticised the assumption that miming is evidence of recognition, arguing that gestures could be elicited by the formal structure of the object, without access to the semantic system. This account is not very convincing for a patient who was able to produce appropriate gestures for 79 out of 80 objects. The interpretation given by Beauvois et al. (1978) was that, though the patient adequately processed objects at the perceptual and semantic level, the lesion of the left angular gyrus prevented the transmission of information to the temporal language centre. Rapcsak et al.’s (1987) patient named 5/15 visually presented objects and 4/15 tactually presented objects, but all of the 15 meaningful sounds, and his spontaneous speech was fluent and had good information content. Name comprehension was intact. He never produced paraphasias or circumlocutions and simply failed to name. However, he was able to provide functional descriptions of the objects he could not name and mimed their use, thus showing that they were recognised. CT scan showed a left lobar haematoma in the areas 21 and 37, which disconnected the infero-medial temporal region, where conceptual representations of objects are stored, from Wernicke’s area. Implicit in this

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account is that the semantic information, processed by the right hemisphere, is sent to the left inferior temporal lobe, before being transmitted to Wernicke’s area. Endo et al.’s patient (1992, case 2; 1996) made naming errors (mostly unrelated paraphasias and perseverations) on visual and tactile presentation, while he correctly named meaningful sounds and objects on verbal definition. Both hands were affected. Pointing to a named object was better than naming, but still defective. The diagnosis of tactile aphasia was supported by his good performance on tasks of categorisation and semantic association, carried out in the tactile modality. Admittedly, he failed miming, when the object was held in his hands, but this inability was attributed to the disconnection of the somatosensory recognition region from the left hemisphere area, where engrams for gestures are stored, and not to defective recognition. The authors gave a rather complex anatomo-clinical interpretation of their data. For each hand recognition occurs in the

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inferior temporal cortex of the contralateral hemisphere, where tactile information is conveyed from the somatosensory association cortex via the arcuate and the inferior longitudinal fasciculus. As these connections were damaged in the left hemisphere, the right hemisphere took care not only of left hand information, but also of the input from the right hand, received through transcallosal fibres. Although objects were recognised, they could not be named, because the lesion of the left posterior callosal radiations disconnected the right-sided recognition region from the language area. Whatever the interpretation, it is apparent that tactile aphasia has a fairly definite profile, even if only Endo et al.’s (1996) patient has been thoroughly investigated. It always affects both hands and is characterised by the discrepancy between the naming performance and the performance on tests of nonverbal recognition.

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17 The Neuropsychology of Music Anna Basso

Neuropsychology has, as one of its main aims, the study of the relationships between specific cerebral structures and psychological processes of cognitive functions (music capacity, in this case) but not all human capacities can be selectively compromised by cerebral damage. Some functions, such as language and memory, have anatomical structures specifically dedicated to them. Others, such as the ability to play chess, are based on more general cognitive abilities. For chess playing, these more general cognitive abilities might be logical reasoning (also important for the resolution of other problems, but which can be more developed for chess problems), visual memory and so on. It is highly improbable that a cerebral lesion can selectively damage the ability to play chess and leave all other cognitive abilities undamaged and functioning normally. The chess player will not only play chess less well, he or she will also be functionally damaged in other activities based in the same cognitive capacities underlying chess playing ability. The first question that must be answered is whether or not music capacity is modular, i.e. functionally independent of other cognitive functions with specific cerebral structures; if this is

not the case, then musical competence is the result of more general cognitive functions. The definition of music found in Zingarelli (1984) is: “the art of combining sounds based on determinate rules that differ according to place and time”. The definition given by the Petit Larousse (1954) is: “the art of combining sounds in a way pleasant to the ear”. The Universal Garzanti Encyclopedia (1991) says “the art of combining sounds according to determinate laws and conventions that constitute a normative code”. These definitions are not totally coincident but they agree in defining only musical composition as music. Larousse stresses pleasantness, Zingarelli and the Universal Garzanti Encyclopedia underline the fact that there are acquired rules that are culturally determined. The universal aspects of music are directly linked to the brain, as language is directly linked to some brain areas; the relationship between the brain and the culturally determined aspects of music is not direct, and passes through the relationship between the brain and the cognitive functions underlying these aspects of music. Psychologists of music have tried to separate the innate musical categories and those that are 409

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culturally determined. Burns and Ward (1982), for instance, concluded that the use of a relatively small number of discrete intervals in music (12 semitone intervals in the chromatic scale used in Western music) is probably a consequence of the intrinsic limitations of the human sensory system in the elaboration of highly informative stimuli. They also maintain that natural intervals, i.e. those that have a minimal sensory dissonance when presented simultaneously, have had an influence on the evolution of scales in many cultures. Natural intervals as well as the small number of intervals in scales thus appear to be determined by the structure of the human auditory system. On the contrary, a given culture considers the learned categories of the intervals of their culture’s scales melodic. In Western music, for instance, the diatonic scale is formed by the following intervals: tone, tone, semitone, tone, tone, tone, semitone. Apparently then, what we generally call music is almost totally culturally determined, and innate categories refer to basilar but very limited components, such as the capacity to identify a musical interval. Moreover, melodies are generally perceived as Gestalten rather than as successive individual intervals, and it is possible that perception of individual intervals plays an even less important role in music perception than does perception of single phonemes in comprehension of a sentence (see Caplan, 1992, for discussion of the relationship between phoneme perception and word comprehension). Besides melody, the other essential component of music is rhythm. The temporal structure of music has two levels of organisation: the first refers to tempo (4/4; 3/4) and the second to rhythm. Some researchers (Benjamin, 1984; Povel & Essens, 1985) consider tempo as something that allows one to regroup a series of rhythms into wider repeated units. However, rhythm is inherent to many human activities. It is possible that mechanisms inherent to temporal organisation of music are specific to music and independent from those used in other cognitive activities, but at the moment we do not have sufficient experimental evidence to prove it. To conclude, many aspects of melody are culturally determined, and rhythm does not seem to be something specific to music. It is therefore

unlikely that we have cerebral areas exclusively dedicated to music that are not used for any other cognitive function. Notwithstanding the fact that music capacity is not a modular cognitive function, functionally independent from other cognitive functions, neuropsychologists have been studying relationships between music and the brain for many decades. In this chapter we will first see results from experimental studies with normal subjects; those for groups of brain-damaged patients and single patients will follow. The chapter will end with a short note on music production.

NORMAL SUBJECTS The majority of experiments on hemispheric specialisation for music with normal subjects has used the dichotic listening technique. In the dichotic listening technique, two different stimuli are simultaneously presented to the two ears. Due to the superiority of the crossed auditory bundle over the uncrossed, the ipsilateral pathway—right ear/right hemisphere and left ear/left hemisphere — is momentarily blocked while the crossed pathway—left ear/right hemisphere and right ear/left hemisphere —is working. Auditory stimuli resulting in a right ear advantage indicate a left hemisphere superiority, and vice-versa. When results are the same for both ears, it is considered that the stimuli are equally processed by the two hemispheres. In the first researches only verbal stimuli were used and an advantage for the channel right ear/left hemisphere was shown. Very soon the same technique was used in experiments with musical stimuli. Kimura (1964) presented two melodies in dichotic listening, one to each ear; the subject had to choose the previously presented melodies among four alternatives presented in free listening. Kimura found a clear dominance of the right hemisphere for recognition of melodies: the number of correct responses for melodies presented to the left ear/right hemisphere was greater than the number of correct responses for melodies presented to the right ear/left hemisphere. Gordon (1970, 1978), in two subsequent studies, confirmed the superiority

17.

of the left ear/right hemisphere channel for recognition of chords, but he did not find differences between the hemispheres in recognition of melodies. These studies showed superiority of the right hemisphere for music, and very soon the idea that the left hemisphere is dominant for language and the right for music came to be accepted. However, dominance of the right hemisphere for music is not as clear-cut as dominance of the left hemisphere for language, and the hypothesis of a dichotomy— language to the left/music to the right—has rapidly been recognised as too simplistic. Bartholomeus (1974) presented in dichotic listening to 12 musicians two series of letters sung with different melodies by two different singers. Sometimes subjects were required to recognise letters, sometimes melodies. Subjects showed a predominance of the left hemisphere for letters, and of the right hemisphere for melodies. A later study using series of digits either spoken or sung (Goodglass & Calderon, 1977) showed similar results. It is then possible to conclude that hemispheric dominance is not only determined by the nature of the stimulus to be processed (in these last cases the stimuli were the same) but can also be influenced by the specific requirements of the task. Besides the nature of the stimulus and the requirements of the task, a third important factor in determining hemispheric specialisation is the musical cultural level of subjects. Bever and Chiarello (1974) have studied a group of musicians and a group of naive subjects, without any musical culture, in two tasks. In both cases a melody was presented monaurally; the first task consisted of identifying a two-note sequence present in the melody; the second task consisted of saying whether the melody had already been presented in a previous trial. As predicted, musically naive subjects showed a left ear advantage in the first task; on the contrary, musicians showed a right ear superiority. The researchers consider this result a consequence of the strategy adopted: naive subjects listen to music in a global way, musicians listen to it analytically. The analytic/global dichotomy corresponds to the different ways the two hemispheres elaborate stimuli: the left hemisphere

THE NEUROPSYCHOLOGY OF MUSIC 411

is analytic and the right hemisphere elaborates stimuli in a global way (for a revision on hemispheric specialisation see Bradshaw & Nettleton, 1981). Bever and Chiarello’s results were received with great interest and many researchers followed along the same line. Johnson et al. (1977) tried to identify which aspect of the musical culture causes the left hemisphere’s superiority in music perception. They used the same experimental paradigm as Kimura (1964): subjects were requested to recognise among four melodies presented binaurally the two melodies previously presented in dichotic listening. There were four experimental groups, one of naive subjects and three of subjects with some musical preparation, differing in their capacity to read and write music and to play an instrument. Only subjects able to read and write music and to play an instrument had a left ear/right hemisphere advantage; all other groups showed a left ear/right hemisphere superiority, independent of their musical competence. The capacity to write music was the most important variable in determining the number of errors, independently of which ear/hemisphere was stimulated. Other studies have also shown a bimodal distribution among musicians. In the Gordon (1980) study, five groups of subjects with variable musical proficiency underwent a test of chord recognition: two chords were presented to one or the other ear in dichotic listening and had to be recognised among four chords presented binaurally. Except for the two groups with the highest musical proficiency, all other groups showed a right ear advantage. Approximately half of the subjects in the first two groups had a left ear advantage, the second half had a right ear advantage. In a very similar experiment, Morais, Peretz, and Gudansky (1982), found very similar results: left ear advantage for naive subjects, bimodal distribution for subjects with musical competence. To conclude, the results of the studies with dichotic listening in normal subjects are ambiguous; as for chord recognition, left ear/right hemisphere advantage seems sufficiently well established in naive subjects but results in musicians are heterogeneous. It is possible that these differences are not due to musical education

412 BASSO

per se but rather to a different way of processing, as already advocated by Bever and Chiarello (1974): results can differ according to the task or the strategy adopted. This hypothesis has been subjected to experimental verification and confirmed by Shanon (1980) and Peretz, Morais, and Bertelson (1987). In three tasks of increasing difficulty, a group of musicians showed a left ear advantage for the easiest task and a right ear advantage for the other two tasks (Shanon, 1980). Similarly, a group of musicians showed a right ear/left hemisphere advantage when the suggested approach was analytic, but not when the instructions given suggested a global approach (Peretz et al., 1987).

BRAIN-DAMAGED SUBJECTS The first experimental study on musical capacity in a group of brain-damaged patients was that of Milner (1962). Groups of patients with temporal lobectomy for treatment of epilepsy and a group of control subjects underwent a standardised evaluation of their musical competence with the Seashore test (Seashore, Lewis, & Saetveit, 1960). For some tasks (as, for instance, in a task of discrimination of rhythms) brain-damaged patients did not differ from normal controls; right-braindamaged patients had significantly lower scores than left-brain-damaged patients and normal controls in other tasks (timbre perception and discrimination of two short musical sequences). Similar results were found by Shankweiler (1966) who studied a group of patients before and after intervention. After intervention patients with right lobectomy performed clearly worse than before intervention in a task of melody recognition. These and other results (see Zatorre, 1985) point to a hemispheric specialisation for music, with the right hemisphere predominant at least for subjects without musical preparation. However, as had already been seen in experiments with dichotic listening in normal subjects, later studies suggest that the hypothesis of a simple hemispheric dominance in elaboration of musical stimuli is too simplistic.

Milner, Kimura, and Taylor (1965; cited by Samson & Zatorre, 1992) found that in a more complex task such as recognition of melodic sequences, both groups of lobectomised patients showed a deficit of memory for melodies. Zatorre’s (1985) results were similar: patients with right lobectomies fared worse than normal controls and patients with left lobectomy in a task of melody discrimination, but both brain-damaged groups fared poorly in a task of melody recognition. In a later research, Samson and Zatorre (1992) investigated memory for melodies. Control subjects and patients with right lobectomies were presented with 16 melodies and were asked to recognise them among two alternatives. They were given immediate feedback. Each subject underwent the test five times consecutively, and a last time 24 hours later. Both brain-damaged groups showed learning from the first to the fifth presentation, but they fared less well than control subjects without difference among the two groups. 24 hours later, left lobectomised patients showed a slight improvement and right lobectomised patients a slight worsening. We can summarise research with patients with lesions localised in the temporal lobes as follows: the right temporal lobe has a slight degree of specialisation in the elaboration of some aspects of musical stimuli; for more complex elaboration the interaction of both temporal lobes is necessary. Finally, it is possible that the right temporal lobe has a peculiar way of initially elaborating musical information and this causes greater efficiency for long-term memory for melodies.

SINGLE CASES Table 17.1 reports cases described in the literature of patients with left-hemispheric lesions, righthemispheric lesions, and bilateral lesions who underwent a more or less detailed musical evaluation. The reported cases are very heterogeneous and the reasons for which they were studied are different from case to case. The encounter between a neuropsychologist and a braindamaged musician has generally caused the study

17.

of the patient’s musical ability, independently of the researcher’s interest for music. A second group of subjects was studied because of the interest of the researcher for amusia; in this case patients were studied independently of their previous musical preparation. Finally, a last group of subjects was studied because of their auditory agnosia; among other stimuli, musical ones have also been used. Due to heterogeneity of the evaluations performed and, above all, due to the variability of musical competence in the subjects studied, these single case clinical studies are not very useful to investigate the neuropsychology of music. There are however a few exceptions where the research has been conducted within the framework of a specific model of normal music processing (see for example Peretz, 1993). However, Table 17.1 allows some tentative conclusions. A large lesion in the left hemisphere coupled with a severe language disorder is not prejudicial to good musical competence; the capacity to read and write words can be dissociated from the capacity to read and write music, even if they both depend on left hemisphere processing; a right hemisphere lesion probably causes difficulty in instrument playing and in singing. As for bilateral lesions, the few known cases are heterogeneous both as regards their musical competence and their etiology, the size and location of the lesion. It is therefore not unexpected that after onset their musical competence is varaible. Ravel (Alajouanine, 1948) was incapable of any musical task; CN was amelodic but rhythm was normal (Peretz & Kolinsky, 1993); and GL (Peretz, 1993), was totally incapable of recognising a familiar melody and no longer enjoyed music. Peretz explains GL’s incapacity to recognise a melody by a well delimited deficit in the capacity to abstract the pitch of a sound relative to a musical scale. I will briefly describe patient NS, a conductor with a degree in violin playing, (Basso & Capitani, 1985) as an example of a patient with large left-hemisphere lesion and severe language disturbances but preserved musical competence. At the age of 67, following a cerebral ischemic infarction, NS showed right hemiparesis, severe global aphasia, and severe ideomotor apraxia with

THE NEUROPSYCHOLOGY OF MUSIC 413

very little improvement in the following years. NS died a few years later from a second cerebral infarction in the right hemisphere. Notwithstanding his severe aphasia, and ideomotor apraxia, NS had once again taken up conducting, even very complex operas like Verdi’s Nabucco, with very positive comments from the newspapers.

MUSIC PRODUCTION Music production has been almost ignored in the study of amusia. Music production essentially consists of instrument playing and singing. Instrument playing can only be studied in those subjects who had studied and acquired the capacity to play an instrument before the brain damage. It cannot be studied with unselected groups of braindamaged patients. Singing, however, can be studied in large groups of patients but there is no a priori certainty that they were able to correctly reproduce melodies and did not sing out of tune before the brain damage. The only experimentally sound data on singing (beside some anecdotal stories of globally aphasic patients who could sing) are those from patients before and after pharmacological inactivation of a hemisphere. Results from these studies (Gordon & Bogen, 1974; Borchgrevink, 1980; Zatorre, 1984) come from a limited number of subjects and are sometimes ambiguous; however, they suggest a right hemisphere superiority for singing. As for instrumental playing, Table 17.1 shows that some musicians lost their capacity to play — accordion or organ — following a right hemisphere lesion (McFarland & Fortin, 1982; Botez & Wertheim, 1959).

CONCLUSION Initially, the neuropsychology of music was mainly concerned with the relationship between music and language competence; that is, with the relationship between aphasia and amusia, with particular attention to the relationship between reading and

•fe.

Plays the piano regularly. Receptive amusia; unable to read the alto key; loss of the absolute ear. Teaches and composes music as before. Professional piano player in chamber orchestras. Discriminates melodies, repeats rhythms, and sings; doesn’t identify well known melodies. Amusia: doesn’t discriminate intensity and frequencies. “Music doesn’t have much sense to me.”

Severe Wernicke aphasia Moderate Wernicke aphasia Severe sensory aphasia Wernicke aphasia Word deafness: recognises but doesn’t name sounds Auditory agnosia (but very rapid recovery); rare phonol. errors

Piano teacher Professional violinist Composer

None. Science teacher

None. Great music lover

T, angular gyrus white matter Left hemisphere

Souques & Baruk 1926

Wertheim & Botez 40 y, M, R 1961

T

HB, 64 y, M

Assai 1973

Severe and persistent receptive and expressive amusia (due to arhythmia?). Initial severe non-fluent aphasia with good recovery Music teacher Violinist

Left hemisphere

61 y, M, R

Mavlov 1980

Severe expressive amusia; alexia and agraphia more severe than for letters. Moderate conduction aphasia Normal

Double-bass player

Posterior T, Inferior P

N.2, 42 y, M

Brust 1980

Alexia and agraphia (less severe than for letters). Plays guitar; professional singer.

Alexia and agraphia; moderate anomia and comprehension deficits. Normal

Resected T - P meningioma

N .1,22 y, F, R

Brust 1980

Student of music

T

Tho., 47 y, M, L

Haguenauer et al. 1979

Denes & Semenza RR, 69 y, M, R 1975

T -P

Shebalin, 57 y, M

Luria et al. 1965 Normal

o f m u s ic a l c o m p e te n c e s

Pianist and chamber orchestra’s director

E x a m in a tio n

P r a x is E x a m in a tio n

M u s ic a l E d u c a tio n ;

Language

P a ti e n t s

P r o f e s s io n

A u th o r s

S ite o f le s io n

Left-hemisphere lesions.

TABLE 17.1

-U

Ol

y = Years T = Temporal

L eg en d s:

M = Male O = Occipital

F = Female P = Parietal

R = Right-handed F = Frontal

Organist and composer

T, supramarginal and angular gyrus

JL, 77 y, M, R, blind

Signoret et al. 1987

Clarinet player

T

Lechevalier et al. 1985

MJ, 50 y, M, R

MH, 32 y, M

Lechevalier et al. 1985 None. Agriculture teacher

NS, 67 y, M, R

Basso & Capitani 1985

Composer, director and music teacher

P

0 -T

BL, 77 y, M, R

Judd et al. 1983

Piano teacher

Director

Posterior T - P

MB, 55 y, M, R, bilingual

As sal & Buttet 1983

P r o f e s s io n

M u s ic a l E d u c a tio n ;

Left hemisphere

S ite o f le s io n

P a tie n ts

A u th o r s

Left-hemisphere lesions continued.

TABLE M A continued

Language

Wernicke aphasia

Alexia and agraphia

Wernicke aphasia

Global aphasia

Alexia; moderate anomia

Wernicke aphasia with severe agraphia

E x a m in a tio n

L = Left-handed

Severely impaired

Normal

P r a x is

Organ player, music teacher and director.

Alexia.

Recognises but doesn’t identify well known melodies. Doesn’t sing any more.

Moderate difficulties in piano playing. Directs orchestra, as before.

Some errors in music reading and writing and in piano playing. Intact music perception. Still able to compose.

Moderate difficulties in piano playing; pleasure in listening; good music writing.

o f m u s ic a l c o m p e te n c e s

E x a m in a tio n

05

y = Years T = Temporal

L e g en d s:

Lechevalier et al. 1985

M = Male 0 = Occipital

Madame C 56 y, F, R

F = Female P = Parietal

P

R = Right-handed F = Frontal

Few years of flute and organ study

L = Left-handed

Recognises simple melodies but not symphonies. Doesn’t identify musical instruments. Annoyance in listening. Moderate auditory agnosia with difficulties in recognising noises

Amateur organist

Superior T. Supramarginal gyrus

78 y, M, R

McFarland & Fortin 1982

Cannot play organ; moderate difficulties in identification of well known melodies and in reproduction of rhythms.

Doesn’t recognise the instruments’ timbre; recognises time, rhythm and intervals.

Auditory agnosia: doesn’t recognise sounds such as motors, voices and tones

Music lover

T

BP, 58 y, M

Mazzucchi et al. 1982

Normal

Names melodies but doesn’t sing them any more; doesn’t reproduce rhythms; loss of aesthetic pleasure.

Recognises familiar noises but doesn’t localise them

None

Métastasés

Bau. 55 y, M, R

Haguenauer et al. 1979

Normal

Doesn’t play any more; tone errors. Intonational and rhythmic errors in singing.

Disprosody

Amateur accordion player. Farm worker

Resected. F oligodendroglioma

Botez & Wertheim DM, 26 y, M, R 1959

Right-hemisphere lesions.

TABLE 17.1 continued

"Nl

-t*.

GL, 61 y, M, R

Peretz 1993

y = Years T = Temporal

Legends:

M = Male O = Occipital

Peretz & Kolinsky CN, 35 y F, R 1993

Ravel; onset at52y

Alajouanine 1948

Bilateral lesions.

TABLE 17.1 continued

Composer

F = Female P = Parietal

Bilateral T

R = Right-handed F = Frontal

None. Nurse

Left T, Right pars None. Opercularis Businessman (retired)

Progressive disorder

Normal

Wernicke aphasia with good recovery. Recognises noises.

Progressive aphasia

L = Left-handed

Normal

Normal

Severe apraxia

Amelodia (without arrhythmia).

Doesn't recognise any melodies and feels no pleasure in music listening.

Severe expressive amusia; completely unable to play and compose.

418

BASSO

writing words and reading and writing music (see, for instance, Brust, 1980). In this first period, single cases of left or right brain-damaged musicians were described and their residual linguistic and musical abilities were compared (Table 17.1). This led researchers to hypothesise their anatomical contraposition: the left hemisphere is dominant for language and the right hemisphere is dominant for music. Right hemisphere dominance for music, however, is much less well established than left hemisphere dominance for language, and may vary according to the musical competence of subjects and the type of task. These last years have witnessed the appearance of models, still generic, of music perception, and patients’ musical difficulties have been studied within the framework of a cognitive theory of music and a model of music processing (see, for instance, Peretz, 1993; Peretz& Kolinsky, 1993). A cognitive theory of music must differentiate between the universal aspects of music and the learned ones, and must study naive subjects and musicians separately. Still another group comprises those people who

have an extraordinary musical competence, because for the moment we do not have any hypothesis of what makes a Mozart a Mozart. To conclude, I would like to underline the fact that an important aspect, if not the most important, of music perception has not been studied. The definitions of music at the beginning of the chapter define music only in terms of composition. Psychologists and neuropsychologists have stressed perception of rhythm and melody, and have stressed the importance of the listener rather than that of the composer. However, the listener, besides being more or less able to identify a melody (which is what has been studied by neuropsychologists), is someone who enjoys music because music kindles one’s emotions. Musical research has not yet developed a theory about the relationship between music and emotional phenomena. It is possible that what pertains to humanity in toto are the emotions that music kindles in those who listen to it. Other aspects of music, particularly the rules of musical composition, are largely culturally determined.

Part V

Movement Disorders

Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

18 Apraxia Ennio De Renzi and Pietro Faglioni

Apraxia designates the impaired ability to perform a gesture, in spite of preserved motor, somatosensory, and coordination functions in the limb engaged in the action. In point of fact, the term gesture is too narrow to define the deficit, as it is also apparent when the patient is requested to imitate meaningless actions. The following features characterise apraxia:

but, once it has been chosen, they have no difficulty in repeating it. 3. It follows that although apraxia is detectable in a substantial proportion of left brain-damaged (LBD) patients with appropriate tests, it disrupts their daily life far less than one might expect. The derangement of gesture organisation can take two forms: either patients do not know what to do, i.e. they fail to retrieve the formula of the movement that is typical for a certain object (ideational apraxia, IA), or they do not know how to implement it, i.e. they are unable to translate the formula into an appropriate innervatory programme (ideomotor apraxia, IMA). Another important distinction concerns the part of the body in which the deficit appears, i.e. whether it affects the limb, oral, or axial musculature.

1. It disrupts the choice of the shape and sequence of the single movements that compose the gesture and is not related to the metric or kinematic variables of the movement (its amplitude, direction, rapidity, strength, etc.). 2. It is a typical example of the automaticvoluntary dissociation, first pointed out by Jackson (1932) in the language area, i.e. its occurrence is a function of the purposeful character of the action and the absence of contextual and motivational cues. The same gesture that is failed on the examiner’s request can be correctly performed if produced as an automatic response to a habitual stimulation (e.g. the patient who is unable to make the sign of cross to command, does so correctly on going into a church). Apraxic patients fail when they must select the appropriate movement formula,

IDEOMOTOR APRAXIA IMA is a disorder that occurs when patients fail to implement the mental representation of a gesture in a motor programme that specifies the correct innervation of the involved muscles. As a consequence, the shape, order, and spatial features 421

422

DE RENZI AND FAGLIONI

of the movement are distorted. The assumption that the mental representation of the gesture is preserved and the deficit occurs at the executive level rests on different strands of evidence. In a small number of cases, among which is the famous Imperial Counsellor (Regierungsrat) reported by Liepmann (1900), a conceptual deficit can be ruled out, as the disorder is confined to the limbs of one side. However, this represents an exception and, more frequently, the deficit is bilateral. In such cases, it is the error analysis that shows that the general idea of the action is retained, but poorly performed. A decisive criterion is the persistence of apraxia on imitation, namely, in a condition that does not call for the retrieval of the plan of action, because it is presented by the examiner. Finally, evidence that patients know the meaning of the gesture may be provided by their ability to match a gesture made by the examiner with the object to which it refers.

Testing ideomotor apraxia The assessment of IMA can vary, according to the nature of gestures, the modality through which orders are given, and the purpose of the examination (De Renzi, 1985). In a clinical setting, when the aim is simply to ascertain whether apraxia is present, imitation of gestures carried out by the examiner is the most expeditious way of testing, as it circumvents the ideational stage and eliminates the possible interference of oral comprehension deficits, which may be a source of confusion, given the frequent coexistence of aphasia and apraxia. Imitation also permits the administration of meaningless gestures, which do not lend themselves to verbal description. Table 18.1 reports the list of gestures we currently use to assess IMA and Fig. 18.1 illustrates items 12,15and20, which are difficult to describe. The test (De Renzi et al., 1980) consists of 24 gestures, half symbolic and half nonsense, half requiring finger movements and half proximal movements, half involving single positions and half sequences, all factors being orthogonal to each other. Each gesture is repeated up to three times, if it is not reproduced correctly, and scored 3, 2, 1, or 0, depending on whether the imitation is correct after the first, second, or third administration or never. This procedure makes scoring easy and consistent across different

examiners. The score distribution of more than 200 normal subjects has shown that the diagnosis of IMA is highly reliable if the patient scores below 53, is likely for scores between 53 and 62, and can be confidently excluded for scores above 62. When the different types of movements were compared (symbolic vs. nonsense, fingers vs. arm, single position vs. sequence), no difference in their power to discriminate apraxic from nonapraxic patients was found (De Renzi et al., 1980). Goldenberg (1996), however, found a difference in the imitation of meaningless movements, depending on whether they involved the position of the hand relative to the head, finger configuration remaining invariant, or the position of the single fingers. In the former case, there was a selective failure of left brain-damaged patients (LBD), in the latter both LBD and right brain-damaged (RBD) patients were impaired. Goldenberg and Hagmann (1997) speculated that the two hemispheric groups failed imitation tasks for different reasons: LBD patients because they have a defective knowledge of the human body and RBD patients because they make a faulty visuospatial analysis of gestures. The hypothesis that LBD patients’ failure is due to an impaired conceptualisation of the human body rather than to apraxia had already been advanced by Goldenberg (1995) in a previous study, which had found apraxics impaired in imitating gestures not only on their own body, but also on a mannikin, whose articulated limbs could be placed in different positions in space. It must be stressed that, when the gestures were reproduced on the mannikin, the movements the patients performed with their own hand were approximately the same across different items and only differed in terms of spatial coordinates. It would, therefore, be difficult to attribute the errors made on the mannikin to the impaired selection of motor programmes typical of apraxia. Admittedly, these data are new and intriguing. However, the assumption that they are consequent to a defective knowledge of the human body remains merely conjectural, in the absence of independent evidence that this knowledge is in fact disrupted and of a more precise specification of which aspects of the body image are impaired. Moreover, it would be necessary to extend the investigation to the assessment of how patients

18. APRAXiA

reproduce hand and finger positions, displayed by the first mannikin, on their own body and on a second mannikin , and whether errors also occur when the spatial arrangement of the parts of a model bearing no resemblance to the human body must be replicated on a copy. The study of the nature of apraxia and not of its mere presence demands the use of other tests. An important variable are the sensory channels, through which orders are given, as their comparison may provide data relevant to the uncovering of modality-specific dissociations (Alexander et al.,

423

1992; De Renzi et al., 1982; Ochipa et al., 1994). For instance, miming the use of a series of objects can be requested verbally, on visual presentation (without handling them), or on tactile presentation, out of sight. Miming the use of objects on command is a popular testing procedure, but not easily interpreted, because in a few cases the examiner may be left with doubts as to whether the deficit affects the ideational or the executive stage (Barbieri & De Renzi, 1988; Cubelli & Delia Sala, 1996) and to what extent the deficit is consequent to oral comprehension disorders. Goodglass and

Gestures used in the limb imitation test. Preliminary items. 1. Reach out your hand with your fingers spread out. 2. Reach out your fist. Finger movements, 1. The victory sign. 2. Sign of O.K. 3. Index and little finger pointing upwards, other fingers bent. 4. Index pointing upwards, other fingers bent. 5. Middle finger arched on the extended forefinger, other fingers bent. 6. Thumb imprisoned between the forefinger and middle finger, other fingers flexed. 7. Flicking three times. 8. Snapping the fingers three times. 9. Miming a walking man, using the index finger and middle finger. 10. Index finger and middle finger extended forward and open and closed (like a pair of scissors). 11. Tapping the table with the four lateral fingers of one hand in succession. Action is repeated three times, always starting with the index finger. 12. Back of the hand on the table with index finger and middle finger extended. The index finger is flexed and moved forward to touch the thumb and then returned to the extended position. The same is done with the middle finger. Action is repeated three times (see Fig. 18.1, A,B,C). Hand and limb movements 13. Arm is raised laterally, perpendicular to the body. The open hand is swept from one side to the other and brought, palm down, into contact with the opposite shoulder 14. Open palm is slapped against the back of the neck. 15. Hand is open, palm down, under the chin (Fig. 18.1, D), 16. Saluting. 17. Hand is held like a tube against the mouth. Patient blows through it. 18. Raised hand, palm open forward, as for the sign of stop. 19. Closed fist, thump sideways on table. Open hand, slap palm down on the table. Repeat three times. 20. Fist on the forehead and then on the mouth. Repeat three times (see Fig. 18.1, E, F). 21. Fingertips and thumb tip together in ring, all touching forehead. Hand moves out from forehead, rotating and opening wide as it moves. 22. Cross yourself. 23. Hand perpendicular to the body, fingers downwards. Hit forehead three times. 24. Send a kiss. Fingertips together in ring on the mouth. Hand opens wide as it moves out. Repeat three times.

424

DE RENZI AND FAGLIONI

Kaplan (1963) emphasised that in miming tests, apraxics often use body parts as objects (e.g. making cutting movements with their forefinger and middle finger to indicate the use of scissors), but the value of this sign for the diagnosis of apraxia has probably been overemphasised, as it has also been found to be frequent in normal controls (Duffy & Duffy, 1989; McDonald et al., 1994; Ska & Nespoulous, 1987). By and large, the inter-test comparison has not proved enlightening, apart from providing evidence that there can be modality-specific dissociations (see later). McDonald et al. (1994) and Belanger et al. (1996) compared the performance of LBD patients with IMA on various tasks, but found no difference, even when outliers, i.e. single patients showing a significant inter-test dissociation, were expressly sought. However, Goldenberg and Hagmann (1997) reported two patients with damage to the left angular gyrus who were severely impaired in the imitation of nonsense gestures, involving hand position, but performed within the normal range in all other tests (imitation of gestures involving finger positions, imitation of

FIGURE 18.1

A, B and C: item 12. D: item 15. E and F: item 20.

mimes, execution of symbolic gestures, and miming the use of objects). A priori, a qualitative analysis of performance would be expected to contribute to the understanding of the mechanism underlying apraxia. Unfortunately, the many attempts at error classification (Haaland & Flaherty, 1984; Poizner et al., 1990; Rothi et al., 1988) have yielded a bewildering list of error categories, which have not gained general consensus (Tate & McDonald, 1995). This may be due in part to the difficulty of categorising a performance that is both fleeting and complex. In general, errors concern the spatial location of the limb, the use of wrong muscle groups, the fragmentation, augmentation, or omission of movements, and the perseveration of a previous movement.

Liepmann’s model No other author has ever had such a long-lasting and seminal influence on a field of neuropsychology as Liepmann in apraxia. From 1900 to 1920 he repeatedly returned to this issue and, capitalising on the data he garnered, developed

18.

an interpretation, couched in psychological and anatomical terms, that more recent research has refined, but not substantially modified. The essence of Liepmann’s (1905b) interpretation can be summarised as follows. 1. Gestures are elicited by stimuli coming from sensory areas on either side of the brain, which converge in the sensory and motor areas (called by Liepmann sensomotorium) of the left hemisphere, where the kinesthetic-innervatory engrams or “memories of motor commands and their relative proprioceptive sensations” are stored. Engrams are activated as a whole and without attentional load, when the gesture represents an automatic response to a customary situation and need not be adapted to unforeseen circumstances. However, if the situation is new or unusual, it is necessary, first, to visually imagine the motor programme, then to intentionally select and order the engrams and, finally, to be ready to modify the action plan, if its effects fail to reach the goal. Apraxia leaves gestures of the former type intact, while it disrupts the latter and assumes ideational features when the deficit concerns the retrieval of the plan, or ideomotor features when it concerns its execution. 2. The left hemisphere has a dominant role in gesture organisation, as the left sensomotorium not only stores the engrams dedicated to right limb movements, but also monitors, through transcallosal pathways, those located in right sensomotorium, which are committed to the execution of left limb movements. 3. The model envisages different patterns of apraxia, (a) Bilateral ideomotor apraxia ensues a lesion of the white matter underlying the left parietal lobe, where the fibres carrying sensory information to the left sensomotorium run. Bereft of this information, gesture execution is impaired in both hands, (b) Left limb apraxia and right limb hemiplegia. When the lesion is located more anteriorly and encroaches upon the left sensomotorium, right limb apraxia cannot manifest itself, because it is masked by hemiplegia and only left limb apraxia is apparent, (c) If damage to the left motor area is

APRAXIA

425

mild, the right limb will show awkward and unrefined movements, a condition called melokinetic apraxia. However, until recently, its existence has been questioned, as its discrimination from paresis is not easy (see later), (d) When the lesion interrupts the callosal pathways, it results in left limb apraxia, whereas, when it is located in the right sensomotorium, it will cause left limb hemiplegia or, if it is less destructive, melokinetic apraxia of the left limb. A few comments are in order. The concept of the sensomotorium, as the repository of motor engrams, has been abandoned and substituted by that of the premotor association cortex (Geschwind, 1965), which would represent the end station at which the sensory information, guiding the gesture performance, arrives. The left premotor area projects to both the ipsilateral motor cortex and the contralateral premotor cortex, which in turn controls its own motor cortex. Liepmann was adamant that his model did not envisage the existence of a centre dedicated to gesture planning, which—he assumed—resulted from the cooperation of the whole brain, particularly its sensory areas, with the left sensomotorium. The prominent role he assigned to left parietal lobe damage in causing apraxia was not attributed to cortical damage, but to the lesion of the underlying white matter (Liepmann, 1907, p.768): “Contrary to what has been repeatedly attributed to me, I by no means conceive of the existence of a praxic centre and of its location in the supramarginal gyrus. I interpreted my patient’s apraxia as due to the isolation of the left sensomotorium from the rest of both hemisphere cortex.” In his last paper on apraxia, Liepmann (1920) localised IMA at the level of the left inferior parietal lobule and ideational apraxia (IA) at the level of the left parieto-occipital junction (Fig. 18.2), but the schematic drawing he presented in the same study (Fig. 18.3) did not point to an intermediate centre, processing the information before it reached the frontal cortex. We will now review the extent to which subsequent research has confirmed or modified Liepmann’ s model.

426 DE RENZI AND FAGLIONI

FIGURE 18.2 1: Territory of melokinetic apraxia. 2: Territory of ideomotor apraxia. 3: Territory of ideational apraxia. (From Liepmann, 1920.)

FIGURE 18.3

Liepmann’s (1920) drawing of the fibre pattern underlying gesture execution. Fibres from the occipital cortex (Co), the parietal cortex (Cp) and the temporal cortex (Ct) of either side converge on the right hand motor centre, located in the right hemisphere, via callosal pathways. Dotted lines indicate accessory pathways which run from the sensory areas of one hemisphere to the hand centre of the opposite hemisphere.

Left hemisphere dominance for gestures in right-handers The hypothesis that the left hemisphere is dominant for praxis was grounded by Liepmann (1905b) on the results of a study he performed in patients with right and left hemiplegia, which is also worth mentioning, because it was the first systematic

group investigation in the history of neuropsychology. An apraxic impairment was present in 20 out of 41 patients with right hemiplegia and in none of 42 patients with left hemiplegia. The left hemisphere dominance was confirmed by several studies, carried out after World War II (Table 18.2), showing that apraxia is

18. APRAXIA

almost exclusively associated with left brain damage. Moreover, the concept of left hemisphere dominance for praxis is bolstered by the occurrence of left limb apraxia following callosal lesion, an association that provides evidence that the right motor areas are unable to control gesture execution if they cannot avail themselves of the assistance of the left hemisphere. This finding, first pointed out by Liepmann and Maas (1907) in their patient Ochs, has been repeatedly confirmed by the literature (see later). Finally, the inactivation of left hemisphere functions following amytal injection in the left carotid artery was found to cause a transient inability to mime the use of objects much more frequently than the inactivation of the right hemisphere (Foundas et al., 1995). Thus praxis is similar to language in being an ability predominantly represented in the left half of the brain. However, the dominance is not absolute and is subject to individual variations, as shown by the aforementioned study of Foundas et al. (1995), in which speech was suppressed after injection in the left carotid artery in all of the nine right-handed epileptics submitted to the Wada Test, while miming was disrupted in seven patients after left injection and in two after injection to either side. Less consistent dominance is also suggested by the presence of negative cases (i.e. LBD patients who would be expected to show apraxia, given the location of their left lesion, and yet do not show it) and of cases in which apraxia was not

bilateral, but confined to the limb contralateral to the side of damage (divided dominance). In the literature there are two famous instances of divided dominance, the Imperial Counsellor, reported by Liepmann (1900), whose apraxia was confined to the right limb only and Geschwind and Kaplan’ s (1962) callosal patient, who showed left limb apraxia on command, but not when the gesture was elicited through other modalities. More recently, patients with right hemisphere competence for planning left limb gestures were reported by Riddoch et al. (1989) and Pilgrim and Humphreys (1991). One should also consider that a minority of RBD patients, ranging from 20% (De Renzi et al., 1980) to 34% (Barbieri & De Renzi (1988), were found to score below the cut-off point on an imitation test performed with the right limb (i.e. with the limb steered by the left hemisphere). A poor performance was also reported when the gesture was elicited verbally, tactually (Faglioni & Basso, 1985; Mozaz et al., 1990; Verstichel et al., 1994), or visually (Barbieri & De Renzi, 1988). In most of these cases the impairment was mild and could have been due to nonspecific factors, but in a few cases it was moderate and raised the question of whether it should have been labelled as apraxic. What accounts for the left hemisphere dominance for praxis? Two hypotheses have been advanced, which see it as secondary to the same hemisphere dominance for other skills.

TABLE 18.2 Incidence of IMA in left and right brain-damaged samples. A p r a x ia

I n c id e n c e

I n c id e n c e

C o n tr o ls

A u th o r s

T e stin g

in L B D p t s

in R B D p t s

( N o .)

Ajuriaguerra et al. (1960) Pieczuro et al. (1967) De Renzi et al. (1968) De Renzi et al. (1980) De Renzi et al. (1982) Barbieri et al. (1988) Haaland et al. (1994)

clinical assessment imitation of 20 gestures imitation of 10 gestures imitation of 24 gestures imitation of 24 gestures imitation of 24 gestures imitation of 15 gestures

* Data reported by Faglioni and Basso (1985).

427

47/206 32/70 45/160 50/100 48/150 32/56 12/25

=23% =46% = 28% =50% = 32% = 57% =48%

0/154? 3/35 1/45 16/80 3/110 13/38 3/18

= = = = = = =

0% 9% 2% 20% 12%* 34% 17%

0 40 40 100 70 60 32

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Is dominance for praxis linked to dominance for handedness ? Liepmann (1913) and Geschwind (1975b) argued that the hemispheric asymmetry in the representation of praxis skills, pointed out by clinical studies, is closely related to the disruption of the same mechanism that underlies handedness, namely, the superior capacity of most people’s left hemisphere to store information concerning learned movements. This left hemisphere specialisation would provide the basis for both the greater adroitness of the right hand, shown by 90% of human beings, and the leading role played by this side of the brain in the bilateral organisation of gestures. There are two sets of findings that militate against this theory. First, it is not clear how it accounts for the apraxics’ inability to imitate meaningless (i.e. not previously learned) movements. Second, it implies that no case of crossed apraxia, i.e. apraxia associated with a lesion of the hemisphere ipsilateral to the preferred hand, can ever occur. The data from the early literature (for a review, see Faglioni & Basso, 1985) were apparently in agreement with this prediction and the few cases disproving it were not, with the possible exception of case 11 of von Monakow (1914), adequately documented. The same conclusion was reached by Donoso (1984), who focused on right-handed patients with crossed aphasia (aphasia after a right brain lesion, pointing to inverted dominance for language) and found that they do not have apraxia. Junqué et al. (1986) went as far as to maintain that praxis is the only cognitive ability that does not “cross”. A review of the recent literature, however, shows that this contention no longer stands, as apraxia has been documented in both right-handers after a right brain lesion (Assal et al., 1981; Basso, Capitani et al., 1985; Berthier et al., 1987;Cappaetal., 1993; Fernandez-Martinet al., 1968; Heilman et al., 1986; Marchetti & Della Sala, 1997; Perani et al., 1988; Starkstein et al., 1988) and left-handers after a left brain lesion (Critchley, 1953; Ettlinger et al., 1956; Hécaen & De Ajuriaguerra, 1963; Hécaen & Sauguet, 1971). The attempt made by Kertesz and Ferro (1984) and Kertesz et al. (1984) to attribute these exceptions, on the basis of CT scan data, to the reversal of cranial asymmetries (putatively pointing to a reversal of hemispheric asymmetries) was refuted in

a larger series of patients by Faglioni and Scarpa (1989).

Is dominance for praxis linked to dominance for language? The frequent association of apraxia with aphasia led some authors to envisage a common origin of the two deficits, tentatively identified in the impairment of either conceptual or sequencing abilities. The former interpretation, variously construed as a deficit of abstraction (Goldstein, 1948), conceptualisation (Bay, 1962), or the ability to use symbols for communication (Duffy et al., 1975), can be traced back to the concept of asymbolia, proposed by Finkelburg (1870) to account for the inability shown by his five patients to encode and decode meanings in every form of communication, oral, graphic, gestural, etc. This holistic approach to the interpretation of neuropsychological deficits now seems rather outdated and, in any case, could at most be invoked to interpret IA, not IMA, which also affects the imitation of meaningless gestures and can be confined to certain body parts. A deficit in the organisation of motor sequences was thought by Kimura (Kimura, 1976; Kimura & Archibald, 1974) to represent the common factor of both aphasia and apraxia. They found LBD patients who were impaired in reproducing a series of three meaningless gestures, but not single gestures, and speculated that in the evolution of mankind the left hemisphere progressively acquired a specialisation for sequencing, which represented the foundation for developing the ability, first to use tools and then to produce speech. However, the finding that only sequences are well suited for demonstrating the presence of apraxia was not confirmed by subsequent studies. Three-gesture sequences did not discriminate the performances of LBD patients from those of normal controls better than single gestures (De Renzi et al., 1983) and longer sequences did not discriminate LBD from RBD patients better than shorter ones (Harrington & Haaland, 1991). Kimura herself (1977) recognised that the most frequent errors made by LBD patients, in carrying out a sequence of three gestures, did not affect their order, but involved single gestures or were errors of perseveration.

18. APRAXIA

right-handers the left premotor cortex represents the end station of the pathways running in the white matter of the parietal lobe and transmitting sensory information, damage to the left parietal and frontal region should cause apraxia of an equal frequency and severity. This is not the case. While the association of apraxia with parietal damage has been repeatedly documented, that with frontal damage is much less well supported by either single case reports (reviewed by Faglioni & Basso, 1985) or group studies. Freund and Hummelsheim (1985) did not find IMA in 11 patients with lesions of the lateral premotor cortex, but only a disorder of coordinated movements in the proximal musculature of the contralateral limb, which was present after both left and right brain damage. A direct comparison of the performance on imitation tasks of left parietal and left frontal patients showed a more frequent and severe impairment in the former (De Renzi et al., 1983) and even no apraxia at all in the latter (Haaland & Harrington, 1994). Comparable results were reported by Kolb and Milner (1981), Basso, Faglioni, and Luzzatti. (1985), Faglioni and Scarpa (1989), and Goldenberg et al. (1985) These data present a strong case for making the following amendments of Liepmann’ s model.

A unitary account of apraxia and aphasia runs into the same difficulty that undermines the theory of a common source for praxis skills and handedness, namely the occurrence of dissociations in either direction. There are single case reports of both right-handed patients, who, following left brain damage, show aphasia without apraxia (Kertesz et al., 1984) or apraxia without aphasia (Heilman et al., 1974; Junque et al., 1986; Lanoe et al., 1990; Seines et al., 1991) and of left-handed patients, who, after a right brain lesion, show apraxia, but not aphasia (Heilman et al., 1973; Margolin, 1980). In large series of left braindamaged patients, in whom both praxis and language were systematically tested, the dissociation ranged from 14% to 64% (see Table 18.3). In agreement with these data, the correlation between the severity of apraxia and aphasia has been generally found to be rather low (Goodglass & Kaplan, 1963; Haaland & Flaherty, 1984; Kertesz et al., 1984; Lehmkuhl et al., 1983) and likewise the correlation between the improvements of these scores during recovery (Basso et al., 1987). It is, therefore, legitimate to conclude that apraxia and aphasia are independent disorders, which frequently coexist, because in right handers the left hemisphere cerebral areas involved in gesture and language functioning are contiguous and partially overlapping.

First amendment. The bearing of parietal damage on apraxia is not entirely attributable to damage to its white matter, but also to the involvement of the inferior parietal lobule cortex, which plays a crucial role in programming the action and controlling its performance, by specifying how the motor engrams, stored in the premotor cortex, must be

Revision of Liepmann’s model By and large, the model proposed by Liepmann (and substantially accepted by Geschwind, 1965) has withstood the test of time, but needs refining. According to its main assumption, namely that in

TABLE 18.3 Incidence of IMA in aphasie samples and dissociations between IMA and aphasia. A uthors

Liepmann (1905b) De Renzi (1964) Pieczuro et al. (1967) De Renzi et al. (1968) De Renzi et al. (1980) Papagno et al. (1993)

In c id e n ce o f IM A

In c id e n ce o f dissociations

in aphasies

in L B D pts

14/20 19/71 32/54 41/127 48/60 ?/?

429

= = = = = =

70% 27% 59% 32% 80% ?%

10/41 53/83 22/70 90/160 14/100 159/699

= = = = = =

24% 64% 31% 56% 14% 23%

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DE RENZI AND FAGLIONI

selected and ordered (Clark et al., 1994; Poizner et al., 1995). This contention was bolstered by the praxic impairment, found by Kolb and Milner (1981) , in patients who had undergone left parietal corticectomy. Whether the same structures also participate in recognising the meaning of gestures carried out by another person, as claimed by Heilman et al. (1982), remains open to question. Second amendment. If discrete sensory pathways convey to the parietal centre the information eliciting the gesture, then, following their selective interruption, modality-specific forms of apraxia would be expected to ensue. De Renzi and al. (1982) compared the performance of 150 left braindamaged patients in miming the use of objects on verbal, visual, and tactile presentation and found 6 patients who were impaired on the verbal test only, 6 on the visual test only, and 2 on the tactile test with respect to the verbal or the visual test, respectively. Single cases with apraxia in the visual but not the verbal modality (Pena-Casanova et al., 1985), or in the visual but not the verbal and tactile modality (Assal & Regli, 1980), or in the visual and tactile but not the verbal modality (Endo et al., 1996), have been reported. In a way, the disorder shown by these patients may be construed as preapraxic, in that the dysfunction affects the input to the store, where motor programmes are kept, and not the mechanism, whereby they are retrieved or implemented. Third amendment. The low frequency with which left hand apraxia is found in patients with left premotor cortex damage, is difficult to reconcile with the assumption that the parietal output must necessarily reach this area before making connections with the right premotor cortex and suggests that the left parietal lobe can use alternative pathways. Their identification, however, is problematic. Direct transmission of information from the left to the right parietal lobe is unlikely, because right parietal lesions are not usually associated with left hand apraxia (Geschwind, 1975b). Heterologous, direct connections with the right premotor area lack anatomical evidence (Pandya & Seltzer, 1986). A subcortical loop, involving the basal ganglia and the thalamus, is a

possibility, as fibres reaching the contralateral thalamus through the callosum have been reported (Jones, 1985), but the issue remains unsettled (see later). Supplementary motor cortex. A cortical region, not envisaged by Liepmann (1905a, 1920), which some authors (Goldenberg et al., 1985; Watson et al., 1986; Yamadori et al., 1988) have implicated in the genesis of apraxia, is the left supplementary motor area (SMA). It is, however, difficult to disentangle its damage from that of the adjacent corpus callosum and callosal fibres. Moreover, the few positive cases must compete with the far more numerous negative cases. Of 16 consecutive patients with an infarct in the territory of the left anterior cerebral artery, which supplies blood to the SMA, only one showed left limb apraxia and, moreover, the lesion also encroached on the corpus callosum (Bogousslavsky & Regli, 1990). A sign that has been attributed at least in part to damage of the SMA is the alien hand (Della Sala et al., 1994). This condition consists of unintended gestures of one hand, which occur in isolation (picking up an object) or reproduce movements of the other hand or interfere with them (intermanual conflict, e.g. when the right hand is trying to open a drawer, the left hand pushes it shut). The last type of actions has been called diagonistic dyspraxia by Akelaitis (1945), but in fact the movement is correctly carried out and is pathological only because it is involuntary. The word dyspraxia is, therefore, misleading. Goldberg et al. (1981) attributed the alien hand syndrome to the simultaneous damage of the contralateral SMA and the corpus callosum, while Tanaka et al. (1996) interpreted diagonistic apraxia as consequent to the disconnection of the two superior parietal lobes. Callosal apraxia The existence of left hand apraxia in patients with an acquired callosal lesion has been reported in more than 30 cases. To those reviewed by Faglioni and Basso (1985) the following must be added: Alpers and Grant (1931, case 1), Klein and Ingram (1958), Goldenberg et al. (1985), Watson and Heilman (1983), Watson et al. (1985), Graff-

18. APRAXIA

Radford et al. (1987), Starkstein et al. (1988), Boldrini et al. (1992), Buxbaum et al. (1995), and four of the six cases reported by Tanaka et al. (1996). The sector of the callosum, where the interhemispheric fibres engaged in motor regulation run, is the trunk, which connects the supplementary motor areas, the lateral premotor areas, the superior and inferior parietal lobules, and the primary motor and somatosensory areas, with the exception of the region where the hand is represented (Pandya & Seltzer, 1986). Callosal apraxia has both ideational and ideomotor features, but the deficit is more frequent and severe when the gesture must be evoked than when it must be simply imitated (Graff-Radford et al., 1987). It has to be said, however, that not all of the data from callosal pathology tally with Liepmann’ s claim that the callosal commissure is necessary for transmitting left hemisphere information to the right premotor cortex. Apart from negative cases (two out of eight in the consecutive series of patients with infarct of the trunk, reported by Giroud & Dumas, 1995), there are two pathogical conditions in which the absence or severing of these pathways does not result in apraxia. The first is represented by patients with callosal agenesis, who at most show some impairment in the transfer of the manual skills, learned with one hand, to the other, but no true praxic disorder (Ettlinger et al., 1972, 1974; Jeeves, 1979, 1984; Lassonde et al., 1995). The other is represented by epileptic patients who have undergone surgical callosotomy for the relief of their seizures. They show left hand apraxia only when the information eliciting the action is confined to the hemisphere contralateral to the acting hand, namely, when their left hand must carry out a gesture on command, or imitate a gesture presented to the opposite visual field (Risse et al., 1989; Volpe et al., 1982). On the contrary, either hemisphere of these patients is able to plan and enact the gesture with the hand it rules, when it receives the information directly (Bogen, 1969, 1985; Gazzaniga et al., 1967, 1977; Risse et al., 1989; Volpe et al., 1982; Zaidel and Sperry, 1977). It is true that Milner and Kolb (1985) found callosotomised patients who were impaired in imitating with either hand oral and manual threemovement sequences, but it is likely that their

431

deficit was mnestic rather than praxic, as single movements were correctly reproduced and it is known that these patients suffer from memory impairment (Zaidel & Sperry, 1974). Admittedly, the data from patients with callosal agenesis and section are puzzling and hard to reconcile with those gleaned from patients with acquired, spontaneous pathology. They have led some authors (Nass & Gazzaniga, 1987) to question the assumption that the motor engrams of the left premotor cortex exert control over those stored in the right premotor cortex. Yet it would be unwise to ignore the bulk of evidence drawn from acquired pathology. It is possible that a crucial factor is the patient’s age at the onset of disease. When the disease is congenital (agenesis) or begins during infancy (all patients submitted to callosotomy had been epileptic since the early years of life), it may have promoted the reorganisation of nervous functions and the development of new intra- and interhemispheric connections. This condition would provide the basis for a bilateral representation of praxic skills (Geschwind, 1965), in analogy with what occurs for language (Baynes et al., 1995). An interesting dissociation between the impairment of gestures and writing movements was pointed out in a few callosal cases, some of which showed agraphia, but not left hand apraxia (Degos et al., 1987; Gersh & Damasio, 1981; Kawamura et al., 1989; Sugishita et al., 1980; Yamadori et al., 1988) and one the opposite pattern (Kazui & Sawada, 1993). These findings suggest that the pathways linking the left writing centre with the hand motor centre of the right hemisphere have a callosal location distinct from those of the fibres connecting the two hand centres and provide information about their location. Kazui and Sawada (1993) analysed the relevant data and concluded that the fibres carrying information related to gestures run in the more rostral part of the posterior half of the callosum with some sparse representation in the anterior half, while those carrying information for writing movements run in the posterior end of the callosum. Apraxia associated with deep nuclei lesions Liepmann’s (1920) model did not envisage the participation of subcortical structures in the

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DE RENZI AND FAGLIONI

execution of gestures and none of the subsequent authors associated their lesion with apraxia, with the exception of Von Monakow (1914), who cited three (possibly four) cases with a view, however, to challenging the anatomical schema of Liepmann. It was only with the introduction of imaging techniques that interest was rekindled in this locus of lesion. Pramstaller and Marsden (1996) carefully reviewed the literature and were able to garner 82 cases, of which 88% had left-sided lesions, 6% had bilateral lesions, and 6% right-sided lesions; 9% had pathological findings and 72 neuroimaging documentation. IMA was found in 88% of patients, IA in 6%, and oral apraxia in 45%. The authors took a rigid stance with respect to the relation of basal ganglia lesions to apraxia, excluding cases in which damage extended to the white matter because, they argued, it could have encroached on the superior longitudinal (arcuate) fasciculus, which runs at the outer, superior margin of the putamen and is assumed to transmit movement formulae to the premotor cortex. This left them with 12 cases with damage confined to the lentiform nucleus or also extending to the caudate nucleus or the thalamus. Rather surprisingly, they too were discarded, on the assumption that CT scan may have not detected additional damage to the peristriate white matter. This position seems rather dogmatic and one wonders why the investigation was carried out, if the authors had decided a priori that apraxia was attributable to the dysfunction of the arcuate fasciculus, even when there was no evidence of its involvement. In 12 patients apraxia was linked to the left thalamic lesion, which in 8 cases was isolated. Pramstaller and Marsden (1996) thought that they represented true instances of subcortical apraxia. We agree that the concomitant involvement of the arcuate fasciculus deserves attention, but its occurrence cannot be taken for granted in every case of basal ganglia damage, even in the absence of specific documentation. The participation of subcortical structures in cognitive disorders, traditionally thought to be the province of the cortex, has been ascertained in different areas (aphasia, neglect, etc.) and it would not be surprising if apraxia were to be added to the list. The cerebral cortex projects not only to the

ipsilateral deep nuclei, but also to the contralateral ones through callosal pathways, joining the associative areas of both sides (Jones, 1985). Thalamic apraxia is in line with the hypothesis that also basal ganglia may be involved by the disorder, because the thalamus is the main recipient of the lenticular outflow.

The anatomical correlates of the intentional-automatic dissociation An important feature of IMA is that it affects intentional movements and spares movements that are carried out in an automatic way, either because they are habitual in a given situation (waving goodbye when leaving) or because they are repetitive and, once initiated, do not require further intentional selection. For instance, apraxics do not differ from nonapraxics on performances needing motor skill, such as screwing in a screw (Pieczuro & Vignolo, 1967), finger tapping (Kimura, 1977; Haaland et al., 1980), and grooved pegboard (Haaland et al., 1980), in which the same action must be repeated over and over again. The distinction between automatic and intentional actions is reminiscent of that between “predictive” and “responsive” behaviour, proposed by Goldberg (1985). Predictive actions are pre-planned, can only be retrieved en bloc and are not modifiable during their execution. A typical example is represented by ballistic, reaching movements. In responsive actions the implementation of motor programmes needs to be supervised by a “motor plan”, i.e. a complex system of commands that activates and controls the available programmes and can be interrupted, modified, or amplified, depending on motivational or environmental factors. Responsive behaviour is typically adopted during motor learning, as long as the gesture has not become a stable pattern of motor engrams, suited to being automatically activated as a whole. Apraxia disrupts responsive behaviours, by impairing the acquisition (Gonzales-Rothi & Heilman, 1984; Motomura et al., 1989) or the consolidation (Faglioni et al., 1990) of gestural engrams. Predictive and responsive behaviours are underpinned by two discrete anatomo-functional systems, the medial and the lateral systems, which are centred around the supplementary motor area

18. APRAXIA

(SMA) and the lateral premotor area (LPA), respectively (Goldberg, 1985). They have different phylogenetic origin — the medial system from the hippocampal archicortex and the lateral system from the pyriform paleocortex — and different patterns of connectivity (see Fig. 18.4). The SMA has reciprocal connections with the supplementary somatosensory area and both are linked with the prefrontal medial cortex, the latero-dorsal premotor cortex, and the superior parietal lobe. All of these regions communicate with the cingulum and, through it, with the hippocampus. The LPA is reciprocally connected with first-order associative visual and auditory areas, the secondary somatosensory area, and the prefrontal lateroventral cortex, as well the inferior parietal lobule (Pandya & Kuypers, 1969). It communicates with the piriform cortex, via fibres to the insula and the temporal pole. It follows that the only sensory input to the SMA is proprioceptive, while the LPA also receives visual and auditory information. In the lateral system a key role is played by the angular and supramarginal gyri, corresponding in the monkey to areas PF, PFG, PG, PGH, and POG (Eidelberg & Galaburda, 1984), which are connected with polymodal second-order associative areas, such as the superior temporal sulcus and the periarcuate region (which in man

433

corresponds to the LPA), but not with the unimodal associative areas (except the somatosensory one). Thus the angular and the supramarginal gyri would represent a high-level stage of integration of somatic and environmental information, which they transmit to the LPA to guide the performance of gestures. The connections with subcortical structures also differentiate the lateral and medial system (Schell & Strick, 1984). The former are thought to be predominantly engaged in a subcortical loop, involving cerebellar information and to project to spinal neurones via the red nucleus and the reticular formation. The medial subcortical loop would be mainly based on information from the basal ganglia and the SMA would directly project to the spinal cord (Murray & Coulter, 1981). The different functional specialisations of the lateral and medial system, suggested by the pattern of their anatomical connections, is borne out by data from experiments of cortical ablation in animals and cortical activation in humans. Cortical ablations in the monkey Caution should be exercised when attempting to assess the bearing on apraxia of monkey lesion experiments, because the motor tests used in them are based on operant conditioning and call for the

FIGURE 18.4

Main cortical and subcortical connections of the lateral premotor area and the supplementary motor area (adapted from Goldberg, 1985). LPA: lateral premotor area; MA: motor area; SMA: supplementary motor area; area X: thalamic area X; VPLo: ventral postero-lateral thalamic nucleus, oral part; VLc: ventral lateral thalamic nucleus, caudal part; VLo: ventral lateral thalamic nucleus, oral part; VLm: ventral lateral thalamic nucleus, medial part.

434

DE RENZI AND PAGLIONI

repetition of the same sequence in response to a given stimulus. The situation is basically different from that suitable for eliciting apraxia in humans, which is marked by the preserved ability to perform a repeated sequence and by failure when a new sequence must be selected for every item. With these limitations in mind, it can be said that the bilateral lesion of the medial system impairs gestures that are under proprioceptive control (Halsband, 1987; Passingham, 1987), while that of the lateral system also impairs gestures that are visually or auditorially guided (Deuel, 1977; Goldman & Rosvold, 1970; Passingham, 1985). The unilateral removal of the postarcuate cortex disrupts the organisation of the movements needed to grasp a target in the contralateral peripersonal space with the mouth or the contralateral limb (Rizzolatti et al., 1983). The area lying behind the arcuate angle is concerned with hand movements, that lying behind the inferior limb of the arcuate sulcus with mouth movements. Interestingly, neurones have been identified in the inferior and rostral portion of the LPA, which discharge both when the animal grasps a target of interest and when it sees the examiner perform the same gesture (Gallese et al., 1996; di Pellegrino et al., 1992), as if execution and recognition shared at least some common substrates. Regional blood flow More enlightening are the changes in regional cerebral blood flow occurring in normal subjects during the planning and execution of a movement. Different patterns of activation have been reported, depending on the nature of the movement. When it requires isometric muscular contraction (pressing the foot against resistance, Orgogozo & Larsen, 1979) or the repetition of the same elementary motor sequence (clenching and unclenching one’s own fist, Olesen, 1971; repeatedly squeezing a spring between the thumb and index finger, Roland, Skinhoj et al., 1980), the activation is confined, in the former case, to the contralateral motor cortex and, in the latter case, to the contralateral sensorimotor cortex. When the motor formula has already been learned and automatised, but its complexity demands a choice among other possible movements (e.g. opposing the thumb twice to the forefinger,

once to the middle finger, three times to the ring finger, twice to the little finger and then repeating the sequence in the reverse order, Orgogozo & Larsen, 1979; Roland, Larsen et al., 1980; Roland et al., 1982), the blood flow also increases in the opposite SMA and the same occurs when the sequence is simply imagined and not performed (Gelmers, 1981; Roland, Larsen et al., 1980). This pattern of findings has been confirmed by PET studies (Deiber et al., 1991; Wessel et al., 1995). When the patient has to select a motor formula, which cannot be programmed in advance, in response to new, external stimuli (e.g. tracing with the forefinger an unknown route on a chessboard following verbal instructions or imitating with the finger a spiral movement made by the examiner, Roland, Skinhoj et al., 1980), the posterior parietal lobe and the LPA are also activated bilaterally, though more on the contralateral side. The same pattern of activation is seen when the movement is simply imagined (Ingvar & Philipson, 1977). PET studies, which use repetitive movements (e.g. Grafton et al., 1995; Hazeline et al., 1997) or call for spontaneous movements that are independent of external contingencies (e.g. Crammond, 1997) bear no relation to apraxia, as neither programmed nor programmable action activity is implied.

MELOKINETIC APRAXIA In Liepmann’s (1920) model, melokinetic apraxia (MKA) is construed as resulting from the degradation of kinesthetic, innervatory engrams, which are located in the sensomotorium of either hemisphere and represent the physiological substratum, whereby the motor programme is transcoded into appropriate muscle movements. According to Liepmann, MKA is marked by the following features: it is confined to the limbs contralateral to the damaged cortex, mainly affects skilled actions, no matter how well-practised they are, and gives rise to clumsy, fragmented, and “inexpert” movements. The concept of MKA was reproposed by Kleist (1934) under the name of innervatory apraxia, but

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it failed to gain wide acceptance, because of the difficulty incurred in differentiating it from mild paresis. Moreover, it has never been adequately documented by single case reports. Freund and Hummelsheim (1985) used it to designate the deficit shown by patients with premotor frontal cortex damage in the limbs contralateral to lesion, when they were requested to perform a windmill movement with their arms, one moving in the forward direction and the other in the backward direction, or to make cycling movements with both legs. More germane to Liepmann’s (1920) conceptual framework is the use of the term MKA by Della Sala and Spinnler (this book, Chapter 33) to define the pattern of motor deficits shown by patients with slowly progressive apraxia, a clinical picture hallmarked, at least in its early stages, by an increasing loss of manual skills, with no other neurological or cognitive deficits. Patients’s functional capacity for daily activities is severely limited by their inability to perform differentiated movements with their fingers and hands, which become “useless appendages” (De Renzi, 1986). However, provided the deficit is not too severe, the awkward and ineffective movements still betray the ideational plan of action. The impairment can long remain unilateral. Unfortunately, on the basis of available data, it is impossible to establish whether these patients’ damage is confined to the premotor areas or also involves the basal ganglia. This is the case for corticobasal degeneration, a disease that is also distinguished by a form of apraxia that has been defined as melokinetic (Okuda et al., 1992).

IDEATIONAL APRAXIA In comparison with IMA, the investigation of IA has been relatively neglected by the literature, probably because its boundaries appeared less well defined. Pick (1902, 1905) first described it with the misleading name of motor apraxia, which he used with the intent to stress its independence from recognition disorders, but which was soon abandoned for that of ideational apraxia, proposed by Liepmann. His patients made gross errors in the use of objects, e.g. brought the bowl of a pipe to

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their mouth, as if it were something to drink from, used a pair of scissors as a spoon and put them into their mouth, were unable to light a candle and aimlessly toyed with the unstruck match around the candlestick. Although the examples given by Pick concerned the inability to use single objects, it has become customary to test IA with actions involving more than one object (e.g. lighting a candle), on the assumption that they are more suited for bringing out the errors of omission, inversion of the correct sequence, misuse, etc., thought to characterise the disorder. The following excerpt from De Renzi and Lucchelli (1988, p. 1178), exemplifies the behaviour of an ideational apraxic, when a candle, a candlestick and a matchbox were laid on the table and he was asked to light the candle: “The patient puts the candle vertically on the table, ignoring the candlestick, takes a match out of the matchbox and brings it close to the wick, without having struck it. After a while, he realises that the match must be lighted and strikes it on the candle, beside the wick”. Before taking this kind of behaviour as evidence that AI is an autonomous disorder, we must rule out that it simply reflects the disruption of other abilities at the motor level. The following possibilities can be entertained. IA is thought to depend on visual agnosia. This hypothesis can be easily ruled out on the grounds that patients often name correctly the objects they misuse, thus showing that they have recognised them. Moreover, the fact that they fail when handling them means that the deficit is not limited to one sensory channel, as the concept of agnosia would imply. Also, error analysis is more suggestive of impaired recall of how the objects must be used than of the inability to recognise them. In the foregoing example, the fact that the patient first brought the match to the wick and then struck it on the candle suggests that he recognised the objects and had also retained some notion of their relationship, but was unable to remember how to strike a match. It would appear that in IA patients there is a dissociation between the knowledge of object meaning and use. IA is thought to depend on dementia. The circumstance that IA was originally described in

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patients with senile dementia (Marcuse, 1904; Margulies, 1907; Pick, 1906) or post-epileptic confusional states (Pick, 1902) led some authors to argue that it was but one of the multifarious manifestations of dementia or confusion. Pick (1906) countered that such a striking misuse of objects was rarely seen in demented patients of a comparable severity and also adduced an anatomical argument, namely that in one of his patients cerebral atrophy was not generalised, but prevailed in the left temporal lobe. We now know that IA can be associated with circumscribed lesions of the left hemisphere, not differently from what occurs for aphasia, and have evidence that LBD patients with IA do not differ from those without IA in their performance on a general intelligence test, such as Raven Progressive Matrices (De Renzi et al., 1966). IA is thought to be a very severe form of IMA. Although in principle IMA errors should be clearly distinguishable from IA errors, because they still betray the general idea of the gesture, it may be difficult to decide whether the object use errors made by a patient with severe IMA are due to defective ideation or defective execution (Sittig, 1931; Zangwill, 1960). However, if IA is but an extreme form of IMA, then every patient with IA must have severe IMA and the correlation between the two deficits should be fairly high. Three studies have disproved the former prediction. De Renzi et al. (1966) assessed 160 LBD patients with an IMA test (gesture imitation) and an IA test (object use), and found that 34 patients failed both of them, 11 only the IMA test, and 11 only the IA test. Barbieri and De Renzi (1988) used a more stringent criterion for determining a dissociation in task performance, by computing the number of LBD patients who showed a difference between the two test scores that exceeded the highest difference found in normal controls. Twelve left brain-damaged patients were found to show a “pathological” difference score, due to a disproportionate impairment on the IA test. Also the search (De Renzi & Lucchelli, 1988) for a significant correlation between imitation scores and the scores on a multiple object use test turned out to be negative. Granted that IA is an autonomous symptom, then which ability is disrupted by it? Poeck and

Lehmkuhl (1980b) thought of a disorder in the sequential organisation of the gestures composing a complex action and emphasised that errors of sequencing prevail, while the use of single objects would be generally correct. This was not the conclusion reached by De Renzi and Lucchelli (1988), when they analysed the performance of 20 left brain-damaged patients with IA, who were requested to carry out a series of complex, albeit common actions, involving more than one object. Six types of errors were recorded: 1. Perplexity: patients look hesitantly at the objects, make some attempts to use one of them, then try with another, clearly not knowing what to do. 2. Clumsiness: the action appears conceptually appropriate, but is carried out in an awkward and ineffectual way, due to the poor control of hand movements. This error likely reflects IMA. 3. Omission: patients forget to perform an action necessary to complete the sequence, e.g. they forget to strike a match, when trying to light a candle. 4. Mislocation: the action is appropriate, but carried out in a wrong place, e.g. the stamp is stuck on the back of the envelope. 5. Misuse: the object is used in a conceptually inappropriate way, e.g. the candle is rubbed on the table. 6. Sequence error, the order in which gestures follow each other is illogical, e.g. the match is struck before putting the candle into the candlestick. (For an alternative coding system of activities of daily living, providing a detailed, quantitative picture of the patient’s action disorder, see Schwartz et al., 1991). The most frequent types of errors were those of omission, mislocation, and misuse, which point to a defective evocation of the gesture associated with a given object, while sequencing errors were relatively rare. Moreover, there was a very high correlation (0.85) between the performance on the complex action test and that on a test requiring the actual use of single objects. De Renzi and Lucchelli (1988) concluded that the basic deficit underlying IA is “amnesia of usage”, namely

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the inability to retrieve from semantic memory the particular attribute of an object that specifies how it should be used. In keeping with this assumption, a left-handed patient, who showed a severe IA following a right brain stroke (Ochipa et al., 1989), was unable to use objects, mime their use, identify an object when its typical action was described, and say what an object was used for. This impaired ability to remember how an object is used is germane to other deficits of access to the semantic store that have been pointed out in LBD patients, such as the inability to associate an object with its sound, or its typical colour (for an exhaustive discussion of this issue, see Vignolo, Chapter 13). It would, therefore, appear that the left hemisphere plays a crucial role in storing and retrieving gestural representations as well as other features defining the meaning of an object. However, it is likely that these attributes are organised separately in the semantic store and are, therefore, liable to independent disruption. Of interest in this regard is the patient described by Sirigu et al. (1995) who showed a pattern of deficit opposite to that of IA: he was able to show how his hand had to be positioned for manipulating an object, but did not know what the object was used for. Poeck and Lehmkuhl (1980a) maintained that, unlike IMA, IA is apparent in daily life, but De Renzi and Lucchelli (1988) disagreed, at least for the less severely impaired cases. An interesting dissociation between actions performed out of context and naturalistic actions was pointed out by Buxbaum et al. (1995) in a patient with a callosal disconnection syndrome. On a test requiring him to mime the use of objects on command and on visual and tactile presentation, he performed correctly with the right hand and poorly with the left hand, as expected in callosal apraxia. When asked to carry out naturalistic actions (e.g. to prepare a slice of toast with butter and jam), both hands made errors, which decreased in the left hand, but not in the right hand, when they performed the task separately. Buxbaum et al. argued that the right hemisphere has greater praxis competence than predicted by the classical theory when the action is carried out in a contextual frame, and that there is a risk of

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overestimating the left hemisphere dominance, if it is assessed with tests that require single actions out of context.

Location of lesion On the basis of autopsy findings from single cases, several authors (Foix, 1916; Morlaas, 1928, Hécaen, 1972; Liepmann, 1920) have associated IA with damage to the temporo-parietal-occipital region of the left hemisphere. However, in the absence of systematic studies, it is difficult to draw a definite conclusion. In the series of IA patients with CT scan documentation, reported by De Renzi and Lucchelli (1988), the deficit was present in almost all (7/8) of their parietal patients, but also in three out of six patients with frontal damage, in one patient with posterior cerebral artery infarct, and in one patient with a lenticular haematoma. IA has also been observed in patients with dementia of Alzheimer type (Della Sala et al., 1987; Foster et al., 1986), both with and without IMA (Benke, 1993; Ochipa et al., 1992).

TRUNK APRAXIA Geschwind (1975a) claimed that patients with IMA do not show apraxia when requested to make total body movements that involve the axial musculature. For instance, patients who are unable to punch, salute or pretend to stamp out a cigarette end with their foot, can walk backwards, kneel, dance, assume the position of a boxer, etc. on command. He speculated that this dissociation was contingent on the different pathways that link Wernicke’s area, where the command is decoded, with spinal neurones. Because hand movements are carried out through the pyramidal system, verbal orders must be transmitted to areas 6 and 4, via the arcuate fasciculus and are, therefore, liable to be blocked by a parietal lesion. On the contrary, this interruption is dodged by the pathways innervating the axial muscles, which would directly project from the temporal cortex to the subcortical motor system. It is not clear what Geschwind thought of axial movements that are not guided by verbal instructions, e.g. those carried out on imitation. He

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based his hypothesis on anecdotal observations and never put this to test. This was done by Poeck et al. (1982), who requested 60 aphasic patients to perform movements with different body parts and the whole body, both on command, and by imitation. They found that on command patients scored lower with the limbs than with the axial musculature (although the difference was significant for global aphasics only), but that on imitation there was no significant difference. On the whole, the results were not thought to bolster Geschwind’s hypothesis, but Howes (1988) reanalysed the data gleaned by Poeck et al. on the verbal task and showed that axial commands were indeed performed better than oral and limb commands. The same conclusion was reached by Alexander et al. (1992).

ORAL APRAXIA The same dissociation between intentional and automatic movements pointed out for limb apraxia has also been found in the pharyngeallingual-facial musculature. Jackson (1932) was the first to draw attention to the aphasics’ inability to put out their tongue on command, although they were able to move it when chewing or in response to a stimulus (e.g. they sometimes lick a crumb off their lips). He viewed this disorder as a manifestation of the same inability that is apparent in speech, when patients fail to say on command the same word they easily utter as a stereotypy or when prompted by emotion. Oral apraxia (OA) involves every kind of intentional oral movement: patients are unable to whistle, kiss, clear their throat, etc. The same occurs on imitation. Jackson (1932) also mentioned aphasic patients’ inability to move their eyes in a given direction during fundoscopic examination and subsequent authors have used the term apraxia to indicate the inability to keep eyelids closed or open on command, but this extension of the concept of apraxia to ocular movement disorders has not been accepted. There have been several attempts to develop a qualitative classification of oral praxic disorders

and to relate them to aphasic syndromes, but no consistent association has been demonstrated (Poeck & Kerstschensteiner, 1975). Watamori et al. (1981) contrasted an anterior OA syndrome, characterised by a poorer performance on coordinated movements (e.g. to whistle) as compared to simple movements (e.g. tongue protrusion), with a posterior OA syndrome, characterised by the opposite pattern of deficit. This dichotomous classification is in need of replication, given the small number of patients investigated. Mateer (1978) focused on the difficulty shown by aphasics in learning a three oral gesture sequence, but no difference was found in the distribution of the various types of errors among fluent aphasics, RBD patients, and controls. Moreover, the task turned out to be too difficult for nonfluent aphasics, i.e. the group in which oral OA usually prevails. Also Square-Storer et al.’s (1989) painstaking analysis of oral movements, produced in isolation or in sequence, provided data that hardly justify their laborious error classification. Table 18.4 reports a test of oral movements that we have standardised in 100 normal controls. The examiner faces the patient and performs a movement that he or she is requested to imitate. If the imitation is not correct, the movement is repeated a second and, if necessary, a third time. The patient’s performance is scored 3, 2, 1, or 0, depending on whether it is correct at the first, second, or third presentation or never. The maximum score is 24 and the cutoff point is 20.

Relation of oral apraxia to left brain damage The association with left brain damage is as close for OA as it is for IMA, but there is evidence that the two disorders can dissociate and are, therefore, subserved by discrete anatomical structures. In a sample of 136 LBD patients (De Renzi et al., 1966) there were 30 patients with OA , but not IMA, and 8 patients with the opposite pattern, and in the entire sample the correlation between the two scores was far from impressive (0.46). The incidence of OA in two unselected samples of LBD patients (De Renzi et al., 1966; Pizzamiglio et al., 1987), was found to be 43% and 45%, respectively. Kimura (1982) divided LBD and RBD

18. APRAXIA

patients into an anterior and a posterior group and gave them two oral imitation tests, one made up of single movements and the other of three movement sequences. In agreement with a previous study (Mateer & Kimura, 1977), the mean scores of both left-sided groups were impaired on the sequence test, but only that of the left anterior group on the single movement test, suggesting a more specific role of anterior areas. Likewise, a single-movement test revealed a greater incidence of OA in patients with phonetic-articulatory disorders, which are typical of damage to the Broca area (De Renzi et al., 1966; Watamori et al., 1981). This conclusion was supported by a study in which the relationship between the performance on single oral movement imitation and CT scan findings was explored (Tognola & Vignolo, 1980). In the majority of cases, OA was associated with damage to the frontal and central opercula and the posterior portion of the insula, while the inferior parietal lobule was involved in one third of patients. The findings with sequence imitation tests are not as easy to interpret. Kimura (1982) found that left parietal patients were as impaired as left frontal patients, and Kolb and Milner (1981) reported a poor performance in epileptics, following left as well as right frontal corticectomy. Sequence tests, however, entail a memory load that can undermine their specificity and confound the interpretation of results. This probably explains why Milner and Kolb (1985) found that epileptics, submitted to callosotomy, were impaired on an oral sequence test, a finding at variance with the absence of OA

in single oral movements repeatedly reported in patients with extensive callosal lesions, even when they do show left limb apraxia (Geschwind & Kaplan, 1962; Graff-Radford et al., 1987; Sweet, 1941; Watson & Heilman, 1983). Indeed Geschwind (1965) relied on the discrepancy between the effect of callosal damage on limb and oral praxis to hypothesise a different role of the left hemisphere control for the two types of movements. While the organisation of oral movements would be the province of only the left premotor cortex, which directly guides the motor nuclei of the cranial nerves, that of left limb movements would also require the subordinate participation of the right premotor cortex.

Oral apraxia and speech disorders The frequent association of OA with phoneticarticulatory disorders led some authors to submit that the speech impairment is the consequence of the inability to programme oral movements. In a way, this hypothesis was implicit in Broca’s (1861) interpretation of the aphemia shown by his patient Tan-Tan as being due to the loss of the “procedure that must be followed to articulate words”. Within the realm of Broca aphasia disorders, Pierre Marie (1926) isolated anarthria, which he construed as a motor, not a language deficit. Liepmann (1913) was more explicit, arguing that motor aphasia is basically a form of apraxia, a position shared by Nathan (1947) and Bay (1957). More recently, Darley (1964) proposed the term apraxia of speech to designate a specific difficulty in performing the

TABLE 18.4 Oral movement imitation test 1. Puffing. 2. Whistling. 3. Blowing a raspberry. 4. Kissing. 5. Smacking your lips. 6. Clicking the tongue imitating the sound of a galloping horse. 7. Repeatedly pressing and pulling off the tongue against the inner side of teeth, (making a sound like a /t/ by sucking rather than by forcing air out). 8. Clearing your throat.

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oral acts in articulating speech sounds and ordering them sequentially into words (for a review of apraxia of speech, see Johns & LaPointe, 1976). Also lending support to the thesis that OA and speech disorders share a common mechanism is the finding that the electrical stimulation of cortical points located in the left inferior premotor area causes both arrest of speech and inability to perform facial movements in patients selected for temporal lobectomy (Ojeman & Mateer, 1979). This account implies that phonetic-articulatory disorders are a constant accompaniment of OA and that the correlation between the severity of the two deficits is high. OA was found in 90% of Broca

aphasics (De Renzi et al., 1966) and in most of the patients with apraxia of speech (La Pointe & Wertz, 1974), but the correlation between motor and speech disorder was not high (Bowman et al., 1980; La Point &Wertz, 1974) and both severe motor aphasics without OA and patients with OA without speech impairment have been reported (De Renzi et al., 1966; Mateer, 1978). Particularly telling are two case reports of crossed OA (Kramer et al, 1985; Mani & Levine, 1988), documenting OA in righthanded patients, who showed neither aphasia nor limb apraxia, following right brain damage. They provide irrefutable evidence that oral movements and speech can be organised independently.

19 Constructional Apraxia Dario Grossi and Luigi Trojano

complex cognitive tasks, whereas others considered it the consequence of a visuoperceptual disorder (see Gainotti, 1985 for a full review of the literature). The existence of divergent opinions gave rise to a terminological confusion, and it gradually became customary to use the term CA to refer to any anomaly observed during the performance of a constructional task, despite the attempts of researchers to formulate a more precise definition (e.g. CA denotes “an impairment in combinatory or organising activity in which the details must be clearly perceived and in which the relationship among the component parts of the entity must be apprehended if the desired synthesis of them is to be acheived”; Benton, 1967, p.3). In other words, there was a general tendency to ignore Kleist’s original definition and to use CA as an umbrella term for any “constructional disability” (Gainotti, 1985), irrespective of the presence or absence of a visuoperceptual deficit. The legacy of this theoretical debate is a single diagnostic category which fails to acknowledge the various hypotheses put forward to account for different types of constructional disability. The only reference to theory has been in the definition of “constructional skills” as those identified by Kleist through his clinical research. In reality, however, drawing, assembling, and building

DEFINITION The inability to construct a complex object, arranging its component elements in their correct spatial relationships, was observed as early as the beginning of the twentieth century (Reiger 1909). Even so, it wasn’t until years later that the specific nature of this disability was recognised, thanks to the work of Kleist (1934), who coined the term “constructional apraxia” (CA). According to Kleist the syndrome comprised a disturbance in the activities of drawing, assembling and building, in which the spatial form of the product proves to be unsuccessful without there being an apraxia for single movements. Kleist set out to differentiate constructional-apraxic disabilities from other motor programme disorders (e.g. ideomotor apraxia) and elementary visuoperceptual deficits, proposing that they derived from an alteration in the connections between visual functions, that is visuospatial, and the kinetic engrams that control manual activity. In spite of Kleist’s efforts to arrive at a specific definition, at the beginning of the Second World War, attempts to formulate a theoretical interpretation of CA fell into two main camps. Some researchers saw CA as an executive disorder, on the basis of observations of performance on 441

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(Kleist’s constructional skills) cannot be considered equivalent because they rely on various cognitive mechanisms (sustained attention, reasoning, motor, perceptual, and visuospatial skills) to different extents. Even though some researchers have noted a significant correlation between drawing, threedimensional object construction, and visuospatial tasks (e.g. replication of spatial arrangements of counters, Arrigoni & De Renzi, 1964) in right and left hemisphere lesion patients, numerous studies have yielded contrasting data. Benton and Fogel (1962), for example, observed low intercorrelations between two- and three-dimensional constructional tasks, a copying task, and the block design subtest of the WAIS in a group of 100 braindamaged patients. Furthermore, cases of patients who fail at graphomotor tasks but not at threedimensional constructional tasks and vice-versa (Dee, 1970) have also been reported. Despite these observations, most CA researchers adhere to the traditional approach, for which reason it is useful to briefly summarise the tasks that explore “constructional abilities” before moving on to discuss the threads of clinical and experimental research.

ASSESSMENT OF CONSTRUCTIONAL ABILITIES The presence of a constructional disability is tested by asking the patient to assemble or draw a simple two-dimensional model. Studies of CA have always employed tasks that require the produced shape to have component lines of equal length and arranged in their given spatial relationships. An example of this type of test is that compiled by Benson and Barton (1970). The block design subtest of the WAIS (Wechsler, 1974)—where the patient has to reconstruct a two-dimensional pattern using multicoloured cube faces—is used for the same purpose, yet it is perhaps the clearest example of how a so-called test of constructional skills taps different cognitive mechanisms, i.e. attentional, perceptual, motor, and visuospatial. Other tests investigate three-dimensional constructional abilities, beginning with simple

shapes. One such test has been standardised by Benton and Fogel (1962). It has been posited that there could be differences between the mechanisms involved in two-dimensional and threedimensional constructional tasks, for which reason some researchers recommend testing both competences (Benton, 1989); others, however, consider this an unnecessary procedure (De Renzi, 1980). Drawing tasks are those most widely used to tap constructional abilities, although it should be underlined that unlike the aforementioned tests, they rely on the presence of intact graphomotor skills. In fact, a dissociation between drawing and constructional tasks has recently been reported amongst aphasic patients (Kashiwagi et al., 1994). However, not even copying and free drawing (traditional constructional tasks) can be considered completely analogous. Free drawing—in which the patient is asked to draw a named object (e.g. a watch, a face, and so on)—is perhaps the most immediate test of constructional skills. It reveals information about the patient’s ability to draw complete shapes or a tendency to omit parts; his or her ability to organise the figure as a whole, with its component parts in their correct spatial relationships, and the features of the lines drawn. Even so, this kind of assessment does not easily lend itself to standardisation and relies on the presence of intact non-constructional cognitive abilities. Regarding the latter point, Gainotti et al. (1983) demonstrated that drawing abilities were more compromised in aphasics than in nonaphasic left hemisphere and right hemisphere brain-damaged patients; in other words, the resulting damage seemed to be more significantly related to a lexical-semantic deficit than to a visualconstructional disorder. Similarly, Grossman (1988) observed that in many cases, brain-damaged patients made errors in associating shape with appropriate size when drawing single objects, revealing a disorder that was not purely constructional in nature. In the assessment of constructional skills then, the complexity of free drawing tasks should be recognised, in terms of the role played by lexical-semantic mechanisms and imaginative ability (see Trojano & Grossi, 1994 for a more detailed discussion).

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These considerations are not relevant to copying tasks, which more directly assess the patient’s ability to reproduce a figure (Fig. 19.1). However, there hasn’t always been consistency in the selection of stimuli for tests (simple shapes, e.g., circles, squares, and complex designs, e.g. the Rey figure; see Fig. 19.2), and above all in the formulation of diagnostic criteria for CA. Confirming the need for standardisation, Arrigoni and De Renzi (1964) have highlighted that although it is easier to classify patients with an obvious disorder at a clinical level, there may be substantial differences among those who present with milder disabilities. It therefore seems clear that a diagnosis of CA should be based on the administration of copying, drawing, or constructional tasks (remembering that, in the opinion of some researchers, both graphomotor and constructional skills should be tested; Benton, 1967, 1989) which

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incorporate stimuli of gradually increasing complexity, do not draw on general intellectual resources to a great extent, and above all, have been tested on a sample of normal subjects (De Renzi, 1982). In Italy, a copying task that meets these requirements can found in the test battery standardised by Spinnler and Tognoni (1987). The terminological uncertainty just outlined, the use of non-standardised tests and the selection of nonhomogeneous patient groups have all contributed to a lack of consensus regarding the anatomical and functional etiology of CA. In the first instance, there is inconsistency between estimates of the incidence of CA following left and right hemisphere damage; most studies report incidence rates of 3CM-0% for right brain-damaged patients although the figures for left lesioned patients vary considerably. Kleist’s original work drew attention to a link between CA and dominant

FIGURE 19.1

Copying of geometric drawings: (a) models; (b) drawings by left brain-damaged patients— spatial relationships appear to be relatively spared— (c) drawings by right brain-damaged patients without hemineglect but with gross visuospatial defects.

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parietal lesions, but early studies of broader samples of patients with focal lesions indicated that CA was less prevalent and less severe following damage to the left hemisphere (see Piercy, Hecaen, & Ajuriaguerra, 1960; Piercy & Smyth, 1962), suggesting a right hemisphere dominance for constructional-praxic abilities. Other studies, however, attribute the higher incidence of CA in right hemisphere patients to greater severity of the lesion (Arrigoni & De Renzi, 1964) and to hemiinattention errors, which are more prevalent in this group (Gainotti & Tiacci, 1970). In fact, more recent studies, which have controlled these variables, demonstrate a similar prevalence of CA following lesions to either

hemisphere (Carlesimo et al., 1993; Kirk & Kertesz, 1989; Villa, et al., 1986), giving less weight tout-court to the "dominant right hemisphere" hypothesis and reinforcing the idea that there could be qualitative differences between the mechanisms responsible for CA in the two groups of brain-damaged patients. The first writer to explicitly propose an interhemispheric distinction was Duensing (1953), who maintained that right hemisphere patients failed at copying tasks because of defective visuospatial mechanisms (a spatial agnosic form of CA), whereas left hemisphere patients were affected by an ideational form of apraxia. This hypothesis was born from the observation that right

FIGURE 19.2

Copying of Rey figure: (a) model; (b) drawing by a left braindamaged patient; (c) drawing by a right brain-damaged patient; (d) and (e) drawings by patients with primary degenerative dementia: in the second case, severe visuospatial defects lead to complete disintegration of the copy.

a)

b)

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e)

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brain-damaged patients tend to produce drawings with the wrong orientation and disorganised spatial relationships between component parts whereas patients with left-sided lesions tend to simplify the model, omitting some details but preserving the original spatial relationships (see Figs. 19.1 and 19.2). Numerous studies have confirmed the presence of these characteristics in the drawings of brain-damaged patients (see Gainotti & Taicci, 1970). Several noteworthy studies seem to acknowledge the presence of a specific executive disorder (Hecaen & Ajuriaguerra, 1960) or motor programming deficit (Warrington, James, & Kinbourne, 1966) in left hemisphere apraxics. Experimental proof of the latter hypothesis has been provided by Hecaen and Assal (1970) who devised a copying task with “planning” tokens, in the form of geometric shapes which guided the reproduction of the stimulus. In this study, left hemisphere patients (as opposed to their right hemisphere counterparts) benefited from the availability of an explicit planning strategy, confirming the presence of a planning deficit. Gainotti et al. (1977) later tried to replicate these results, comparing the copying performance of a series of right and left hemisphere patients with performance on an analogous task that made use of “planning” tokens. The results were inconsistent with those of Hecaen and Assal after the effects of general intellectual deterioration and spatial hemineglect were equally weighted. The existence of a specific visuoperceptual deficit in right hemisphere apraxics has been confirmed by some studies (see Mack & Levine, 1981), although the majority reveal comparable visuospatial disorders in patients with right- and left-sided lesions (Gainotti, 1985). Given the data for and against a distinction between apraxias of right and left lesion origin, it is only possible to retain the lateral hypothesis in its “weak” version i.e. in right brain-damaged patients, a deficit in visuospatial analysis appears to predominate, whereas in left lesioned patients, visuoconstructional disabilities probably have more complex origins—in movement planning disorders, but also in general intellectual deficits or disorders of visuospatial analysis (De Renzi, 1980).

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This greatly researched interhemispheric difference in the mechanisms underlying CA can only be demonstrated by designing an experiment in which certain skills are seen to correlate with constructional performance in one patient group but not in the other, while other abilities exhibit the opposite tendency. A study of this nature has been published by Kirk and Kertesz (1989), who noted that drawing disabilities correlated strongly with performance on a visuoperceptual task in patients with right hemisphere lesions while correlating more strongly with tests of verbal comprehension and severity of hemiparesis in the left hemisphere group. Kirk and Kertesz concluded that CA can originate from a visuoperceptual deficit other than hemi-inattention in right brain-damaged patients whereas it could be linked to disorders at the semantic or elementary motor level in patients with left-sided lesions. It should, however, be highlighted that as Kirk and Kertesz employed a freedrawing task in their study, their conclusions may not be replicated with a simple copying task. Furthermore, the visuospatial deficit in right lesioned patients was identified using Raven’s Progressive Matrices, which tap not only perceptual mechanisms but also general intellectual ability. A more recent study with a similar experimental design (Carlesimo, Fadda & Caltagirone, 1993) used copying performance as an index of constructional ability and judgement of line orientation, comparison of distorted geometric figures, a “tapping” test (elementary motor skills) and a “tracking” test (spatially guided motor skills) to explore the various subskills involved in the process of construction. To complete the battery, Raven’s Progressive Matrices were incorporated as a measure of intellectual ability. Carlesimo et al. observed that tracking performance significantly correlated with drawing ability in right braindamaged patients. Moreover, in left hemisphere patients, constructional performance correlated strongly with the results of the tapping test. They concluded that the basic disturbance in right hemisphere apraxics is more likely to be an alteration in their ability to carry out spatial manipulations than a visuospatial deficit per se (in this group, judgement of line orientation correlated

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only marginally with drawing performance) whereas in left hemisphere patients, a disorder at the elementary motor level could play a more crucial role—in accordance with Kirk and Kertesz’s (1989) hypothesis. Though once again, note how two more or less similar studies reach conclusions that are at least partially inconsistent. With regard to the intrahemispheric locus of CA, it is generally accepted that CA is more frequently associated with parieto-occipital lesions (De Renzi, 1982), although it can also be observed in patients with frontal lesions. As in the case of the left-right issue, it has been argued that lesions with different intrahemispheric loci give rise to qualitatively different types of constructional disabilities. Luria and Tsvetkova (1964), for example, proposed that CA in patients with posterior lesions (parieto-occipital) is caused by a defect in the analysis of spatial relations whereas a deficit in movement planning could underlie apraxia of frontal lesion origin. A series of studies seems to confirm on the one hand, the role of caudal regions (predominantly right hemisphere) in visuospatial analysis and on the other hand, the role of the frontal lobes in the programming of drawing (see Gainotti, 1985, for a review). The first study that simultaneously verified both hypotheses and demonstrated a double dissociation between the behaviour of patients with anterior and posterior lesions was that of Pillon (1981). Pillon observed that patients with posterior lesions, whether left- or right-sided, performed better on copying tasks when provided with visuospatial reference points. On the other hand, the copying performance of patients with anterior lesions was facilitated by the provision of a copying plan. It should be noted that the guided copying task in this study is extremely similar to Hecaen et al.’s copying task, although the goal here is different (to facilitate the processing of an executive plan); yet Pillon’s study does not support the interhemispheric theory More recent data fail to support the crucial role of intrahemispheric localisation in determining the nature of CA. Kirk and Kertesz observed no difference between the performances of patients with anterior and posterior lesions in free-drawing tasks (1989) and likewise for those with cortical and subcortical lesions (1993). Similarly, Marshall et al.

(1994) observed that constructional disabilities in a series of patients with focal right hemisphere damage were, as a rule, associated with hemiinattention in the case of posterior lesions while subcortical anterior lesions gave rise to a disability regardless of the presence or absence of hemi-inattention. A different approach to constructional disabilities has aimed to establish whether focal brain damage alters constructional strategies. The first formalised observations of copying performance were those of Osterreith (1944) who presented brain-damaged patients with the Rey figure. It has been asserted that observation of copying strategies in certain patients reveals the presence of a constructional disability more effectively and accurately than analysis of the final result. Semenza et al. (1978) noted that right and nonaphasic left hemisphere patients tended to use a global strategy, similar to that adopted by “normal” subjects in copying tasks, whereas left hemisphere aphasics, in the absence of an adequate self-generated plan, used a more analytical strategy, copying the model piecemeal. A study by Binder (1982), in which the Rey figure was used as a model, contradicts these observations. Binder demonstrated that control subjects tended to use a global strategy while those with right- and leftsided lesions broke the task down into successive steps. Analogous results have been obtained by Trojano, De Cicco, and Grossi (1993) who asked a group of patients without severe constructional disabilities to copy the Rey complex figure. This study confirmed that regardless of the lesion locus, brain-damaged patients adopt a line-by-line copying strategy, in response to the difficulties posed by the task. An alteration in drawing strategies (i.e. in planning the copy) is therefore not sufficient to induce a constructional disability; other cognitive anomalies (e.g. visuoperceptual, general intellectual or spatial position coding and so on) have to be present to determine a clinical picture of CA. Studies of the link between CA and diffuse cognitive deficits also merit a glance. As the previous discussion suggests, general intellectual deterioration has been attributed a causal role in the etiology of constructional disabilities in patients

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with focal brain damage because apraxic patients often show intellectual abilities that are inferior to those of nonapraxic patients with focal lesions (Arrigoni & De Renzi, 1964). Adding weight to the argument, several studies have noted that the presence of apraxia represents an index for diffuse cognitive deterioration, especially in left braindamaged patients (Borod et al., 1982). On the other hand, CA is considered one of the most common behavioural alterations in Alzheimer’s disease (see Fig. 19.2). For a long time it has been noted that constructional disabilities are present in the early stages of Alzheimer’s disease and become more prominent as the illness progresses (Ajuriaguerra et al., 1960). A recent piece of research by Kirk and Kertesz (1991) demonstrates that the drawings of Alzheimer’s patients contain simplifications, fewer angles, spatial alterations, and a lack of perspective; together, these characteristics do not constitute the type of drawings typically produced by left or right hemisphere patients. Furthermore, patients’ scores on this task do not correlate with performance on language or memory tests, suggesting that constructional disabilities develop relatively independently during the course of the illness, although it should be remembered that there are cases of individual patients in the advanced stages of Alzheimer’s disease who do not have constructional disabilities (Denes & Semenza, 1982). One particular constructional anomaly noted in the drawings of demented patients is the tendency either to overlap the copy with the model, reproducing the original using its parts as a reference point, or to trace the pencil over the lines of the model, producing a scrawl (see Fig. 19.3). This phenomenon, termed “closing-in”, was first described by Mayer-Gross (1953) and since then has often been reported in demented patients (Ajuriaguerra, Muller & Tissot, 1960; Gainotti, 1972), but rarely in patients with focal lesions. Gainotti (1972) observed closing-in in only 15 of a series of 200 patients with focal lesions. Some writers regard this phenomenon as a primitive trigger reflex in patients with diffuse cognitive deterioration (Gainotti, 1972), while others suggest that closing-in occurs when patients who are unable to structure an empty space look for a reference

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point to solve difficult constructional dilemmas (De Renzi, 1959). Recently, it has been confirmed that the presence of this phenomenon in the course of dementia syndromes is consistent with a diagnosis of “primary degenerative type” (Gainotti et al., 1992).

One constructional task in particular: Drawing Two points emerge from this brief review of the literature. First, even though CA is a symptom that is recognisable by the administration of simple tests—even at the patient’s bedside—clinical and experimental studies have nonetheless failed to generate a homogeneous picture of its various facets. One thing that seems certain is that the incidence of CA in patients with left and right hemisphere lesions is more or less similar, and that other cognitive disorders (e.g. hemi-inattention, visuoperceptual and general intellectual deficits) can interfere with the execution of a constructional task. The nature of CA and the presence of qualitative inter- and intra-hemispheric differences are issues that remain open to discussion. Second, the study of CA is becoming more directed towards an analysis of drawing processes. Almost all the studies cited in this review have employed graphomotor tasks, probably because they are versatile, easy to carry out and to score, although it is also plausible that the heterogeneity of constructional disabilities (and the theory’s lack of defining power) have urged various researchers to focus their attention on one constructional skill in particular. As a result, drawing disabilities have become considered as constructional disabilities per se. This implicit decision has paved the way for substantial changes in approaches to the study of CA. Rather than proceeding from an operational definition of constructional abilities, a specific cognitive skill—drawing—has been taken as a starting point and researchers have tried to identify the individual processes that contribute to its execution. The traditional approach proceeded from an analysis of the correlations between various visuoperceptual, executive, and constructional tasks without looking for clear relationships between the performance of subjects on specific tests and their constructional abilities. This has

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been superseded by attempts to apply cognitive neuropsychological principles to drawing, as in other cognitive domains, i.e. reading, writing, visual recognition, and so on. One of the first cognitive models of drawing was proposed by Roncato et al. (1987). According to them, the copying of a figure comprises four basic stages: two preparatory stages (exploration of the model and preparation of the drawing plan), execution, and checking. These operations are probably hierarchically organised and each stage in turn consists of a series of substages. The preparatory phase involves the processing of an internal representation of the model, which guides copying. This representation contains specifications of global form, the constituent parts of the stimulus, its details, and their spatial relationships. The

FIGURE 19.3

Closing-in phenomenon: (a) the patient produced a scrawl over the model; (b) the patient overlapped the copy with the model, taking the original as a reference point.

preparation of a drawing plan implicates decisions concerning the scale and the positioning of the copy. The executive stage starts with decisions about the initial shape of the drawing and proceeds in accordance with the drawing plan. Checking processes perform comparisons between the copy and the stimulus, allowing the copying process to proceed while making corrections if necessary. Roncato et al. have also designed a series of tests which provide an insight into the various stages of copying and therefore permit identification of the defective cognitive process in a particular patient. The test battery uses two simple geometric forms as stimuli in a series of tasks: copying, drawing from verbal description, assembly of a requested shape, visual comparison, and comparison of a picture with a sentence that describes it. The final test requires

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the patient to decide if two sentences describe the same spatial arrangement of shapes (e.g. the circle is on the left of the square; the square is on the right of the circle). Using this battery, Roncato et al. have identified a patient with a specific deficit at the level of internal representation and a patient with a specific disorder at the executive level. Another cognitive model of drawing has been proposed by van Sommers (1989). This model sees the internal representation of a percept or mental image as the starting point for its graphic representation. The key moment in the planning of a drawing is the stage of depiction decisions and processes, where a person decides how to draw the object represented in short-term visual memory; decisions at this stage include: variety of object (e.g. an open or closed umbrella), two- or threedimensionality, orientation, level of detail and so on. Having made these decisions, the drawing is planned (a drawing strategy is selected, i.e. which parts will be drawn first and which later) taking into account the individual’s drawing ability and properties of the graphic motor system (the greater ease with which certain movements, motor routines etc. are carried o u t). One of the most interesting aspects of this model are the links between the imagery system and the semantic system. Van Sommers underlines that some forms of constructional apraxia can be limited to free-drawing and related to alterations at the level of mental representation (so-called “visuoimaginative apraxia”, Grossi et al., 1986, 1989) or specific defects at the depiction decisions and processes stage. The latter clinical picture, characterised by an intact ability to generate mental images and a selective inability to carry out spontaneous drawing, was reported in van Sommers’ (1989) patient. A final model of the mental processes involved in drawing has been described by Grossi and Angelini (Grossi, 1991). They also distinguish four sequential steps in copying tasks: preliminary analysis, central processing, execution, and checking. Preliminary analysis consists of a search for an interpretative hypothesis of the model: on the one hand, the individual tries to identify in the stimulus objects that have already been drawn in the past, and at the same time he or she analyses

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the spatial relationships between elements of the picture and those between the picture and the paper on which it is drawn (orientation, size etc.). In this initial phase, there is an interaction with long-term memory because in interpreting the picture, the individual activates visual, spatial, and constructional knowledge (there may also be a long-term store for familiar constructional schema, a so-called “constructional lexicon”). The elements identified by preliminary analysis, are then processed in order to formulate a drawing plan (the complex of instructions that are subsequently transformed into graphics). The drawing plan, the fruit of central processing, results from a series of procedural decisions concerning what to draw first, where to start, the order in which sucessive parts are drawn and so on. The plan is preserved in a short-term memory buffer for as long as is necessary to complete its translation onto paper via the activation of motor programmes. Grossi and Angelini propose two copying procedures: a “lexical” route which predominantly involves activation of familiar visual or constructional schema (for example in the drawing of a square or a face) and a second “line-by-line” procedure, based on a spatial analysis that doesn’t use constructional representations (activated when copying a doodle, for example). Both procedures may be adopted for copying complex pictures, but some patients might be constrained to use either one or the other. Here, the reader is reminded of the slow, slavish “line-by-line” copying procedure adopted by visual agnosic patients (Wapner, Judd, & Gardner, 1978), who perhaps cannot access the lexical route for familiar objects. On the contrary, a patient has recently been described who successfully uses the lexical route in simple drawing tasks but is unable to activate spatial analysis for more complex tasks, producing pictures with distorted spatial relationships (Grossi et al., 1996). The diagnosis of a cognitive defect at the heart of a constructional disorder is therefore possible via a specific test battery that has recently published (Angelini & Grossi, 1993) and which explores the various stages involved in copying. The aforementioned models distinguish some fundamental stages in the process of drawing.

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TABLE 19.1 Summary of the cognitively oriented models of drawing. R o n ca to et al. (1 9 8 7 )

van Som m ers (1 9 8 9 )

Visual exploration of the model - Elaboration of internal representation Preparation of the drawing plan

G rossi a n d A n g e lin i (1 9 9 1 )

Preliminary analysis - Activation of long-term memory systems (Constructional lexicon) Depiction decision

Preparation of the drawing plan

Elaboration of the drawing plan Executive processes

Executive processes

Control processes

There are certain parallels (see Table 19.1) between them, although they are differentiated in terms of their formal characteristics, depth of analysis, and in certain theoretical aspects. None of them has, at present, received general acceptance, in the absence of adequate clinical and experimental proof. In particular, the heuristic value of each model (its ability to interpret the errors made by patients and to predict the various symptomological permutations that are classed as drawing disabilities) has yet to be demonstrated. In the past, it was said that the study of CA, in view of its great complexity, could not contribute

Executive processes Control processes

to an understanding of the organisation of spatial abilities in the brain (De Renzi, 1982). Nonetheless, having abandoned the traditional operational definition of CA—leaving room for diverse interpretations of constructional tasks and disabilities— the cognitive approach seems to offer new hopes for an improved theory. In fact, by focusing attention on a single constructional task and developing more systematic, theoretically driven assessment techniques it may be possible to increase the defining power of interpretative hypotheses and to resolve many unanswered questions.

Part VI

Spatial Disorders

Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

20 Visuospatial and Imagery Disorders Paolo Nichelli

Different spatial strategies are used in everyday life, concurrently or one after the other. Specially devised experimental procedures force subjects to use a specific strategy, or they can reveal which strategy subjects have spontaneously chosen to solve a given problem. As an example, in Acredolo’s Test (1976) children are brought into a nondistinctive room with a door and a window on two opposite walls and a table along the third wall. They are walked to a comer of the table and then blindfolded. While blindfolded they are walked around back and forth to the door and to the window. Then the blindfold is removed and they are asked to return to the spot of the room where they were when they were blindfolded. Unknown to the children, sometimes the table has been moved. Acredolo (1976) demonstrated that 3-yearold children, when the blindfold is removed, turn in the same direction in which they had turned previously to get the table: i.e. they use a position response. Older children use a cued response and it is only after 6 years of age that children can use place responses, i.e. they can reach the starting point, independently of any movement of the table.

The concept of “space” is a very complex one. Spatial activities have been classified according to different criteria. O’Keefe and Nadel (1978) divided them based on sensory-motor responses that people makes when they move around in their environment. In position (or egocentric) responses subjects use their body as a reference. These responses include acts such as turning to the right or left, and moving limbs or body parts. Only kinestesic and vestibular information is needed to perform these actions (Potegal, 1982). Once the movement is learned, it is performed almost automatically, without conscious monitoring. Cued responses are movements guided by an external cue. They include walking to or away from objects, and following sounds or odours. These responses are guided by stimulation gradients: sounds get louder and odours more intense when approached. Place responses are movements directed by mutual relationships between external references. A common example is that of a person who has parked a car in an empty parking lot and wants to find it in the same lot, which is now full of cars. 453

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Spatial behaviour can be further classified by considering the space around the subject as consisting of three functionally different “subspaces” (Griisser, 1987): the body surface, the grasping space, and the distal space. The latter goes beyond the grasping space and also include the time space (past and present) and the order space (the sequence in which events happen). Each of the different spatial strategies we have described earlier (position, cued, and place responses) can be used for operation in each subspace. Classification of spatial behaviour into strategies and subspaces can help us to better understand the complex nature of space and can allow us to break down the disorders of spatial cognition into its constituent parts. Furthermore, even if we are far from knowing the neural representation of different subspaces and strategies, we might argue that different operations correspond to distinct neural representations. Neuropsychological analysis discriminates between spatial perception, spatial memory, and visuo-motor coordination disorders. In this chapter we will analyse different aspects of spatial cognition from a clinical perspective. For this reason, besides examining spatial disorders in isolation, we have devoted special sections to complex clinical syndromes (e.g. Balint-Holmes and Right Hemisphere Developmental Learning Disorder). A section on visual imagery disorders has been added because their neurophysiological mechanisms are at least partly common to those subserving visuospatial disorders.

SPATIAL PERCEPTION AND ITS DISORDERS With the term “spatial perception” we refer to the analysis of spatial relationships both between stimulus and observer and between different stimuli. Spatial information can be obtained through various sensory modalities. Furthermore, specific spatial abilities (e.g. stimulus localisation, judgement of line orientation, depth perception) can be selectively impaired after neurological damage.

Visual perception Current theories maintain that visual information follows two distinct pathways: the occipitotemporal (ventral) pathway which conveys information about shape and patterns, and the occipito-parietal (dorsal) pathway which is involved in spatial analysis. Evidence for the ventral/dorsal pathway distinction comes both from behavioural studies on monkeys with selective cortical lesions (Ungerleider & Mishkin, 1982), from intracortical recording (Desimone & Ungerleider, 1989; Maunsell & Newsome, 1987), and from a double dissociation between object recognition and spatial perception deficits in patients with selective cerebral lesions (Newcombe, Ratcliff, & Damasio, 1987). From a clinical standpoint occipito-temporal lesions cause visual agnosia (failure of object recognition), prosopagnosia (face recognition deficit), and acromatopsia (colour blindness). On the other side, occipito-parietal lesions are associated with visuospatial neglect, optic ataxia (visuomotor incoordination), constructional apraxia (deficit in assembling, building, and drawing), gaze apraxia (inability to plan ocular movements to targets), and akinetopsia (motion perception blindness). Neuroimaging studies have provided further evidence that ventral and dorsal pathways have distinct functions. Haxby and colleagues (1991, 1993) measured regional cerebral blood flow (rCBF) with Positron Emission Tomography (PET) while subjects performed face identity and spatial position matching-to-sample tasks (Fig. 20.1). Within the occipitotemporal cortex, areas in the posterior and mid-fusiform gyrus (Brodmann areas 19 and 37) were selectively activated by the facematching task. Within the occipitoparietal cortex, areas in the dorsolateral occipital cortex (Brodmann area 19), superior parietal cortex, and the cortex near the fundus of the intraparietal sulcus (both Brodmann area 7) were selectively activated by the location-matching task. Furthermore, in a recent PET study on chess players (Nichelli, Grafman, Pietrini, Alway, Carton, & Miletich, 1994) cortex was activated when subjects were requested to judge the relative distance of chessmen on the chessboard. In both

20. VISUOSPATIAL AND IMAGERY DISORDERS 455

FIGURE 20.1 Cortical regions of the dorsal and ventral streams that are selectively activated by perception of face or location. The numbers in symbols refer to the PET study reporting each activated focus: (1) face and location matching to sample (Haxby et al., 1993); (2a) gender discrimination and (2b) face identity (Sergent et al., 1992); (3) shifting attention to spatial locations (Corbetta et al., 1993); (4) spatial working memory (Jonides et al., 1993). (Figure modified from Ungerleider & Haxby, “What and “where” in the human brain. C urrent O pinion in Neurobiology, 4 , 157-165).

PET studies occipitoparietal cortex was bilaterally activated. However, in Haxby et al.’s study (1993, 1991) the right side was more activated than the left while the opposite was true in Nichelli et al.’s (1994) study. Relative hemisphere specialisation in a PET activation study might depend on both practice effects and specific cognitive strategies adopted by subjects. In the current wisdom the right hemisphere plays a crucial role in visuospatial tasks. However, there are instances of visuospatial tasks in which the left hemisphere appears to be more important than the right one (Kim, Morrow, Passafiume, & Boiler, 1984; Mehta, Newcombe, & Damasio, 1987; Metha& Newcombe, 1991). More specifically, Kosslyn et al. (1989) demonstrated that spatial categorical judgements (on/off, left/right, above/below) are faster when stimuli are presented to the left hemisphere, while judgements in terms of visuospatial coordinates (evaluations of distance) are faster when stimuli are presented to the right hemisphere. Accordingly, Laeng (1994) showed that right brain-damaged patients are selectively impaired in tasks requiring judgements in terms of visuospatial coordinates, while left brain-damaged patients have difficulties in categorical judgements that are independent from their language deficit. Stimulus localisation, perception of line orientation, and depth perception are different

aspects of visuospatial perception that can be selectively impaired after brain lesions. We will discuss each of them separately. Stimulus localisation Different methods have been proposed to examine this aspect of visuospatial perception. Warrington and Rabin (1970) presented two cards, either simultaneously or in succession, and asked subjects to evaluate whether the position of a dot in the two cards was the same or different. Hannay, Varney, and Benton (1976) projected on a screen one or two dots for 300ms and, after a two-second delay, presented a display with 25 numbers that identified the positions where dots could have appeared: the subject’s task was to read aloud the numbers corresponding to the dots. Faglioni, Scotti, and Spinnler (1971) required subjects to reproduce the position of a number of small crosses with paper and pencil, a task that also involves an executive component. Patients with right posterior hemisphere lesions were found to be mostly impaired with all these procedures. However, it is difficult to rule out errors in spatial localisation depending on visuospatial neglect, a disorder that is particularly frequent in right brain-damaged patients and that can apparently cause a globally distorted space representation (Nichelli, Rinaldi, & Cubelli, 1989).

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Perception o f line orientation Single cell recording studies (Hubei & Wiesel, 1959) have shown that area 17 contains neurones selectively responsive to linear stimuli with a given orientation. In humans there is large evidence that the right hemisphere can discriminate line orientation better than the left hemisphere (Umiltà et al., 1974). In the same line, De Renzi et al. (1971) observed a strong association between right hemisphere damage and inaccuracy in setting a rod at an oblique angle to match a standard. A similar predominance of right hemisphere deficit was found on a simpler task requiring same/different judgement of slope, without an overt motor component (Warrington & Rabin, 1970). The most used approach to this aspect of visuospatial perception is the test devised by Benton, Varney, and Hamsher (1978a), which requires subjects to identify the orientation of a pair of lines on an 11-line multiple choice display (Fig. 20.2). About 50% of right brain-damaged patients fail at this task, while only 10% of left brain-damaged patients show defective scores (Benton, Hamsher, Varney, & Spreen, 1983; Hamsher, Capruso, & Benton, 1992). Accordingly, it has been demonstrated that normal subjects performing this

FIGURE 20.2

Judgement of line orientation (Benton et al., 1983). Example of double-line stimuli.

task show a significant increase of cerebral blood flow in the right temporo-occipital region (Hannay, Falgout, Leli, Katholi, Halsey, & Wills, 1987). As a consequence of the functional reorganisation after brain damage, line orientation perception can get better as a function of time elapsed after an acute brain lesion. Indeed, Metha (1987) demonstrated that soldiers with a right focal, unilateral, missile injury of the brain which occurred more than 20 years before testing are not impaired at this task with respect to the control group. After such a long distance from injury, only left hemisphere damaged subjects perform at the task significantly worse than controls. Normative values of the Benton et al.’s line orientation task are available for both adults (Benton et al., 1983) and children (Lindgren & Benton, 1980; Riva & Benton, 1993; Riva, Pecchini, & Cazzaniga, 1986). Performance at this test shows a slight decline with age, most noticeably after 65 years old (Eslinger & Benton, 1983; Mittenberg, Seidenberg, O’Learly, & DiGiulio, 1989). However, a group of well educated elderly people scored well within the normal range until after age 75 (Benton, Eslinger, & Damasio, 1981). On the contrary, most dementia patients fail this test, many receiving scores in the severely defective range (Eslinger & Benton, 1983; Ska, Poissant, & Joannette, 1990). Depth perception It has been long known that a lesion in the visual cortex can selectively impair the ability to see objects in depth. Riddoch (1917) described a patient who had an “inability to appreciate depth or thickness in objects seen ... The most corpulent individual might be a moving cardboard figure, for his body is represented by an outline only. He has color and light and shade, but still to the patient he has no protruding features: everything is perfectly flat” (quoted by Zeki, 1993, p.282). Depth vision is obtained from a number of both monocular and binocular (Livingston & Hubei, 1988; Parker, Cumming, Johnston, & Hurlbert, 1995) sources. Monocular cues include apparent size of familiar objects, texture and brightness gradients, linear perspective, occluding contours, shading, and monocular parallax (i.e. the ability to

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analyse disparate retinal images successively produced by the same object on the retina). Stereopsis is the ability to discriminate depth based on binocular information. Following the fact that our eyes are located in the frontal plane, monocular visual inputs are partially overlapping. As a consequence, the two retinas receive slightly different images of the word. The angular difference of a retinal image with respect to the fovea is called retinal disparity or binocular parallax, and contributes to depth perception. In Fig. 20.3 all points in the object space passing through the focal point “X” fall on corresponding retinal elements and thus are seen as single. The geometrical locus of all these point is a curved surface called “horopter”. Objects closer than the horopter have a crossed disparity (i.e. you must cross your eyes to fixate them). On the contrary, convergence is relaxed to view objects beyond horopter, which are said to have uncrossed disparities. Stereoacuity of about 10” is commonly observed in normal subjects. Back to Fig. 20.3, differences between oil (or (3l ) and ocr (or (Jr ) of 10” are usually large enough to determine depth perception The Titmus Test (Titmus Optical Co., Petersburg, Virginia, USA) is one of the most common tests to assess stereoacuity. It presents horizontally offset stimuli which reflect polarised light in orthogonal directions. With appropriately polarised lenses, different images are transmitted to each eye and the subject can view the stimulus (a circle) on a closer plane with respect to the background. Target stimuli have graded disparities. However, the first three circles on the test are easily distinguished from the background because they look fuzzy. As a consequence, this test tends to yield better than real stereoacuities. A different approach involves using Julez’s random dot stereograms (1971). Each stereogram consists of a pair of computer generated arrays of black dots. They only differ in a group of dots in a geometric form that have been shifted by a precise amount with respect to the identical random sequence in the other member of the stereopair. When viewed stereoscopically, the geometric form is seen above or below the plane of the random background.

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Note that the processes examined by stereoacuity and random dot tasks are different. The Titmus Test, as well as similar tests requiring depth evaluation of well defined patterns, involves a mechanism of local stereopsis by which depth information is extracted on the basis of a dot-bydot comparison. Random dot stereograms, on the contrary, involve global stereopsis, a process by which one set of matched pairs of dots is selected based on their depth value as the only one providing the recognition of a three dimensional form. Global stereopsis can be assessed by the TNO Test for Stereoscopic Vision (Laméris Instrumenten b.v., Utrecht, The Netherlands). Neurones tuned to different disparities have been found in many cortical visual areas of the

FIGURE 20.3

Schematic drawing illustrating retinal disparity (also called binocular parallax) for objects in two different locations (A and B) with respect to the “horopter” (i.e. the curved surface passing through the eyes and the fixation point). (Figure adapted from Maffei & Mecacci, La visione: dalla neurofisiologia alla psicologia, Milano: Mondadori, 1979, p.77.)

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monkey and especially in VI (Poggio, 1984), V2 (Hubei & Livingstone, 1987), V3, and V3A (Poggio, Gonzalez, & Krause, 1988; Zeki, 1978). More recently, neurophysiological studies (summarised by Sakata et al., 1997) have revealed that the parietal association cortex also plays a crucial role in depth perception. Different classes of neurones have been identified, covering various aspects of depth perception. Some of these neurones are axis-orientation-selective or surfaceorientation-selective and are sensitive to binocular disparities. They are located in the caudal intraparietal sulcus and represent the 3-D orientation of the longitudinal axes and flat surfaces, respectively. Different visual fixation neurones are depth-selective. They are located in the inferior parietal lobule and represent egocentric distance. Cowey and Porter (1979) demonstrated that removing the lateral surface of VI representing macular vision, or the corresponding part of V2, greatly elevated stereoacuity thresholds while leaving global stereopsis intact. Conversely, bilateral temporal lobe damage impairs global stereopsis, as measured by varying the binocular correlation of stereograms, or by keeping it constant and varying the disparity, size, number, and orientation of the elements. Several clinical studies (Benton & Hecaen, 1970; Carmon & Benton, 1969; Hamsher, 1978) demonstrated that patients with right rather than left hemispheric lesions have greater difficulties in perceiving random dot stereograms. In agreement with a right hemisphere superiority for global stereopsis, random dot stereograms are better recognised in the left visual field (i.e. by the right hemisphere) of normal subjects (Durnford & Kimura, 1971; Grabowska, 1983). However, no hemispheric difference was detected in a sample of patients with selective temporal or frontal lobectomy (Ptito & Zatorre, 1988). In contrast, studies aimed at examining local stereopsis yielded conflicting results. Hamsher (1978) reported impaired global stereopsis in the presence of intact local stereopsis in right hemisphere damaged patients. However, Ross (1983) found that right hemisphere damaged patients demonstrate significant impairment of both

types of stereopsis. Rothstein and Sacks (1972) found that greater impairment in performance on the Titmus test was associated with unilateral parietal lesions on the left rather than on the right side, while Lechman and Walchli (1975) found no significant difference between right and left hemisphere groups on the same test. According to more recent and thorough clinical studies (Rizzo, 1989; Rizzo & Damasio, 1985) stereoacuity is reduced by lesions of either the left or the right visual cortex. However, the highest degree of impairment is always associated with bilateral damage of the superior part of the visual associative cortex (Brodman’s area 18 and 19). Neuroimaging studies (Gulyas & Roland, 1994; Nagahama et al., 1996; Ptito, Zatorre, Petrides, Frey, Alivisatos, & Evans, 1993) support the notion that discrimination of pure disparity information is dependent on a network involving the polar striate cortex and the neighbouring peristriate and parietal cortex. The right striate and peristriate visual areas seem to play a special role in some stereoscopic discrimination tasks (Nagahama et al., 1996; Ptito et al., 1993). The corpus callosum also seems important for processing depth information derived from binocular cues, especially when largely disparate stimuli presented on each side of the vertical meridian must be compared rapidly. However, patients with a complete section of the callosum (a surgical procedure to prevent spreading of epileptic seizures) can still perform binocular tasks during prolonged viewing (Lassonde, 1986). This further demonstrates that each hemisphere has stereoscopic abilities (Gazzaniga, Bogen, & Sperry, 1965). In contrast, acallosal patients cannot apparently take advantage of interhemispheric comparison of depth using relative motion: they have impaired motion parallax when relative motion is extracted from different hemifields (Rivest, Cavanagh, & Lassonde, 1994).

Tactile perception Several studies demonstrate that even without vision it is possible to develop a normal ability to create and manipulate spatial representations of objects (Landau, 1986, 1991; Ruff, 1978). Indeed, we can perceive tactile spatial patterns by means

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of both active exploration (haptic perception) and simultaneous stimulation of different portions of the skin surface (passive touch). Please refer to Kennedy (1978) for an exhaustive discussion of the distinction between passive touch and haptic perception. The issue of side differences in the analysis of basic aspects of touch is still under discussion. In a thorough review of the problem, Corkin (1978) concluded that there are no convincing data demonstrating side differences on pressure and vibration thresholds, two-point discrimination, and tactile point localisation. However, a series of investigators have indicated a left hand superiority in point localisation (Benton, Levin, & Varney, 1973; Carmon & Benton, 1969; Varney & Benton, 1975) and in reproduction of spatial location in the kinesthetic modality (Roy & MacKenzie, 1978). It has been also noted that the left hand is better in analysing complex spatial information. Evidence for this claim derives from studies involving Braille reading. Braille letters are patterns obtained by numerical and spatial permutations of six embossed dots, each with its own unique meaning. In these experiments, a reliable left hand/right hemisphere advantage is typically observed for Braille letter learning (Rudel, Denkla, & Splaten, 1974) as well as for reading speed and accuracy (Harris, 1980; Hermelin & O’Connor, 1971; Mommers, 1980; Rudel, Denkla, & Hirtsch, 1977). Such effects are manifest in both in normal and blind subjects. A recent PET study in seven blind subjects demonstrated that, irrespective of the reading finger, the primary visual cortex, the left lateral occipital cortex extending into the temporooccipital junction, and the left supramarginal gyrus are consistently activated during a lexical discrimination task (Sadato et al., 1995). Occipital lobe activation was also obtained in congenitally blind subjects with no exposure to visual stimulation. Accordingly, transient transcranial magnetic stimulation of the visual cortex (Cohen et al., 1997b) induced errors and distorted tactile perceptions in people who have been blind from an early age as they are trying to identify Braille or embossed Roman letters. It is suggested that somatosensory input can be redirected into primary visual cortex to allow spatial discrimination of the

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patterns that constitute Braille letters. In the PET study by Sadato et al. (1995), coactivation of the lateral occipital cortex (Brodman’s area 18/19) and the association sensory area (area 7) on the same side, was particularly prominent with index finger reading, a finding that can be interpreted as the functional neural correlate of the better proficiency of the right hemisphere in analysing the spatial distribution of embossed dots that constitutes Braille letters. To avoid the confounding effects of linguistic and symbolic factors with spatial factors that is typical of Braille reading, Dodds (1978) investigated hand differences at tasks requiring discrimination and multiple choice recognition of tactile nonlinguistic stimuli. Witelson (1974) studied the same problem with a “dichaptic” procedure which requires the simultaneous stimulation of the two hands with different stimuli. Both the unimanual and the dichaptic procedure confirmed that left hand/right hemisphere is significantly more proficient in analysing nonlinguistic (unfamiliar, meaningless) shapes (Dodds, 1978; Kleinman & Cloninger, 1973; Witelson, 1974), in discriminating line orientation (Benton, Varney, & Hamsher, 1978b; OscarBerman, Rehbein, Porfert, & Goodglass, 1978), and in enumerating embossed dots patterns (Young & Ellis, 1979). In contrast, right hand/left hemisphere is superior for tactile identification of “easily namable” geometric figures (Kleinman & Cloninger, 1973) and letters (O’Boyle, Van WyheLawler, & Miller, 1987; Oscar-Berman et al., 1978). Yandell and Elias (1983) have argued that the typical left hand/right hemisphere advantage with visuospatial tactile information can only be observed when the task is made more difficult. However, Nachson and Carmon (1975), using a vibrotactile stimulation task, reported a left hand/right hemisphere advantage for the identification of spatial patterns of stimulation and a right hand/left hemisphere superiority for the perception of the same patterns through sequential stimulation. O’Boyle et al. (1987) maintained that it is the process and not the categorical nature of the stimuli that dictates the magnitude and direction of tactile asymmetry. Whenever spatial factors (like

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directionality, orientation, and configural relationships) are critical to accurate identification, the right hemisphere exhibits superior tactile processing even for ostensibly verbal material. The clinical consequences of the hemisphere asymmetry on tactile spatial tasks is the right braindamaged patients’ impairment in blindfold line orientation judgement (Carmon & Benton, 1969; De Renzi et al., 1971; Fontenot & Benton, 1971) and three-dimensional shape recognition (De Renzi & Scotti, 1969). The frequent occurrence of patients with right hemisphere injury with defective performance on both visual and tactile spatial tasks is strongly suggestive of a supramodal spatial role of the right hemisphere. However, it is also possible that spatial analysis can be accomplished at least in part independently by each sensory modality. In this case the co-occurrence of spatial deficits in different modalities might be due to anatomic contiguity of brain areas devoted to spatial analysis in the visual and in the tactile modality.

Auditory perception Unlike what occurs for touch and vision, spatial information in the auditory domain is not topographically represented on peripheral receptors (i.e. at the cochlear level). In the mammalian cochlea, sensory cells are filters arranged along a frequency axis: different frequencies of sound are encoded to different regions of the cochlea. As a consequence, sound source localisation must be derived computationally by the brain using spatial cues that are generated by the acoustical properties of the ears and head (King & Carlile, 1995). For a sound source located off midline, the difference in path lengths to each ear will give rise to a difference in time of arrival of the sound: interaural time difference (ITD), whereas the acoustic shadow cast by the head produces an interaural intensity difference (IID). As the head is a most effective acoustic obstacle for highfrequency sounds, IIDs are mostly used to determine sound localisation at these frequencies. In contrast, ITDs appear to be restricted to lowfrequency sounds. There is substantial psychophysical (Middlebrooks & Green, 1991) and physiological (Irvine, 1992) evidence consistent with this so called “duplex theory” of sound

localisation. Besides binaural information, monaural cues (i.e. spectral transformations provided by the outer ear) are also involved in determining the location of a sound source on the midsagittal plane or in localising sounds under monaural listening conditions. The position of a sound in space is topographically encoded by the central nervous system in an analogic fashion as demonstrated by electrophysiological studies (Palmer & King, 1982) and by measurements of the time to move auditory attention from one location to another (Rhodes, 1987). The ability to localise sound sources is acquired by infants as early as 4 months old (Walsh, 1957). In adults with normal hearing accuracy it ranges from 1° to 17° depending on the position of the sound source. Convergence of information from the two ears first occurs in the nuclei of the brainstem, where the initial processing of ITD and IID takes place (Irvine, 1992). The position of a sound in space is encoded in the deeper layers of the superior colliculus. However, despite a considerable amount of subcortical processing, in primates the pivotal role in ruling sound localisation behaviour is played by the auditory cortex (Clarey, Barone, & Imig, 1992). Thus, studies on animals demonstrate that unilateral auditory cortical lesions produce localisation deficits in the contralateral hemispace (Jenkins & Masterton, 1982). Also, lesions made in discrete isofrequency regions of the primary auditory cortex result in localisation deficits that are restricted to the frequencies deprived of their cortical representation (Jenkins & Merzenich, 1984). Measurements of sound localisation accuracy after brain damage have provided different results. According to Sanchez Longo and Forster (1958) patients with temporal lobe damage are mostly inaccurate in localising a sound source contralateral to the brain lesion. Shankweiler (1961), using the same method, was unable to replicate Sanchez Longo and Forster’s findings. An absence of selective contralateral impairment was also reported by Haeske-Dewick (1996), while Klingon and Bontecou (1966), with a simple bedside technique, found localisation errors in the field contralateral to the lesion, although with no clear

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association to the injury of a specific lobe. In a subsequent analysis of Klingon and Bontecou’s data, De Renzi (1982) demonstrated that sound localisation deficits are significantly more frequent after right than left hemisphere damage. A selective impairment of right brain-damaged patients was also reported by Ruff and Volpe (1981) in two tasks requiring pointing either to the loudspeaker producing the stimulus or to the midpoint between two loudspeakers sequentially delivering it. These findings are in agreement with results in normal subjects (Duhamel, Pinek, & Bruchon, 1986) that apparently identify spatial positions with greater homogeneity and stability in the left than in the right hemispace. In study of three hemispherectomised patients (Poirier, Lassonde, Villemure, Geoffroy, & Lepore, 1994) the patients’ responses were less accurate than controls’ in the hemifield contralateral to their removed hemisphere. Moreover, the performance obtained with fixed sound sources was generally more precise that those obtained with moving sources. The age at surgery and the post-surgical interval appeared to be related to the magnitude of deficits, thus suggesting the possible influence of functional reorganisation and cerebral plasticity.

OPTIC (VISUOMOTOR) ATAXIA Optic ataxia is an impairment of the ability to reach for visually presented stimuli, not related to motor, somatosensory, visual acuity, or visual field deficits. To detect subtle visuomotor ataxia, the symptom is to be tested by asking to reach for objects that require a precision grip, i.e. true opposition of thumb and index finger. In a clinical setting, examiners will hold between their index finger and thumb the borders of either a paper clip or a coin and will ask subjects to grasp the object. In the most severe cases, the disorder is also present when patients are fixating the object to reach. More frequently, the impairment is only apparent when the target is located at the periphery of the visual field or when patients are not allowed to observe the reaching limb (Levine, Kaufman, & Mohr, 1978; Perenin & Vighetto, 1988). Optic ataxia can

involve the whole visual field (bilateral optic ataxia) or only objects located in the half field contralateral to the damaged hemisphere (unilateral optic ataxia). Both bilateral and unilateral optic ataxia may affect both hands or only one hand. In direct ataxia the reaching disorder involves the hand homolateral to the examined hemifield, while in crossed ataxia the affected hand is contralateral to the examined hemifield. Rondot et al. (1977) have expounded the different forms of optic ataxia in disconnectionist terms, as shown in Fig. 20.4. According to this model, the connections between the occipital areas involved in visual perception and the frontal areas subserving motor programming are both direct and crossed. In unilateral direct visuomotor ataxia (Fig. 20.4, panel a), occipitofrontal connections are interrupted, causing an impairment of the contralateral upper limb in the visual field of the side opposite to the lesion. In the case of a unilateral crossed visuomotor ataxia (Fig. 20.4, panel b), only crossed occipitofrontal connections would be affected, while to determine bilateral crossed visuomotor ataxia the lesion should interrupt both crossed occipitofrontal connections at the level of the corpus callosum (Fig. 20.4, panel c). In order to test for misreaching, accuracy of precision grip needs to be examined in all possible combinations of the following experimental conditions: with each hand, with targets both in the centre of vision and in the periphery of the visual field, and both permitting the view of the moving arm (closed loop condition) and preventing it (open loop condition) by means of a screen. Furthermore, one should separately evaluate both the proximal component of the movement (the reaching or transportation phase) and the distal component of the movement (the grasping or manipulation phase). Perenin and Vighetto (1988) have proposed a task to discriminate the distal component. However, examining in detail both the transportation and the manipulation component usually requires video recording the movement and then analysing it frame by frame. Reaching and grasping are commonly considered the manifestation of two visuomotor channels respectively devoted to determining the target coordinates in a body-centred space and to

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FIGURE 20.4 Clinical varieties of visuomotor ataxia explained according to the visuo-motor disconnection hypothesis (Rondot et al., 1977). (a) unilateral direct visuomotor ataxia (impaired reaching of one hand in the homonymous field), (b) unilateral crossed visuomotor ataxia (impaired reaching of one hand in the opposite visual fiel). (c) Bilateral crossed visuomotor ataxia (impaired reaching of each hand in the opposite visual field). (Figure adapted from Rondot et al., Brain, 1 0 0 , 364,1977).

computation of shape, size, and weight of the target object (Jeannerod, 1988; Jeannerod, Arbib, Rizzolatti, & Sakata, 1995). Studies in monkeys have shown that specific brain lesions can alter one of these components without affecting the other (Brinkman & Kuypers, 1972). A unilateral leukotomy of the parieto-occipital junction in splitbrain monkeys determines a selective impairment of the distal component of the movement (Haaxma & Kuypers, 1974), while a larger posterior parietal lesion, including area 5 and 7 (Lamotte & Acuña, 1978) or limited to area 7 (Faugier-Grimaud, Frenois, & Stein, 1978) leads to a deficit of both the components. Also, developmental studies in human infants indicate that reaching and grasping do not mature at the same postnatal time and may remain rather independent from each other before they become fully coordinated (for a review see Jeannerod & Biguer, 1982). More recent electrophysiological studies in monkeys has been

interpreted (Jeannerod et al., 1995) as suggesting that the transformation of objects’ intrinsic properties into specific grips takes place in a circuit that includes the inferior parietal lobule and the inferior premotor area (area F5). Neurones in both these areas code size, shape, orientation of objects, and specific types of grips that are necessary to grasp them. Grasping movements appear to be coded more globally in the posterior parietal cortex, whereas they are more segmented in area F5. Explanation of optic ataxia as due to a disconnection of visual input from motor mechanisms involved in programming a reaching movement are tenable for those cases in which the disorder is limited to a specific combination of arm and half-field. However, evidence from neurophysiological and ablation studies in nonhuman primates (Hyvarinen & Poranen, 1974; Mountcastle, 1975) suggests that in most cases misreaching requires damage to cortical areas

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specialised in controlling the spatial coordinates of goal directed movements (Ratcliff, 1982; Riddoch, 1935; Rousseaux, Delafosse, Devos, Quint, & Lesoin, 1986). Also, it has been noted that optic ataxia patients show constant rather than random errors, i.e. they systematically deviate their pointing toward the side of the lesion, when they use their arm contralateral to the damaged hemisphere in the absence of visual feedback (Castaigne, Pertuiset, Rondot, & de Recondot, 1971; Garcin, Rondot, & De Recondo, 1967; Levine et al., 1978; Ratcliff & Davies-Jones, 1972). Systematic deviation of pointing following unilateral parietal lesion may reflect displacement toward a new position of the “egocentric” coordinates (Jeannerod, 1986). The notion of egocentric coordinates includes both the representation of target position with respect to the body, and the representation of the position of body parts with respect to the egocentre. It opposes that of “allocentric” coordinates, which correspond to position of the target on the retinotopic map. Indeed, optic ataxia is a direct demonstration of dissociation between the two systems of spatial coordinates because the patients with the purest instances of this symptom can correctly locate objects with respect to each other, but incorrectly locate them with respect to the body. According to a recent theory (Goodale & Milner, 1992) grasping activity defines better than anything else the function of the occipito-parietal visual pathway as opposed to that of the occipitotemporal pathway. In this view, separate processing modules have evolved not so much depending on input distinctions (e.g. object location versus object qualities, or “where” versus “what”) but mostly to mediate different uses of vision (i.e. prehension versus apprehension, “how” versus “what”, pragmatic versus semantic analysis). Goodale and co-workers have convincingly demonstrated a double dissociation between optic ataxia and form agnosia patients. Following bilateral parietal damage, optic ataxia patients had no difficulty in recognising line drawings of common objects although their ability to pick them up might be quite impaired (Jakobson, Archibald, Carey, & Goodale, 1991). On the other hand, patients with most severe visual-form agnosia following damage to the occipito-temporal pathway, despite their severe

inability to recognise the size, shape, and orientation of visual objects, could still show strikingly accurate guidance of hand and finger at the very same objects (Goodale, Milner, Jakobson, & Carey, 1991). The location of the lesion that is mostly associated to optic ataxia is the posterior parietal region. Electrophysiological studies have demonstrated that a number of neurones in the superior part of the posterior parietal lobe discharge when the monkey reaches out its limb for an object of interest, while other cells are active when the monkey makes finger movements to grasp the object (Hyvarinen & Poranen, 1974; Mountcastle, 1975). Within the posterior parietal cortex the location that appear to be critical in determining optic ataxia is the interparietal sulcus and the superior parietal lobule (Perenin & Vighetto, 1988; Pierrot-Deseilligny, Gray, & Brunet, 1986). This clinical finding is also supported by a recent functional neuroimaging study (Kawashima et al., 1995a) demonstrating that this region was bilaterally activated by reaching and grasping tasks. Interestingly, the typical lesion associated with unilateral spatial neglect involves the ventral portion of the inferior parietal lobule and the temporo-parieto-occipital junction (Heilman, Watson, & Valenstein, 1994; Vallar & Perani, 1986), a region that is close but distinct from that associated with optic ataxia. Indeed, optic ataxia and neglect are symptoms that can occur independently of each other. In agreement with these clinical observations, several data suggest that the posterior parietal cortex is composed of different modules with distinct functional caracteristics. Anatomical evidence both in humans (Eidelberg & Galaburda, 1984) and in monkeys (Pandya & Seltzer, 1982) shows that distinct regions have different connections and architectonics. Single cells recordings have demonstrated regional segregation of functionally distinct groups of neurones (Hyvarinen, 1982). Yet, there is wide overlap (Lynch, 1980). A better understanding of the functional role of different regions in the parietal lobe is hindered by difficulties in establishing the correspondence of the parcellation of this lobe in humans and in rhesus monkeys. Also, there is evidence of asymmetry

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(both anatomical and functional) in humans but not in monkeys. With regard to optic ataxia, also note that in monkeys the symptom is limited to the contralateral upper limb while in humans there is a difference depending on the side of the lesion. In the case of a right parietal lesion, ataxia involves both arms reaching for targets in the left visual field, whereas after a left parietal lesion the right hand shows defective visual guidance toward targets in both hemifields and the right hand (Perenin & Vighetto, 1988; Vighetto & Perenin, 1981). The extent of recovery of visual motor apraxia after an acute lesion is variable. A patient with bilateral parieto-occipital haemorrhages showed good clinical recovery from optic ataxia 17 months after the stroke. However, a detailed kinematic study (Jakobson et al., 1991) showed that the directional component of the movement was normal in a pointing task but severely impaired in a prehension task, in which reaching and grasping movements had to be integrated.

BÂLINT-HOLMES SYNDROME In its complete form Balint-Holmes syndrome consists of four symptoms: (1) gaze apraxia or defective visual scanning; (2) optic ataxia or defective visual reaching; (3) impaired visual attention; (4) defective estimation of distance and impaired depth perception. Balinfs (1909) and Holmes’s (1919) patients shared many symptoms but differed in one important respect, namely that oculomotor disturbances were not mentioned by Balint. For this reason we follow De Renzi’s (1985) advice of adding Holmes’s name to the eponym of the syndrome. Note, however, that the four symptoms are to a certain extent independent from each other, i.e. they can occur separately.

Gaze apraxia This is the inability to shift gaze so as to bring peripheral stimuli into fixation. Gaze apraxic patients can move their eyes in any direction, but they do it purposelessly. Thus, if they are asked to look at an object in the peripheral visual field, they stare open-eyed in a wrong direction, or they make

random saccades. When eventually they get to fixate the target, either they lose it very easily or they steadily maintain it without purpose (spasmodic fixation). Gaze apraxia is usually associated with defective fixation, impaired ocular pursuit, and faulty vergence movements. On the contrary, vestibulo-ocular reflexes and rapid eye movements during sleep are preserved (Girotti, Milanese, Casazza, Allegranza, Corridoni, & Avanzini, 1982). In some but not in all cases the oculomotor impairment has been also observed for saccades toward auditory, tactile, or proprioceptive stimuli. Gaze apraxia can sometimes occur in isolation (Cogan & Adams 1953; Waltz, 1961, case 2; Monaco et al. 1980). Mills and Swanson (1978) have reported a patient whose impairment was limited to vertical saccades (horizontal saccades and both random saccades and pursuit in all directions were preserved). There is also a congenital variant of ocular motor apraxia, first described by Cogan (1952, 1966). This abnormality is more frequent in males and is usually recognised in infancy when the child does not appear to fixate on objects normally. Within a few months, characteristic thrusting horizontal head movements appear, sometimes with prominent blinking, when the child attempts to change fixation. The head thrust probably reflects a compensatory strategy to facilitate gaze shifts. In a number of cases a genetic factor seems to be involved as suggested by reports of the disorder in identical twins (Robles, 1966), and in other children of the same family (Gurer, Kukner, Kunak, & Yilmaz, 1995; Moe, 1971). Patients with congenital ocular motor apraxia usually improve with age (Prasad & Nair, 1994) and the head movements become less prominent as the patients are better able to voluntary direct their eyes (Leigh & Zee, 1983). Balint-Holmes syndrome, of which gaze apraxia is a major component, is associated to a damage of the posterior parietal lobe and more commonly involves saccades, ocular pursuit, and fixation. This pattern of deficit is in keeping with electrophysiological studies in monkeys demonstrating (Lynch, Mountcastle, Talbot, & Yin, 1977; Mountcastle, Lynch, Georgopoulos, Sakata, &

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Acuna, 1975) that in the posterior parietal cortex there are neurones just active just prior to a saccade, neurones discharging in the course of pursuit movements, and neurones enhancing their activity while animals are fixating a stationary target. Using a memory saccade task to separate sensory from motor responses, Andersen et al. (1985) showed that posterior parietal neurones have both visual (in the area 7a) and saccade-related (in the lateral intraparietal area) activity. Accordingly, it has been suggested that posterior parietal cortex is involved in sensori-motor integration rather than being a strictly sensory or motor structure. It function might be to integrate visual signals with information about eye position, vergence angle, and head position to form a specific, distributed representation of space (Andersen, 1995).

Optic ataxia In Balint-Holmes syndrome it is possible to observe all the different kinds of misreaching that have been already described. In the most severe patients, defective reaching occurs with both hands and even when the patient is fixating, thus disrupting everyday life activity. It has been noted (Husain & Stein, 1988) that the patient described by Balint in 1909, showed a striking dissociation between the right upper limb (which showed severe misreaching) and the left hand (which was nearly unimpaired). It was based on this dissociation that Balint, after rejecting the explanation of optic ataxia in terms of defective spatial localisation, hypothesised a visuomotor disconnection.

Impaired visual attention Typically, patients with this syndrome show an extreme narrowing of attention that prevents them from noticing objects of special interest that are presented in their peripheral visual field. Holmes (1930) attributed this disorder to “spasm of fixation” and interpreted it as due to disinhibition of the occipital fixation reflex. Following Martha Farah (1990), this symptom is better referred to as “dorsal simultanagnosic^ in order to distinguish it from “ventral simultanagnosia”, which is caused by temporo-occipital lesions and is not typically found in Balint-Holmes patients. Ventral simultanagnosic patients (Wolpert, 1924) are

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generally able to recognise single objects but do poorly in understanding the meaning of complex pictures. Unlike “dorsal simultanagnosic” patients, they can see multiple objects. However, they are slow in recognising them (Kinsbourne & Warrington, 1963) and they tend to read words slowly, letter-by-letter, showing special difficulties with visually similar letter strings (Levine & Calvanio, 1978). On the contrary, dorsal simultanagnosics, despite full visual fields, act as if they were blind so that, when they are presented with a visual array, they have trouble in indicating an item named by the examiner. Apparently, these patients have a disorder of visual attention so severe that they cannot see unattended objects. However, the nature of this attentional limitation is still under discussion. According to some authors the limitation concerns the region of the space that can be attended to. Posner (1995) argued that unilateral spatial neglect can be interpreted as due to a failure to disengage attention so as to redirect it toward a target located in the direction opposite to the damaged hemisphere. Patients with Balint-Holmes syndrome might be viewed as having difficulty in disengaging attention to move it in any direction (Farah, 1990). In agreement with this hypothesis, Tyler (1968) described patients with Balint-Holmes syndrome who could report two stimuli only when they were within a visual angle of no more than 2-4°. These patients showed a better performance at perceiving far rather than close stimuli. In a patient that I have followed for more that 10 years after she suffered a post-eclamptic occipito-parietal ischemia, Balint-Holmes syndrome recovered almost completely except for slow reading of texts written with large fonts (such as in newspaper headlines). Small fonts were read at normal speed. In many other instances, the attentional impairment appears to be independent from stimulus dimension. These patients cannot say which of two objects is smaller, which or two lines is longer, whether or not two angles are the same or different, even when they are very close to each other. They may also fail to detect two dots when they are only a few millimetres apart (Sorgato, 1976). Holmes and Horrax (1919, quoted by Rafal & Robertson, 1995, p.640) noted in their patient:

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“Though he failed to distinguish any difference in length of lines, even if it was as great as 50 per cent, he could always recognise whether a quadrilateral rectangular figure was a square or not ... He explained that in order to decide whether a figure was or was not a square, he did not compare the length of its sides but ‘on a first glance’ he saw the whole figure and knew whether it is a square or not.” According to Holmes and Horrax (1919) their patient’s spared ability to promptly recognise the shape of simple geometrical figures “demonstrates that in this we do not naturally depend on the comparison of lines and angles, but that we apprehend shapes as a whole and accept them as units.” Typically, when we show a six-pointed star constructed of two triangles of different colours, Balint-Holmes patients report seeing only one triangle (Luria, 1964). A patient described by Rafal and Robertson (1995), when looking at the investigator, was unable to tell whether he was wearing glasses, although she has no difficulty seeing the investigator’s face or the glasses if viewed individually. In all the former examples the patients’ impairment cannot be attributed to a deficit in disengaging attention from a position in space but rather to a deficit in disengaging it from an object. As a consequence of such an impairment, the patient cannot direct attention toward another object, even if it occupies the same spatial position. In other words, simultanagnosia appears here to be determined by impairing a mechanism of attentional selection which is based on perceptual rather than spatial characteristics of the object. Humphreys and Riddoch (1992) have provided an experimental demonstration of object-based attentional restriction in Balint-Holmes syndrome. They presented to patients with Balint-Holmes syndrome visual displays with 32 circles, each of which was all red, all green, or half-red and halfgreen. The task was to report whether each display contained one or two colours. In two experimental conditions the lines connected either pairs of circles with the same colour or pairs of circles of different colours. A couple of Balint-Holmes patients examined with this task were better at reporting the presence of two colours when lines connected pairs

of circles with different colours. It was thus apparent that circles connected by lines were perceived as a single objects. Whenever objects (interconnected circles) contained a single colour, patients had great difficulty in reporting two colours, as their attention was locked onto the object. Several observations have demonstrated that what falls outside the attentional focus, even if it is not perceived at a conscious level can influence these patients’ performance. An example was provided by Coslett and Saffran (1991). They described a simultanagnosic patient that, with brief simultaneous presentation of two words or drawings, could identify a higher proportion of stimuli when they were semantically related. It has been also noted that in these patients, as in normal subjects, preattentive perceptual processing can influence orienting attention. For instance, simultanagnosic patients, as normal subjects, are more likely to detect a Q among several Os than a O among several Qs. In summary, objects that capture the attention of a simultanagnosic patient are not chosen at random but following precise rules that favour those with higher perceptual saliency. We can orient attention both toward spatial position and toward objects. Simultaneagnosia, as shown by BalintHolmes patients, is a mainly a disorder of orienting attention toward objects. However, the characteristics of the patient’s impairment sometimes suggest that a focal restriction of spatial attention is also part of the syndrome.

Defective estimation of distance and impaired depth perception Balint (1909) reported that his patient could not tell which of two objects was closer. He attributed his patient’s impairment to the inability to see two objects at the same time. Holmes (1919), after a careful analysis, ascribed it to a more general disorder of visual orientation. He noted that his patients could not evaluate the spatial aspects of stimuli they could otherwise recognise. They showed an impairment in localising an object in space, in evaluating its length and its depth. Defective evaluation of distance, combined with other symptoms typically found in Balint-Holmes syndrome, leads to serious consequence in

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everyday life. These patients often stumble on objects (because they cannot judge how close they are) and they run the risk of falling every time they sit down (because they have problems in establishing how the chair is oriented with respect to their body). Balint-Holmes syndrome is usually caused by a bilateral lesion at the parieto-occipital junction. The post-mortem examination of a Balint-Holmes patient reported by Pierrot-Deseilligny (1986) demonstrated two small ischemic lesions bilaterally involving the borders of the intraparietal sulcus, the superior part of the angular gyrus, and, to a lesser extent, part of the superior parietal lobule. As demonstrated by Furey-Kurkjian et al. (1996) patients with the Balint-Holmes syndrome can also be found at an early stage of degenerative diseases such as Alzheimer’s dementia. In this case positron emission tomography can demonstrate a distinctive metabolic impairment in the parietal and occipital cortices (Pietrini et al., 1996).

(1995) CT and MRI scans were normal but a PET scan revealed a marked hypometabolism of the right hemisphere, such supporting the claim that the Right Hemisphere Developmental Learning Disability syndrome is indeed associated with functional abnormalities of the right hemisphere, even when evidence of structural anomaly is entirely lacking. The fact that visuospatial disorders are not usually reported after extensive right hemisphere lesions acquired early in life (Damasio, Lima, & Damasio, 1975; Temple, 1992) raises the issue of why the left hemisphere is not able to play a subsidiary role in the case of the Right Hemisphere Developmental Learning Disability syndrome. The most likely explanation (Nichelli & Venneri, 1995) is that the right dysfunctional hemisphere might play an inhibitory role that prevents the left hemisphere from taking over the damaged processing systems. However, this hypothesis still lacks supportive evidence.

RIGHT HEMISPHERE DEVELOPMENTAL LEARNING DISABILITY

SPATIAL MEMORY AND ITS DISORDERS

Visuospatial disturbances are salient features of a developmental syndrome that has been described quite recently (Denckla, 1993; Grace & Malloy, 1992; Rourke, 1982; Tranel, Hall, Olson, & Tranel, 1987; Voeller, 1986; Weintraub & Mesulam, 1983) and that is currently attributed to functional abnormalities of the right hemisphere (Nichelli & Venneri, 1995). These little patients show severe difficulties with mathematics and drawing, are often abnormally shy (Abramson & Katz, 1989), avoid eye contact, and lack the gestures and prosody that normally accompany or accentuate speech (Weintraub & Mesulam, 1983). However, they show normal verbal memory, normal verbal intelligence, and normal reading skills. In some of these patients the neuropsychological picture is associated with subtle left-sided motor signs or with computed tomography (CT) and magnetic resonance (MR) signs pointing to a right hemisphere atrophy. In a case recently reported by Nichelli and Venneri

One of the main distinctions in the study of human memory is that between short-term and long-term memory (see Chapter 15).Within spatial memory it is possible to distinguish between a short- and a long-term component. As these two kinds of memory can be selectively affected by brain damage, we will analyse them separately.

Short-term spatial memory According to a widely accepted theoretical framework (Baddeley, 1986; Baddeley & Hitch, 1974) short-term memory is viewed as a “working memory”, i.e. a sort of temporary storage that allows us to keep information for the purpose of using it in a wide range of cognitive tasks. It is by means of short-term memory processes that we can keep in mind the words that we are reading, for the time that is necessary to get a sense from the whole sentence. Also, we can navigate in threedimensional space because short-term memory processes keep track of our current position and of any displacements that occurred just before.

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Working memory, in its turn, is composed of an attentional system of limited capacity (the so-called “central executive”) and by at least two “slave subsystems”: the “articulatory loop” and the “visuospatial sketchpad”. These slave subsystems respectively store phonological and visuospatial information and keep it activated “on line” for subsequent processing by the central executive. Generation and retention of visual images in the absence of a direct sensory stimulation is in close relationship with spatial abilities (Baddeley & Lieberman, 1980; Logie, 1986) and constitutes the basis for the functioning of the visuospatial sketchpad. The simplest way to test, in a clinical setting, visuospatial short-term memory is to measure its “span”, i.e. the maximum amount of information the subject can hold in memory. This is commonly done by means of the Corsi test (Milner, 1971). The test consists of nine blocks arranged on a board (see Fig. 20.5). Blocks are numbered on the examiner’s side but numbers are not visible to the subject. The examiner taps series of increasing numbers of blocks and after each series the subject is requested to repeat the sequence tapped by the examiner. The longest series of blocks the subject can correctly tap in the same order shown by the examiner constitutes his or her spatial memory span. There are several lines of argument supporting the existence of a specialised visuospatial shortterm memory system (see Logie, 1995, chapter 3). One of the most convincing pieces of evidence is based on a double dissociation that has repeatedly

FIGURE 20.5

Corsi’s block tapping board. The numbers are facing the examiner and cannot be read by the subject.

found been found in the brain-damaged population between visuospatial and verbal short-term memory impairment. For example, De Renzi and Nichelli (1975) described two patients with damage to the right hemisphere who scored poorly on the Corsi block span task but achieved a normal score on digit span. Their deficit could not be accounted for by space perceptual disorders and contrasted with normal performance on a spatial long-term memory test. They also found two left braindamaged patients who were severely impaired on digit span but were normal on the Corsi block span task. More recently, Hanley et al. (1991) reported a right hemisphere damaged patient who showed very poor performance on Corsi block, on mental rotation, and in using visual imagery mnemonics but was unimpaired in her ability to recall letter sequences with auditory and visual presentation. A double dissociation has been also reported in neurophysiological studies. In a series of experiments, Goldman-Rakic and co-workers (Goldman-Rakic, 1987; Wilson, Scalaidhe, & Goldman-Rakic, 1993) have trained monkeys to remember the spatial location of a stimulus before making an ocular movement toward it. They demonstrated that neurones in the region of the principal sulcus are active during the interval between stimulus presentation and ocular movement (i.e. when animals were trying to remember the spatial location of the stimuli), while neurones located in the inferior prefrontal region discharge when animals are trying to remember faces or specific objects.

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The region surrounding and lining the principal sulcus in the nonhuman primate brain corresponds in man to Brodmann’s area 46 (see Fig. 20.6). Several neuroimaging studies (McCarthy, Blamire et al., 1994; Petrides, Alivisatos, Evans, & Mayer, 1993; Sweeney et al., 1996) support the notion that Brodmann’s areas 46 and 9 are involved in performing spatial memory tasks. There is also good evidence that different working memory buffers are used for storing spatial and object information (Courtney, Ungerleider, Keil, & Haxby, 1996; Smith, Jonides, Koeppe, Awh, Schumaker, & Minoshima, 1995a). A couple of recent neuroimaging studies (Cohen, Perlstein, Braver, Nystrom, Noll, Jonides, et al., 1997a; Courtney, Ungerleider, Keil, & Haxby, 1997) have also showed that different regions of the brain can be dissociated according to the temporal profile of their activation during working memory tasks. Those with sustained responses correlate most strongly with delay periods and with the greatest

memory load and are located in the prefrontal cortex. In agreement with the results of neurophysiological and neuroimaging studies, lesions of the dorsolateral frontal cortex, particularly those involving the region around the principal sulcus, impair monkey’s performance on spatial delayed alternation tasks that tax animal’s ability to hold information in memory for a short period of time and to update information from moment to moment. On the contrary, the same lesions do not impair information that relies on associative memory or sensory guided responses (Butters, Pandya, Sanders, & Dye, 1971; Goldman-Rakic, 1987; Goldman-Rakic & Rosvold, 1970; Mishkin & Pribram, 1955, 1956). Accordingly, patients with prefrontal lesions perform poorly on a human version of the delayed response task (Verin, Partiot, Pillon, Malapani, Agid, & Dubois, 1993) and they show a preeminent difficulty in monitoring the spatial component

FIGURE 20.6

Views of the human and monkey brain illustrating the location of the area 46 that is associated with spatial working memory. (Figure adapted from GoldmanRakic, A nnals o f the N ew York A cadem y o f Sciences, 7 6 9 , 73, 1995.)

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within the working memory (Dubois, Levy, Verin, Teixeira, Agid, & Pillon, 1995). Prefrontal involvement in spatial working memory is also supported by a number of studies using different tasks. These include the Spatial Conditional Associative Learning Task, developed by Petrides and Milner (1985), and the Owl Spatial Working Memory Task developed by Miotto et al. (1996). In the former, the subjects view an array of randomly positioned lights which are switched on and off in turn. They have to learn to associate each light with a specific spatial location. The second task requires subjects to search for “owls” that may be hidden in any one of a number of different circles. Only two circles are displayed at the same time. A key design feature is that, within a search, a location that has been tried by a subject is not given again. Notably, impairments in both Spatial Conditional Associative Learning Task and Owl Spatial Working Memory tasks are observed in patients with both right and left frontal lesions, with equivalent levels of impairments. In the same vein, Smith et al. (1995b) demonstrated that frontal lobe lesions diminish human ability to suppress interference in memory from spatial location. The task they used requires subjects to remember the location of an array of small pictures in which the trials only varied with respect to the relative locations of the pictures in the array. Results showed a selective disturbance when the spatial arrangement of objects varied from trial to trial. On the contrary, patients with the same kind of lesion were not impaired on recall of stable spatial locations of objects (Smith & Milner, 1984).

Long-term visuospatial memory Memory for location is tested by presenting a number of figures or objects on a sheet and then requiring the patient to relocate them on another sheet in exactly the same position at various time delays (Smith & Milner, 1981). Smith and Milner (1981) demonstrated that both right and left temporal lobectomy patients are impaired in the delayed recall of objects, but only right temporal lobectomy patients are impaired in delayed recall of location. Furthermore, they demonstrated that deficits after right temporal lobectomy are contingent on radical excision of the

hippocampal region. Jones-Gotman (1986) and Chiba et al. (1990) have confirmed with different methods defective memory for location after right hippocampal removal. In a follow-up study, Smith and Milner (1989) found that right lobectomy patients are impaired in delayed but not in immediate recall. Also, interpolated activity during the delay did not accentuate the deficit, showing that right hippocampal lesions cause abnormally rapid forgetting of location despite normal ability for encoding. A dissociation between memory for objects and memory for their spatial location has been also demonstrated by Shoqeirat and Mayes (1991). These authors tested a group of amnesic patients of different etiologies on a task in which 16 nameable shapes were placed on different squares of a 49-square grid. All etiologic subgroups showed a disproportionate deficit of memory for location as compared with memory for target material. The spatial memory deficit was related with amnesia severity but not with frontal lobe dysfunction. Distinct neural correlates of visual long-term memory for spatial location and object identity was also demonstrated with positron emission tomography by Moscovitch et al. (1995) while subjects were studying set of displays consisting of three unique representational line drawings arranged in different spatial configurations. To investigate path learning in a clinical setting one can use the stepping stone maze shown in Fig. 20.7. The apparatus consists of a stylus and a matrix of 10 x 10 bolt-heads. The subject is to learn, by trial and error, the path connecting two distant boltheads of the matrix. When subjects touch with the stylus boltheads belonging to the path, the apparatus remains silent, while bolt-heads not included in the path produce an unpleasant sound. Learning is measured in terms of the number of trials needed to flawlessly perform the task three times in a row. Clinical studies on temporal lobectomy patients demonstrate that performance at this task is disrupted when the surgical lesion includes the right hippocampus (Milner, 1965). The same results have been obtained in patients with right posterior cerebral lesions (De Renzi, Faglioni, & Previdi, 1977; Ratcliff & Newcombe, 1973).

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Newcombe et al. (1969,1987) have associated the most severe maze learning deficits with damage to the right superior parietal lobe, in the region of area 7 and adjacent cortices. Patients with topographical amnesia commonly fail to learn the path on the maze even after more than a hundred trials (De Renzi, Faglioni, & Villa, 1977; Hecaen, Tzortzis, & Rondot, 1980). Yet, a few notable exceptions of dissociation between fair performance at this task and severe disorientation in real space have been reported (De Renzi, 1985; Ratcliff, 1982). Right temporal lobectomy (Corsi, quoted by Milner, 1971) and right brain-damaged (De Renzi et al., 1977) patients are also impaired in the supraspan Corsi block learning task, which requires subjects to learn a block sequence exceeding by one or two items their spatial memory span for blocks. This latter task might be therefore considered as an alternative way to test long-term spatial memory. As for verbal memory, neuropsychological studies indicate a double dissociation between short-term and long-term spatial memory. De Renzi (1982) first described two patients with right posterior lesions that were markedly impaired on Corsi’s block span task but unimpaired on tasks of perception, spatial exploration and maze learning. Newcombe et al. (1987) reported the reverse pattern of deficit.

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and to each other. To do that, it is necessary to process visual inputs and to associate the result of visuospatial processing with information already stored in long-term memory (Griisser & Landis, 1991). Disorders at any of these levels may affect route finding ability. Two different mechanisms can cause topographic disorientation (De Renzi, 1982; Paterson & Zangwill, 1944b): topographical agnosia, i.e. a perceptual failure to recognise localities and their landmarks with their unique orienting value (Landis, Cummings, Benson, & Palmer, 1986) while retaining the ability to identify and recognise classes of objects such as hills, or buildings, and topographical amnesia which refers to an inability to remember topographical

FIGURE 20.7

DISORDERS OF TOPOGRAPHICAL ORIENTATION Disorders of route finding are a common symptom of diseases diffusely affecting the cerebral association cortex. They can also be part of global amnesic or visuo-perceptual disorders and they can occur as a manifestation of visuospatial neglect. In a much smaller proportion, topographic disorders can also be found in isolation or may appear disproportionally severe compared with other symptoms of cognitive dysfunction. These instances are referred to as “pure topographical disorientation”. To successfully navigate in the environment, one must get an integrated viewpoint that represents objects in their spatial position relative to oneself

Stepping stone maze used to evaluate long-term spatial learning. The subjects can see a 10 x 10 matrix of boltheads. By means of a stylus, subjects have to find out, by trial and error, the only path connecting the starting point with the finish. The path is characterised by the fact that boltheads along it, when touched with the stylus, do not produce an unpleasant buzzing sound. In the illustration, the target path is signalled with shaded circles.

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relationships between landmarks that can be identified individually. In topographic agnosia (which according to Benson (1994) is better referred to as “environmental amnesia”) patients cannot recognise well known buildings, streets, and landmarks. They claim that all places appear unfamiliar, as if they were seeing them for the first time. However, they retain the ability to imagine the schema of the pathway, to describe the appropriate route for walking from one point to another, as well as the capability to draw the corresponding maps (De Renzi, 1982). Interestingly, one of these patients was still able to play chess (Pallis, 1955). Topographic agnosia is commonly associated to colour agnosia, prosopagnosia (inability to recognise familiar faces), and recognition of animal drawings. Due to this association pattern, according to De Renzi (1982, 1985), topographic agnosia might be considered a minor form of apperceptive agnosia (Lissauer, 1890), apparent any time a subtle discrimination is required to identify individual items that share high inter-item similarity within the categories they belong to. While topographic agnosic patients are unable to find their way about in familiar confines, they may have no difficulty in pointing to suggested places on a map or in orienting themselves on either a map or a floor plan. Indeed, the two disorders of orientation seem to follow different neural systems (Benson, 1994). All cases of environmental agnosia reported by Landis (1986) had pathologies that involved the right medial occipital area. In contrast, patients with a deficit in orienting themselves to an abstract spatial representation such as a map or a floor plan had lesions involving the dorsal convexity of the right parietal lobe (Hecaen, Penfield, Bertrand, & Malmo, 1956; McFie, Piercy, & Zangwill, 1950; Paterson & Zangwill, 1944b). In topographic amnesia, patients recognise landmarks but cannot give them any specific localising value. They can identify an individual building but cannot remember whether it is on the right, on the left, in front of, or behind another landmark. As a consequence, they are unable to draw a map or to describe the path to reach one place from another (De Renzi et al., 1977). However, they

perform well on tasks of visual discrimination (i.e. face identification, recognition of overlapping or fragmented patterns) as well as on space perceptual tasks, while they fail to learn paths on visually guided mazes (De Renzi et al., 1977; Hecaen et al., 1980). Studies of the location of lesions responsible for topographical amnesia (Bohbot, Kalina, Stepankova, Spackova, Petrides, & Nadel, 1997; Habib & Sirigu, 1987) point to the involvement of a restricted portion of the right parahippocampal gyrus posterior to the uncus and rostral to the subsplenial region (Fig. 20.8). Topographic amnesia has been also reported following a small angioma at the border of areas 24d and 23 of the right cingulate cortex, a region that is strategically located in a network that links the posterior parietal (area 7 a) and parahippocampal cortices (Cammalleri, Gangitano, D’Amelio, Raieli, Raimondo, & Camarda, 1996). The importance of the right parahippocampal gyrus in topographical memory is also supported by a PET study designed to investigate the regional cerebral blood flow changes associated with the formation of representations of large-scale environments necessary for way-finding (Maguire, Frackowiak, & Frith, 1996). Topographical learning of an urban environment from viewing of film footage depicting navigation was associated with activation of the right parahippocampal gyrus and hippocampus, with activation also of the left parahippocampal gyrus. In addition, there was activity in the precuneus. A further neuroimaging study on London taxi driver requested to describe the shortest legal route between a starting point and two destination points in the greater London area demonstrated a significant activation of the right hippocampus (Maguire & Frith, 1997) thus suggesting a specific role of this structure in retrieval of spatial information.

REDUPLICATIVE PARAMNESIA FOR PLACES Reduplicative paramnesia for places, also referred to as “environmental reduplication” (Ruff & Volpe, 1981) was first described by Arnold Pick (1903). Reduplicative phenomena in association with a

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brain lesion have been noted for persons, time, events, body parts, and objects (Weinstein, 1969; Weinstein & Burnham, 1991; Weinstein, Kahn, & Sugarman, 1952). More recently Jospeh (1986) brought together these all these phenomena as instances of delusional misidentification syndromes. The term “reduplicative paramnesia” for places refers to the false belief that a place familiar to the patient exists in more than one physical location. Thus, patients may insist that the hospital they are staying in has been duplicated and relocated from one site to another, usually one they knew very well earlier in life. The patients may maintain that two hospitals, both with the same name and with the same characteristics, coexist in different places at the same time (Filley & Jarvis, 1987; Paterson & Zangwill, 1944a; Ruff&Volpe, 1981) and that they have stayed in both of them (Patterson & Mack, 1985). Luzzatti and Verga (1996) pointed out that there are different kinds of delusion: in some cases the reduplicated world produces a sort of parallel double world, while in other instances the “old” world is displaced from one place to another. The latter was the case of a patient described by Pick (1903), who insisted that the clinic in Prague she was staying at had been moved with all the staff to

her home town, a small village in the vicinity of Prague. Typically, patients with reduplicative paramnesia express their false beliefs with absolute conviction, demonstrating stubborn endurance against compelling counterevidence. However, they do not extend their confabulation to other subjects. Temporal disorientation and erroneous identification of familiar people are often present. Yet, reduplicative paramnesia may persist even when other memory deficits and, in particular, topographical disorientation are no longer present (Benson, Gardner, & Meadows, 1976; Filley & Jarvis, 1987; Vighetto, Aimar, Confareux, & Devic, 1980). Different authors have provided different explanations for reduplicative phenomena and, in particular, for reduplicative paramnesia for places. Filley and Jarvis (1987) have noted that reduplicative phenomena can occur several months after a brain lesion and that reduplications usually move the place where the patients are living (the hospital) closer to their home. Weinstein and Friedland (1977) remarked that reduplicative statements are not often volunteered by the patients, but emerge only if specific questions are posed. It follows, according to the same authors, that this disorder might have a symbolic meaning and an adaptative

FIGURE 20.8

Inner aspects of the right hemisphere displaying lesion location in four patients with pure topographical disorientation. The damaged area common to the four patients is a restricted portion of the parahippocampal gyrus posterior to the uncus and rostral to the subsplenial region. (Figure adapted from Habib & Sirigu, 1987, Pure topographical disorientation. Cortex, 2 3 , 73-85.)

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value, as it represents a defence mechanism against the devastating effect of the disease, an unconscious attempt to deny it. Staton et al. (1982) have proposed that reduplicative paramnesia is a disconnection syndrome of memory, a disorder in integrating newly acquired information with older memories. Patterson and Mack (1985) have proposed that reduplicative phenomena derive from combining perceptual and memory deficits with defective integrative mechanisms. Nonetheless, patients with reduplicative paramnesia in the presence of normal memory have also been reported (Luzzatti & Verga, 1996). Bilateral frontal lesions, associated with right hemisphere pathology, is the structural brain damage most commonly associated with reduplicative phenomena (Alexander, Stuss, & Benson, 1979; Benson et al., 1976; Filley & Jarvis, 1987; Weinstein & Kahn, 1955). It has been also observed that a relative preservation of the left hemisphere is required to allow for the symbolic representation of the patient’s feelings and experiences (Levine & Grek, 1984; Weinstein, Cole, Mitchell, & Lyerly, 1964) More recently, Mentis et al. (1995) have noted that Alzheimer disease patients with delusional misidentification syndromes (including reduplicative phenomena for places, for persons, and for events) differ from patients without delusional misidentification syndromes in having significant hypometabolism in paralimbic (orbitofrontal and cingulate) areas bilaterally and relative hypermetabolism in sensory association cortices (superior temporal and inferior parietal). They have proposed that dysfunctional connections among multimodal association areas and paralimbiclimbic structures might cause mnestic- and perceptual-affective dissonance that cannot be resolved by a malfunctioning dorsolateral prefrontal cortex. The delusion would be the patient’s solution to the dissonant information.

VISUOSPATIAL IMAGERY The ability to create and manipulate images plays an important role in many human activities, ranging

from navigation to memory, to creative problem solving (Kosslyn, 1996). By means of imagery, we have access to information that is neither explicitly coded nor can be deduced from other stored information (e.g. from information about the general category to which the object belongs). Think about our ability to answer questions like: “What is the shape of German Shepherds’ ears?”; “Is the green of pine trees darker than the green of grass?”; “How many windows does your house have?”. Introspection suggests and empirical results confirm (Kosslyn, 1980) that images are generated to answer questions like these. Introspection also suggests that imaging an object is like seeing it with the mind’s eye. Indeed, one of the oldest hypotheses about mental imagery is that it is the result of the “top-down” activation of perceptual representations by higher cognitive processes (Finke, 1980; Hebb, 1968; Shepard, 1978). On another side, several theorists (see e.g. Pylyshyn, 1973), based on the conviction that cognition is symbol manipulation, have questioned the claim that there are qualitatively different forms of mental representations and have proposed instead that recalling an image from memory is not different in terms of the underlying informationprocessing from recalling any other kind of memory. Neuropsychological data on patients, as well as the results of neuroimaging studies in normal subjects, have been very informative in trying to solve the debate about the format (propositional vs. visuospatial) of mental images.

The cerebral basis of mental imagery In agreement with the claim that mental images activate the same representations involved in visuospatial processing, most patients with selective disturbances of visual perception manifest corresponding impairments in mental imagery. For instance, patients with acquired colour blindness have impaired colour imagery despite good general imagery ability (Humphreys & Riddoch, 1987), patients with different degrees of impairment in colour vision show parallel deficits in colour imagery (De Renzi & Spinnler, 1967) and patients with colour agnosia or with visuo-verbal disconnection reveal corresponding failures in visual imagery tasks (Beauvois & Saillant, 1985;

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De Vreese, 1991). In the same vein, Levine et al. (1985) demonstrated the distinction between “what” and “where” cortical visual systems extends to mental imagery tasks. They described a patient who, following bilateral parieto-occipital damage, could neither localise visual stimuli in space nor accurately describe the location of familiar objects or landmarks from memory. However, he was good at identifying objects and at describing their appearance from memory. On the contrary, a second patient was impaired at recognising objects and at describing their appearance from memory despite being able to draw and to describe in great detail the relative location of different kinds of items. Farah et al. (1992) studied the effect of occipital lobectomy on visual imagery. She asked a patient to estimate the distance at which an image will overflow. She found that the size of the largest possible mental image was reduced following surgery. Furthermore, the horizontal but not vertical extent of the imagery medium was reduced, as expected from the effect of hemianopia on a spatially mapped representational medium. These findings suggest that early visual representations (dependent on the occipital cortex) are used during imagery tasks. Several neuroimaging studies have provided further and stronger evidence that visual imagery activates occipital cortex in normal subjects performing visual imagery tasks. Goldenberg et al. (1987), using single photon emission computed tomography (SPECT), demonstrated increased occipital activation when subjects were instructed to use visual imagery to memorise a word list. Le Bihan et al. (1993) used functional magnetic resonance (fMRI) to measure regional brain activity as subjects viewed flashing patterns and imagined them. They found focal increases in signal related to changes in blood flow in primary visual cortex (V1 and V2) during the simple recall of the visual stimulation. The notion that mental imagery activates primary visual areas has been under discussion for some time. Roland and Gulyas (1994a, b) claimed that only parieto-occipital and temporo-occipital association areas, i.e. a subset of visual areas engaged in perception, subserve visual imagery. In support of this hypothesis they quoted several

neuroimaging studies that failed to demonstrate occipital activation in imagery tasks (Decety, Kawashima, Gulyas, & Roland, 1992; Kawashima, Roland, & O’Sullivan, 1995b; Roland, Eriksson, Stone-Elander, & Widen, 1987; Roland & Gulyas, 1995). According to their view, conflicting results showing activation in retinotopically organised visual areas (e.g. VI and V2) were mainly due to methodological bias. In agreement with this notion Mellet et al. (1996) did not observe activation of the primary visual areas activation while subjects were constructing mental images of objects made of three-dimensional cube assemblies from auditorily presented instructions. They found instead activation of a bilateral occipitoparietalfrontal network, including the superior occipital cortex, the inferior parietal cortex, and the premotor cortex. A more recent PET study by Kosslyn et al. (1995) seems to solve the debate about the involvement of primary visual areas during imagery. In this study it was found that the size of a mental image is systematically related to the location of maximal activity in the primary visual cortex, as expected based on the spatial organisation of the earliest visual areas. These results were only evident, however, when imagery conditions were compared to a nonimagery baseline in which the same auditory cues were presented (and hence the stimuli were controlled). When a resting baseline was used (and hence brain activation was uncontrolled), imagery activation was obscured because of activation in visual cortex during the baseline condition, a finding that can explain the lack of occipital activation in some of the previous neuroimaging studies.

Generating and maintaining visual images According to Kosslyn (1996) there are at least four classes of imagery abilities: image generation, image inspection, image maintenance, and image transformation. Image generation can involve a single part or a multiple part object. In the latter case, spatial relation representations are also activated and an “attentional window” is used to shift from old to new locations. An open question is whether or not image generation, besides being associated to top-down

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activation of the same representations that are involved in visuospatial processing, also corresponds to activation of specific circuits devoted to generating mental images per se. The issue was brought to the attention of neuropsychologists by a number of patients (Farah, 1984, 1988b; Goldenberg, 1992; Grossi, Orsini, Modafferi, & Liotti, 1986; Pena-Casanova, RoigRovira, Bermudez, & Tolosa-Sarro, 1985; Riddoch, 1990) in which perception appeared to be grossly intact despite a specific deficit in image generation. Behrmann et al. (1992, 1994) and Jankoviak et al. (1992) have also described the opposite case of two agnosic patients who were able to draw from memory those objects they could not recognise. Even if patients with a selective image generation deficit might have subtle visual memory impairments whose role in imagery deficit cannot be easily ruled out (Farah, 1995), the double dissociation between perception and imagery impairments strongly suggests the existence of a distinct image generation component. Controversy has arisen in the literature regarding the role of the cerebral hemispheres in the generation of images. Patients with selective image generation deficit more often have left posterior damage, mostly involving the occipitotemporal area (Farah, 1984, 1995; Tippet, 1992). On the other hand, Sergent (1989) has been critical of the left hemisphere hypothesis and has argued that both hemispheres are equipped with processing structures capable of generation mental images and that in some circumstances (e.g. when a decision has to be made on generated images) the right hemisphere might be more efficient than the left. Sergent (1989) found support for this hypothesis in a divided visual field experiment with normal subjects. However, research with split-brain patients (Corballis & Sergent, 1988; Farah, Gazzaniga, Holtzman, & Kosslyn, 1985; Kosslyn, Farah, Gazzaniga, & Holtzman, 1985) has shown at least an initial or partial superiority of the left hemisphere in image generation. Other neuropsychological methods have confirmed the same trend toward a left hemisphere specialisation. Left temporo-occipital activation has been noted in several neuroimaging studies, using different methods: ERP (Farah & Perronet, 1989; Farah,

Perronet, Gonon, & Giard, 1988; Farah, Perronet, Weisberg, &Monheit, 1989) SPECT (Goldenberg et al., 1987; Goldenberg, Podreka, Steiner, & Willmes, 1988), and PET (Kosslyn, Alpert et al., 1993). In a recent fMRI study (D’Esposito et al., 1997), left inferior temporal lobe (area 37) was most reliably activated across subjects in a task where generating visual mental images of the words’ referents was compared with simple word listening. It is still possible that there are different types of mental image generation mechanisms (e.g. single part and multiple part objects) each associated with a specific neuronal network, but this hypothesis is still waiting for verification

Inspecting visual images One can inspect images by means of the same mechanisms that are used to encode real objects during perception. An example of impaired inspection of mental images was provided by Bisiach and Luzzatti (1978). They asked two patients with unilateral spatial neglect to imagine themselves in a well known square in Milan and to recall as many landmarks as they could while imagining standing in front of the façade of the church. In doing so, the patients tended to name more landmarks on the right side of the image. Then they were asked to do the same from the opposite vantage point. In this case the patients reported many landmarks that were previously omitted and that were now on the right side of the image. Subsequent studies addressed the question of how common is a disorder of scanning mental images in neglect patients and whether or not its severity parallels that of visuospatial neglect. Clinical observations confirmed that there is a wide range of variability, with both patients with selective lateralised deficits of mental scanning (Guariglia, Padovani, Pantano, & Pizzamiglio, 1993) but no visuospatial neglect, and neglect patients who do not show imagery deficits (Coslett, 1997).

Transforming visual mental images An important function of mental imagery is to allow us to simulate displacement of objects. Think about our ability to visualise the luggage in a car

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boot before actually arranging it. To find out the best possible arrangement (or sometimes the only one that can let us close the boot) we can either rotate and displace the suitcases physically or we can do the same in our mind with less effort and time. A number of experimental studies (Kosslyn, Ball, & Reiser, 1978; Moyer & Bayer, 1976; Shepard & Metzler, 1971) have demonstrated that the time to mentally transform an image (e.g. to rotate it) is isomorphic with the physical process being represented (e.g. an external physical rotation). As a consequence, increasingly greater amounts of mental rotation require proportionally greater amounts of time. Neuropsychological studies have provided convincing evidence that the ability to transform mental images is distinct from the ability to generate them. For instance, Farah (1988a) described a patient who could not generate mental images but was unimpaired in mental rotation and in mental size scaling. On the other side a patient, described by Farah and Hammond (1988) was impaired at rotating mental images but could generate them. Studies on brain-damaged patients and visualfield studies with normal subjects have provided conflicting evidence regarding the hemispheric specialisation for mental rotation (see Farah, 1989 and Kosslyn, 1996, pp.372-376 for critical reviews on this topic). A couple of recent neuroimaging papers have helped us to better understand the neural structures involved in mental rotation. Alivisatos and Petrides (1997), using PET, compared the activation during discrimination between normal and mirror images of digits and letters in various orientations with that corresponding to discriminating the same stimuli in the upright position. Results showed that the activity associated with mental rotation was localised in the left posterior parietal region (BA 7 and 40), in the right frontal cortex (area 8) and in

the head of the caudate. A similar pattern of activation was found using fMRI by Cohen et al. (1996). These authors adopted the threedimensional block shapes devised by Shepard and Meltzer (1971). On each trial, subjects viewed a pair of perspective drawings of these shapes, mentally rotated one of them, and determined whether or not the two forms were identical or mirror images. The control condition required the same discrimination except for the fact the two forms had the same orientation. Areas of significant activation related with rotation were identified in the parietal cortex (BA 7 sometimes spreading to area 40) and in the middle frontal gyrus (BA 8) as well as extrastriate activation (including BA 39 and 19), in a position consistent with the human analogue of area V5/MT, the region that is specialised for object motion analysis (Clarke & Miklossy, 1990; Corbetta, Miezin, Dobmeyer, Shulman, & Petersen, 1990; Zeki, Watson, Lueck, Friston, Kennard, & Frackowiak, 1991) but which is also activated when subjects look at a figure yielding illusory motion (Zeki, Watson, & Frackowiak, 1993). Unlike the results obtained by Alivisatos and Petrides (1997), Cohen et al. (1996) did not show strong or consistent evidence of latéralisation to left or right of brain activity related to mental rotation. This might be due to use of nonverbal material and to the fact that fMRI allows a more direct and detailed analysis of each individual subject’s activation pattern than PET. In conclusion mental rotation engages the same cortical areas involved in tracking moving objects and in encoding spatial relationships, in the same way as other aspects of mental imagery involve topdown activation of the neural substrate involved in direct perception. This observation yields to a more general view of the conscious brain that is deeply different from that of a separate observer of sensory events. On the contrary, it appears that consciousness is a property of the same networks that subserve sensation and perception.

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21 Unilateral Neglect and Related Disorders Edoardo Bisiach

The first steps toward the definition of a syndrome comprising unilateral neglect (UN) and other phenomena of disordered representation of the contents of one side of egocentric space were made during the second half of the 19th century. The last 20 years have witnessed a remarkable development of studies of this syndrome. There were two main reasons for this development: (1) the crucial contribution of neurophysiological investigation in animals; (2) the interest raised by UN and related disorders in different areas of cognitive sciences, including the philosophy of mind. The concise treatment of UN offered in this chapter may be supplemented by consultation of the books edited by Weinstein and Friedland (1977), Jeannerod (1987), and Robertson and Marshall ( 1993). Regarding anosognosia related to unilateral symptoms of brain damage and productive phenomena of misrepresentation of the contralesional side of the body, further readings could be McGlynn and Schacter (1989) and Bisiach and Geminiani (1991). A large collection of clinical observations may be found in Critchley’s classic book The parietal lobes (1953).

CLINICAL MANIFESTATIONS In most severe instances, UN may be noticed merely by observing the patient’s spontaneous behaviour. The phenomena described in this section refer to leftside impairments, because, as we shall see, they are much more frequent and severe following lesions of the right hemisphere. In the acute phase immediately following the onset of the brain lesion, patients often show a more or less complete and irreducible head and eye deviation toward the side of the damaged hemisphere. If their level of alertness allows verbal contact with the examiner and the latter approaches them from the left side, they address their responses to the opposite side, even if nobody is there (De Renzi et al. 1982a). They often fail to use their left limbs even in the absence of severe motor impairment (motor neglect, Critchley, 1953). Sometimes, lack of movement on request contrasts with normal participation of these limbs in semiautomatic activities such as unfolding a handkerchief. If they can carry out some everyday activities, they seemingly fail to perceive, 479

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remember, and explore what lies on the left side of their body and environment. Even in the absence of genuine dressing apraxia, they may forget to put on the left sleeve of their jacket, the left leg of their trousers, or the left shoe. If a wall, or any other obstacle, prevents their leaving the bed from the right side, they try to leave it from the left by striding over their left lower limb with disastrous consequences. If their gait is not severely affected, patients may be seen wandering in the ward and perplexedly looking for their intended destination, due not to general loss of topographic orienting but to lack of any spatial reference to what lies at any given time on their left. An endless list of examples could be given. Briefly, patients suffering from severe UN behave as if they were no longer able to perceive and conceive the existence of the left side of somatic and extrasomatic space. Presence of UN may be confirmed—or revealed, when it is not directly apparent in patients’ behaviour—by a great deal of means, ranging from extremely simple, although sometimes very sensitive, bedside tasks to sophisticated tests requiring complex instruments. Among the simplest tests, asking patients to cross out line segments drawn on a sheet of paper (Albert, 1973), or pick up with open or closed eyes a handful of coins spread over a table, may reveal omissions or abnormal latencies on the contralesional side of space. In reading single words or newspaper headlines, UN manifests either as amputation of the left side of the string of letters or words, or— especially with single words—as nonveridical completion: patients substitute the omitted segment with a false one, thus generating different (although, as a rule, real) words. On request, neglect patients usually bisect horizontal lines to the right of the true midpoint. In copying or drawing from memory common objects such as a daisy or a clockface, they omit, misarrange, or distort leftside details. In order to increase test sensitivity and allow for precise quantification of the impairment, the difficulty of cancellation tasks may be increased by varying the arrangement of, and the ratio between, targets and distractors (e.g. Mesulam, 1985b, pp. 101-103). It would nevertheless be unwise to employ tasks involving complex perceptual or executive skills, because the results

might be difficult to interpret due to extraneous factors. It must be kept in mind that dissociations may be found among patients suffering from UN. A particular patient may only read, for example, the last two letters of any word, even if placed on the ipsilesional side of space, while perfectly executing a cancellation task. Other patients may behave in exactly the opposite way. Neglect phenomena may occur outside the visual domain. Regarding the somatic space, they may for example be assessed by asking blindfolded patients to touch their left (contralesional) hand with the right one (Bisiach et al., 1986b) or by means of Zoccolotti and Judica’s scale (1991). As for extrasomatic space, blindfolded patients may be asked to collect objects spread over a table, find a marble in a tactile maze (De Renzi et al., 1970), or remove an array of pegs from holes (Bisiach et al., 1985b). In the auditory modality, a neglect-related phenomenon is, in all likelihood, the mislocation of dichotic stimuli toward the ipsilesional side (Altman et al., 1979; Bisiach et al., 1984). Double dissociations may be found across different sensory modalities. It is therefore advisable to employ an extended and differentiated test battery if a reasonably exhaustive description of a patient’s neglect symptomatology is required. It is also advisable, to this end, to repeat administration of the test battery. Indeed, remarkable variability in a patient’s performance may sometimes be observed from one moment to the next. Such a variability is not always dependent on ups and downs of vigilance or co-operativeness, and its interpretation is therefore problematical. Neglect phenomena may be found in the domain of mental representation, independent of any current sensory input. This may be demonstrated by asking patients to form the image of a familiar vista (such as a townsquare, the layout of a flat, or the map of a country) and to describe its details from a given vantage point. In so doing, patients may omit leftside details, no matter how salient. If, after that, a description of the same prospect is required from the opposite vantage point, it may be found that previously omitted leftside details are recalled (in that they have been mentally transferred to the right) and vice versa.

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ALLIED DISORDERS Among the phenomena known to be more or less frequently associated with UN, the most common is extinction on double simultaneous stimulation (Loeb, 1885). Its assessment is part of routine neurological examination. It may be defined as follows: a stimulus, in any sensory modality, may be detected when singly delivered to the contralesional side of somatic or extrasomatic space, but not when it is given in association with another (identical or different) stimulus delivered to a symmetrical (or even to an asymmetrical) point on the ipsilesional side. One of the most accurate descriptions of the phenomenon has been given by Critchley (1949) in the somatosensory modality. Like UN, extinction is subject to cross-modal dissociations (De Renzi et al., 1984). In current practice, auditory extinction may be assessed by snapping fingers close to either or both ears. In the visual and somatosensory modalities the phenomenon may be assessed by moving the examiner’s fingers in one or both visual hemifields and touching, uni- or bilaterally, symmetrical points of the patient’s skin with cotton-wool or the examiner’s fingertips. A great variety of stimuli have however been used, especially in the somatosensory modality (pinpricks, warm or cold surfaces, vibrations, pressure, etc.). Complex stimuli can also be used, such as objects shown in one or both visual half-fields, or put in one or both hands. According to several authors, the kind of perception most prone to extinction in the tactile modality is graphaesthesia, i.e. identification of letters or numbers drawn on the patient’s skin. A rigorous procedure for the assessment of extinction of complex tactile stimuli (textures) has been described by Schwartz et al. (1979). It has been debated whether extinction on double simultaneous stimulation actually belongs to UN symptomatology or must be regarded as a more elementary sensory dysfunction, as suggested by its possible occurrence following spinal cord lesions. The most plausible hypothesis is that the phenomenon is not homogeneous, in that it may depend on dysfunction at different levels of sensory information processing (Bisiach, 1991a). There are,

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however, proofs that elementary sensory defects contralateral to the brain lesion cannot explain all kinds of extinction. Extinction, indeed, may sometimes occur as paradoxical imperception of a parafoveal stimulus in the ipsilesional visual hemifield, when given in association with a more peripheral stimulus within the same hemifield (e.g. Bisiach & Geminiani, 1991; see Moscovitch & Behrmann, 1994, for similar findings in the tactile modality). Furthermore, Mesulam (1981) and Bellas et al. (1988) have reported contralesional olfactory extinction in patients suffering from UN. As (unlike other sensory pathways) olfactory pathways are uncrossed, a sensory pathogenesis of extinction would entail the opposite outcome, namely ipsilesional extinction. Finally, against an exclusively peripheral interpretation of extinction is a recent report by Smania and Aglioti (1995): somatosensory extinction on the left (contralesional) hand was found to improve when both upper limbs were held across the trunk’s sagittal midplane, so that the left hand lay on the ipsilesional side. Well known, although less frequent than extinction, is allochiria (Obersteiner, 1882), i.e. mislocation of contralesional stimuli to (usually) symmetrical points of ipsilesional somatic or extrasomatic space (e.g. Bender & Nathanson, 1950; Critchley, 1953). Allochiria may also be observed with complex patterns of stimulation; for instance, a patient has been described who referred her motor impairment to the ipsilesional (unimpaired) side of her body (Bisiach & Geminiani, 1991). Anosognosia (Babinski, 1914) and somatoparaphrenia (Gerstmann, 1942) are most relevant for the interpretation of UN and will be described in a later section.

CLINICO-ANATOMICAL CORRELATIONS Hemispheric asymmetries As already mentioned, UN is commonly held to be definitely more frequent and severe following lesion of the right hemisphere. There are statistics that strongly support this belief; Hecaen (1972), for example, found UN in 31 % of 176 cases with right,

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but only in 1 out of 276 cases with left hemisphere lesion. Some authors have suggested caution in evaluating this and similar statistics, which are likely to be biased by exclusion of left braindamaged patients in whom UN could not be properly assessed due to severe dysphasia. Discussions of this issue can be found in De Renzi (1982, pp.90-94) and Ogden (1987). At any rate, the greater incidence of UN and anosognosia following right brain damage seems to be unequivocally demonstrated by observations following unilateral electroconvulsive therapy (Altman et al., 1978) and intracarotid barbiturate injection (Breieretal., 1995; Carpenter etal., 1995; Gilmore et al., 1992;Spiers et al., 1990).

Intrahemispheric localisation Overall, clinico-anatomical studies so far available have confirmed the clinical opinion that in human subjects UN is usually the consequence of damage to the parietal cortex; more precisely, to the inferior parietal lobule. Well known, however, are cases in which the lesion is apparently confined to other structures, such as the frontal lobe or subcortical grey matter (thalamus, basal ganglia). Cases may be found with extensive parietal damage free from apparent manifestations of UN. More frequent are instances of absence of UN following frontal lesions. Such exceptions may in part be interpreted in terms of interindividual variability in the cortical organisation of spatial representation; a further hypothesis is based on presence/absence of decreased blood flow in the cortex ipsilateral to the lesion but not directly affected by it (see Perani et al., 1987). An extended treatment of clinicoanatomical correlates of UN may be found in Vallar and Perani (1987). The reader is also referred to Rizzolatti and Camarda (1987) for an interpretation of neurobehavioural correlations in animals.

THE COURSE OF UNILATERAL NEGLECT UN and related disorders are most commonly due to acute diseases of the brain that do not allow pari passu functional compensation (such as vascular lesions, trauma, or rapidly growing tumours). In a

large majority of cases, the symptoms recede more or less rapidly and completely during the days or weeks following their sudden appearance. This is especially true of anosognosia and somatoparaphrenia, which often only last a few hours or days after a stroke. Instances in which UN phenomena still impair the patient’s behaviour after months or even years are much less frequent. In such cases, a most worrying consequence is the mild disregard of contralesional motor impairment (anosodiaphoria) that may hinder rehabilitation programmes. The mechanisms through which functional restoration or compensation of UN and related disorders take place are still unclear; their understanding constitutes a weighty challenge, both for practical and theoretical purposes. However, restoration and compensation are likely to be provided by structures in the unimpaired hemisphere, as well as by surviving circuits in the hemisphere whose damage had given rise to these disorders (Bisiach & Vallar, 1988).

INTERPRETATION OF THE SYNDROME A satisfactory interpretation of UN and allied disorders cannot ignore the interhemispheric functional asymmetries responsible for the difference between left and right brain-damaged patients regarding incidence and severity of these disorders. A short comment on what has already been said in this connection is therefore necessary before reviewing the different types of explanations so far suggested. A point open to question is the disparity of data resulting from different assessments. One source of disparity is the variety of diagnostic means. Tests involving verbal instructions, for example, may prove inapplicable with left brain-damaged patients due to co-occurring dysphasia. This may lead to false estimates of prevalence of left UN when large samples of left and right brain-damaged subjects are compared. By contrast, results of tests sensitive to minimal forms of neglect, which might equally often occur following left and right hemisphere lesions, would run against clinical wisdom according to which severe UN is much more severe

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following lesions of the right hemisphere. As previously mentioned, however, true hemispheric asymmetries in the pathogenesis of UN and related disorders have been demonstrated by studies based on unilateral electroshock and intracarotid barbiturate injection. Furthermore, these asymmetries are paralleled by hemispheric asymmetries concerning lateral attention found in normal subjects by different authors and through different means (see Bisiach & Vallar, 1988, for a concise review).

Interpretations concerning elementary levels of central nervous activity Albeit somewhat simplistically, three kinds of relatively “peripheral” interpretations may be outlined: 1. Reduced or interfered transfer of sensory information. The clearest example is analogous to the interpretation given by some authors regarding extinction. It may be summarised as follows: a single stimulus addressed to the damaged hemisphere is more or less properly perceived, provided the lesion is not such as to interrupt it altogether; if given in association with another stimulus addressed to the uninjured hemisphere, however, that stimulus undergoes suppression. By generalising this paradigm to the set of stimuli that are at any given time simultaneously sent to the brain from its somatic and extrasomatic environment, UN is viewed as a more or less global extinction of sensory information from the side opposite to the damaged hemisphere (Bender, 1977). According to a more sophisticated (but less definite) version, UN is due to lack of synthesis of manifold elementary stimuli that in normal condition give rise to complex perceptions (Denny-Brown et al., 1952). 2. Impaired exploration of egocentric space due to low-level dysfunction. This interpretation has never been explicitly stated. It alludes to an impairment of eye movements towards the side opposite to the brain lesion, which according to some authors may be found, to varying degrees, in the majority—about 85%—of patients suffering from UN. This interpretation, of

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course, cannot explain neglect phenomena unrelated to visual perception and exploration. 3. Impairment of orienting reflex toward contralesional stimuli. This hypothesis, pointing at relatively low levels of sensorimotor integration, has been incorporated by Heilman and co-workers into a complex model of spatial attention that will presently be considered. These three types of interpretation refer to impaired processing of stimuli originating from outside the central nervous system. Therefore, they lost most of their validity after it was ascertained that neglect may be found at the level of mental imagery (Bisiach & Luzzatti, 1978). This does not necessarily entail that mechanisms considered by these hypotheses play no role whatsoever in the pathophysiology of UN. For instance, it has been found that, in patients in whom UN was associated with hemianopia, exploration of the contralesional side of space was more impaired under conditions of visual control than when the latter was prevented (Chedru, 1976; Gilliatt & Pratt, 1952).

Attentional interpretations Considering the risk of conceptual confusion when dealing with terms such as “attention” and “representation”, it is convenient to state two important caveats. One of them will be stated in linking up attentional and representational explanations. The other one is stated here as a premise to what follows. In brief, it is a warning against fallacious claims reducible to the (obviously caricatural) circular assertion: “Patients suffering from UN do not pay attention to one side of space; UN is therefore a disorder of attention”. In other words, it is of essence to avoid confusion between using the term “attention” as behaviour-related operational definition and explanatory hypothetical construct, which is such only in so far as it provides a model of the mechanisms underlying a particular behviour. Two attentional models, one by Kinsboume and the other one by Heilman and his co-workers, are most frequently implicated in interpreting UN. The first one was originally outlined in merely functional terms (Kinsbourne, 1970), but it can easily be reformulated in neurophysiological terms. Briefly stated, it posits two antagonistic vectors,

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each one depending on one side of the brain and directing attention toward the opposite side of space. The two vectors are held not to be exactly equivalent in the normal brain: the one related to the left hemisphere predominates, so that, other conditions being equal, the right side of space is attentionally privileged. This assumption is supported by a number of observations of normal human behaviour in natural conditions, as well as by experimental data provided by several investigators (see Kinsboume, 1987, for a review). A further assumption of Kinsbourne’s model is that selective involvement of one cerebral hemisphere in current mental activity (e.g. the involvement of the left hemisphere in verbal activity, or the right hemisphere in visuospatial tasks) enhances the corresponding vector at the expenses of the opposite one. This assumption too is supported by experimental data from normal subjects (e.g. Kinsbourne, 1975, p.83). Kinsboume’s model therefore predicts that damage to critical circuits within one cerebral hemisphere causes impairment of the corresponding vector and, consequently, pathological imbalance of attention toward the side ipsilateral to the lesion. If the lesion is located in the left hemisphere, the imbalance is less pronounced because it releases the weaker right-hemisphere vector. By contrast, if the right hemisphere is impaired, the physiologically predominant left-hemisphere vector is released and spatial attention is more vigorously pushed towards the right side, to the detriment of the left which is therefore subject to neglect. This does correspond to clinical findings. More questionable is whether manifestations of UN become more severe when patients engage in activities selectively sustained by the uninjured hemisphere; so far, there is no definite evidence that left neglect be enhanced by the patient’s verbal activity and reduced during the execution of visuospatial tasks held to selectively engage the right hemisphere. Heilman’s model has been explicitly conceived in neurological terms. According to it, each hemisphere is endowed with its own attentional system, composed by a complex reticulo-thalamocortico-limbic circuit. In its early version, the model assumed that the attentional system of the right hemisphere covered the whole egocentric space,

whereas the attentional system of the left hemisphere was only related to the right half. Accordingly, damage to the critical structures of the left hemisphere would not entail severe right neglect, because rightward attention would still be ensured by the right hemisphere. Lesion of the latter, by contrast, would leave the patient unable to attend to the left half of space. As such, Heilman’s model entails that UN is a (uniform) deficit of attention delimited by a sharp boundary. As we shall see, this does not exactly correspond to clinical findings. A possible overcoming of this discrepancy is however suggested in a later elaboration of the original model (Heilman et al., 1987a, p.37). A more exhaustive treatment of Kinsboume’s and Heilman’s conceptions may be found in these authors’ recent writings (Heilman et al., 1987a; Kinsboume, 1987, 1993). An interesting suggestion concerning neural mechanisms implementing the distribution of attention along the left-right axis has been offered by single-neurone neurophysiology. Rizzolatti and his co-workers (1985) found that in the monkey’s postarcuate cortex (whose lesion gives rise to contralateral neglect) 29% of neurones have exclusively contralateral, 3% exclusively ipsilateral, and 68% bilateral receptive fields. Bilateral receptive fields are always located astride the midline and their horizontal extent is not uniform. In agreement with Kinsboume’s directional (as opposed to Heilman’s hemispatial) model, this finding suggests that following lesion of one hemisphere focal attention is impaired along the entire left-right dimension of space, with a continuous gradient ranging from maximum to minimum severity in the most peripheral contralesional and ipsilesional areas, respectively. This is also in agreement with behavioural findings such as the already mentioned paradoxical extinction within the right hemifield of left neglect patients. A model based on the finding by Rizzolatti et al. can be adjusted so as to be compatible with the hemispheric asymmetry of UN in man (see Fig. 3 in Bisiach & Vallar, 1988). Other interpretations of UN in attentional terms have been given by Mesulam (1981), Posner et al. (1982), and Roy et al. (1987). The reader is referred to these authors’ writings for details. Considering

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the implications of recent findings that will be reported later, it is however worth noting that according to Posner et al. the basic disorder underlying UN is an impaired disengagement of attention from stimuli located on the ipsilesional side of space.

Representational explanations The earliest thoughtful attempt to give an interpretation of phenomena that constitute UN, or are bound to it by still poorly elucidated syndromic relationships, was published by Zingerle in 1913; it was conceived in terms of mental representation (Bisiach & Berti, 1987). Afterwards, other authors followed this (or a similar) line of interpretation, by referring to concepts such as body scheme (Head, 1920) and scheme for external space (Brain, 1941). A disorder of one half of these schemata was held responsible for UN (see Bisiach, 1993). Following a period of relative oblivion, a series of observations made during the last two decades has revived the representational interpretation of UN and phenomena such as anosognosia, somatoparaphrenia, etc.; it was indeed demonstrated that UN does not only manifest as a deficit of perception and exploration of one side of the somatic and extrasomatic environment, but also as a deficit of the endogenous mental representation of the latter. As already mentioned, patients asked to remember and describe a familiar view from a determinate vantage point may neglect contralesional details. This was found by asking patients to imagine and describe a town square (Bisiach & Luzzatti, 1978; Bisiach et al., 1981), the map of their country (Barbut & Gazzaniga, 1987; Halsband et al., 1985) or the layout of their home (Bisiach & Luzzatti, 1978; Meador et al., 1987). A similar finding was observed in two left neglect patients who were unable to correctly spell the first letters of words pronounced by the examiner (Barbut & Gazzaniga, 1987; Baxter & Warrington, 1983). Baxter and Warrington observed the phenomenon in forward, as well as in backward, spelling. These findings suggest that patients were spelling words on the basis of a visuospatial (rather than auditory) representation, as if words were laid on an imaginary screen of which the left side was clouded.

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Comparable data were obtained in a condition in which the content of mental representation was drawn from short-term memory. The experiments leading to this conclusion were very simple. Patients suffering from UN were first shown pairs of horizontally elongated meaningless shapes. The members of each pair were given one after the other and were identical or different either on the left or the right side. Patients had to decide whether the shapes were identical or different. As expected they gave correct responses when the two shapes were identical or differed on the ipsilesional side, while often misjudging as identical shapes that differed on the contralesional side. In the second part of the experiment, the shapes were not stationary and exposed to unconstrained view as in the former condition. They were shown while moving left- or rightward behind a screen with a narrow vertical slit that limited vision to only a segment of the stimulus, whose global configuration had therefore to be reconstructed through a mental process of spatio-temporal integration. Despite the fact that in this condition each portion of each shape could be perceived in central vision, the contralesional side of mentally reconstructed configurations was neglected and the patients’ same/different judgements were prone to the same type of error found in the first part of the experiment (Bisiach et al., 1979; Ogden, 1985b). It is worth noting that UN may be evident in visual imagery tasks, though undetectable by a score of visuoperceptual tasks (Guariglia et al., 1993). A most important (though often disregarded) point is that the demonstration of UN at the level of internally generated mental representation does not ipso facto entail that interpretations of the disorder in attentional terms are inadequate. It only entails that the concept of attention can be referred to mental contents, independently of whether they arise from current sensory input or endogenous brain activity. When referred to contents that are not directly sensory-driven, attention might metaphorically be likened to a searchlight exploring details of the mental representation and UN might accordingly be interpreted as a disordered survey of a normal representation. This interpretation would be unsatisfactory for at least three reasons: (1) In so far as positing besides the hypothetical construct

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“representation” a further hypothetical construct relative to the survey of the former, it runs against the principle of ontological economy (Occam’s razor); (2) It views representation as something that is given to the cognitive system much in the same way as the external world is given to our sensory organs; (3) It tacitly entails a surveying Homunculus (the mind’s eye) that is either unsusceptible to further analysis, or leading to infinite regression if it is implied that its survey must be guided by a second-order representation. If we want, as is often the case, to use the term “attention” both in the description and the interpretation of neglect phenomena, nothing prevents us from extending this term to the processes of generation and transformation of mental representations; representational neglect would therefore be defined as a spatially circumscribed disorder of attention in the sense of inadequate generation and re-elaboration of the contralesional side of a representation whose content includes spatial attributes. The concept of attention would thus refer to the dynamics of representational processes themselves, rather than to separate processes; it would therefore be a concept abstracted from the concept of representation. It follows that contraposing attentional and representational theories of UN would be an evident mistake of scientific logic (Bisiach, 1993). At any rate, interpretations in exclusively attentional terms would scarcely suit productive phenomena of contralesional misrepresentation associated with UN (see later).

Perceptual and premotor factors A possible distinction between perceptual and premotor components in the pathophysiology of UN was suggested by Watson et al. (1978). The term directional hypokinesia (Heilman et al., 1985) was used to designate the patient’s reluctance to initiate and carry out movements toward the contralesional side of space, independent of the side of the limb(s) involved in those movements. The phenomenon may manifest as absence, delayed inception, slowed execution (bradikinesia), and/or reduced amplitude (hypometria) of movement. It may also manifest as inability to sustain activity on the contralesional side of space, e.g. when patients are required to start

cancellation tasks from the contralesional side of the stimulus array (Bisiach et al., 1995). Recent attempts to unequivocally ascertain the differential contribution of perceptual and premotor dysfunction in the causation of UN have given positive results, whose interpretation is however still very problematical (Bisiach etal., 1990b, 1995; Tegner& Levander, 1991). On the one hand, in fact, it might be claimed that all neglect phenomena revealed by tasks such as those so far employed may be due to premotor dysfunction, selectively affecting either limb- or eye-movements, or both. The problem is greatly complicated by the fact that no sharp divide exists between perceptual and premotor processes. Results recently obtained by means of an auditory task (Sterzi et al., 1996), and especially by means of Milner’s “Landmark test” (Milner et al., 1992, 1993), are in support of the existence of true input-related and output-related components of neglect. A satisfactory assessment of this important issue, however, must wait for further investigation and speculation.

Recent challenges to current interpretations of UN In a recent study (Bisiach et al., 1994), two patients suffering from left neglect were asked to mark the endpoints of a virtual 18cm long horizontal line on the basis of its midpoint, printed in the middle of a sheet of paper. Both patients were found to make a systematic error: they misplaced both endpoints leftward with respect to the centre. Similar results were recorded by asking patients to extend linear segments so as to double their original length (Chokron et al., 1997; Ishiai et al., 1994a, 1994b). In all these experiments, therefore, the result of the task reproduced the disproportion usually found with UN patients on canonical line bisection. Nonetheless, the action leading to such a disproportion in these experiments runs against interpretations of UN in terms of: (1) Ipsilesional distortion of attention; (2) Defective disengagement of attention from ipsilesional stimuli; (3) Inability to represent the side of space opposite to the brain lesion; (4) Directional hypokinesia. These data suggest that a basic feature of the dysfunction underlying unilateral neglect may be a directional disorder of the metrics of the brain’s

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representational medium, such that the left-right axis is set, as it were, on a logarithmic scale with relative expansion on the contralesionai and contraction on the ipsilesional side (Bisiach et ah, 1996). Accordingly, any object confronting that scale would subjectively shrink on the contralesional and stretch out on the ipsilesional side. Thus, for example, if a horizontal segment were to be bisected with reference to the logarithmically distorted scale, its subjective midpoint would lie (according to Euclidean metric) nearer to the right than to the left endpoint. Apart from a few problematical exceptions, this is indeed the typical error made by left neglect patients. This hypothesis can easily account for data such as those recently published by Milner and Harvey (1995): left neglect patients were found to underestimate the horizontal extent of stimuli presented on the contralesional side of their egocentric space. A further challenge to current explanations of neglect is the “cross-over” effect, a puzzling phenomenon first discovered by Marshall and Halligan (1989) and then confirmed by other authors: the typical rightward error made by left neglect patients on bisection of horizontal lines reduces and then reverses with progressive decrease of line length (see Marshall & Halligan, 1990, and Chatterjee, 1995, for tentative explanations). Anderson (1996) has recently published a simple and neurologically plausible mathematical model apt to explain Marshall and Halligan’s crossover phenomenon, and the results of Bisiach et al. (1994) with the virtual line endpoints task, as well as those obtained by Harvey et al. (1995) with the landmark test. Although Anderson’s model requires further validation (and, in all likelihood, elaboration) vis-à-vis aspects of UN he has not yet considered, it is undoubtedly a first interesting step toward the understanding of data that seem, so far, to defy unitary explanation.

SPATIAL FEATURES This section only gives a concise overview of an area in which a great number of important contributions have appeared in recent years. The

interested reader may find wider and more updated information elsewhere (Bisiach, 1997).

Spatial frames in the frontal plane Left and right may be defined with respect to different, ego- and allocentric, co-ordinate systems. Regarding egocentric frames, UN could in principle be related to frames centred on the sagittal midplanes of the patient’s head or trunk, to a retinotopic frame, or to a frame centred on the axis of a limb ready to engage in any action in its workspace. Neglect relative to the trunk’s sagittal midplane was first demonstrated by Heilman and Valenstein (1979): the rightward bisection error made by patients suffering from left neglect was found to be larger with lines to the left than with lines to the right of that plane. This finding was largely confirmed by other investigators. Bisiach et al. (1985b) gave left neglect patients a fourcondition tactile exploration task without visual control: the stimulus array was located at 0° or 60° to the right with respect to the trunk’s sagittal midplane, with gaze conjointly or disjointly directed straight ahead (0°) or 60° to the right. It was found that the spatial gradient of neglect was unrelated to the axis of the exploring limb, but related to the trunk’s sagittal midplane as well as to the line of sight. The two frames were not mutually exclusive, but there was a double dissociation: two patients showed neglect relative only to the trunk’s sagittal midplane, while one patient showed neglect relative only to the direction of gaze. Kooistra and Heilman (1989) reported a case in which neglect was related both to the head’s and the trunk’s sagittal midplane—the head being kept unrotated with respect to the trunk—and to retinotopic coordinates; the patient, indeed, behaved as if she had left hemianopia when looking straight ahead or 30° to the left, whereas no visual field defect was evident when she looked 30° to the right. Given that in the experiment by Bisiach et al. (1985b) patients were free to move their heads, it was not possible to assess whether neglect was head-centred or retinotopic; in the study by Kooistra and Heilman, by contrast, the sagittal midplanes of head and trunk were always coinciding, which did not allow distinguishing between head- and trunk-related neglect. To summarise, it has been shown that in UN left and

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right may be defined in terms of retinotopic coordinates, as well as in terms of trunk-centred coordinates. As for a co-ordinate system centred on the head’s sagittal midplane, no attempt has so far been made to disentangle it from retinotopic and trunk-centred systems. Finally, regarding a possible reference system centred on the axis of a limb in its workspace, there are so far only the negative results of Bisiach et al. (1985b). Concerning allocentric coordinates, i.e. coordinates relative to the way stimulus arrays are parsed into perceptual units, Apfeldorf (1962) had already noted that UN may affect the contralesional side of separate components of a complex figure drawn by the patient, rather than the contralesional side of the entire drawing. In the same year, Kinsbourne and Warrington (1962c) demonstrated that left neglect and pathological completion could be observed even when patients had to read words tachistoscopically presented in the right visual hemifield, despite the integrity of the pathways conveying visual information from that hemifield to the brain. A few years later, it was observed that in reading a text patients may neglect (or wrongly complete) the contralesional side of single words, rather than the contralesional side of the whole page (Schott et al., 1966); the same may happen when patients are asked to copy a series of drawings aligned from left to right (Gainotti et al., 1972b). Of special interest is the case described by Caramazza and Hillis (1990a): NG, a left brain-damaged patient with right neglect, neglected or miscompleted the terminal segment of words he was asked to read even when words were printed vertically or mirror-reversed. Observations demonstrating the involvement of allocentric frames in neglect have multiplied in recent years (e.g. Driver & Halligan, 1991). A striking one has been published by Halligan and Marshall (1993): patients may neglect the left flower in copying the picture of two flowers originating from a single stem, while neglecting the left side of each flower if the common stem is erased from the model. The most amazing instance, however, is perhaps the following: patients who are unable to detect obvious differences on the contralesional side of a pair of otherwise identical pictures are still unable to detect them when they faultlessly trace, on the examiner’s request, the outline of each picture (Bisiach &

Rusconi, 1990; Vallar et al., 1994b; see also Young et al., 1992, for a related finding). In the same way in which different egocentric frames may conjointly be involved in neglect, different allocentric frames may combine, so that, for example, patients who globally neglect the left side on Albert’s cancellation task may neglect the left side of lines they do not miss by crossing them out with strokes that are systematically nearer to the right endpoint (Bisiach, 1997). It is important to note that, also in the case of allocentric reference, left and right are always contingent upon the perceiving subject and, therefore, the distinction between ego- and allocentric systems is not absolute. Furthermore, the interaction between these two kinds of systems is demonstrated, for example, by the fact that patients who neglect the left side of a visual array in upright position may neglect the same area after clockwise or counterclockwise 90° rotation of their heads in the frontal plane, in combination with the area that after rotation lies on their left in terms of retinotopic coordinates (Behrmann & Moscovitch, 1994; Calvanio et al., 1987; Farah et al., 1990; Ladavas, 1987). To conclude, data collected from patients suffering from UN suggest that space representation is a complex process in which manifold components may be envisaged. Our phenomenal experience of a unitary space is likely to depend on unifying factors such as gravity, which confers a canonical orientation both regarding the perceiving subject and the perceived object or stimulus array, and a drive toward the alignment—through processes of mental rotation, translation, etc.—of the different systems of spatial reference in a unitary virtual system whose composite character is revealed by the study of UN and related disorders.

Proximal and distal frames of reference Further complication in the construction of space representation is added by the distinctness of frames related to the perceiver’s body itself, to its immediate surroundings and farther environment. Somatic and extrasomatic neglect were assessed by Bisiach et al. (1986a) in a large group of right brain-damaged patients. Neglect phenomena were more frequently, and sometimes exclusively, found in the extrasomatic domain; nonetheless, one

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patient who showed severe body-part neglect was exempt from neglect of extrasomatic space. A similar dissociation was found by Guariglia and Antonucci (1992). Rizzolatti et al. (1983, 1985) demonstrated a double dissociation between somatic-perisomatic and extrasomatic neglect after lesion of different cortical areas in the monkey. Lesion of postarcuate area 6 or inferior parietal lobule (Area 7b, intimately connected with Area 6) was found to cause contralateral bimodal (tactual and visual) neglect of stimuli near to the mouth, but not of stimuli that, though located in the very same area of the visual field, were beyond reaching distance. The converse was found following lesion of prearcuate Area 8. Halligan and Marshall (1991) described a patient who showed neglect in bisecting lines close to his body while accurately bisecting, by means of a light-pointer, lines that subtended the same visual angle though being located more than two metres apart. Pizzamiglio et al. (1989b), by contrast, found no evidence of dissociation between proximal and distal neglect by using a test that did not involve manual responses; they therefore suggested that such a dissociation could only concern attentional mechanisms closer to motor output than to sensory input.

The gradient of neglect The typical performance of UN patients on cancellation and drawing tasks is very often suggestive of a sharp gradient between an area within which the patient’s attention is uniformly distributed and an area uniformly subject to neglect. This may be false, however. A progressive decline of attention from the ipsilesional to the contralesional side might reach a critical point, so that on one side of it performance may still appear to be normal while being immediately and completely disrupted on the opposite side. Several data have been interpreted as evidence of a continuous gradient of neglect, i.e. of a gradient that is always present between any two adjacent points, wherever located on the left-right axis. On close consideration, some of those data appear to be equivocal (Bisiach, 1997). There are nevertheless at least two findings that seem unambiguosly to support the hypothesis of a continuous gradient: (1) The location in the coronal plane of the auditory

image resulting from fusion of dichotic stimuli of equal frequency but variable intensity-ratio is systematically pushed, in UN patients, toward the side of the lesion, with no discontinuity along the left-right axis (Altman et al., 1978; Bisiach et al., 1984); (2) In patients suffering from UN, the execution time of discrete movements along a horizontal array of targets, to be touched one after another by the patient’s fingertip, shows a smoothly progressive increase from the ipsilesional to the contralesional side (Mattingley et al., 1992).

Altitudinal neglect Neglect of upper or lower visual space was found in the cat after lesion of different sectors of the mesencephalic system (Matelli et al., 1983) and suggested in patients suffering from progressive supranuclear ophthalmoplegia (Posner et al., 1982). Evidence of altitudinal neglect was then found in patients suffering from bilateral brain damage. In two instances, it was relative to the lower area of space (Butter etal., 1989; Rapcsaketal., 1988b);in two other instances it involved the upper area (Henaff & Michel, unpublished; Shelton et al., 1990). None of these cases can be interpreted in terms of sensory disorders because neglect was evident in the tactile modality (i.e. on bisection of solid line segments with closed eyes), as well as in the visual modality, or relative to the upper part of a visual stimulus, independent of its location with respect to the horizontal meridian of the visual field. These data are most important because they confirm the topological relationships between brain structures and space representation: in the same way as left and right neglect may follow right and left hemisphere damage, respectively, upper and lower altitudinal neglect could be caused by bilateral lesion, depending on its location—ventral or dorsal, respectively—within posterior brain areas.

INFLUENCE OF STIMULATION Vestibular stimulation Transitory changes of visuospatial neglect following vestibular stimulation were occasionally observed (Marshall & Maynard, 1983;

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Silberpfennig, 1941) and then confirmed by Ruben’s (1985) systematic investigation. Rubens reported temporary mitigation of the disorder after cold-water irrigation of the contralesional, or warmwater irrigation of the ipsilesional ear. Opposite manoeuvres— contralesional warm-water and ipsilesional cold-water irrigation—led to temporary worsening of neglect. The phenomenon cannot be explained as being due to oculomotor responses to vestibular stimulation, because it was later observed with body-part neglect independent of visual control (Cappa et al., 1987c) and visual imagery neglect (Geminiani & Bottini, 1992; Rode & Perenin, 1994). Vallar et al. could obtain temporary mitigation of somatosensory deficit attributable to neglect by means of vestibular stimulation (1990, 1993b). In some instances, vestibular stimulation was also found to affect anosognosia related to hemiplegia (Cappa et al., 1987c; Geminiani & Bottini, 1992; Vallar et al., 1990b) and somatoparaphrenic delusions (Bisiach et al., 1991; Ramachandran, 1995; Rode et al. 1992).

Ophthalmokinetic stimulation Amelioration and worsening of UN on line bisection was found by Pizzamiglio et al. (1990b) during ophthalmokinetic stimulation (OKS) toward the contralesional and ipsilesional side, respectively. The effect is likely to be independent of improved visuoperceptual scanning of stimuli, because, like the effect of caloric vestibular stimulation, it was also observed with respect to somatosensory deficit attributable to neglect (Vallar et al., 1993). It is worth remarking that Pizzamiglio et al. (1990b) found a double dissociation between the effects of caloric vestibular stimulation and OKS on line bisection.

Proprioceptive stimulation Transitory remission and worsening of UN was also obtained by mechanical vibration of posterior neck muscles on the contralesional and ipsilesional side, respectively (Kamath et al., 1993; Karnath, 1994). The effect has been shown by Kamath (1994) to be additive to the effect of vestibular stimulation. Similar results were obtained by Vallar and coworkers (e.g. Vallar et al., 1995b) by means of

transcutaneous electrical (TENS) of neck muscles.

neural

stimulation

Conclusions Taken together, the influence of vestibular, ophthalmokinetic, and proprioceptive stimulation may help in probing neural mechanisms of neglect and related disorders in complex ways that are still difficult to envisage, and with results that would raise further interesting questions. A pertinent example are the results recently obtained by asking neglect patients to set the endpoints of a virtual horizontal line (see earlier) during OKS. Contralesional OKS was found to exacerbate, rather than reduce the abnormality of neglect patients’ performance (see Bisiach et al., 1996, for an interpretation of this puzzling result).

ANOSOGNOSIA Unawareness and explicit denial of illness may accompany many different disorders (Weinstein & Kahn, 1955) and are therefore likely to reflect heterogeneous dysfunctions. In this chapter, the term “anosognosia”, is exclusively used to refer to conditions in which unawareness and denial of neurological disorders may be considered as a component of such disorders, rather than the symptom of accessory, nonspecific, and pervasive dysfunctions such as mental deterioration, confusion, and reduced arousal. This operational definition of anosognosia includes unawareness-denial of unilateral neurological disorders—hemiplegia, hemianopia and hemianaesthesia—that have problematical relationships with UN. These are, therefore, the only manifestations of anosognosia considered in this chapter. The reader interested in a more comprehensive overview is referred to the book edited by Prigatano and Schacter (1991).

Clinical features The first observations of anosognosia relative to hemiplegia were made around the end of the 19th and the beginning of the 20th century (Anton, 1893; Pick, 1898;Zingerle, 1913). Babinski (1914,1918)

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coined the term when he first defined unawareness-denial of hemiplegia. Since then, the phenomenon has been the subject of a great number of studies, while less attention has been devoted to anosognosia relative to hemianopia and, particularly, unilateral somatosensory impairment. Assessment Any attempt to quantify unawareness of disease (e.g. Bisiach et al., 1986b) runs into substantial difficulties. First and foremost, anosognosia appears in association with neurological impairment whose severity is largely variable from patient to patient. The coherence of any scores in evaluating the severity of anosognosia is therefore limited to patients showing the same degree of impairment. Second, apart (perhaps) from cases in which the patients’ attention to impaired bodyparts is apparently normal or even exalted, it is not possible to distinguish anosognosia from UN, of which it may appear to be one among the consequences. This problem, however, does not arise if anosognosia and UN are considered aspects of a single underlying dysfunction. Incidence The difficulties inherent in the assessment of anosognosia entail the impossibility of exactly defining the general incidence of the disorder. As for its incidence with respect to the side of the brain lesion, difficulties are even greater. However, despite contrary opinions based on the likely underevaluation of the disorder in left braindamaged patients because of the presence of dysphasia, the majority of clinicians share the view that anosognosia is definitely more fequent following lesions of the right hemisphere. This asymmetry has been confirmed by studies based on intracarotid barbiturate injection (Breier et al., 1995; Carpenter et al., 1995; Gilmore et al., 1992). As regards right brain-damaged patients, a rough estimate of the incidence of anosognosia may be found in the survey by Bisiach et al. (1986b). Medium and severe anosognosia was found by these authors to be present in 12 out of 36 patients with severe motor impairment of their left upper limbs. Unawareness-denial of left hemianopia was found to be much more

frequent: 28 out of 32 patients. A similar proportion was reported by Hecaen (1972) regarding anosognosia relative to motor impairment, while authors who used less strict criteria reported higher frequencies. Associations and dissociations Anosognosia relative to hemiplegia is very frequently associated with somatosensory impairment. There are cases in which a complete absence of the latter was reported, but no watertight demonstration of this crucial dissociation has so far been given. Also very frequent is its association with hemianopia. Somatic and extrasomatic UN is very often, but not invariably, found in patients showing unawareness-denial of hemiplegia and/or hemianopia (Bisiach et al., 1986b). When hemiplegia and hemianopia co-occur, anosognosia is usually more severe regarding the latter. It is worth noting the possible disproportion of anosognosia with respect to upper vs. lower limb paralysis: out of five patients in whom the disproportion was evident, anosognosia was found to be more severe with respect to the lower limb in four patients and to the upper limb in one (Bisiach et al., 1986b). In consideration of the important theoretical implications, it is worth emphasising that general intellectual impairment of various degrees is frequent in anosognosic patients, but not necessarily present. On the other hand, as stressed by Angelergues et al. (1960), severe general intellectual impairment does not necessarily entail unawareness of neurological hemisyndromes. Evolution Even in want of systematic investigations, there is no doubt that, in the great majority of patients, severe anosognosia relative to hemiplegia appears at the same time as the acute disease that causes it, but abates in a few hours or days, more rapidly and completely than UN. Chronic cases, however, are also on record. Anatomy For the time being, neurophysiological and neuroimaging data have not revealed definite differences between anosognosia and UN regarding

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the site of the responsible lesions. In particular, the sparing of frontal lobes in many well documented cases must be underlined . As with UN, there is no totally satisfactory explanation for the lack of anosognosia in some cases with massive lesions of the right hemisphere.

Interpretation A tentative unitary interpretation will be outlined after a short description of somatoparaphrenic phenomena. Nevertheless, it is first of all convenient to clear the ground of two kinds of interpretation based on nonspecific and pervasive factors such as the impairment of critical self-observation and evaluation and the hypothetical psychodynamic mechanism suppressing mental representation of a grievous condition. It has already been remarked that anosognosia is double-dissociated from severe intellectual impairment. Against an interpretation in terms of general intellectual deterioration is also another double dissociation —see later—by which knowledge of one’s own disease may be absent in verbal but deducible from nonverbal behaviour, or vice versa. Finally, interpretations in terms of defective self-observation and evaluation are also undermined by some of the arguments against psychodynamic interpretations. Such arguments are manifold and cogent; they have been listed elsewhere (Bisiach & Geminiani, 1991) and will not be reiterated here.

SOMATOPARAPHRENIA Focal brain damage, especially when it affects the right hemisphere, may give rise to delusional beliefs concerning the contralesional side of somatic and/or extrasomatic space. These productive phenomena of delusional misrepresentation were already well known before their classical description given by Gerstmann (1942), who coined the term “somatoparaphrenia” with reference to those (relatively much more frequent) related to the contralesional side of the body. As evident since the earliest observations

(Anton, 1893; Pick, 1898; Zingerle, 1913), these phenomena may be found in association with the merely defective phenomena of UN. Although somatoparaphrenia is much less frequent than UN and anosognosia, any clinical neurologist is familiar with some at least of its multifarious manifestations. Patients affected by somatoparaphrenic delusions usually disown the paralysed limbs. They claim their contralesional limbs—thenupper limbs, in most cases—to belong to the doctor, or a relative, or to another patient formerly lying in the same bed in which they are confined, etc. These absurd beliefs are often in extremely striking contrast with the intact rationality of all other thought processes, with respect to which they may be sharply segregated and totally impenetrable. Examples are patients LA-0 and PR (Bisiach & Geminiani, 1991, pp.32-34), and GH (Halligan et al., 1995). In some instances, the patient’s absurd beliefs are amazingly expressed with no apparent emotional involvement; less frequently, the patient is visibly annoyed or even irritated by the alien limb(s) and insistently demands removal of the disgusting “thing”. In rare instances, the patient’s repugnance is such as to require physical constraint in order to prevent violence against contralesional body-parts; these are the extreme instances of what has been termed by Critchley (1974) misoplegia. There are also episodic observations of patients who simply deny the existence of one limb or of one side of the body (Gooddy & Reinhold, 1952), or claim that one side of the body has been substituted by some kind of nonorganic structure (Ehrenwald, cited by Hecaen et al., 1954). A patient was also described who not only denied ownership of her left hand, but also of the rings worn by that hand (Aglioti et al., 1996).

DYSCHIRIA AND ITS INTERPRETATION If UN and productive manifestations of disordered representation of the contents of one side of egocentric space were to be considered different aspects of a unitary syndrome, i.e. reducible to dysfunction of a definite component of higher

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nervous activity, any interpretation of UN in terms of merely attentional deficit would be unsatisfactory. A more comprehensive interpretation would more adequately be contrived in terms of a representational disorder manifesting through defective (UN) and/or productive symptoms (such as somatoparaphrenia). The term dyschiria (from Greek cheir. “hand” and in wider sense “side”), adopted by Zingerle in 1913, may conveniently designate the conjunction of these two aspects of the (putative) unitary syndrome. It remains to be settled the extent to which the two orders of symptoms, defective and productive, reflect a unitary disorder. For the time being, there are at least three arguments supporting a unitary conception: two empirically and one theoretically based. The first empirical argument comes from important observations made in the cat by Sprague et al. (1961). Following lateral brain stem lesion that did not involve the reticular formation, these authors observed abnormal behaviour characterised by a composite of UN and unilateral stereotyped overexploration, interpreted by them as consequent to hallucinatory activity. Defective and productive symptoms were suggested to result from deafferentation of superordinate neural structures functionally connected with the lesioned area. The deafferentation would cause functional paralysis of such structures and release of autochthonous activity uncontrolled by a normal flow of sensory input. The second empirical argument is based on the observations reported earlier: vestibular stimulation may not only remove neglect phenomena but also explicit denial of hemiplegia and even somatoparaphrenic delusions. The theoretical argument is based on a neural model whose distinct lesions can mimic defective and productive phenomena of contralesional misrepresentation (Bisiach & Berti, 1987, 1995). The model shows that, in principle, it is possible to envisage a unitary interpretation of UN and phenomena ranging from pathological completion in reading and drawing (for recent data and speculation see Halligan & Marshall, 1994, and Chatterjee, 1995) to complex manifestations of somatoparaphrenia and similar delusions about the contralesional side of extrasomatic space.

IMPLICATIONS FOR COGNITIVE SCIENCES Dyschiria may or may not turn out to be accepted as a unitary syndrome. However, independent of whether they are better described as reflecting different disorders of an individuate neural subsystem or occasionally associated when lesions involve heterogeneous circuits, UN and productive manifestations of contralesional misrepresentation have important theoretical implications for the understanding of cognitive processes. Only an outline of these implications is offered here; the interested reader may find wider treatment elsewhere (Bisiach, 1988a, b, 1991c, 1995; Bisiach et al., 1985a; Bisiach & Berti, 1987, 1989, 1990, 1995; Bisiach & Geminiani, 1991; Brewer, 1992; Kinsboume, 1988, 1993). In the first place, data collected from patients suffering from UN provide a principal clue for the understanding of the structure of mental representation. It has been long and punctiliously debated whether mental representation consists in (linguistic or quasi-linguistic) symbolic structures, despite the fact that phenomenal experience suggests to many people its kinship with perceptual more than linguistic processes, or analogue structures. Analogue relationships between represented objects and representing neural activity are evident in the first steps of sensory input processing. From the retina to the surface of the striate area, for example, there are topological relationships between neural structures and environment: lesion of the upper bank of the right calcarine sulcus causes blindness in the lower quadrant of the left visual hemifield, etc. The economy of principles underlying these topological relationships is nicely demonstrated in Braitenberg’s delightful book “Vehicles” (1984). Analogue relationships between “distal” stimulus and brain structures leading to its perception are also known in other sensory modalities, e.g. in the auditory modality (Merzenich & Kaas, 1980). Some people refuse to admit that analogue relationships, such as those existing between perceived objects (and events) and the perceiving system, may also exist between those

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objects (and events) and the brain mechanisms capable of representing them even in their absence. The existence of such relationships is suggested by a large number of psychological investigations in normal subjects (e.g. Kosslyn, 1980; Shepard, 1975), but there are authors who oppose radical criticism of interpretations given of these results (see Pylyshyn, 1984) or are sceptical about the possibility of resolving the dilemma on merely psychological grounds, i.e. without help from cognitive neuroscience (Anderson, 1978). Neuropsychological evidence supporting the analogue theory of mental representation comes from UN. In the same way as lesion of part of calcarine cortex gives rise to a sensory scotoma, so spatially circumscribed lesions of critical brain structures may give rise to topologically correspondent representational disorders. Lesions of the right and, less frequently and severely, of the left hemisphere cause defective or productive phenomena of misrepresentation relative to the opposite side of somatic and/or extrasomatic space. Altitudinal neglect, as mentioned earlier, is very likely to reflect a similar topological correspondence. In most pronounced cases of UN, the patients’ behaviour (e.g. in drawing or in executing a cancellation task) does suggest the presence of a representational scotoma. This term must be taken cum grano salts. There is in all likelihood an enormous difference between the way in which visual space projects to calcarine cortex and the way in which spatial properties of mental representation are mapped on the cerebral tissue. To caution against a literal acceptation of the term “representational scotoma” it should be enough to reiterate what has been said earlier about the behaviour of UN patients asked to mark the endpoints of a horizontal virtual line on the basis of its midpoint (or to double on either side the extent of horizontal segments) and also about the side-to-side gradient of neglect. Furthermore, the idea of an absolute representational lacuna would not be compatible with what will presently be said about phenomena of (so-called) implicit knowledge of what lies on the “neglected” side of space. Before turning to this point, however, a specification is necessary regarding the mental representation of

spatial properties. It might be objected that empirical data drawn from observation of neglect patients pertain to a particular type of representation, relatively peripheral with respect to the core of cognitive activity. Phenomena of neglect concerning one side of a representation, such as those found on recall of familiar places, have in most instances been observed under conditions where patients had been instructed to imagine and describe something according to a definite and stationary vantage point. It could be objected that under such conditions subjects generate a surface (quasi-externalised) representation, preluding to obviously analogue motor behaviour such as drawing. Upstream with respect to this kind of representation, a cognitive structure could exist free from any isomorphism between that which is being represented and that which is representing. This is, of course, an empirical question. So far, it can only be remarked that the hypothesis of a nontopological structure of the “deep” representation of spatial attributes is in fact weakened, at least, by an empirical finding: patients have been described who, if asked to describe familiar routes from memory with no explicit instructions to form any visual image, were in evident trouble whenever routes involved contralesional turns (Bisiach et al., 1993; Duhamel & Brouchon, 1990). Another issue intimately connected with UN and kindred disorders is the dissociation between “implicit” (nonconscious) and “explicit” (conscious) knowledge. A recent review is available on this subject (Bisiach & Berti, 1995); therefore only a summary account will be given here. The reader is referred to Chapter 29 of this volume for a broader and more critical perspective. In the somatic domain, implicit knowledge of hemiplegia in anosognosic patients had already been inferred by Anton (1899) from the observation that most of these patients do not rebel against being confined to bed. It can also be noted that, usually, these patients do not even try to engage in activities requiring participation of paralytic limbs. Marcel and Tegner (unpublished) have carried out with interesting results the first systematic study of implicit knowledge of motor impairment among anosognosic hemiplegics, some of whom claim to be perfectly able to execute activities requiring the

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use of limbs of both sides, though giving negative answers when asked whether the examiner would have been able to carry out those same activities if he were in their conditions. In the extrasomatic domain, an example of how contents apparently barred from consciousness may nonetheless reach high levels of cognitive processing is patient EB (Bisiach et al., 1990b), who often neglected or miscompleted the left side of words she was given to read. If that side was substituted by a string of consonants, thus turning words into nonpronounceable nonwords, the patient’s neglect dyslexia dramatically improved: letter after letter, she would correctly spell the left side of nonwords shown to her, as if neglect phenomena and miscompletion originated at a stage different from that at which graphemic legality was checked. Marshall and Halligan (1988; see also Bisiach & Rusconi, 1990) reported the well known case of patient PS who denied any differences between two drawings of a house that only differed for the presence of bright red flames on the left side of one of them, but consistently pointed at the nonbuming house when asked to indicate which house she would have preferred to live in. Processing of neglected information up to the semantic level was more convincingly demonstrated in priming

experiments by Berti and Rizzolatti (1992) and Ladavas et al. (1993). These data relate to more general problems concerning the definition of conscious aspects of mental activity and of their neurological mechanisms. Alongside the study of amnesia and agnosia, of commissurotomy patients, and of patients suffering from blindsight and similar disorders, research on UN and productive phenomena of contralesional misrepresentation has already provided basic empirical data and speculation (see the volumes edited by Marcel & Bisiach, 1988, and Milner & Rugg, 1991). Other issues within the wide area of cognitive sciences may receive relevant contributions from research on dyschiria. One of them concerns the relationships between thought and language (Bisiach, 1988a). Another one concerns the socalled “propositional attitudes” (desires, fears, beliefs, etc.); this is especially true of beliefs, of which somatoparaphrenia and similar phenomena constitute pathological manifestations. Data and speculation collected in Prigatano and Schacter’s book (1991), and the striking effect of vestibular stimulation mentioned earlier demonstrate how close to the hidden structure of normal beliefs we may be taken by progress in the study of dyschiria.

Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

22 Disorders of Body Awareness and Body Knowledge Gianfranco Denes

body movements (for a review see Carey et al., 1997). The concept of the existence of an anatomofunctional apparatus specific to body knowledge is, however, less straightforward. This concept was developed at the end of the 19th century and the beginning of the 20th century, in an attempt to provide an explanation for some symptoms, mainly of psychiatric interest, which were interpreted as resulting from the complete or partial loss, or the non-utilisation by the consciousness, of a mental representation of the configuration of the body. This mental representation forms the basis of comparison for perceptive and motor reactions along with appreciation of one’s own body. Despite the poor methodology of the survey on which the theoretical construction was based (see later), within a short space of time, the terms schema and body image came into use and were firmly established in the neurological and psychiatric lexicons. A specific neuronal base (left parietal) was postulated for these functions. While for some authors the two terms were synonymous, others preferred to restrict the term body image to the conscious representation of the image, and schema

INTRODUCTION From a neurophysiological point of view, a number of studies of both animals and humans have shown that the neural representation linked to the perception of the position of body parts and changes in their position both in relation to the body itself and to the external world, is expressed at thalamic and cortical level in somatosensory topographical maps. These maps have been identified both in humans, through stimulation experiments during surgery (Penfield & Jasper, 1954, 1958; Penfield & Roberts, 1959), and in animals (Woolsey, 1952,1958). In addition, a series of neurophysiological studies have demonstrated that such maps are not fixed, but may potentially be modified through alterations of sensory input so that, for example, the perception of the position of a limb can be influenced by different signals from a muscle (for a review see Lackner, 1988). In the monkey, two distinct types of cells have been identified: the first type responding selectively to particular static body postures, while other neuronal populations are selective to particular 497

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to the unconscious representation. More generally, the term image is prevalently of psychiatric use, while in neurological and neuropsychological literature the preferred term is body schema. The experimental evidence for such a model was consolidated by several positive and negative signs and symptoms. The most important was thought to be the phantom limb phenomenon, that is the conscious persistence of the feeling of a limb, or more generally of a part of the body, despite its amputation, or more rarely, a congenital absence of the limb (see later); this phenomenon does not therefore represent the loss of a body model but instead appears to reflect the persistence of an intact model despite mutilation or aplasia (Benton, 1959). Amongst the negative symptoms the most significant were thought to be autotopagnosia (Pick, 1908,1915) and finger agnosia (Gerstmann, 1924), interpreted as being due to the total or partial loss of a spatially organised mental representation of body awareness. On the psychodynamic front, a series of symptoms with great emotional charge and with interpersonal implications have been attributed to a distortion of body image ( 700ms depending on the number of elements to recall, is related to the analysis of the stimulus and the search and attempts at comparisons (Pratt, Michaelewsky, Barrett, & Starr, 1989). The alpha rhythm of the electroencephalogram also mirrors the asymmetrical hemispheric involvement in selective spatial attention. In fact, on the left hemiscalp it is desynchronised by stimuli expected on the right, and on the right hemiscalp, by stimuli expected on either the left or the right. Heilman and Van Den Abell (1980) argued that while the left hemisphere only provides for attention in the right hemispace, the right hemisphere governs attention in the entire space. It should be added that heminattention can be provoked by amobarbital only through right endocarotid injection, and is followed by specific frontal EEG slowing (Spiers et al., 1990). A different surface electrical phenomenon, namely, ”stimulus-preceding negativity” (Damen & Brunia, 1987, 1988) was identified in an experimental paradigm involving selective attention toward the temporal characteristics of the stimulus. Subject were required to press a button at time intervals they had to establish themselves. After each response, three distinct visual signals indicated whether it was correct, i.e. no sooner than 20 seconds and no later than 22 seconds following the last button press, or it was early or late. A slow negative wave, likely related to attentive processes underlying signal anticipation, preceded the information signals. It had a parietal epicentre, but was also evident on the frontal site where it was larger over the right hemisphere, irrespective of the movement side. The frontal lobe seems to be more involved in the “intentional”, than in the “automatic” displacement of attention, as it is activated above all when stimuli call for intentional withholding of prepared

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motor responses. Indeed, the frontal P300 was increased in no-go tasks more than in go tasks (Roberts, Rau, Lutzenberger, & Birbaumer, 1994). Yamaguchi, Tsuchiya, and Kobayashi’s (1994), using Posner’s (1980) paradigm, provided results that led to the same conclusion. A visual target could appear 10° away from the central fixation point to the left or to the right, and was preceded by directional cues at intervals of 200, 500, or 800ms. In 80% of the cases, the cue signalled the side on which the target would appear and in the remaining 20%, the contrary. Central or lateralised cues are thought to provoke voluntary and reflexive shifts of spatal attention, respectively. Responses consisted of simple reaction time to target detection, and event-related evoked potentials were recorded during the intervals between cue appearance and target detection, bilaterally in the occipital, posterior temporal, parietal, central, and frontal sites. The difference between event-related potentials with cue signalling the right or the wrong side of the target increased frontally with central cues, when attention was directed intentionally, more than with peripheral cues, when attention was drawn reflexively.

Regional cerebral blood flow Measuring regional variations of the cerebral blood flow during task performance constitutes the most recent method of studying the functional neuroanatomy of the human brain, i.e. of identifying the brain structures and neural circuits engaged by cognitive functions. Despite having the advantage of allowing the study of brain activity during mental and behavioural tasks in normal healthy subjects, and thus overcoming the major problem of the lesion study approach, i.e. of drawing conclusions about the normal brain from damaged brains, functional neuroimaging is not without its own set of complexities and concerns. To disentangle flow changes specific to a target task and those already present, requires at least two cognitive tasks, which must be identical except for a single component. The challenge for cerebral blood flow researchers is to design such tasks that differ by only one meaningful component. Once levels of blood flow during the reference task have been subtracted from the corresponding levels of

the target task, the resulting pattern of activation is assumed to represent the localised blood flow associated with the different component between the two tasks. Thus, the resulting brain map is only as meaningful as the analysis of the cognitive ingredients of the compared tasks. Despite this drawback and the ensuing discrepant findings, the results produced by the “subtraction method” extend those of classical neuropsychology. Flow increase confirms the participation of the frontal cortex in the exercise of selective attention, concomitant with that of the primary and associative sensory areas specifically involved in the various tasks. The researches on regional blood flow changes during attentional tasks reviewed in this section call the premotor areas into question, and most of them also the prefrontal areas. This is hardly surprising given the pervasive regulatory role of the prefrontal cortex. Early studies using the radioactive tracer 133Xe, and researches with positron emission tomography using nC, 13N, 150 , or 18F to yield dynamic information on cerebral metabolism and neurotransmitter synthesis as well as receptor binding, and the more recent functional magnetic resonance studies, support the functional compartmentalisation of the premotor and prefrontal cortex according to a great variety of attention-demanding tasks. During tactile (Roland & Larsen, 1976), auditory (Roland, Skinhoj, & Lassen, 1981), or visual (Roland & Skinhoj, 1981) discrimination tasks, flow increases bilaterally in both mesial and upper dorso-lateral frontal cortex. Area 8 appears to be more involved in the discrimination of visual and auditory than of tactile stimuli. Flow increases also when subjects simply expect the stimulus, without even perceiving it (Roland, 1981). The involvement of the mesial and upper dorso-lateral prefrontal cortex, primarily in the right hemisphere, is even more marked when subjects are required to discriminate the signal from noise in one of three sensory modalities—tactile, auditory, and visual— while ignoring the competing stimuli of the other two (Roland, 1982). As this occurs irrespective of the target modality, the attentional role of this region can only be interpreted as a supramodal one.

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Thus, Roland (1981) proffers the view that the prefrontal cortex prepares and tunes the sensory areas by planning the processing of sensory information according to the instructions the subject has received or according to his or her autonomous intention. The findings of Deutsch, Papanicolaou, Bourbon, and Eisenberg (1987) agree with this interpretation: during a large battery of visuospatial, verbal, and mnesic-visual tasks, cerebral blood flow increased in all frontal areas, more than in the central, parietal, temporal, and occipital ones, with a clear prevalence for the right hemisphere over the left. As the increase in frontal flow was independent of the type of task, it was related once more to the exercise of attention. The more attention-demanding the task, the greater the frontal prevalence; for example, when recognition concerns previously viewed shapes with respect to the discrimination of simultaneous shapes (Deutsch, Papanicolaou, Eisenberg, Loring, & Levin, 1986). Risberg and Ingvar (1973) also found dorso-lateral and probably mesial frontal activation of the dominant hemisphere (the other one was not examined) during “intellectual” tasks, such as backward digit repetition and identification of the odd one out of five complex figures. The authors interpreted frontal activity as resulting from the “logical” nature of the tasks. However, in light of the reported experiments, it is equally plausible to envisage it as the expression of the attentional demands of the the tasks. Sustained voluntary visual fixation activated the dorso-lateral prefrontal cortex, while saccades toward a remembered site activated the anterior portion of the supplementary motor area. The frontal eye field was active in both tasks and also during reflexive saccades (Anderson, Jenkins, Brooks, Hawken, Frackowiak, & Kennard, 1994). Monitoring for possible sporadic dimming of a near-threshold central fixation mark, which never actually disappeared, and focusing attention upon either of one’s own big toes so as to detect pauses in a volley of supra-threshold touches increased blood flow in the right frontal eye field and the right prefrontal middle convolution, respectively, regardless of which big toe was stimulated (Pardo, Fox, & Raichle, 1991). When subjects expected

variations in one of three stimulus characteristics, velocity, shape, or colour, blood flow increased in the lateral orbito-frontal cortex, whereas when they expected variations in any of the three characteristics, blood flow increased in the dorsolateral prefrontal cortex (Corbetta, Miezin, Dobmeyer, Shulman, & Petersen, 1990, 1991); where hypermetabolism was found also during auditory discrimination (Cohen, Semple, Gross, Holcomb, Dowling, & Nordhal, 1988). Rezai, Andreasen, Alliger, Cohen, Swayze, & O’Leary (1993) found bilateral increase of blood flow in the mesial frontal cortex, somewhat greater on the left side, when subjects were required to detect a blue M following a red H that were flashed on a screen in a random mixed order with other variously coloured capital letters at a rate of 1/700ms. In contrast, during an equally demanding sustained attentional task, which consisted of identifying a target numerical sequence in a quick succession of digits on a screen (100-200 numbers/min), the focus of the activation was to the right, in the upper frontal gyrus rostrally (Coull, Frith, Frackowiak, & Grasby, 1996). Keeping and processing information in working memory, which typically involves the intentional form of attention (Baddeley, 1993), increases the blood flow frontally, in most instances on the dorsolateral surface. Roland and Friberg (1985) found this bilaterally in the dorso-lateral premotor and prefrontal areas during silent nonmotor tasks in which information had to be processed mentally according to previously interiorised rules: starting with 50 and then continuously subtracting 3, jumping every second word in a well known jingle, imagining walking out of the front door and then turning alternatively to the left and to the right every time a corner or a road is reached. Also D ’Esposito, Detre, Alsop, Shin, Atlas, and Grossman (1995) localised the cortical structure involved by the central executive of the working memory in the dorso-lateral prefrontal areas, where blood flow increased when two concurrent tasks were performed. This did not occur when the two tasks were performed separately. The dual-task paradigm consisted of a semantic judgement task, which required the subject to identify exemplars of a target category in a series of orally presented

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words, and a spatial rotation task, which required the subject to indicate which of two squares had a dot in the same location, relative to a double line, as a spatially rotated target square. Positron emission tomography studies support both the right parietal dominance for “spatial attention” and the involvement of the premotor areas in “spatial intention” (see Limb and orofacial movements). Actually, whereas the right parietal cortex appeared active during attentional tasks directed to either hemispace, left parietal activation occured only during attentional tasks that tapped the contralateral right hemispace (Corbetta, Miezin, Shulman, & Petersen, 1993). As compared to nonexploratory movements, active exploration of the right hemispace with movements of the right hand increased blood flow in the right posterior parietal cortex and anterior cingulate gyrus as well as the right lateral premotor area, and, perhaps bilaterally, in the supplementary motor area (Gitelman et al., 1996). Memorising spatial data in working memory increased blood flow in the dorso-lateral prefrontal cortex bilaterally, although more consistently in the right hemisphere (Decety, Kawashima, Gulyas, & Roland, 1992; Jonides et al., 1993; McCarthy et al., 1994). Decety et al.’s subjects were first asked to point to seven targets in a specific order on a screen, and then, after a blind delay, to point the targets in the same order. McCarthy et al.’s subjects had to judge whether the location occupied by the current simulus had been previously occupied by a sequence of 14 or 15 stimuli presented in various locations. Jonides et al.’s subjects had to judge whether a probe circle was centred over the previous location of one of three dots.

Gaze movements: Visual scanning and searching Cases of defective spatial exploration following damage circumscribed to the frontal eye field are exceptional (De Renzi, 1988a; Sharpe, 1982). However, there is evidence that the frontal lobe intervenes in generating the motor initiative necessary for active looking towards an expected direction. When normal subjects are shown a picture of a complex scene around a central event, they explore

it systematically, looking at various details until spotting the most relevant one (Stark & Ellis, 1981). The general sense of the scene can be grasped only by considering the details one at a time, selecting the informative parts, elaborating plausible interpretations of the whole scene, and finally educing an appropriate meaning from several possible alternatives. The process ends with a synthesis of the details into a unitary structure, centred on the one judged to be pivotal. Frontal lobe patients are unable to carry out an organised exploration by purposeful analytical searching, verification, hypothesis-making, and correction, as shown by their unsystematic movements of gaze. Despite the examiner’s prompts, they stop on a single detail before completing the search, and are thus prevented from achieving a total understanding of the picture (Luria, Karpov, & Yarbuss, 1966; Tyler, 1969). In the comprehension of complex figures, which Fogel (1967) borrowed from Murray’s Thematic Apperception Test, frontal lobe patients were impaired not only with respect to normal subjects but also to post-rolandic patients. This may reflect unsystematic visual exploration as a result of inability to monitor and update the quality of the ongoing products, by carefully comparing, integrating, and synthesising the single details (Luria, 1980). In a pioneering study, which however was performed on a very limited number of cases, Teuber (1964) provided evidence for deficient active visual scanning. Forty-eight stimuli of different shapes and colours were scattered on a table in front of the subject who was required to identify which one of them matched a target stimulus presented in the middle. Frontal lobe patients had prolonged search times, particularly in the field contralateral to the lesioned hemisphere, relative to patients with rolandic or post-rolandic lesions and normal subjects. The frontal areas involved in scanning eye movements are area 8 and the supplementary motor area, likely its anterior part. In fact, relative to normal subjects and patients with upper or lower dorso-lateral frontal lobe lesions, patients with damage in the left or right supplementary motor area were less capable of

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suppressing reflexive saccades toward sudden novel peripheral stimuli within the contralateral visual hemifield. No brain-damaged group differed from normals when fixation was maintained automatically, because the task consisted of analysing a figure in the central field (Paus, Kalina, Patockova, Angerova, Cerny, Mecir, Bauer, & Krabec, 1991). Guitton, Buchtel, and Douglas (1982, 1985) studied saccadic movements in epileptic patients after corticectomy. The task consisted of directing gaze to analyse a target appearing laterally at the fixation point, either in its previously signalled position (“pro-saccade” trial) or in the opposite one (“anti-saccade” trial). Patients with removal of the frontal eye field, and possibly the supplementary motor area, as well as temporal lobe patients and normal subjects, had no difficulty with the pro-saccade task, demonstrating the ability to detect the stimulus even in the field contralateral to the lesion. They were also able to direct their gaze toward the stimulus reflexively with normal accuracy and latency. The defect of frontal lobe patients, with lesion in the frontal eye field, which in most cases also involved the supplementary motor area, was revealed by their performance on the anti-saccade task. They directed their gaze erroneously, and then brought it to the correct position so slowly that they were not left with enough time to analyse the stimulus. The most marked errors were found when the signal was expected contralateral to the lesion. These results support the view that “the frontal lobe, particularly the dorso-lateral region which contains the frontal eye field and possibly the supplementary motor area contribute to the generaction of saccadic eyemovement behaviour. More specifically, they appear to aid in suppressing unwanted reflex-like oculomotor activity and in triggering the appropriate volitional movements when the goal for the movement is known but not yet visible” (Guitton, Buchtel, & Douglas, 1985, p.455). Also Henik, Rafal, and Rhodes (1994, p.400) uphold the notion that “the frontal eye field facilitates the generation of voluntary saccades and inhibits reflexive saccades to exogenous signals”. However, Paus (1996), in a review of the results of cerebral blood flow and lesion studies,

questioned the role of the frontal eye field in the execution of anti-saccades and drew attention to the anterior cingulate cortex. Butter, Rapcsak, Watson, and Heilman (1988) recorded eye movements to and away from visual stimuli from a patient with left-sided inattention following a right latero-frontal infarct involving the frontal eye field but not the supplementary motor area. They were able to distinguish three different defects in his oculomotor behaviour related to contralateral sensory inattention, contralateral directional motor neglect, and release of visual grasp to left (inability to suppress inappropriate reflexive movements); only the last two were permanent. The patient was examined using two tasks similar to those developed by Guitton et al. In the “uncrossed-response test”, the subject had to move his eyes from a fixation point centred at the examiner’s nose to the examiner’s left or right index finger, located approximately 30° laterally, when one of them moved. In the “crossed-response test”, whenever the examiner moved his index finger, the subject had to move his eyes to the opposite side, toward the index finger that was not moving. Percent trials with no eye movements to right when stimulus on left was presented in crossed-response test (general sensory inattention or left sensory inattention) minus percent trials with no eye movements to right when stimulus on right was presented in uncrossed-response test (general sensory inattention) was taken as measure of left sensory heminattention. Relative to normal control subjects, it was higher in the first three weeks after the stroke, and then it normalised. Percent trials with no eye movements to left when stimulus on right was presented in crossed-response test (general motor inattention or left motor inattention) minus percent trials with no eye movements to right when stimulus on right was presented in uncrossed-response test (general motor inattention) was taken as measure of directional left motor inattention. This lasted for more than five months. Percent trials in which the patient moved eyes to target on left in crossedresponse test was taken as a measure of release of visual grasp towards the left. This increased progressively after the first week and in large measure after the second week. Like Guitton et al.’s

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patients, latencies of the patient’s saccades directed towards the side opposite the lesioned hemisphere were not longer than the latencies of his saccades directed towards the ipsilateral side. In contrast, lesions involving the right parietal lobe selectively increased the latencies of eye movements towards contralateral targets (Sundqvist, 1979). These findings suggest that the contribution of the parietal lobe to visually directed saccades differs from that of the frontal lobe. This view is further supported by results of Zihl and Hebei (1997), who assessed the patterns of oculomotor scanning using spatial configurations made of ungrouped and grouped dots. In the grouped dots task, the scanning pattern of the control subiects closely resembled the spatial configuration of the stimulus display. In contrast, the scanning pattern of the parietal lobe patients showed no resemblance to the stimulus display. Indeed, these patients had difficulties in spatially guiding their eye movements according to the spatial properties of the dot pattern. The frontal lobe patients made many more fixations within the dot groups because they had working memory difficulties in selecting the best fixation locations for stimulus sampling, updating of fixation locations, and planning the scanpath with regard to the selection of the “centres of gravity”.

Limb and oro-facial movements As far as limb movements are concerned, four types of attentional defect can be envisaged following unilateral frontal damage. Unilateral hypokinesia and unilateral motor neglect, which affect the automatic and intentional movements of the contralesional limbs, must be distinguished from unilateral directional hypokinesia and unilateral sensory inattention, which impair the motor and perceptual activities in the contralesional hemispace. Sensory extinction has also been reported in frontal patients, which involves the contralesional hemisoma in the tactile modality, and the contralesional hemispace in the auditory and visual modality. Poor automatic movements of the contralesional limbs or “unilateral hypokinesia” and the reluctance to move the contralesional limbs irrespective of the direction of movement, or

“unilateral motor neglecf\ can be considered as a hallmark of the supplementary motor area. Voluntary movements are delayed, slow, and more limited than they should be, as occurs in Parkinson’s hypokinesia, hypometria, and bradykinesia. The patient does not swing the upper limb when walking, does not gesture with it, and tends to protect it when acting spontaneously. When the patient is forced to use the limb he or she moves it awkwardly and clumsily, tries to control it with their gaze as if he or she were using it for the first time. It is as if the patient has lost the ability to operate automatically, and must compose a succession of movements only through intentional effort. Akinesia due to a frontal lesion was observed by Hartmann (1907, case 1). It was associated with apraxia and right sensory heminattention in a case of anterior callosal neoplasia, invading the entire left frontal lobe and the right mesial cortex. Three cases (two right- and one left-sided lesions) were reported in detail by Castaigne, Laplane, and Degos (1972), and another 15 (10 right- and 5 left-sided lesions), with akinesia without sensory inattention, by Laplane and Degos (1983). All had impaired supplementary motor areas. Following a right hemorrhage encroaching on the supplementary motor area and the anterior cingulate gyrus, the patient described by Meador, Watson, Bowers, and Heilman (1986) showed hypokinesia, bradykinesia, and hypometry of the left more than of the right limbs. A Parkinsonian syndrome, prevalent in the contralateral limbs, following a lesion involving the supplementary motor area, was reported by Straube and Sigel (1988) and by Fukui, Hasegawa, Sugita, and Tsukagoshi (1993). Two cases suffering from infarcts in the anterior limb of the internal capsule, a site for cortico-basal ganglia connections of the frontal lobe, also showed unilateral motor neglect, independent from unilateral sensory extinction and unilatereal sensory or motor inattention (De La Sayette, Bouvard, Eutache, Chapon, Rivaton, Viader, & Lechevalier, 1989; Viader, Cambier, & Pariser, 1982). Automatic motility of the face is impaired by a mesial frontal lesion (Laplane, Orgogozo, Meininger, & Degos, 1976). Also the patients of Kolb and Milner (1981) with left or right frontal

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cortical excisions, which included the lateral convexity as well as parts of the mesial aspect, exhibited a reduction of facial spontaneous expression, as compared with patients with temporal, parietal, or central lesions. Another defect distinct from unilateral hypokinesia and unilateral motor neglect is “unilateral directional hypokinesia” or “unilateral motor inattention”, i.e. the reluctance to initiate and carry out motor activities toward the contralesional hemispace, irrespective of the side of the limbs involved in such activities. This defect presents as the motor counterpart of “unilateral sensory inattention”, i.e. the difficulty in noticing and evaluating events occurring in the contralesional hemispace (Bisiach, Geminiani, Berti, & Rusconi, 1990). Both phenomena can result from a frontal lesion, although they are more frequent and severe after parietal damage (De Renzi, 1982; Vallar & Perani, 1986, 1987). Hartmann’s (1907) case 1 is paradigmatic. Objects and gestures shown to him in the left visual field were immediately recognised, named, or imitated, and evoked adequate motor responses. By contrast, when shown visual stimuli in the right field, the patient behaved as if he were hemianopsic. He responded readily to words or noises presented to his left ear, naming them, understanding their meaning, or repeating them. However, when the same stimuli were presented to his right ear, he seemed to be affected by central deafness, and often turned his head and eyes toward the left. He was able to perceive tactile stimuli in the left hemisoma, to explore objects with the left hand, recognising and naming them. In contrst, he reacted with incomplete movements to stimuli in the right hemisoma. The active exploration of objects placed in his right hand was poor, and he was never able to recognise and name them. He did not even help himself by turning his gaze toward them or moving his head. Silberpfenning (1941) reported two cases with right frontal neoplasia, and Gloning (1965) described a patient with a right frontal abscess, whose behaviour was analogous to that of Hartmann’s (1907) patient. Van Der Linden, Seron, Gillet, and Bredart (1980) reported three patients with large right frontal tumours, who neglected the left parts of a drawing they were required to reproduce from memory or to copy.

They also halved horizontal segments erroneously to the right, neglected Wechsler’s cubes to the left, wrote on only the right half of a sheet of paper, and missed details to the left when describing a drawing of a scene. Left heminattention in halving horizontal segments was also reported following a right frontal hematoma by Bisiach, Bulgarelli, Sterzi, and Vallar (1983). It is possible that space occupying processes interfere with the functioning of other structures involved in spatial attention, such as the parietal lobe, the basal ganglia (Healton, Navarro, Bressman, & Brust, 1982; Hier, Davis, Richardson, & Mohr, 1977; Valenstein & Heilman, 1981), and the thalamus (Bogousslavsky, Regli, & Uske, 1988; Perani, Nardocci, & Broggi, 1982; Watson & Heilman, 1979; Cambier, Elghozi, & Strube, 1980; Watson, Valenstein, & Heilman, 1981), due to compression, infiltration, oedema, or intracranial hypertension. This hypothesis, however, does not hold for nontumoral stabilised pathologies. Besides Heilman and Valenstein’s cases (1972b), whose probative value has been questioned (De Renzi, 1982), spatial inattention has also been described by Halsband, Gruhn, and Ettlinger (1985), with motor, somesthetic, auditory, or visual tasks, in two out of three patients after right frontal softening, and in one out of eight after left frontal stroke. Ogden (1985a) examined patients, who were partly tumoral, with drawing tests (Albert’s crossing lines test, drawing in the numbers on a clock face, copying drawings: a Necker cube, a 5-pointed star, a tree, a fence, a house, and another tree). There were no differences between frontal and post-rolandic patients in the occurrence of heminattention. Binder, Marshall, Lazar, Benjamin, and Mohr (1992) studied right brain-damaged patients with a line bisection test and a cancellation test (they had to search and circle 60 As among 375 capital letters pseudorandomly arrayed on a sheet of paper); 58% of the patients, whose softening encroached on the frontal but not the parietal lobe, neglected the left half of the sheet on the cancellation test but performed normally on the line bisection test. In contrast, most parietal and parieto-frontal lobe patients showed left-sided neglect on both tests. As the target cancellation task tapped the active motor

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exploration ability and the line bisection task required perceptual or representational abilities, a different role of the two lobes in spatial attention can be evisaged. Sensory and motor unilateral inattention is frequently, but not necessarily, associated with “unilateral sensory extinction”, i.e. the failure to report a tactile, auditory, or visual stimulus delivered to the side contralateral to the lesion when a symmetrical ipsilateral stimulus is given. Unimodal sensory extinction may be due to a mild impairment of the ascending sensory pathways (thalamus, posterior limb of the internal capsule, and the adjacent white matter, primary sensory areas). Multimodal sensory extinction, which is usually associated with motor or sensory inattention, may be linked with a unilateral sensory attentional defect and has its anatomical focus in the parietal higher-order associative areas or in the dorso-lateral frontal cortex (Vallar, Rusconi, Bignamini, Geminiani, & Perani, 1994). Findings in two patients, studied by Maeshima, Funahashi, Ogura, Itakura, and Komai (1994), support the hypothesis that the frontal lobe is involved, not only in spatial attention, but also in multimodal sensory extinction. Following a right frontal haematoma, both patients became inattentive to the left on line bisection, line cancellation, figure copying, and describing scenic pictures. Moreover, they showed left-sided extinction in the tactile, auditory, and visual modality. Single photon emission computerised tomography disclosed hypoperfusion along the circumference of the haematoma; blood flow was normal elewhere. It seems likely that the structures involved in motor and sensory heminattention are partly distinct, also at the frontal level. Support for this suggestion is provided by cases in which they present separately. Two patients, one studied by Daffner, Ahern, Weintraub, and Mesulam (1990) with right latero-frontal softening, and one reported by Liu, Bolton, Price, and Weintraub (1992) with right frontal haemorrhage, were unable to actively explore and act on stimuli to the left, whether they had to locate the As randomly scattered on a sheet of paper among 375 capital letters, or whether they had to detect by blindfolded palpation a small pin fixed to a covered board,

even though they did not have either tactile, auditory, or visual extinction. Unilateral hypokinesia can also be independent from unilateral sensory extinction and unilateral sensory or motor inattention, as supported by the aforementioned cases of Viader, Cambier, and Pariser (1982) and De La Sayette et al. (1989). Analogously, pure unilateral sensory inattention was ascertained by Ishiai, Watabiki, Lee, Kanouchi, and Odajima (1994) in three patients with right frontal softening by means of a barrage of scattered lines, halving of lines presented in the right, central, or left field, and copying figures. Unilateral motor inattention was excluded by asking the patients to double lines presented on the left, centre, or right of the median line. Stein and Volpe (1983) related frontal inattention to parieto-frontal disconnection due to damage of the white matter. Three of their patients with softening of the right frontal lobe, involving the caudal part of the orbital and dorso-lateral surfaces, the underlying white matter, and sometimes also the basal ganglia and the insula, were heminattentive to double visual and tactile stimuli, halving of horizontal segments, copying or drawing from memory, block construction, and sentence reading. While the parietal and frontal hypoperfusion found in two heminattentive patients after softening of the white matter supplied by the right anterior choroidal artery (Bogousslavsky et al., 1988) is consistent with this hypothesis, the findings reported by Vallar and Perani (1986) are more controversial. Only one of their 19 patients with right hemisphere lesions restricted to the white matter presented heminattention. There is a large body of clinical and experimental observations supporting the notion of an asymmetrical involvement of the two hemispheres in spatial attention. In right-handed subjects, right hemisphere lesions produce more frequent and severe left inattention than left sided lesions produce right inattention (De Renzi, 1982). Analogously, left-handed subjects may develop the reverse inattentional pattern following a left cortico-subcortical frontal damage (Dronkers & Knight, 1988). It has been suggested that in right-handed subjects the right hemisphere controls attention in

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both the left and right hemispace, while the left hemisphere governs attention only in the right hemispace (Heilman & Van Den Abel, 1980; Heilman, Valenstein, & Watson, 1985; Mesulam, 1985; Weintraub & Mesulam, 1987). Further evidence for this suggestion is provided by hemispheric inhibition with sodium amytal (Spiers et al., 1990). Alternatively, it may be hypothesised that each hemisphere governs selective attention in the two hemispaces, but prevalently in the contralateral one, and that in right-handed subjects the role of the right hemisphere predominates (Plourde & Sperry, 1984). A third interpretation is suggested by findings of Kinsboume and Warrington (1962), Ladavas (1987), Mark, Kooistra, and Heilman (1988) and by De Renzi, Gentilini, Faglioni, and Barbieri (1989). Right-handed subjects with lesion of the right hemisphere become heminattentive not only because they neglect events to their left, but rather because they ignore all events situated on the left of others, regardless of whether they are located on either side of the subject’s space. Heminattention regards the left part of the perceptual field, be it located to the left or to the right of the subject. It is almost as if right lesions attract toward the right. All three interpretations attempt to justify the behaviour following a unilateral hemispheric lesion. However, as De Renzi (1988b) observed, they are at odds with the experience of the normal subjects, who pay the same attention to information pre-eminently reaching their right hemisphere (supposedly more efficient) from the left space as to information from the right space and received by their left hemisphere (supposedly less efficient). Findings in brain-damaged patients and normal subjects can be reconciled by conceding that the attentional devices are equally efficient in the two hemispheres, and that those on the right are ensured by circumscribed areas of the parietal lobe, whereas the attentional devices on the left hemisphere are dispersed over broad areas of the cortex, including the frontal cortex. Thus a lesion in the critical right parietal lobe will result in contralateral attentional loss; by contrast focal lesions in the left hemisphere can hardly impair attention to right completely.

This hypothesis was advanced by De Renzi, Colombo, Faglioni, and Gibertoni (1982) in relation to the visual heminattention associated with defective spatial exploration. Contralesional gaze paresis prevailed in patients with retrorolandic lesions when the right hemisphere was involved; whereas in patients only with lesions of the entire sylvian area when the left hemisphere was impaired. De Renzi’s hypothesis predicts that right hemispheric prevalence for spatial attention, so marked in the parietal lobe, decreases, in fact reverses, in favour of the left hemisphere, in the frontal lobe. Other experimental findings support this view. Using the line barrage test, Albert (1973) found that heminattention prevailed among right brain-damaged patients when the lesion was post-rolandic (36% if right and 24% if left), and among left brain-damaged patients when the lesion was frontal (29% if left and 25% if right). Using drawing tests, Ogden (1985a, 1987) discovered an even more marked prevalence of heminattention for right lesions among post-rolandic patients (67% if right and 45% if left) and for left lesions among frontal patients (75% if left and 20% if right). Vallar and Perani (1986) who, unfortunately, only considered right brain-damaged patients, found heminattention in 63% of their parietal patients and only 8% of their frontal patients using a barrage test analogous to Albert’s. Similarly, Heilman and Valenstein (1972a) studied 10 patients with tactile, visual, and auditory extinction, in whom the lesional site was ascertained by scintigraphy, and found that all the 9 right brain-damaged patients had parietal damage and the only left braindamaged patient had frontal softening. These results make it less surprising that Hartmann’s (1907) patient, who became heminattentive following a frontal lesion, had a tumour primarily involving the left lobe, and that the patients tested by Kim, Morrow, Passafiume, and Boiler (1984) on five visuoperceptual and five visuomotor tasks showed different performance impairments depending on lesion side and site. Specifically, whereas the right posterior braindamaged patients fared worse than the right anterior brain-damaged patients, the left posterior patients fared better than the left anterior patients.

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The left frontal and right parietal prevalence not only affects visual perception and exploration, but also becomes manifest in visual “imagination” of space. In the test devised by Bisiach, Luzzatti, and Perani (1979), subjects observed a figure moving slowly from left to right and vice versa behind a vertical slit located at the centre of the visual field. As only a small strip of the figure was visible at all times, the whole figure could be constructed only by imagining it. The task consisted of comparing two successive figures and judging whether or not they were the same. During the test, pairs of identical figures alternated unexpectedly with other pairs of figures which differed on their right or left part. Heminattentive subjects neglected details located at the extreme of the figure contralateral to their damaged hemisphere. Among right braindamaged patients, the defect was more marked due to parietal damage, whereas among left braindamaged patients, it was more marked due to frontal damage (Ogden, 1985b). The frontal lobe, not only intervenes in processes of motor or sensory spatial attention, but also participates in selective attention for the physical characteristics of the stimulus, regardless of its position in right or left hemispace. Salmaso and Denes (1982) asked patients with frontal or retrorolandic lesions in either hemisphere to detect a pair of novel signalstimuli among other similar repeated noise-stimuli presented at the middle of their visual field. The stimuli were letters or segments slanting in different directions. Compared with posterior brain-damaged patients, frontal lobe patients gave more false positive responses because they adopted a larger and less reliable criterion, and detected fewer signals, showing decreased sensitivity. Left or right lesion side made no difference to the patients’ detection of either the letters or the segments. Both defects seemed to indicate reduced capacity for sensory attention in frontal patients. Capitani, Scotti, and Spinnler (1978) studied colour discrimination (Farnsworth, 1943) in patients, who underwent surgical lobectomy. Right frontal lobe patients made more errors than left frontal and right or left occipital or temporal lobe patients, although they performed better than parietal lobe patients. The frontal lobe controls “voluntary” more than “passive” attention. Wilkins, Shallice, and

McCarthy’s (1987) frontal lobe patients failed, relative to temporal lobe patients, regardless of right or left lesion side, in counting tactile or auditory stimuli when the presentation rhythm was slow enough (one stimulus every second) to allow voluntary sustained attentional effort, but not when it was rapid (seven stimuli every second) and attention was sustained automatically. Vilkki and Holst (1989b) agree with this explanation for the failure of their right frontal lobe patients, relative to left frontal and post-rolandic patients, to optimise the speed/accuracy ratio in reproducing from memory the simplest figures in Benton’s (1963) visual retention test but not the more complex figures. “Sustained attention” and “divided attention” tasks, which entail remembering the task for a long period of time and keeping more than one task in mind simultaneously, are particularly exacting for the frontal patient. In both cases the subject is required to make a great intentional effort. Sustained attention was impaired following predominant frontal lobe lesions, especially if located in the right hemisphere, as compared with normal subjects (Rueckert & Grafman, 1996). Divided attention was impaired following left prefrontal damage, especially when it encroached on the mesial or dorso-lateral cortex, rather than the basal aspect or the right hemisphere, compared with normal subjects as well as post-rolandic brain-damaged patients (Godefroy & Rousseaux, 1996a,b). “Motor impersistence” is a phenomenon of a presumably attentional nature. It consists of the inability to deliberately sustain certain positions for more than a few seconds, and it usually results from right hemisphere damage (De Renzi, Gentilini, & Bazolli, 1986). Central and frontal (likely premotor) lesions seem to be more responsible for motor impersistence than posterior lesions (Kertesz, Nicholson, Cancelliere, Kassa, & Black, 1985).

Concluding remarks about premotor “function” Clinical and experimental evidence supports the view that the frontal lobe intervenes in phenomena of both motor and sensory attention, chiefly in its intentional form. However, the frontal lobe is by no means the only structure involved. The basal

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ganglia, thalamus, mesencephalic reticular substance, and, above all, the parietal lobe are involved with seemingly greater frequency and strength. At present, we can only speculate on the specific role of the frontal lobe. The supplementary motor area seems to be involved in supplying the motor initiative in tasks that can be executed according to schemata (programs) already internalised by the subject, so the damage is manifested as contralesional hypokinesia. The frontal eye field and the lateral premotor area seem to be involved in programming and organising movements under sensory guidance. This implies their participation in directing attention to the relevant physical or spatial features of the stimuli and to body parts called to action. Their participation depends on the characteristics of the attentional task. The frontal eye field is involved in perceptual-motor tasks in which the auditory or visual stimulus is located in the space within reach of the gaze, whereas the lateral premotor area is involved in perceptual-motor tasks in which the somesthetic, auditory, or visual stimulus is in the space within reach of the limbs. It is likely that the prefrontal areas are responsible for planning the activities of other frontal and sensory areas and subcortical structures according to the goal set by either the subject or the examiner. To this end, it is essential that the goal remains the focus of attention for the duration of the experiment, and that the sensory areas are kept ready to select significant stimuli, the mnesic structures to call to consciousness only useful memories, and motor structures to ensure appropriate behaviours. At the same time, the interference of extraneous stimuli, memories, or inappropriate strategies must be avoided.

FUNCTIONS OF THE PREFRONTAL CORTEX: PLANNING FOR THE FUTURE “We almost never think of the present, and when we do, it is only to see what light it throws on our plans for the future” (Pascal, 1670; cited by Damasio, 1994, p. 165).

The prefrontal cortex has a unique position in the cerebral economy, in that there is no cognitive function to which it is extraneous, or that is unaffected by its damage. Moreover, there is no function that it accomplishes alone, and which entirely fails in its default. Its peculiarity seems to consist of providing all cognitive and behavioural activity with rules and strategies that enable the subject to widen his or her horizon enough to make coherent choices and fruitful decisions, avoiding harmful or useless ones. In this way, it appears to be at the core of the nervous activity that is coupled with cognitive and emotional qualities connoting the subject’s personality and life style. Here the functions that appear to involve the prefrontal cortex are distinguished according to a criterion of convenience based on the most current cognitive categories. Several defects typical of the prefrontal patient, such as the tendency toward perseveration, can thus recur with reference to more than one function.

Memory and temporal organisation of experiences. (He’s a muddler and liar) Contrary to widespread opinion, the content of long-term explicit memory is not impaired in the frontal patient. Frontal tumours (Angelergues, Hecaen & De Ajuriaguerra, 1955; Baruk, 1926; Boudouresque & Bonnal, 1956; Hecaen, 1964), frontal hemorrhages and anterior cerebral artery softenings (Lindquist & Norlen, 1966; Talland, Stuss, Alexander, Lieberman, & Levine, 1978; Sweet & Ballantine, 1967) or frontal injuries (Claude, Le Guillant, & Masquin, 1932) can provoke semantic and episodic amnesia. However, any attempt at drawing conclusions concerning the functions of the frontal cortex from such cases is fraught with serious difficulties, as amnesia may be due to damage of the neighbouring structures, such as the columns of the fornix or the basal magnocellular nucleus, Broca’s diagonal band or the hypothalamic paraventricular nucleus (Alexander & Freedman, 1984; Damasio, GraffRadford, Eslinger, Damasio & Kassell, 1985; Morris, Bowers, Chatterjee, & Heilman, 1992; Salazar, Grafman, Schlesselman, Vance, Mohr, Carpenter, Pevsner, Ludlow, & Weingartner, 1986). The same doubts were raised with regard to

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Baddeley and Wilson’s (1988) patient, who, following traumatic bilateral frontal hemorrhage, showed a pattern of deficits consistent with a combination of a “hippocampal amnestic syndrome” with a “frontal dysexecutive syndrome”. There is no evidence suggesting that the frontal cortex contributes to short-term or recent memory. Frontal lobe patients repeat sequences of digits normally (Baddeley & Wilson, 1988; Canavan, Passingham, Marsden, Quinn, Wyke, & Polkey, 1989b; Mettler, 1952; Milner, 1962; Partridge, 1950; Petrie, 1952b; Pigott & Milner, 1994; Ricci & Blundo, 1990; Stuss, Alexander, Lieberman, & Levine, 1978; Stuss, Benson, Kaplan, Weir, & Della Malva, 1981; Teuber, 1964), though in a few studies they were deficient (Smith & Kinder, 1959; Hamlin, 1970). Likewise, they are no more impaired than other brain-damaged patients in immediate and 15-second delayed recall of geometric figures or locations (Ghent, Mishkin, & Teuber, 1962; Owen, Downes, Sahakian, Polkey, & Robbins, 1990), or of a story or paired associate words (Frisk & Milner, 1990; Incisa Della Rocchetta & Milner, 1993; Milner, 1962, 1964; Pigott & Milner, 1993), or of word lists learned 15 minutes previously (letter, Poser, Freeman, & Markowitsch, 1986), or of gestures executed 28-45 minutes previously (Jason, 1985b). The contrast between the behaviour of Smith and Milner’s (1984) epileptic patients and these results is deceptive. After prefrontal dorso-lateral and mesial excisions they had difficulty in recalling the names of 16 objects they had examined the day before in order to estimate their price, even if they were able to place them back into their original locations. However, the deficit of frontal lobe patients in delayed recall of objects may be secondary to their deficit in price estimation, as the pricing task would serve to orient their identification of the objects, letter, Poser, Freeman, and Markowitsch (1986) also sustain that the difficulty shown by their frontal lobe patients compared with other post-rolandic patients, irrespective of the damaged hemisphere, in recalling three lists of 16 words after one day, was not due to a true memory defect. In fact, the retrieval failed only in a free recall condition, and not in cued recall or in recognition testing. This

pattern of deficits would suggest that encoding was preserved and that the patients were selectively impaired in retrieval, when internal generation of the semantic categories was required. Like explicit memory (Shimamura, Janowsky, & Squire, 1991), implicit memory (Shimamura, Gershberg, Jurica, Mangels, & Knight, 1992) appears preserved in prefrontal patients. What differentiates the prefrontal patients from normal subjects is not the content of memory, but the inconsistent strategy in handling the informations stored in memory. This appears evident on memory tests with composite and complex structures, featured by a multiplicity of spatial or temporal constituents, whose simultaneous processing engages the ability to update disparate elements in an orderly way. The test devised by Phillips (1974) requires the subject to memorise the spatial locations of an equal number of black and white squares displayed in rectangular matrices of increasing complexity. Several seconds after each presentation, the subject is asked to detect which of the white squares has been changed to black on a matrix otherwise identical to the first pattern. The number of filled squares in the most complex of the remembered patterns provides a measure of the pattern span. The task demands active simultaneous maintenance in short-term memory of a number of items and forming a coherent representation of an array against which the changed version of the pattern can be compared. The active control process required to perform the task successfully makes it possibly sensitive to prefrontal damage. Further, as it involves visuo-spatial rather than verbal capacities, it is probably more sensitive to right than left hemisphere damage. Pigott and Milner (1994) tested lobectomised patients, using matrices with 2 to 44 squares, under four different retention conditions: a 2 or 10 second interval, during which the subject could be distracted or not by counting backwards by three. Under all four testing conditions, the right frontal lobe patients were impaired on the pattern span measure relative to normal control subjects, as well as to left temporohippocampal, right or left temporal lobe patients and, although not significantly, to right temporohippocampal and left frontal patients. The frontal

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lobe patients’ poor performance on Phillips’s test is relevant, given their good memory for the figurative aspects of complex visual scenes, which, on the contrary, was impaired in right temporal lobe patients (Pigott & Milner, 1993). Analogous results were reported by Owen, Sahakian, Semple, Polkey, and Robbins’s (1995), except for the lack of hemispheric asymmetry. Compared with normal subjects, frontal lobectomised patients were impaired on a visuospatial recognition memory task, but not on a pattern recognition memory task or a simultaneous and delayed matching to sample task. The opposite pattern of deficits was shown by the temporal or amygdalo-hippocampal patients. A second aspect of the prefrontal mnesic defect regards the way personal experiences are ordered along the time dimension. For the past, the chronological order (recency) and frequency of events are confused. For the future, forecasting what is expected to happen and what is still to be done is confused. Memory for temporal order of past events appeared impaired in epileptic patients following dorso-lateral and mesial prefrontal ablation. Milner (1971) presented these patients a deck of 184 cards with two words on each card. They read the words aloud and then turned to the next card. From time to time they were asked which of the words on the card they had seen more recently. Compared with normal subjects, left temporal lobe patients were impaired in recognition, while left frontal lobe patients were impaired in recency judgement of words that had already appeared. When words were replaced by abstract figures, a complementary pattern of deficits emerged: right temporal lobe patient had poor recognition and right frontal lobe patients poor recency judgment performances. Analogous results were replicated by Milner, Corsi, and Leonard (1991) on a broader sample with concrete words, representational drawings, and abstract paintings. These results led to the suggestion that the dorso-lateral cortex centred in area 46 is crucial for temporal order judgements. The typical frontal lobe dissociation between spared item recognition and impaired recency judgement was further validated by Kesner, Hopkins, and Fineman (1994), who, however,

found hemispheric asymmetries in the expected direction only when stimuli consisted of spatial locations and not when they were words, abstract pictures, or hand positions. Further support was provided by Shimamura, Janowsky, and Squire (1990), whose subjects were required to rearrange 15 common words sequentially and to place 15 well known public events in chronological order. To sum up, in all tasks, be they verbal, figurative, or spatial, the prefrontal cortex appears to be necessary for time ordering of experienced events. The left frontal lobe appears to play a greater role in the performance of verbal tasks, and the right frontal lobe a greater role in the performance of figurative or spatial tasks. When double verbal and figurative coding of the items was allowed, both frontal lobes appeared to be of equal importance (MeAndrews & Milner, 1991). Also the poor performance of frontal lobe patients in repeating digit sequences backward (Canavan et al., 1989b; Villa, Gainotti, De Bonis, & Marra, 1990) may be related to a temporal ordering defect. Prefrontal patients confuse not only the time order but also the relative frequency of past events they have experienced. Epileptic patients after dorso-lateral and mesial prefrontal corticectomy, but not those with temporal and temporohippocampal excision, failed with respect to normal subjects when they tried to remember how many times they had seen each of 24 abstract designs, which had repeatedly appeared at five different frequency levels (0, 1, 3, 5, 7) (Smith & Milner, 1988). The result was analogous when, instead of figures, words were used, whether provided by the examiner or generated by the subject in response to cues (Smith, 1996). Frequency estimation of abstract designs was more impaired after right than left frontal lobectomy, and of words after left than right lobectomy. In a recent study by Jurado, Junque, Pujol, Olivers, and Vendrell (1997) 12 sets of 3 common nouns were read aloud to subjects who then attempted to recall each following a filled interval. Subjects were then read 22 words one at a time (the original 16 plus 6 distractors) and had to say whether or not and how many times (1, 2, 3, 4, or 5) they had heard each word before. Frontal lobe patients recognised the target words, but

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failed, relative to normal subjects, at estimating the frequency of their occurrence. The consequences of this defect are more severe than they may appear at first. Patients who have no way of knowing the probability (relative frequency) of an event happening, cannot even make realistic predictions about the future and will thus be unprepared for it. Even more disconcerting is prefrontal patients’ inability to distinguish the past and the future. Despite being able to carry out the single acts necessary to perform a complex task, they are incapable of putting them into a productive sequence according to an organised strategy and of monitoring their responses during the action, because they forget which stages have already been passed and which are still to be faced. Petrides and Milner (1982) tested patients with unilateral dorsolateral and mesial prefrontal or temporohippocampal lobectomy and compared them with normal subjects. Subjects were presented six sheets of paper, each showing the same six words written in different locations. The subjects had to touch a single word on each sheet, without touching any word more than once on successive sheets, until they had touched all six words during the entire trial. Subjects were not allowed to touch the stimuli in an alphabetical order, nor to respond consistently to the same location. Increasingly difficult 8-, 10-, and 12-word series were used. The task was repeated twice, with high-imagery words and lowimagery words. The left prefrontal patients failed on both tasks, while the left temporo-hippocampal patients failed to a lesser degree only on the second task. When representational drawings and abstract designs were used instead of words, both the left and right prefrontal patients failed along with right temporo-hippocampal ones. Wiegersma, Van Der Scheer, and Hijman (1990) found the same selfordering defect in patients who had undergone surgery to remove a frontal tumour, when they were presented series of 4,6, 8,10, or 12 numbers. Owen et al. (Owen, Downes, Sahakian, Polkey, & Robbins, 1990; Owen, Sahakian, Semple, Polkey, & Robbins, 1995) devised a more elaborate self-ordering task, in which subjects were required to memorise where targets had been discovered during previous trials. Subjects had to search

through a number of boxes and collect the “blue tokens” hidden inside. In any one trial, there would be a single blue token hidden inside a different box, which would never be used again to hide a token. An efficient strategy for completing this task is to follow a predetermined search sequence, beginning with a particular box and then returning to start each new sequence with the same box. Frontal lobe patients made more errors than normal subjects, exploring locations they should have known were empty or insisting on going to those they had already found to be occupied. Furthermore, they differed from temporal lobe patients in their typical unsystematic searching. Self-ordering tasks require subjects to formulate a general plan for sequencing responses and for monitoring at each step past responses that must be avoided and future responses that must be chosen. Poor performance may either result from a memory defect for past responses, what happens in temporohippocampal patients, or from the lack of a plan and the inability to respect it, as is the case in frontal lobe patients. In all probability, underlying the difficulty shown by prefrontal patients is a poor working project to keep all elements to be assessed present in the right chronological order and to distinguish them at any time during the performance. In this sense, the prefrontal defect is due to “working memory” failure. Regional blood flow studies in normal subjects support a role of the prefrontal cortex in working memory. A working-memory task, such as Petrides and Milner’s (1982) self-ordering of abstract drawings, activates area 46, more in the right than in the left hemisphere, and area 9 in the left hemisphere. On the contrary, a task that takes advantage of the conditional association already learned between colours and shapes, and involves selective recall of information from long-term memory, activates the left area 8 (Petrides, Alivisatos, Evans, & Meyer, 1993). Explicit memory tasks increase the metabolism in the prefrontal areas. The increase involves the left hemisphere in relation to encoding in episodic memory and retrieval from semantic memory, while it prevails in the right hemisphere in relation to the retrieval from episodic memory (Tulving,

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Kapur, Craik, Moscovitch, & Houle, 1994, for the pertinent bibliography; Fletcher, Frith, Grasby, Shallice, Frackowiak, & Dolan, 1995). As far as episodic memory is concerned, left prefrontal activation during encoding and right prefrontal activation during retrieval have been consistently found for a wide variety of verbal and visual materials and tasks (see Wheeler, Stuss, & Tulving, 1997, for the pertinent bibliography). In agreement with these findings, the right dorso-lateral prefrontal areas showed hypometabolism during an attack of transient global amnesia (Baron, PetitTaboue, Le Doze, Desgranges, Ravenel, & Marchal, 1994). Just how much the frontal involvement actually relates to mnesic functions, rather than to working memory, which they necessarily involve, still remains an open question. As in Korsakoff’s syndrome, confabulation may be a salient symptom of the frontal patient. The patient either invents false events and places real events in a false temporal or spatial context in response to a probe of his or her memory, apparently to fill memory gaps (“momentary or embarrassment confabulation”, Berlyne, 1972), or abandons him or herself spontaneously to persistent florid fantasies and generates dream-like tales that he or she pretends really happened (“fantastic or productive confabulation”, Berlyne, 1972). It is as if the patient is unable to control, direct, and organise the flow of memories, or monitor their adequacy to the current environmental requests. Stuss, Alexander, Lieberman, and Levine (1978) reported fantastic confabulations in five frontal lobe patients, two of whom also had alcohol abuse damage (bilateral traumatic hematomas or softenings in the territory of the anterior cerebral artery). Baddeley and Wilson (1986) also reported similar findings in two other patients with closed frontal lobe injuries. Kapur and Coughlan’s (1980) patient, after softening in the territory of the left anterior cerebral artery following subarachnoid hemorrhage, became amnesic for past events and developed a frontal “dysesecutive” syndrome. He initially displayed both momentary and fantastic confabulations, but the latter disappeared within seven months, together with the other frontal symptoms, leaving only momentary confabulations associated with residual amnesia. Fantastic

confabulations, more than a component of the amnesic syndrome, are likely due to frontal disinhibition. In fact, Mercier, Wapner, Gardner and Benson’s (1977) and Shapiro, Alexander, Gardner and Mercier’s (1981) findings on 11 and seven patients, respectively, support the claim that confabulation is no more related to the degree of amnesia or confusion or suggestibility as to the failure to withhold answers, monitor one’s responses, and provide self-corrections, features that characterise the frontal disinhibition syndrome and not the amnesic behaviour. De Luca (1993) also maintains that confabulation requires both frontal lobe impairment and a concomitant amnestic disorder, and Johnson, O ’Connor, and Cantor (1997) actually reach the same conclusion. By comparing eight confabulating with nine non-confabulating amnesic patients, Moscovitch and Melo (1997, p.1017) were able to identify the frontal locus of confabulation, in that they found that “confabulation is associated with impaired strategic retrieval processes resulting from damage in the region of the ventro-medial frontal cortex”. Thus, confabulation, especially fantastic confabulation, is related to frontal damage. It appears as an instance of the inability to inhibit impulsive verbal productions, as occurs for motor behaviour (see Inhibition and self-control). Frontal damage, predominantly in the right hemisphere, has been advocated for duplicative paramnesia and Capgras syndrome, phenomena that, like confabulation, denote a defect in awareness. Duplicative paramnesia consists of subjective certainty that familiar peoples, places, or events have been doubled, and Capgras syndrome consists of delusional belief that a person close to the patient has been replaced by one or more impostors (Alexander, Stuss, Benson, 1979; Bogousslavsky, 1994).

Learning and learning strategies. (She’s stubborn and obtuse) The frontal lobe patient has a learning defect related to the inability to construct, automatise, and spontaneously use an operational strategy. In Milner’s (1964, 1965) maze test, subjects had to discover by trial and error and remember the one hidden path leading from the lower left-hand

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comer to the upper right-hand comer through 100 dots aligned in a 10 by 10 array. They were required to respect few simple rules: to proceed one step at a time from dot to dot; not to move diagonally across the dot board; to go back to the preceding dot whenever a loud click let them know that they strayed off the right path; and not to retrace portions of the correct path. Cortical excisions, mostly carried out for relief of focal epilepsy, impaired maze performance differently depending on locus of lesion. Mean trials and errors to criterion of the parietal and left temporal lobe patients approximated those of the normal subjects, whereas those of the right temporal, right parieto-temporooccipital, and frontal lobe patients were markedly increased. Unlike temporal and parieto-temporooccipital patients, the failure of frontal lobe patients bore no relation to the spatial and mnestic nature of the task, but, as revealed by the qualitative analysis of errors, it was contingent on repetitive rule-breaking: jumping to distant dots, diagonal moves, disregarding the warning click, and backtracking towards the starting-point. Thus, frontal lobe patients did not learn because they were unable to conform to the rules the examiner imposed and to change their response set in accordance with environmental warnings (Milner, 1965). M ilner’s (1965) results were replicated by Canavan (1983): frequent rule-breaking errors characterised the behaviour of frontal patients. Canavan tested frontal lobe patients under two different conditions, by signalling either wrong moves, as in Milner’s paradigm, or correct moves, in order to discriminate whether their defect resided in the inability to use any kind of information or only negative information. Emphasis on either errors or correctness did not differentially affect mean errors or rule-breaking, nor the linear improvement over 15 trials, seemingly supporting the first hypothesis (however, see Category discovering and abstract thinking). The impairment of prefrontal patients on the maze test is not confined to the visual modality. It also manifested under tactual-kinesthetic control (Corkin, 1965). Karnath, Wallesch, and Zimmerman (1991) allowed their subjects only a partial view of the maze display, thus requiring them to generate a

mental plan or cognitive map of each of seven mazes in order to perform the task correctly, and recorded 19 parameters during the first attempt, when the task was new, during the second, when it was no longer new, and during the last, by which time following the correct path had become routine. Fronto-mesial patients were the most severely impaired, above all on the second attempt. In the acute stage of illness (under 40 days) their behaviour was characterised by a larger number of false moves, especially perseverative, with respect to post-rolandic patients, subsequently requiring a greater number of trials than control subjects to pass the maze. In the chronic stage of illness (over 40 days) they typically made more frequent rule-breaking errors, relative not only to normal subjects and post-rolandic patients, but also to dorso-lateral frontal lobe patients, although significantly only with respect to the temporal lobe patients. The fact that frontal lobe patients could make use of their mental maze plans with the same efficiency as the compared groups during the first attempt, when the task was new, would appear to challenge Shallice’s assumption (see Planning and farsightedness) of la selective frontal lobe impairment in non-routine tasks. Positron emission tomography studies point to right areas 8 and 10 as the frontal focus of covered maze learning (Flitman, O’Grady, Cooper, & Grafman, 1997). The difficulty of the prefrontal patient in building up and using an organised learning strategy was stressed by Eslinger and Grattan (1994). The task consisted of learning a list of 15 unrelated words through five study-recall trials. During study trials, when the words are presented in the same serial order, under conditions of free recall the stimulus items at the extremes of the list have the highest and the mid-list items the lowest probability of being recalled (primacy and recency effects). Thus, the resulting performance is reflected in a U-shaped serial position curve, with the first branch slightly higher than the second. Patients with prefrontal lesions, especially if dorsolateral, failed, relative to post-rolandic patients, to maintain primacy and recency effects across the

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five learning trials. Underlying this failure was their inabilty to impose a sequential structure on semantically unrelated words. Prefrontal patients encounter difficulties not only in conforming to environmental requests, but also in developing internal behavioural rules, which would make them autonomous from external feedback. Leonard, Milner, and Jones (1988) studied uniand bimanual sequential tapping in epileptic patients after dorso-lateral and mesial prefrontal or temporal corticectomies. In the unimanual task, subjects were presented with a round plate and a stylus. They were then allowed 30 seconds to tap each of the four sectors of the plate, as quickly as possible, in a requested order. In the bimanual task, subjects had to tap simultaneously with both hands the sectors of two plates as quickly and accurately as possible, each hand following a different order. Both frontal and temporal lobe patients failed with respect to normal subjects on the spatially ordered unimanual tapping, but only patients with lesions of either the right or the left frontal lobe failed on the bimanual tapping task. Essentially, the uni- and bimanual tapping tasks differed in that, in the former the subject could pay attention to the single hand movements whereas in the latter he or she could only move correctly according to a previously automated internal algorithm, which no longer relied on visual and kinesthetic feedback. Thus, the poor sequential tapping in the bimanual task may reflect the frontal lobe patient’s impairment in developing internal representations of complex movement sequences. In agreement with Leonard’s view are Jason’s (1985b, 1986) results, and the difficulty in performing unimanual sequential movements smoothly or in alternating bimanual movements in a co-ordinate fashion, which Luria (1969) described as typical in the frontal lobe patient (actually, premotor). Frontal patients’ impairment in devising learning strategies and organising items in memory was well documented by Incisa Della Rocchetta (1986). His subjects were asked to recall 36 coloured pictures of common objects, reproduced singly on cards. Before learning, subjects were invited to arrange the pictures into clusters in the way that they thought would best help them

remember the names of the objects. Actually, the objects could be grouped into three major semantic categories (food, household, and animals), which in turn could be divided into four subcategories (fruits, vegetables, meat, and sweets; garden tools, workshop tools, parts of a house, and kitchenware; birds, bears, cats, and horses). Compared to normal subjects, patients who had undergone left or right frontal corticectomy disclosed a learning defect that paralleled their poor semantic clustering (see Category discovering and abstract thinking), whereas left temporal lobe patients were impaired only in recalling picture names, but not in the sorting task, and right temporal lobe patients performed normally on both tasks. Also in Incisa Della Rocchetta and Milner’s (1993) study, recall of categorised word lists was impaired both in left and right frontal lobe patients, and left damaged patients benefited from strategic retrieval cues. It is likely that the inability to reproduce 10 sequences of three hand gestures found by Canavan, Passingham, Marsden, Quinn, Wyke, and Polkey (1989b) in patients who had sustained damage to frontal lobe compared with normal subjects is also related to a defective planning strategy for learning sequential items. Frontal lobe patients do not use learning strategies spontaneously, even when they are able to. Gershberg and Shimamura’s (1995) left or right dorso-lateral frontal lobe patients exhibited, relative to normal subjects, impaired free recall and reduced use of organisational strategies on verbal learning through five study-recall trials. Reduced subjective organisation was observed during recall of 15 unrelated words, and reduced category clustering as well during recall of 15 words belonging to three to five semantic categories. Patients benefited from strategy instruction at either study or recall, suggesting that both encoding and retrieval processes were impaired by frontal lobe damage. Hirst and Volpe (1988) studied the learning of 20 words presented for five minutes on the same number of cards spread out in front of the subject who could arrange them in any way he or she deemed appropriate. The learning of unrelated words and of words that could be clustered by fives into four semantic categories was compared. After

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a two-minute filled interval, frontal lobe patients (all bilateral) showed normal recall of unrelated words but were impaired in recalling categorised words because, unlike normal subjects, they did not use any criterion for rearranging them spontaneously. However, when they were forced to categorise, their performances improved almost to the normal level. Also, difficulties in conditional associative learning are related to a more general and basic defect of the prefrontal patient, which may be defined as the inability in decision-making, which is manifested in selecting, from a set, the appropriate response to a given stimulus (Milner, 1982). This is not confined to the learning process; it also surfaces when the associative links between stimuli and responses have already been acquired. Petrides (1985) required patients, who had undergone unilateral prefrontal or temporal corticectomies, to learn by trial and error to associate a set of six random locations and a set of six aligned cards. Compared with normal subjects, left and right frontal lobe patients made a greater number of errors. When patients had to learn to associate hand positions and colours, again left or right frontal lobe patients made more errors than normal subjects. Instead, temporo-hippocampal patients selectively failed on the spatial or the non-spatial task depending on whether the lesioned hemisphere was the right or the left. Analogously, Canavan, Passingham, Marsden, Quinn, Wyke, and Polkey’s (1989a) frontal lobe patients were impaired compared with normal subjects on both visualvisual and visual-motor associative learning tasks, whereas left temporo-hippocampal patients selectively failed the visual-motor task, and right temporo-hippocampal patients performed almost at a normal level on both tasks. Results of multiple-choice tests that did not involve discovering the contingencies provided similar evidence. In a study by Alivisatos and Milner (1989), subjects were required to respond with their right or left index finger to a square and diamond respectively, which could appear above, below, or to the right or left of a large central square. In another study by Alivisatos (1992), subjects had to discriminate between normal and mirror image presentations of two capital letters or

two Arabic numerals, which would appear in one of six different orientations. Cues indicating the impending target location (around the central square) or the target identity (which letter or numeral) and its degree of rotation shortened reaction times of normal subjects to the same extent as those of the temporal lobe patients, but significantly more than those of the frontal lobe patients. Also, Decary and Richer (1995), who used multiple-choice tests in which the stimulus-response mapping did not have to be learned because it was already acquired, provided results that are consistent with a basic defect of the response selection processes or of applying associative rules in the prefrontal patient. In agreement with PET studies, which posit right prefrontal activation during attempts at retrieval from episodic memory and left prefrontal activation during episodic encoding, are the findings of Stuss, Alexander, Palumbo, Buckle, Sayer, and Pogue (1994). Right, but not left, frontal lobe patients tested on a word list learning task showed peculiar inconsistencies in retrieval performance from trial to trial and a selective tendency to perseverate by repeating words that had already been successfully recalled from the study list. Their overall recognition and recall performance was comparable with healty controls. The autors referred to these deficits as impairment in “retrieval monitoring”. Proactive interference and release from proactive interference are phenomena related to learning. Prefrontal patients show increased sensitivity to proactive interference and increased resistance to release from proactive interference, at least on verbal learning tasks. Gershberg and Shimamura’s (1995) frontal lobe patients were more susceptible to proactive interference compared with normal subjects only in the experimental conditions most favourable to the phenomenon. Further, the left frontal lobe patients, whose corticectomies always involved the mesial areas, studied by Incisa Della Rocchetta and Milner (1993), showed increased sensitivity to proactive interference in retrieval, compared with right frontal lobe and right or left temporal lobe patients. Moscovitch and Milner (Moscovitch, 1982) studied patients after unilateral frontal or temporal

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lobectomy with five different lists of 12 words each to be recalled immediately after presentation. Release from proactive interference was expected to be associated with poor memory. Somewhat surprisingly however, the left frontal lobe group demonstrated the least amount of release from proactive interference, even if the left temporal lobe group had the worst recall performance. Frontal lobe patients’ resistance to release from proactive interference may be due to their impaired ability to judge the temporal order of the events. Cerebral blood flow studies also support the suggestion that the frontal lobe plays a role in controlling proactive interference. After having learned 14 pairs of words, subjects were asked to learn a second list, where the paired associates of the first list had to be unlearned and the items had to be recombined in new word pairs. During the second list learning, blood flow increased in the right dorso-lateral frontal cortex, relative to first list learning, (Uhl, Podreka, & Deecke, 1994). At variance with results of verbal tests, neither proactive interference nor release from preactive interference could be shown, however, with figurative-spatial tasks (Smith, Leonard, Crane, & Milner, 1995).

Productivity and creativity: Spontaneous flexibility. (He’s sluggish and repetitive) “Cognitive flexibility” refers to the capacity to shift a course of thought and action to meet changing environmental demands. Spontaneous production of ideas and solutions in response to a single stimulus (“spontaneous flexibility” or “productivity”) can be distinguished by the ability to change behaviour when required to do so by the context (“reactive flexibility”). Both forms of flexibility are typically, even if not exclusively, reduced by prefrontal lesions (Grattan & Eslinger, 1989). The first type of defect (“rigidity”) is examined in this section, the other (“perseveration”) is considered primarily in the context of “learning and learning strategies” and “category discovering and abstract thinking.” The reduced spontaneous speech following frontal lesions outside Broca’s area (Bonner, Colb, Sweet, & White, 1953; Feuchtwanger, 1923; Kleist, 1934; Luria, 1980; Zangwill, 1966), as well as the

more general lack of initiative shown by many frontal lobe patients (Penfield & Evans, 1935), led Milner (1964) to assess the amount of cued verbal production (“verbal fluency”) in patients before and after cortical removals for antiepileptic purposes. She allowed them five minutes to write down as many words as possible beginning with the letter S, and then four minutes for as many fourletter words beginning with the letter C. Failure was selective for left dorso-lateral and mesial frontal lobe patients compared with right frontal and left temporal ones. The latter patients were impaired on verbal memory tasks (delayed recall of prose passages and paired associate words). Benton (1968) gave subjects one minute to say as many words as they could think of that began with a given letter of the alphabet (F, A, and S). Once again, bilateral and left frontal lobe patients fared worse on verbal fluency tasks as compared with right frontal patients. Paus et al. (1991) found that verbal fluency performance was impaired by mesial or lower dorso-lateral frontal lesions but not by upper dorso-lateral frontal damage. The severe impairment of left frontal lobe patients on verbal fluency tasks may acknowledge two basic components: verbalising difficulties, due to the left hemisphere lesion, whether pre- or postrolandic, and lack of initiative, due to the frontal lesion, whether in the right or left hemisphere. Ramier and Hecaen’s (1970) results, as well to some extent those of Vilkki (1989), are consistent with this hypothesis, because the effects of both the hemisphere (left vs right) and the site (pre- vs postrolandic) additively impaired performance on Benton’s test of verbal fluency. Vilkki and Holst’s (1994) left and right hemisphere patients, who underwent pre- or post-rolandic brain surgery, were asked to say 20 animal names (semantic cue), then 10 words beginning with the letter S (phonetic cue), and alternately 10 animal and 10 letter words, as quickly as possible. The authors measured their errors, perseverations, and the time they took to produce a specified number of words rather than the number of words produced in a specified time. In this way, the number of errors and perseverations referred to the same total of produced words. Once again, left frontal lobe patients fared worst on the letter S and alternate words tasks (but not on the

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animal names task), in agreement with Ramier and Hecaen’s (1970) results. The poor performance of frontal lobe patients on verbal fluency tasks can actually be seen in a different light if we consider that it is normal on tasks in which the cue is semantic rather than a phonetic; for example, saying the names of animals (Newcombe, 1969; Vilkki & Holst, 1994), of objects (Newcombe, 1969), or alternatively of birds and colours (Newcombe, 1969). It is possible that frontal lobe patients run into difficulty only when they are forced to rely on unusual searching strategies, as occurs with phonetic cues, and that this is not the case when they can proceed in the way words are usually found, as with semantic cues. This hypothesis is supported by Perret’s (1974) findings on a word fluency task with phonemic cues and a modified version of the Stroop (1935) test. On both tests frontal lobe patients performed worse than temporal and parieto-occipital lobe patients. Patients with left frontal damage fared worst of all, presumably owing to combined detrimental effects of left hemisphere and frontal lobe damage. As both tests engage verbal abilities, the left hemisphere effect on either task was interpreted as being of a verbal nature. However, the frontal lobe effect on the Stroop performance could hardly be related to loss of initiative, as subjects were forced to give one response to each item. Indeed, subjects were presented with names of colours printed in ink of a different colour from the meaning of the word and had to say the print-colour, rather than to read the colour-name as usually happens. Thus, in order to give correct responses, subjects had to suppress their habitual behaviour in order to adapt to task demands, which required them to separate two conflicting categories within the same stimulus, and to choose the less commonly used one. The same ability is challenged by the word fluency tasks. They require the subject to explore the content of his or her semantic memory by considering solely the initial letter of the words while disregarding their natural meaning. This can be seen as the ability to adopt unusual strategies for analysing reality and planning behaviour. The involvement of the prefrontal cortex (albeit in the right more than left hemisphere) in the Stroop test was further

validated by Vendrell, Junque, Pujol, Jurado, Molet, and Grafman (1995). According to Ramier and Hecaen (1970), as well as Perret (1974), performance on fluency tasks that tap spatial rather than verbal abilites is expected to be most impaired in patients with right frontal lesions. This is what Jones-Gotman and Milner (1977) actually found with design fluency tasks in which subjects were required to invent abstract meaningless designs. The task was to outline in five minutes as many figures as possible, and then to draw in four minutes as many four-line figures. Patients who underwent right dorso-lateral and mesial prefrontal corticectomy were the most severely impaired: on the first task relative to normal subjects, and on the second task also relative to left frontal and to right and left temporal or parieto-occipital lobe patients. Beside impoverished output, perseverative responses were the most striking feature of the performance of the right frontal lobe patients, just as if they could not shift from older to novel models. Further evidence of task-specific left and right frontal lobe engagement in fluency tasks was provided by studies using gesture fluency tests. Jason (1985a) asked patients with unilateral cortical excisions to produce as many different finger positions as they could in two minutes, and then as many different meaningful gestures (symbolic gesture, pantomime of object use, or iconic representation of an object or shape) in two minutes. In both tasks, left and right frontal lobe patients produced the same total number of positions and gestures as the normal subjects and the left or right temporal lobe patients. Nevertheless, left frontal lobe patients produced significantly fewer novel digit positions and a larger number of perseverative and rule-breaking errors relative to all the other experimental groups. Left and right frontal lobe patients produced fewer novel meaningful gestures and made more perseverative errors relative to normal controls. Eslinger and Grattan (1993) asked patients, who had sustained brain infarction, to explain all the possible uses of an object. Again, left or right dorsolateral and mesial prefrontal patients did not differ from either normal subjects and post-rolandic patients in the total number of responses, but

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produced fewer object uses and made more perseverative errors than all the other experimental groups. Lesion sudies have failed to identify crucial prefrontal areas for fluency tasks. Dorso-lateral lesions, be they rostral, intermediate, or caudal, have been shown to be as disruptive on verbal fluency performance as mesial ones (Hecaen & Ruel, 1981), whether or not they involved the supplementary motor area (Wallesch, Kornhuber, Kollner, Haas, & Hufnagl, 1983). Similarly elusive is evidence for the localisation of gesture fluency within the left frontal lobe (Jason, 1985a). Regional blood flow studies have also been unsuccessful in this regard. Blood flow increased in the left dorso-lateral and mesial frontal cortex during word fluency tasks, whether words were semantically or phonetically cued (Frith, Friston, Liddle, & Frackowiak, 1991; Rueckert, Appollonio, Grafman, Jezzard, Johnson, Le Bihan & Turner, 1994), and during object use generation (Petersen, Fox, Posner, Mintun, & Raichle, 1988; Raichle, Fiez, Videen, MacLeod, Pardo, & Fox, 1994; Warburton, Wise, Price, Weiller, Hadar, Ramsay, & Frackowiak, 1996; Wise, Chollet, Hadar, Friston, Hoffner, & Frackowiak, 1991), whereas it increased in the right mesial cortex with the Stroop effect (Larrue, Celsis, Bes, & Marc-Vergnes, 1994). The rigidity of the frontal lobe patient also involves perceptual activity. Ricci and Blundo (1990) asked patients who underwent lobectomy to recognise two images in ambiguous figures. Frontal lobe patients, with lesions involving the dorsolateral and in some cases also the orbital or mesial cortices, recognised fewer figures, regardless of the lesioned hemisphere. They failed both without and with prompting by the examiner, not only with respect to normal subjects but also to parietotemporal patients. The right frontal lobe patients, studied by Meenan and Miller (1994), failed relative to normal subjects on the same test, while left frontal lobe patients had near normal performance, possibly due to their less extensive lesions. Canavan, Passingham, Marsden, Quinn, Wyke, and Polkey (1990) also found perceptual rigidity in frontal lobe patients after cortical excisions, who, compared with normal subjects, failed to adapt their vision through prisms that rotated images 30°. In

Miller and Tippett’s (1996) matchstick puzzles, subjects were required to demonstrate as many ways as possible of removing a particular number of sticks from a two-dimensional geometric design to achieve a specified shape. Right frontal lobe patients showed selective impairment in the ability to shift strategy, as compared with normal subjects, left frontal lobe, central, parietal, and temporooccipital lobe patients. An unusual disorder in visual perception, which, however, has nothing to do with perceptual rigidity, was reported by Solms, Kaplan-Solms, Saling, and Miller (1988) in a patient with a bifrontal basal abscess. The patient claimed to experience paroxysmal episodes of upside-down vision. Between the attacks he continued to misread alphabetical letters isolated from their contextual framework, i.e. taken out of a word, by confusing the top and bottom, thus, for example, not distinguishing the letters “d” and “q”. The uniqueness of this patient resides in the lesion site, which, in the other rare case reports, was always parietal or vestibulo-cerebellar.

Category discovering and abstract thinking: Reactive flexibility (She’s banal and superficial) The cognitive behaviour of the frontal lobe patient often is deemed to stem from the inability to “abstract” or to “identify categories”, that is, to grasp similarities and essential features in the manifold aspects and elements composing reality, which, from time to time, unite and differentiate them (Goldstein, 1936a,b, 1944, 1949; Goldstein & Scheerer, 1941). Lacking abstract concepts, the patient relies on the more concrete, immediate and fragmented surface clues, at the mercy of his or her automatic and habitual reactions (Ackerly, 1964; Halstead, 1947; Nicholls & Hunt, 1940; Rylander, 1939; Willett, 1960). Various tests have been devised in the attempt to assess abstract thinking ability. They have provided clear-cut evidence that the abstract thinking defect of the frontal lobe patient, if any, is rather singular. In the first and most paradigmatic of them, namely, the Weigl (1927) colour-form sorting test, the subject is presented with scattered figures of

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different colours and shapes, and has to sort them first according to colour and then according to shape, without prompts from the examiner. McFie and Piercy (1952) found that Weighs test was sensitive to left hemisphere damage, regardless of aphasia, whereas, with a modified colour-shapethickness-size-suit Weigel-type test, De Renzi, Faglioni, Savoiardo, and Vignolo (1966) found aphasia to be the critical factor. This apparent contradiction may be due to the different prevalence of frontal lobe lesions among nonaphasic patients. In McFie and Piercy’s sample, consisting primarily of tumours or traumas, 75% of the nonaphasic patients had frontal lobe damage, whereas in the De Renzi, Faglioni, Savoiardo, and Vignolo’s sample, consisting of cerebrovascular accidents, frontal lobe patients were exceptional. Accordingly, among Vilkki’s (1988) tumoral or traumatic patients, the left frontal lobe group identified fewer categories in a colour-form-size test, than the normal subjects, as well the right frontal, and the left and right post-rolandic groups. Grant and Berg’s (Berg, 1948; Grant & Berg, 1948) Wisconsin card sorting test (WCST) developed from Weighs test. In the version used by Milner (1963), the subject faces four stimulus cards, differing in colour, form and number: one red triangle, two green stars, three yellow crosses, and four blue circles. A total of 128 response cards are presented individually. The cards vary along these same dimensions of colour, form, and number and share one or more chacteristics with three of the four stimulus cards; thus, for example, a response card with two red crosses corresponds to stimulus card 1 in colour, to stimulus card 2 in number, and to stimulus card 3 in form, while it is completely different from stimulus card 4. The subject has to place each response card in front of one or other of the stimulus cards, wherever he or she thinks it should go, and the experimenter informs him or her whether the answer is right or wrong. The patient has first to sort for colour, all other responses being called wrong; then, once he or she has achieved 10 consecutive correct responses to colour, the required sorting rule shifts to form without warning, and colour responses are therefore wrong. After 10 consecutive correct responses to form, the rule shifts to number, and then back to colour once

more. The test is discontinued following the completion of six categories, or when the 128 response cards have been exausted. Milner (1963) tested patients who underwent cortical excisions for relief of focal epilepsy. Patients with right or left dorso-lateral and mesial prefrontal ablations showed consistent impairment on the card sorting test: they achieved fewer sorting categories (half) and made more errors (double) than patients with post-rolandic, orbito-frontal, or lower dorso-lateral frontal lesions. However, underlying this failure was not their random sorting, but their persistence in sorting according to a particular category long after this had ceased to be appropriate. They were often aware of their failure and manifested verbal annoyance, and yet did not modify their responses accordingly. Thus, the abstract thinking defect of frontal lobe patients appeared to be due to an inability to shift from one sorting principle to another, owing to perseverative interference of previous modes of responses. Notwithstanding claims that performance on the WCST fails in discriminating frontal lobe patients from those with brain lesions elsewhere (Anderson, Damasio, Jones, & Tranel, 1991; Heck & Bryer, 1986; Shallice & Burgess, 1991), or from normal subjects (Mountain & Snow, 1993; Van Der Broek, Bradshaw, & Szabady, 1993), Milner’s (1963) results have been consistently replicated by many researchers: by Ricci and Blundo (1990) in neoplastic patients, by Eslinger and Grattan (1993) in cerebro-vascular patients, and by Arnett, Rao, Bernardin, Grafman, Yetkin, and Lobeck (1994) in multiple sclerosis patients. Nelson’s (1976) simplified version of the WCST, which circumvents some of the ambiguity of the original form, has proved to be just as useful for detecting the prefrontal defect. Of Milner’s 128 response cards, Nelson chose the 48 that shared one and only one attribute with each of the stimulus cards and removed cards with two or more attributes. He allowed the subjects to choose the first category; and warned them when the category changed after six consecutive correct responses. Finally, all responses that followed the same category concept as the immediately preceding response were scored as perseverative errors, but not if they followed the category concept that had

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previously been correct. His left or right frontal lobe patients, most with tumoral pathologies, obtained fewer categories and made more perseverative errors than post-rolandic patients, who fared worse than normal subjects as well. Delis, Squire, Bihrle, and Massman’s (1992) sorting test includes eight classification criteria (rather than three), three of which place greater demands on verbal analysis and five on spatial analysis, and allows three testing conditions (rather than one), spontaneous sorting, structured sorting, and cued sorting. The test aims to isolate and assess the specific abilities engaged by sorting tasks: for identifying, verbalising, and using categories, both spontaneously and following abstract or concrete hints, and for recognising and verbalising categories chosen by the examiner. Like Korsakov amnesics, left, right, or bilateral frontal lobe patients, were impaired compared with normal subjects and non-Korsakov amnesics in detecting, using, recognising, and naming categories, and made a higher number of perseverative errors both in category choice and verbalisation. The striking failure of frontal lobe patients in shifting category on sorting tasks relates to perseveration. Owen, Roberts, Hodges, Summers, Polkey, and Robbins (1993) devised a test to distinguish in set-shifting the ability to “shift from” a perceptual dimension that had previously commanded attention from the ability to “shift to” an alternative perceptual dimension that had previously been irrelevant. Subjects had to learn by trial and error simple and reversal binary discrimination tasks along one of two alternative stimulus dimensions (say colour and number), until a criterion of six consecutive correct responses was achieved. Then, without warning, (a) the previously relevant dimension became the irrelevant one (and the previously irrelevant dimension was replaced by a novel one) (shift from), so that failure to shift to the new relevant dimension could be attributed to perseveration on the previously learned rule, or (b) the previously irrelevant dimension became the relevant one (and the previously relevant dimension was replaced by a novel one) (shift to), so that failure to shift to the new relevant dimension could not be attributed to prior learning about the old relevant stimulus dimension, as this was no longer

present. Frontal lobe patients only differed from normal subjects under testing condition (a), thus showing an inability to disengage their attention from a relevant perceptual dimension (perseveration), and performed at normal level under testing condition (b), thus showing a spared ability to engage attention in a previously irrelevant stimulus dimension (learned irrelevance). Sorting tasks likely involve the mesial prefrontal cortex, not the orbital or lower dorso-lateral frontal areas, while the importance of the upper dorso-lateral ones is still doubtful. Indeed, in Milner’s (1963) sample, orbito-frontal as well as lower dorso-lateral excisions did not worsen proficiency on WCST relative to post-rolandic patients, and only excisions encroaching on the upper dorso-lateral cortex and in most patients also the mesial frontal cortex were associated with poor performance. Accordingly, the case reported by Eslinger and Damasio (1985) performed at normal level despite removal of a bilateral orbito-frontal meningioma. Drewe (1974) carried out a systematic search in a large sample of focal brain-damaged patients for the critical loci involved in performance on WCST. Beside greater involvement of the left than the right hemisphere, he found striking deficits after frontal lobe damage as compared to post-rolandic lesions, and, within the frontal lobe, after mesial prefrontal cortex damage as compared to prefrontal lesions outside this area, even if affecting the dorso-lateral ones. Also in Paus, Kalina, Patockova, Angerova, Cemy, Mecir, Bauer, and Krabec’s (1991) patients, fewer sorting categories and more errors on Nelson’s simplified WCST were found to be associated with mesial prefrontal damage. At variance with lesion studies, event related potentials (Barcelo, Sanz, Molina, & Rubia, 1997) and regional cerebral blood flow (Rezai, Andreasen, Alliger, Cohen, Swayze, & O’Leary, 1993) results point to the left dorso-lateral prefrontal cortex as the focus of WCST. The inability of frontal lobe patients to detect structural rules governing events was further evidenced by Villa, Gainotti, De Bonis, and Marra (1990) with a temporal rule induction task, and by Burgess and Shallice (1996) with a spatial rule induction task. In the temporal rule induction task,

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a red (R) and a blue (B) token were successively presented following a binary sequence: RB RB RB, or RRBB RRBB RRBB, or RBB RBB RBB. After three repetitions of each sequence, subjects had to predict the colour of future tokens and explain the rule underlying their appearance. In the spatial rule induction task, a target moved around on a panel of 10 numbered positions following rules that changed without warning through 56 single presentations. On both tasks, frontal lobe patients, regardless of the damaged hemiphere, detected fewer rules than post-rolandic patients. Prefrontal patients are unable to construct hypotheses in order to understand real world processes or to test them critically on available evidence. Essentially two defects surface. They are not able to parse stimuli into useful temporal patterns when the sequential order has to be internally organised, and they are less sensitive to the effects of negative (falsifying) outcomes than of positive (confirming) outcomes. These are the conclusions reached by Cicerone, Lazar, and Shapiro (1983), who used the procedure devised by Levine (1966) to identify subjects’ hypotheses and cognitive strategies during visual discrimination learning. The subject is given a series of two-choice simultaneous visual discrimination problems, with stimuli varying on four binary dimensions (colour, form, size, and position), thus generating eight possible cues (red, here in bold, or blue, here in normal type; X or T; large or small and left or right). The subject receives four 16-trial problems, each having as the correct solution one of the eight cues. Subjects have to point to one stimulus on each trial, and, from being told “correct” or “wrong” after trials 1,6, 11, have to discover the solution to the problem. The patterns of choices in the sequences of four consecutive nonreinforced trials disclose subjects’ working hypotheses, if any. For example, let X in the stimulus pair have been chosen on trial 1. If the examiner says “correct”, the subject has four appropriate hypotheses at his or her disposal (that it is the form X, colour blue, large dimension, left position), and 4 inappropriate hypotheses (the alternatives). The choices made in trials 2,3,4, and 5 allow the examiner to ascertain whether the subject’s hypothesis, if any, conforms to the first

warning or not. The choice of x in the stimulus pair on trial 6, followed by the “wrong” warning, would reduce to two the number of hypotheses appropriate to both preceding warnings (that it is either the colour blue or the large dimension) and increase to six the number of inappropriate ones. During trials 7, 8, 9, and 10 the examiner can still ascertain whether the subject holds an appropriate working hypothesis or not. The choice of x between on trial 11, followed by positive reinforcement, leaves only one hypothesis appropriate to all preceding warnings (the colour blue). During trials 12,13,14, and 15 the examiner notes whether the correct hypothesis has been actually achieved. If it has, the subject will choose t in the stimulus pair on trial 16, thus gaining the confirmation of their hypothesis. Levine’s test follows the stages of the patient’s “concept formation” more analytically than the WCST. It provides grounds on which to infer whether the subject advances hypotheses or not, whether the hypotheses are in keeping or at odds with the information he or she has received, whether positive and negative reinforcements are equally effective. When compared with patients with post-rolandic tumours, left and right frontal lobe patients were found to use an equal total number of hypotheses, thus showing that their defect had no bearing on the readiness to put forward hypotheses. Notwithstanding, they attained fewer solutions and used fewer appropriate hypotheses after the second and even fewer after the third reinforcement, thus showing increasing difficulty in attending to multiple cues. Finally, although they were able to use positive reinforcements confirming their ongoing hypotheses, they showed a striking perseverative tendency to maintain their irrelevant hypotheses despite being informed that they were incorrect. According to Cicerone, et al. (1983, p.522): Although, in quantitative terms, positive and negative outcome trials provide equivalent information, they produce different processing demands on the subject. When told “correct” the subject may directly encode the stimulus without further analyses, and automatically maintain the selected

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hypothesis. On being told “wrong” the subject must reclassify those properties of the stimulus as irrelevant, and perhaps resample the results of previous reinforced trials, in order to select a complementary appropriate hypothesis. This work requires additional time and entails the risk of interference from irrelevant properties of the chosen stimulus hindering the selection of the relevant ones (Levine, 1966). Yet, the perseveration of the frontal lobe patient in the “wrong” hypothesis would seem to result from his or her inability to simultaneously analyse multiple attributes of the stimulus, with the ensuing restricted hypothesis set. However, Owen, Roberts, Polkey, Sahakian, and Robbins (1991), based on different tasks, do not concur with this interpretation.

Judgement and rationality. (He’s thoughtless and silly) Silliness in judging reality, especially in novel and complex settings requiring planned analysis (Luria, 1980), has been emphasised, both by early clinical reports and recent experimental research, as one of the major features that characterise frontal lobe patients (Goldstein, 1936a). Indeed, both left and right frontal lobe patients produced a higher number of bizarre estimates than post-rolandic patients when they had to guess the answers to 15 questions of the type: “On the average, how many TV programmes are there on any one TV channel between 6.00 pm and 11.00pm?”; “What is the length of an average man’s spine?”; “How fast do race horses gallop?” (Shallice & Evans, 1978). Right frontal lobe patients were less accurate when they were asked to estimate the prices of 16 toy objects (Smith & Milner, 1984). To master this type of tasks the subjects themselves must create an appropriate cognitive strategy in order to check any putative answer against information held in long-term memory. First a representative estimate based on the available instant knowledge must be compared with other knowledge and experience pertaining to the problem in order to assure plausibility. Next, a

better estimate may be worked out in light of the final considerations, and so on until memory store is exhausted. Subjects are involved in simultaneously considering past information stored in long-term memory, much in the same way as they deal with information gathered from the environment during “category discovering”. Hirst and Volpe (1988) probed knowledge of memory strategies in organising the to-beremembered material, and found a striking defect in bilateral frontal lobe patients, compared with normal subjects and even with Korsakov and other amnesics. Vilkki and Holst’s (1989a) left and right frontal lobe patients made inaccurate subjective predictions of their learning capacity, in that they failed, relative to normal subjects and post-rolandic patients, when they had to guess in advance the length of the longest spatial sequence they would be able to recall and retap, even if they were actually able to carry it out like the other groups. Prefrontal patients tend to make quick impulsive judgements more than risk-seeking decisions. In a study by Miller (1985), three complementary partial figures of the same object were presented successively. The subject’s task was to guess what the object was after seeing one, two or all three clues. Right frontal lobe patients guessed on the basis of only the first fragment (risk-taking score) more often than left frontal and right and left temporal lobe patients, and frontal lobe groups pooled identified as many figures (synthesising ability score) as the temporal lobe patients. When, instead of drawings, words had to be guessed on the basis of either phonemic or semantic partial information clues, left frontal lobe patients were the most risk-taking group (Miller & Milner, 1985). To differentiate impulsive from risk-seeking behaviour, Miller (1992) used visual and verbal stimuli reproduced in four clue-cards that he presented face down in two conditions. In the addclues condition, each item began with one clue-card and a card was added every 10 seconds until subjects indicated that they thought they had enough clues. In the take-away-clues condition, each item began with four clue-cards and a card was removed every 10 seconds until subjects indicated that they thought the remaining clue-cards were enough. When subjects indicated that they wished

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to try to make a guess, the cards were turned over one by one until subjects made a guess. Impulsive behaviour would lead to quick guesses under both conditions, therefore with few added and few removed cards, whereas risk-seeking behaviour would lead to guesses after very few clues under both conditions, therefore with few added and many removed cards. Frontal lobe patients gave more demonstrations of impulsive behaviour, but not of risk-taking behaviour. The tendency to switch away from a rule that they had previously learned and the willingness to quickly accept new hypotheses were the explanations favoured by Burgess and Shallice (1996) for the high number of bizarre errors made by frontal lobe patients, compared with postrolandics, in a rule-detection task. Subjects had to detect the rule according to which a target moved around on a panel of 10 possible locations. From time to time the rule changed without warning, and the job was to pick up the new pattern. Indifference, minimisation, ignorance, or even frank denial of neurological defects (anosognosia) is a frequent outcome of posterior brain damage, but not of frontal lobe lesions. However, Stuss and Benson (1986) and McDaniel and McDaniel (1991) reported denial of binocular and monocular blindness following bifrontal contusion.

Planning and farsightedness. (She’s careless and rash) Contrary to the belief that the frontal lobe is the site of all higher-order intellectual operations and, therefore, the first place of “intelligence” (Halstead, 1947), intelligence as measured by the usual Stanford-Binet or Wechsler-Bellevue batteries, appears unaltered in most of the many studies triggered by frontal leucotomy practice on schizophrenic patients (see Stuss & Benson, 1986, for a review). The few positive studies are for the most part unconvincing. For example, Drewe (1974) reported that his frontal lobe patients had a lower manual but not verbal intelligence quotient on the WechslerBellevue intelligence scale than post-rolandic patients. Unfortunately, neither quantitative data nor any comments regarding intelligence are reported in the paper.

Actually, the test batteries devised for evaluating intelligence assess only a limited sample of the abilities that deal with the personal and social environment. For example, they never test the ability to plan behaviour according to a prospectus, thus anticipating the effects of one’s own actions. Typically, subjects have a single explicit problem to tackle at any one time, the trials are very short, task initiation is strongly prompted by the examiner, and what constitutes successful trial completion is clearly characterised. Rarely are patients required to organise or plan their behaviour over longer time periods, or to set priorities in the face of two or more competing tasks. Yet these are the sorts of “executive” abilities, which are a large component of many everyday activities, that fail following frontal lobe lesions (Shallice & Burgess, 1991). The Porteus (1918) maze test was devised to tackle this problem, by testing the process of choosing, trying, and rejecting or adopting alternative courses of conduct or thought. It consists of a series of patterns of graded difficulty, where the subject must trace the maze without entering any blind alleys. For a trial to be successful, the subject must try to anticipate the entire path before making the first move. In a broad battery of tests, including Wechsler-Bellevue’s test (also considering the single subtest scores analytically), a complex visuo-manual continuous multiplechoice test, a modified version of Gelb and Goldstein’s (1925) test for abstract attitude, the Weigl colour-form sorting test, and two tests devised by Wegrocki ( 1940) to measure ability to grasp essential differences and analogies, Porteus’ mazes were the only test on which schizophrenic patients failed after bilateral prefrontal lobectomies variously involving Brodman’s areas 8, 9, 10, and 46, compared with normal subjects (H.E. King, 1949; W.R. King, 1949). The sensitivity of the Porteus test to frontal damage was further supported by leucotomy studies (Malmo, 1948; Medina, Pearson, & Buchstein, 1954; Petrie, 1952a,b; Porteus & Kepner, 1944; Porteus & Peters, 1947; Walsh, 1977). Karnath and Wallesch (1992) asked subjects to explore two covered mazes by moving a window over the path. As soon as subjects had managed to

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move the window without entering any false routes, they were asked to follow a reverse or mirror route, thus being forced to reorganise their mental map of the maze structure acquired during the learning phase. Unlike post-rolandic brain-damaged patients, frontal lobe patients were unable to adapt the acquired mental plan to the new task, because of the inflexibility of their mental planning. Dorso-lateral or mesial prefrontal areas seem to be most involved in planning behaviour (Lewis, Landis, & King, 1956), contrary to orbital areas that appear to be irrelevant in this respect (Smith, 1960; Smith & Kinder, 1959). Shallice (1982) identified the basic role of the prefrontal cortex in projecting the outcomes of current actions into the future, in reasoning about the time course and duration of the resulting events, and in evaluating their adequacy with respect to the final goal. In a hierarchical view of cognitive activity, he distinguished two organisational levels. Faced with an already experienced problem the subject “knows” how to solve (as he or she has already confronted it), pre-established algorithms (thought or action schemata) are triggered by environmental cues or by the output of other schemata. Schemata can be activated independently of each other by different aspects of the situation, simultaneously or successively. Automatic selection of schemata is fast, but rigid and crude, as well as dangerous, as the routine activation of a single inappropriate schema may lead to lapses of misunderstanding and inappropriate behaviour. The process of managing the schemata was denoted by Shallice (1982) as “contention scheduling”. In order to tackle novel problems, for which no solution procedure is known, or to lessen danger in routine operations, an additional superordinate control system appears necessary. It does not lead directly to a response; instead it must monitor cognitive and behavioural activity, by selecting schemata and setting priorities for action despite contrary or absent environmental stimuli until the goal is achieved. Constructing and implementing the long-term operational plan, contrasting strong environmental triggers, require time and attentional effort, but allow for flexible and reliable solutions to the problem, thanks to persisting checks and

possible corrections before and during its execution. Shallice (1982) called the control system for flexible and intentional use of schemata the “supervisory attentional system”. Like Luria’s (1980) system, dedicated to the voluntary “programming, regulation, and verification of activity”, it can operate on schemata in every domain. The prefrontal cortex is held to be the anatomical focus of the general-purpose “supervisory attentional system”. Thus, prefrontal damage would manifest itself in impairment of all cognitive functions (perception, motility, attention, memory, etc), as soon as the need to face novel and complex situations emerges, for which no automatic selection of schemata is available. To provide evidence for his dual process theory of schema selection, Shallice and McCarthy (Shallice, 1982) used a test borrowed from research on artificial intelligence and known as the “Tower of London”. As in Porteus’ labyrinths, there are no pre-established schemata for solving the puzzles; every step must be anticipated and planned. The subject has to move three coloured beads between three vertical rods in order to match a goal arrangement. The test comprises 12 tasks of graded difficulty according to the minimum number of moves they require to make the correct match. Four tasks can be solved in two or three moves, and require one or two covert steps; four can be solved in four moves, and require three intermediate steps; and finally four tasks can be solved in five moves, with four intermediate steps. Automatic selection of schemata is of no aid in solving the puzzles. To achieve the final goal the subject must decompose it into secondary goals by programming the appropiate order of simple moves and anticipating all the intermediate steps. Left frontal lobe patients reached fewer solutions at the first attempt, compared with right frontal lobe, left or right postrolandic patients, and normal subjects, above all in tasks requiring four or five moves. In a computerised version of the Tower of London test, modified to allow separate measurements of planning (selection) and execution (movement) latencies for both the first and subsequent moves, prefrontal lobectomy patients, regardless of left or right removals at the pole, orbital, or dorso-lateral surface, made more

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moves than necessary, especially in the five-move tasks, and solved fewer problems in the minimun number of moves, compared with normal subjects. Furthermore, frontal lobe patients spent more time thinking about the problems following the first move than the normal subjects, but there was no difference between the two groups in the amount of thinking time devoted to solving the problems prior to making the first move, as if they had made the first move on impulse, before planning an appriate pattern of action (Owen, Downes, Sahakian, Polkey, & Robbins, 1990). Accordingly, Goel and Grafman (1995) related the failure of the left or right prefrontal patients on the “Tower of Hanoi” test (from which the “Tower of London” is developed), compared with normal subject, primarily to impaired ability to inhibit inappropriate instant responses in favour of a successful alternative. In Grafman’s view (Grafman, 1994; Grafman & Hendler, 1991), Shallice’s interpretation is rather restrictive. Instead he suggests that the basic role of the prefrontal cortex is to create and activate the “managerial knowledge units”, namely the timestructured mental representations of events, actions and ideas necessary for goal-oriented planning of social behaviour and knowledge use. The managerial knowledge units must be created intentionally to face new or unusual situations, but can also exist as result of past experience and in which case, can be automatically available in habitual settings as well. Grafman’s hypothesis was tested by Godbout and Doyon (1995) with a script-generation task, in which subjects were asked to enumerate 10 to 20 actions describing what people generally do during the course of six habitual activities (such as preparing to go work), first placing the actions in the correct chronological order and then in the reverse order. Contrary to Shallice’s expectation, prefrontal patients failed with respect to normal subjects, selectively in the forward but not in the backward arrangement, even though the former required mental representation of the activities in routine and the latter in non-routine situations. Thus prefrontal lesions appear to impair not only the ability to guide behaviour in a novel context or solve unfamiliar or astract problems, but also the

ability to retrieve the stored information about familiar activities as well. Impairment of frontal lobe patients, compared with normal subjects and post-rolandic patients, was found by Sirigu, Zalla, Pillon, Grafman, Agid, and Dubois (1995, 1996) on script-generation and script-analysis tasks. On describing the actions necessary for each of three different activities ranging in the degree of familiarity, although frontal lobe patients did not differ from the other groups in the total number of actions generated, they were more impaired in ordering the actions chronologically and in rating their relative importance. Furthermore, frontal lobe patients were unsuccessful in sorting and ordering the relevant elements in a shuffled array of 20 actions according to four habitual scripts, when they were presented with concurrent actions belonging to several different scripts or with irrelevant distractor elements. Both Shallice’s and Grafman’s interpretations distinguish between intentional and automatic cognitive and behavioural modes. However, a key difference between the two hypotheses resides in the role they assign to the frontal cortex. In Shallice’s view its role is confined to the voluntary planning of mental activity in selecting and setting priorities for goal-oriented thought and action, whereas Grafman extends it to the voluntary as well to the automatic management of structured information and action complexes. It may be that different prefrontal areas (dorso-lateral and mesial?) make different contributions to the two modes. An analogous functional dichotomy was invoked by Goldberg (1985) for motor behaviour with regard to the premotor areas (see the chapter on Apraxia). To date, blood flow studies have shed little light on the dilemma. However, Rezai, Andreasen, Alliger, Cohen, Swayze II, and O’Leary (1993) documented an increase in frontal blood flow on the mesial cortex, prevalently to the right, during the execution of the Tower of London test.

Inhibition and self-control. (He’s impulsive and unstable) The inability to plan actions and anticipate consequences is found with the tendency to display the simplest and most habitual and stereotyped

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reactions, in response to surface cues in the environment, regardless of whether they are senseless or at odds with the patient’s purpose. The inappropriate and rash behaviour of frontal lobe patients figures in many anecdotal reports. For example, instead of waiting for the right train, one patient described by Luria (1980) simply got onto the first that happened to arrive, even though it was going in the opposite direction. Another patient chanced to see the call-button and involuntarily pressed it, but when the nurse arrived he did not know what to say. A third patient went on sanding a piece of wood until nothing remained of it, even then he did not stop, but proceeded to sand the bench itself. Cockburn’s (1995) patient cooked supper immediately after lunch, and then ate it, without waiting for the evening. Lhermitte (1986) used the term “environmental dependency syndrome” to describe this type of dependence on environmental cues. Physical dependence on the environment manifests itself in “utilisation behaviour”: every familiar object compels the patient to grasp and use it without any reason or even being held to do so. Instances of “utilisation behaviour” were first reported by Lhermitte (1983) in four frontal lobe patients. When the patient touched, or even just saw a bottle and a glass on the table, he would pour water from the bottle into the glass and drink it; when there was an apple, plate, and knife before him, he would peel the apple, slice it, and eat it; the same thing happened with a hammer and nail, with bread, butter, and a knife, with a sheet of paper and an envelope, and so forth. Utilisation behaviour was further found by Fukui, Hasegawa, Sugita, and Tsukagoshi (1993) following bilateral lymphomatosis of mesial frontal cortex; by Brazzelli, Colombo, Della Sala, and Spinnler (1994) in a postencephalitic patient with bilateral hippocampal and fronto-basal damage; and it was pointed out even earlier by Mori and Yamadori (1982) following callosal and left fronto-mesial softening. Social dependence on the environment manifests itself in “imitation behaviour”: the patient apes the examiner’s postures, gestures, and utterances, despite being asked not to do so. When the physician bent his head and rested his chin on his hand, or tapped his leg with his hand in time to

various rhythms, or crossed his legs, or made a military salute, or folded a piece of paper and put it in an envelope, or combed his hair, etc., the patient would do likewise, without being able to justify his actions (Lhermitte, Pillon, & Serdaru, 1986). Imitation behaviour was found by Lhermitte, Pillon, and Serdaru (1986) in all their 29 frontal lobe patients (13 cases with and 16 without utilisation behaviour), in 3 (2 with and 1 without utilisation behaviour) out of 6 with deep structures lesions and only in 1 (without utilisation behaviour) of the 21 post-rolandic patients. The sensitivity of imitation behaviour to frontal damage appeared somewhat lower than that reported by Lhemitte et al. (1986) in De Renzi, Cavalleri, and Facchini’s (1996) study, where it affected only 39% of patients with lesions impinging on the frontal or cingulate cortex and in 11 % with damage of the basal ganglia, while its very high specificity was validated, imitation behaviour having been never found in post-rolandic patients and normal subjects. Also in De Renzi et al.’s study utilisation behaviour was found to be a much rarer phenomenon than imitation behaviour, as it was only present in two patients, both of whom had frontal damage. In all the frontal lobe cases of Lhermitte (1983) and Lhermitte, Pillon, and Serdaru (1986) the lower half and mediobasal area of the frontal lobe were affected. In contrast, De Renzi, Cavalleri, and Facchini (1996) found that imitation behaviour was mainly associated with lesions of the mesial and upper dorso-lateral frontal cortex, irrespective of the left, right, or bilateral side of the damaged hemisphere. Assal (1985) described a patient with double frontal and right posterior softenings, who would read aloud any written document she caught sight of, even if it was in an incomprehensible foreign language. Lhermitte (1986) provided a detailed description of the environmental dependency syndrome in natural settings. The behaviour of his two patients, who had undergone left prefrontal lobectomy, was always marked by the most obvious schemata, even if they were inappropriate for the situation. Here are some examples. In the doctor’s office, the patient picked up the blood pressure

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gauge and took Lhermitte’s blood pressure; examined his mouth and throat with the tongue depressor; she then tested his ankle jerks; and finally said she was satisfied with his health, just as if she were the doctor. At a buffet, the patient poured herself a glass of water and drank it; took the glasses that were stacked on the table and laid them out one by one. Walking in the garden, the patient watered the flowerbeds with the drinks. In a lecture hall, where the patient had been taken to be presented to about 20 people, she addressed and thanked the gathering and said how happy and proud she was. Once, after standing for one minute in silence in the garden in front of his house, Lhermitte said “museum” in a neutral tone, while looking at the floor, and opened the door into his home. The patient went in first and started to examine the paintings hanging on the walls, as well as the objects and carpets, as if they were on exhibition, making apt aesthetic remarks. When they went into the bedroom, she got undressed, laid down under the covers and prepared to go to sleep; later, when she saw some clothing, she got up and dressed. In a gift shop she immediately started using the powder and eye make up; and in a games room she went from one table to the next posing as a player. Dependence on the environment, whether social (imitation behaviour) or physical (utilisation behaviour) has been interpreted by Lhermitte and colleagues according to Denny-Brown’s (1956, 1958) schema, as a functional imbalance between the parietal lobe, which limits the subject to the environment, and the frontal lobe, which, through inhibitory mechanisms, leaves the subject independent and free to choose on the basis of inner needs and autonomous decisions. According to Lhermite (1983, p.253): All the information coming from the body and from the outside world is received in areas of the sensory cortex which surround the parietal lobe; systems develop in the parietal area which unite these unending sequences of stimuli. These systems activate other unknown patterns, material counterparts of their meaning, and prepare the response of the patient. The result is that the

normal activity of the parietal lobe tends to create links of dependence between the subject and stimuli from the environment, while some of the functions of the frontal lobe allow the subject to remain aloof from the outside world and to ensure his independence by modulating and inhibiting the activities of the parietal cortex. With normal subjects the balance between these two activities is fluid so that the subject’s behaviour is more or less dependent or independent of the outside world as a function of the quality of the external stimuli and internal mental activity. Frontal damage suppresses to varying degree this function and thus releases the activity of the parietal lobe, that is, it tends to subject the patient to all external stimuli. Two findings that coincide with the balance theory of the parietal and frontal lobes are the acceleration after parietal lesions and the disappearance after frontal lesions of the phenomenon known as “Troxler fading” or Bay’s “local adaptation”, namely, the fading from awareness of a stationary peripheral visual stimulus during central fixation (Mennemeier et al., 1994). Shallice, Burgess, Schon, and Baxter (1989) analysed the utilisation behaviour in a patient with inferior and mesial bifrontal ischaemia. His account is in keeping with the imbalance theory: failure of the frontal supervisory attentional system in monitoring contention scheduling would let utilisation schemata triggered by irrelevant cues be activated. Frontal lobe impulsiveness may manifest itself in persisting on a rule that results in immediate gain even if it is recognised as dangerous in the long run. In the “gambling task” devised by Bechara, Damasio, Damasio, and Anderson (1994), the subject has to turn cards, one at a time, from any of four decks labelled A, B, C, and D. He or she is told that turning any card will result in earning a sum of money, and that every now and then turning some cards will result in both earning money and having to pay a penalty of money. At onset, the examiner does not disclose the amounts of gain or loss in any card, the card’s connection to a specific

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deck, the order of their appearance, or the number of card selections allowed. The amount to be earned or paid with a given card is disclosed only after the card has been turned. The turning of any card in decks A and B is rewarded with $100, while the turning of any card in decks C and D is rewarded with $50. Unpredictably, certain cards require the subject to make payments, which are high enough for decks A and B to clean out the subject’s kitty, and low enough for decks C and D to yield a final profit. Normal subjects and post-rolandic patients began by sampling from all four decks, in search of patterns and clues. Then, lured by the high reward from turning cards in decks A and B, they showed an early preference for those decks. Gradually, however, they switched to decks C and D, and stuck to this strategy until the end. By contrast, ventromedial frontal lobe patients systematically turned more cards in decks A and B, and fewer and fewer cards in decks C and D, even though they knew which decks were bad and which were not. Thus, the inhibitory and regulatory activity of the frontal lobe on sensory, motor and thinking funtions, likely supported by the orbital and mesial areas, appears critical to allow the subject’s freedom of choice with regard to information to accept and operations to carry out in order to achieve future goals, devised primarily by the dorso-lateral cortex.

Personality. (She’s quirky and unreliable) Changes in personality, mood, and emotion have always been the most striking disorders of the frontal lobe patient, since the earliest clinical observations. Harlow (1868) was the first to provide a detailed account of the consequences of an extensive frontal injury. The subject was a certain Phineas P. Gage, a 23-year-old who worked for the Rutland & Burlington Railroad and whose job was to lay down the new tracks for the railway’s expansion across Vermont. On 13 September 1848, he was packing an explosive into rock with the help of an iron rod, in order to level the uneven terrain by controlled blasting, when it blew up in his face. The force of the blast sent the iron rod into his left cheek, piercing the base of the skull, passing through the

front of his brain, and exiting through the top of his head. Damasio, Grabowski, Frank, Galaburda, and Damasio (1994) have recently determined the probable location of the brain lesions by neuroimaging measurements on Gage’s skull: the injury involved prefrontal areas 12,8,9, and 10, cingulate areas 32 and 24 of both hemispheres, and area 11 of the left hemisphere, thus damaging the prefrontal orbital and mesial cortex bilaterally. Harlow’s (1868, pp.339-340) description of Gage’s condition 2.5 months post-injury was as follows: His physical health is good, and I am inclined to say that he has recovered ... The equilibrium or balance between his intellectual faculty and animal propensities seems to have been destroyed. He is fitful, irreverent, indulging at times in the grossest profanity (which was not previously his custom), manifesting but little deference for his fellows, impatient of restraint or advice when it conflicts with his desires, at times pertinaciously obstinate, yet capricious and vacillating, devising many plans of future operation, which are no sooner arranged than they are abandoned in turn for others appearing more feasible. A child in his intellectual capacity and manifestations, he has the animal passion of a strong man. Previous to his injury, though untrained in the schools, he possessed a well-balanced mind, and was looked upon by those who knew him as a shrewd, smart business man, very energetic and persistent in executing all his plans of operation. In this regard, his mind was radically changed, so decidely that his friends and acquaintances said he was “no longer Gage”. Futility, loss of originality and creativity; inflexibility and at the same time impulsiveness and fickleness; apathy, inertia, and aspontaneity or restlessness, exuberance and facetiousness; as well as outbursts of irritability and socially inappropriate behaviour, are the abnormal traits most frequently noticed in the frontal lobe patients. Purposelessness and poor judgement in decision-making regarding

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personal and social matters and inability to translate mood or emotion into appropriate and coherent behaviour immediately appeared to be the salient characteristics of the frontal lobe patient’s morbid personality (Ackerly, 1964; Brickner, 1934; 1936, 1952; Eslinger & Damasio, 1985; Hebb & Penfield, 1940). These patients astonish friends and relatives, who observe them in their everyday environment, much more than they intrigue the physicians, who perhaps did not know them before the pathological event. Furthermore, for the most part, they escape controlled and quantitative neuropsychological evaluation. The “frontal lobe syndrome” is reported in very different ways by different authors and remains entrusted to the description of single cases which vary in terms of the localisation and nature of the lesion, the premorbid personality structure, the insight and sensitivity of the examiner, and finally the author’s theoretical and terminological framework. Laplane, Dubois, Pillon, and Baulac (1988) added a new frontal lobe symptomatological cluster, which they previously had found after bipallidal damage (Laplane, Wildocher, Pillon, Baulac, & Binoux, 1981). Following bilateral injury of the prefrontal white matter, the patient experienced feelings of emptiness and nothingness, which dampened every curiosity and interest, made her affectively indifferent, despite absence of sadness and anxiety, and prevented planning of the future. She momentarily returned to normal when she was prompted from the outside. The authors summarised the patient’s state as a “loss of psychic self-activation”, which could be reversed by “hetero-activation”. Damasio (1994) maintains that impairment in expressing emotion and experiencing feelings, with the ensuing lack of concern, which would follow lesions in the ventromedial prefrontal cortex, is a major source of the frontal lobe defects, because it hinders rational reasoning and decision making in the patient’s personal and social domain. Indeed, emotion and feelings, generated by evocation or representation of the mental images pertinent to alternative future outcomes, would selectively highlight some options, thus functioning as an alarm or an incentive signal that operates to restrain the process of reasoning and selecting over multiple options.

Anatomical data, such as connectivity with the hippocampus and the amygdala, as well as neurophysiological findings, suggest that the frontal areas much involved in emotional behaviour are the orbital and possibly mesial prefrontal areas. Among the many attempts at correlating frontal lobe damage with specific mood disorders, Kleist’s (1934) proposal, further developed by Blumer and Benson (1975), is the most attractive. It contrasts a “pseudodepressed syndrome”, with depressive mood and slowing down and reduction of all activity (apathy, abulia, inertia), to a “pseudopsychopathic syndrome,” characterised by euphoric-manic mood and loss of inhibitions (jocularity, hedonism, egocentrism, impulsiveness, loss of social concern, sexual disinhibition). The pseudodepressed syndrome would follow damage to the mesial cortex and possibly to the polar convexity, the pseudopsychopathic syndrome would follow a lesion of the orbital cortex (Starkstein & Robinson, 1991). An analogous dichotomy has been advocated for schizophrenic and obsessive-compulsive disorders, following respectively dorso-lateral and orbital dysfunction (Abbruzzese, Bellodi, Ferri, & Scarone, 1995). The close link between left brain damage and depression (Gainotti, 1983) is particularly marked in the frontal lobe patient. Following vascular accidents, depressed mood was more severe and persistent after left frontal lobe damage as opposed to any other lesion location (Robinson, Starr, Kubos, & Price, 1983a,b; Robinson, Kubos, Starr, Rao, & Price, 1984). However, beside the general consensus that the frontal lobe intervenes in regulating mood tone, there are contrasting opinions about the relative importance of the two hemispheres and the various frontal areas. According to Irle, Peper, Wowra, and Kunze (1994), depression is related to orbito-frontal damage, regardless of side, while according to Grafman, Vance, Weingartner, Salazar, and Amin (1986), right orbito-frontal lesions would cause anxiety and depression, and left dorso-lateral ones anger and hostility. Finally, many studies did not find evidence that mood disorders are associated with side or site of the hemispheric lesion (House, Dennis, Warlow, Hawton, & Molyneux, 1990).

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Concluding remarks about prefrontal “functions” Despite the numerous attempts at piecing together the results gathered from so many neuropsychological experiments and clinical observations, a comprehensive theory of prefrontal function is still an ongoing project. Nevertheless, many typical ways of thought and actions continue to return in prefrontal patients with significant persistence across all tasks providing some insights into their cognitive and affective world. The frontal lobe patients’ difficulty in selecting, organising, and integrating present as well as past information over time according to a leading principle (see Memory and temporal organisation o f experiences, Judgement and rationality) makes their past experiences useless when current circumstances demand new forms of thought and behaviour (see Productivity and creativity, Category discovering and abstract thinking). They are prevented from learning from their own mistakes (see Learning and learning strategies), anticipating the future consequences of their actions, and conforming behaviour to personal goals and social rules (see Planning and farsightedness).

Lacking the ability to maintain a temporal stream, frontal lobe patients’ consciousness remains ensnared in a noisy and temporally constrained state, deprived of a coherent past and future. They are locked into immediate space and time, and are no longer able to monitor their acts against a model of the self in order to ensure integrity of behaviour over time and to reach decisions with confidence. Their freedom of choice, namely free will and responsibility, is reduced (see Inhibition and selfcontrol). As a result, frontal lobe patients become silly, shortsighted, fragmentary, and unstable (see Personality).

ACKNOWLEDGEMENTS The author gratefully acknowledges the permission of the following publishers to reproduce some of the illustrations in this chapter: Lippincourt-Raven Publishers, Philadelphia (fig. 24.2); Plenum Publishing Corporation, New York (fig. 24.3); McGraw-Hill Companies, New York (fig. 24.4); and Elsevier Science, Oxford (figs. 24.5-24.8).

Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

25 Acute Confusional State Carlo Caltagirone and Giovanni A. Carlesimo

specific psychiatric syndrome, Bonhoeffer proposed considering clinical pictures that were similar and globally denominated “acute-type exogenous reaction” as the result of various systemic illnesses. Bonhoeffer used the term “exogeneous” to indicate that the pathological process responsible for the behavioural disorder had an extra-cerebral origin. Actually, the ACS can be provoked by diffused pathological (Lipowski, 1967) or focal processes (Mesulam, 1985) of the central nervous system as well as by toxic or metabolic disorders of systemic origin. The diagnostic criteria most frequently used to define ACS are those proposed in the Diagnostic and Statistical Manual of the American Psychiatric Association. In the Diagnostic and Statistical Manual, IIIR (American Psychiatric Association, 1987) the following basic symptoms are reported under the term “Delirium”:

INTRODUCTION According to Geschwind (1982), the acute confusional state (ACS), or delirium (the most frequently used term in the current neurological literature) is the most common disorder of the superior cortical functions. Recent epidemiological studies seem to confirm this point of view. Prevalence of the confusional syndrome, assessable at around 10%, has been found in populations of hospitalised patients (Lipowski, 1967). Frequency of the disorder increases drastically with age and reaches a prevalence of over 50% in individuals over 80 years of age (Johnson et al., 1987; Levkoff et al., 1992; Pompei et al., 1994). On the clinical level, identification of ACS is made possible by the presence of characteristic alterations in behaviour and cognitive capacities. However, many pathological processes can be at the base of the syndrome. Bonhoeffer (1912) was the first to perceive that suffering of the encephalic structures produced by different types of pathological events could give origin to essentially similar clinical manifestations. In fact, by going beyond the Kraepelinian position, that is, that for every single noxious pathogen in the central nervous system there must correspond a

A. Reduced ability to maintain and shift attention to external stimuli. B. Disorganised thinking, as indicated by rambling, irrelevant, or incoherent speech. C. At least two of the following: 1. Reduced level of consciousness; 571

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2. Perceptual disturbances: misinterpretations, illusions, or hallucinations; 3. Disturbance of sleep-wake cycle with insomnia and daytime sleepiness; 4. Increased or decreased psychomotor activity; 5. Disorientation to time, space, or person; 6. Memory impairment. D. Abrupt onset of symptoms (hours to days), with daily fluctuation; E. Either one of the following: 1. Evidence from history, physical examination, or laboratory tests of specific organic etiologic factor(s); 2. Exclusion of nonorganic mental disorders when no etiologic factor can be identified.

CLINICAL MANIFESTATIONS OF THE ACUTE CONFUSIONAL STATE The clinical picture of ACS typically shows characteristics of variability, even in the constancy of several basic symptoms. This phenomenon is in large part due to the many pathological events able to determine the onset of the syndrome. Variability regards both severity of the syndrome and qualitative characteristics of clinical manifestations. Thus, even though some infective episodes (primarily in children) can cause light and easily reversible forms of the syndrome, alcoholic intoxication or hepatic encephalopathy produce dramatic pictures, which not infrequently evolve toward coma. Considering the qualitative aspects of the syndrome, it can be noted that in delirium tremens psychomotor agitation and visual hallucinations are almost constant, whereas in the ACS that follows an electroshock therapy patients are usually lethargic and often do not show hallucinatory manifestations. Liptzin and Levkoff (1992) proposed differentiating two subtypes of ACS on the basis of

modifications in the state of vigilance, motor behaviour and presence of disorders in the perceptual sphere. In a large case study of 125 hospitalised elderly patients who satisfied the diagnostic criteria proposed by the Diagnostic and Statistical Manual III (American Psychiatric Association, 1980) for delirium, these authors identified a “hyperactive” group (15% of the subjects), showing the presence of hyperactivity, motor restlessness, easy irritability, and hallucinations; and a “hypoactive” group (19% of the sample) whose main characteristics were reduced vigilance, tendency toward lethargy, and psychomotor slowing down. However, it should be noted that 52% of the patients alternated hyperactive and hypoactive phases (mixed forms), and the remaining 14% of the patients could not be classified in either of the subtypes. In agreement with the majority of authors (Engel & Romano, 1959; Lipowski, 1967; Geschwind, 1982; Mesulam, 1985), it can be stated that the diagnosis of ACS rests on two basic clinical aspects: 1. A prevalent attention disorder invariably accompanied by deficits of other cognitive functions (memory, space-time orientation, abstract reasoning); 2. A characteristic fluctuation of symptoms. The elements completing the clinical picture, even if relatively frequent, are not constant and their presence varies as a function of the basic etiological agent.

Course of the illness The evolution of ACS is generally rapid, from several hours to a few days. According to the etiology, the beginning can be more or less abrupt. In the second case, the presence of warning symptoms is frequent, for example, strong irritability. One of the primary characteristics of the generally accepted clinical picture is the remarkable fluctuation of symptoms, where free intervals alternate with periods of greater impairment. The frequently described (Lipowski, 1967) nocturnal exacerbation of the symptomatology is probably related to reduction of perceptual points of reference that facilitate the patient’s spatial orientation.

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The evolution of ACS is in large part the function of the pathology that produced it. In young patients, removal of toxic agents and/or of metabolic imbalance generally allows a rapid and complete return to normal. On the other hand, in elderly patients, primarily when the ACS is produced by chronic systemic illnesses (for example, hepatic encephalopathy) or illnesses of the nervous system (for example, cerebral ischemia) recovery is usually slow and often incomplete. The residual picture is frequently characterised by selective and/or diffused deficits of cognitive and basic sensorymotor functions. The prognostic evolution of patients presenting ACS has been examined in recent epidemiologicaltype studies. The conclusion of these studies is that in the elderly population, ACS represents an unfavourable predictive factor both for survival and for quality of life (Folstein et al., 1991; Levkoff et al., 1992;Pompeietal., 1994). In a two-year followup study of about 220 patients over 70 years of age, the onset of ACS during hospitalisation resulted in 39% of deaths (compared with 23% of patients who did not have ACS) and a significant residual worsening of functional autonomy and overall intellectual efficiency in surviving patients (Francis & Kapoor, 1992).

General objective examination The clinical examination of the patient with ACS generally does not show elementary deficits of sensorimotor functions except when it is originated by a primitive encephalic disease. In some forms (for example, in delirium tremens) a distal tremor and occasionally myoclonic jerks are characteristic. Primarily in patients presenting an increase in psychomotor activity, an alteration of vegetative parameters with mydriasis, increased heart rate and blood pressure, profuse perspiration and hyperpyrexia can be noted. Vigilance, attention, cognitive functions As mentioned earlier, the level of vigilance in ACS can be reduced (sleepiness to the point of lethargy, reduced awareness of external environment) or increased (increased reactivity to environmental stimuli). Invariably, the attention is impaired. The patient’s attention is

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extremely fluctuating, wandering from one object to another and from one person to another, apparently without reason (Geschwind, 1982). Incoherence in thought flow is evident in the confused patient. Discussion moves from one topic to another when the first has not yet reached a satisfying conclusion. Difficulty in forming ideas and the inability to concentrate corresponds with incoherence of action manifested through seemingly aimless acts or acts that are only fragments of a sequence. The inconstancy of consciousness disorder in an ever present attentive deficit seems to indicate that the ACS is not simply a disorder in vigilance (Mesulam, 1985a). As we have already shown, in ACS the attentive deficit is accompanied by compromise of other cognitive functions. Disorientation is almost constantly present, even if this is not obligatory for diagnosis. Temporal and spatial orientation are more frequently altered. More rare are signs of disorientation with regard to the person. Spatial disorientation often accompanies “familiarisation” with the place where the patient is observed; the hospital environment, for example, is recognised as the home or the workplace (Levin, 1956; Weinstein & Kahn, 1955). The confused patient also frequently presents amnesic disorders. Fixation memory is generally more impaired than remote memory. Typically, “paramnesia”, that is, memories that contain correct elements even though they are globally altered, is produced in these patients. Geschwind (1982) hypothesised that in ACS there is a distortion more than a global compromise of memory; that is, the formation of memory traces is still possible but storing and/or recall occur in a distorted way. In the area of the paramnesias and orientation disorders, reduplicative phenomena must also be remembered; they usually regard the topographic localisation of home, hospital, and workplace but, in some cases, also involve the identity of those around the patient.

Emotional behaviour The most frequently noted reactions are anxiety (Wolff & Curran, 1935) and depression (Engel & Romano, 1959). More rarely, there is an apathetic

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attitude (Lipowski, 1967) or agitation due to a tendency to interpret the behaviours of those around them in a persecutory way (Wolff & Curran, 1935). Sometimes confused patients appear fatuous or playful, bringing to mind what is observed in the frontal lobe syndrome. In many cases this impression is supported by witticisms deriving from involuntary plays on words, probably caused by reduced control of verbal production (Geschwind, 1982). Very often a negation of the state of illness is present, therefore the confusional state has been considered as the most frequent cause of anosognosia (Weinstein & Kahn, 1955). Illusions and hallucinations Frequently reported, but not essential for the diagnosis of ACS, are illusions and hallucinations. The former, erroneous interpretations of environmental stimuli, most frequently involve the visual modality, but are also produced in the auditory and tactile modalities, although much less frequently. The effort that patients seem to make in attempting to give a certain coherence to perceptions and ideas they warn are not adequate, leads to the insertion of false interpretations in a pseudo-logical picture, which at times even seems plausible. Typically, confused patients seem to consider those around them as family or friends. Further, even if they do not seem to identify the place where they are, these patients tend to interpret it as a place they know. These two aspects have been considered as the understandable attempt to reconstruct a reassuring environment and they provide a basis for understanding the particular affective tone that relationships with these patients assume. Hallucinations are also prevalently visual but can also be auditory, tactile, or mixed; content is variable, most often involving animals or persons; however, they can be accompanied by threatening or frightening experiences, but sometimes the pseudo-perception of an animal or a desired person offers the patient comfort and tranquility. In various case studies the presence of hallucinations is reported with a frequency variable between 39% and 73% (Farber, 1959; Wolff & Curran, 1935). This variability is probably due to differences in

sample composition. Even though visual hallucinations are almost always the rule in delirium tremens, they appear much less frequently in ACS supported by other etiologies. An alteration in the waking-sleeping rhythm is also present in confused patients. Even when present, daytime sleeping does not offer sufficient rest for a characteristic reduction or absence of the phases of REM sleep and slow-wave sleep. Instead, in confusional states caused by abstinence there may be an absolute increase in REM activity that can also be produced in the waking state. In this case, hallucinations may be due to the interference of oneiric content, experienced as reality because of the patient’s altered ability to judge.

ETIOLOGICAL FACTORS Many factors can determine the onset of an ACS. In some cases it derives from an identifiable cause, but in others it results from the concomitance of many conditions, none of which alone would have been sufficient to provoke onset of the syndrome; some of these causes can be considered predisposing, others precipitating. Numerous epidemiological studies investigating risk factors for ACS agree that advanced age, preexistence of a cognitive deficit, coexistence of multiple chronic illnesses, a depressed state, and alcohol dependence are the major predisposing causes of the syndrome (Francis et al., 1990; Inouye et al., 1993; Levkoff et al., 1992; Pompei et al., 1994; Schor et al., 1992). Systemic illnesses or previous affections of the central nervous system act on these predisposing conditions as factors precipitating the confusional state. A summary of the pathological events that can be at the root of the syndrome is presented in Table 25.1. With regard to the relative frequency of single etiological factors, on the basis of a large case study, Henker (1979) reported that 34% were provoked by toxic events, 14% by metabolic alterations, 12% were the consequence of surgery, and the remaining 40% had a primarily cerebral origin (infections, traumas, circulatory disorders, neoplasia, degener-

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ative illnesses). The confusional state may occur during the course of hepatic or renal failure, hypoor hyper-glycaemia, hypoxia, anoxia, hypercapnia, decrease or increase in hematic electrolytes, and hypovitaminosis. Both the excessive use as well as abstinence following abuse of various substances such as alcohol, barbiturates, or cannabis can cause an ACS. Various drugs (tricyclic antidepressants, antispastics, and anti-Parkinson drugs) have the property of reducing cholinergic transmission at the level of the central nervous system. Their simultaneous administration, above all in elderly patients with signs of intellectual deterioration, is often the origin of mental confusion. Various authors (Morse & Litin, 1971; Strub, 1982) have noted the high frequency with which an ACS is in some way related to surgery. According to Strub (1982), there are various factors that can contribute toward causing the syndrome in a patient who has undergone surgery: sleep deprivation, reduction of sensory inputs, hyperpyrexia,

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metabolic alterations, and the administration of anticholinergic substances. A diffused compromise of the central nervous system, similar (due to its size) to that found in the course of toxic-metabolic alterations, is found in degenerative illnesses, meningitis, and encephalitis, in diffused microembolisations from disseminated intravascular coagulation or from fat embolism (as can occur following a bone fracture). Head injuries are also a common cause of ACS either as the immediate consequence of the traumatic event or more often in the phase of regaining consciousness after a coma of varying duration. Patients with epilepsy can present mental confusion both during complex partial crises and in the post-critical phase of a generalised attack. Mental confusion can also be the consequence of electroconvulsive treatment (D’Elia, 1970). The group of focal cerebral lesions includes lesions occupying space, such as primitive or metastatic neoplastic processes of the central nervous system, subdural or epidural haematoma,

TABLE 25.1 Etiological factors in the ACS. Systemic illnesses (1) Toxic agents:

(2) Metabolic disorders:

(3) Toxic-infections: (4) Surgery:

• drugs (sedative-hypnotics, tryciclic antidepressants, antihistamines, diuretics, digitalis, antihypertensives, betablockers, cimetidine) • alcohol • alcohol or barbiturates withdrawal • hypoxia (heart failure, respiratory failure, severe anaemia) • electrolyte imbalance • liver or kidney failure • complications of diabetes (ketoacidosis, lactate acidosis, hypoglycaemia) • hypo- and hyper-thyroidism • hyponutrition • pneumonia, urinary infection, septicaemia etc. • cardiac, orthopedic, etc

Primitive cerebral diseases (1) Circulatory disorders: (2) Infections: (3) Tumours: (4) Trauma: (5) Epilepsy: (6) Dementias: (7) Parkinson’s disease

• TIA, stroke, subarachnoidal haemorrhage, subdural haematoma, arteritis • encephalitis, meningitis

• Partial complex seizures and post-critical phase of generalised attacks

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and cerebral abscesses. Due to endocranial hypertension and cerebral oedema, focal cerebral lesions provoke diffused suffering of the cerebral parenchyma as well as focal damage. The literature cites several cerebral areas considered critical because of the frequency with which focal lesions in them lead to mental confusion. The inferior frontal gyrus and the right inferior parietal lobule (Mesulam et al., 1976; Mori & Yamadori, 1987), the hippocampal, parahippocampal, and occipitaltemporal areas of the left hemisphere (Devinsky et al., 1988) are the areas most frequently cited. Episodes of ACS are also noted in subjects with bilateral lesions of the cortical and subcortical areas supplied by the posterior (Symonds & MacKenzie, 1957) or the middle cerebral arteries (Medina et al., 1974).

NEUROPSYCHOLOGY Neuropsychological literature on ACS is very scarce. There are various reasons for this lack. First, neuropsychologists may show little interest in the topic because the cognitive compromise of subjects with ACS is diffused, not specific, and thus of scarce theoretical interest. Also, the obvious practical difficulty of carrying out a detailed neuropsychological evaluation of subjects who are often agitated or have a reduced level of vigilance must be considered. In the most complete study dedicated to evaluating the higher cortical functions in ACS (Chédru & Geschwind, 1972a) a large range of cognitive functions were examined in patients with spontaneous pathology (Delirium tremens, Wernicke’s hepatic encephalopathy, and barbiturate intoxication) and in subjects whose mental confusion was induced by electroconvulsive therapy or by the controlled administration of barbiturates. Performances of subjects with ACS were compared with those of the same subjects following resolution of confusion and with those of a group of controls.

Attention To examine attention, Chédru and Geschwind (1972a) used the Digit Span and Auditory Motor

Attention Test. In the second test cited (Kometsky et al., 1959), the subject is asked to produce a simple, specific behaviour every time a preestablished letter of the alphabet is recognised in a randomised series of letters presented acoustically. In Chedru and Geschwind’s (1972a) study, subjects with spontaneous pathology usually performed deficiently on this type of task. Osmon (1984) reported the case of a patient with an ACS induced by prolonged use of psychoactive drugs. Analysis of the scores obtained by this patient on the Luria-Nebraska Neuropsychological Battery indicated diffused cognitive deterioration. However, a more thorough qualitative examination of performances on individual tests showed that the patient’s level of performance was very inconsistent and characterised by the frequent production of perseverations and irrelevant associations. The author interpreted this profile of compromise as due to a sort of “attentional slipping”, which did not allow the patient adequate control of behavioural responses.

Orientation and memory All subjects examined by Chedru and Geschwind (1972a), with the exception of three with postelectroshock ACS, had orientation disorders. Primarily temporal orientation was altered; orientation for places was less impaired. In a more recent study (Daniel et al., 1987), the three classical aspects of individual orientation were evaluated: orientation in time, space, and with regard to the person. This research included a group of patients who had undergone electroshock for a depressive syndrome; they were evaluated repeatedly at different time intervals from the treatment. Given that mental confusion induced by electroshock gradually improves with time, the authors were able to confirm that in the resolution of disorientation, first personal orientation is recovered, then spatial, and finally temporal orientation. The phenomenon described by Chedru and Geschwind (1972a) as “approach to the present” was also confirmed; this is the tendency shown by patients in the recovery phase to gradually approach their temporal orientation to the present. The patients studied by Chedru and Geschwind (1972a) performed poorly on tests of both

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retrograde and anterograde memory. For remote memory, the decline was more evident in patients in a state of post electroshock mental confusion. In a successive work, Geschwind (1982) pointed out that the memory deficit in ACS seems characterised by distortion and disorganisation of memories more than by their loss, thus causing the production of paramnesia and reduplicative phenomena.

Language The spontaneous language of confused subjects in large part reflects the more general disorganisation of their thought. Informative content seems reduced due to an excessive circumstantiality of sentences and the frequent introduction of irrelevant associations (Osmon, 1984). Chedru and Geschwind (1972a) reported the presence of reduced language fluency (the qualitative analysis of the group with post electroshock ACS was impossible because of the almost total lack of spontaneous verbal production), monotony and stereotyping in prosody, with reduced volume of the voice and slight articulatory disorders. Again, reduction of informative content of a discussion was noted, characterised by the tendency to open parentheses and make parenthetic clauses and then frequently to lose the thread of the discussion. More specifically, the verbal production of patients with ACS shows some characteristics of anomic patients. In particular, verbal lapses, difficulty in finding the right word with hesitations, repetitions, circumlocutions, and use of passepartout words are noted; the substitution of a word always occurs in favour of another with a higher frequency of use. The reduced access to lexicon is also shown by the low performances of these subjects on naming and verbal fluency tests. However, unlike aphasic patients, the production of paraphasias (in spontaneous language and in the naming test) is very rare and verbal comprehension appears generally quite well preserved. In reading and repetition tests, there are substitutions of words and sometimes real paralexias. In a recent study on the qualitative analysis of the naming disorder, Wallesch and Hundsalz (1994) demonstrated comparable percentages of error in two groups of patients with ACS or Alzheimer’s

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disease. Anomias (absence of response) were more frequent in demented patients, and perseverations (repetition of responses made before) appeared more often in patients with delirium. In 96% of the Alzheimer’s patients, the incorrect responses had some type of relation (semantic or perceptual) to the target stimulus. Instead, in patients with ACS responses without any type of correlation to the visual stimulus appeared with greater frequency (30%). The authors concluded by affirming that the naming disorder in demented patients derives from a compromise of the semantic structure and its relationships with perceptual input. In confused patients, instead, the production of many responses not correlated to the stimulus derives from the serious perceptual distortions (illusions, hallucinations) characterising the syndrome. Although not discussed by the authors, it must be noted that the fluctuation of attentional level characterising ACS could perhaps better explain both the high number of perseverative responses and the production of random responses. Finally, with regard to writing, Geschwind (1982) considered ACS as the most frequent cause of pure agraphia, understood as the presence of a deficit in writing abilities in the absence of other consistent alterations in language. In a study dedicated specifically to the examination of writing, Chedru and Geschwind (1972b) administered tests of spontaneous writing, dictation, and copying to 34 confused patients. Analysis of the results showed that the writing disorder in these patients involved motor and spatial organisation as much as the graphemic structure of words and sentence syntax. The motor performance disorder is frequently manifested by shaky graphic production. In some cases writing is completely illegible, reduced to a series of scribbles. Problems in spatial orientation are present both for letters and lines. Some patients write to the edge of the page, demonstrating a sort of “fear of emptiness”. In copying, sometimes the phenomenon of closing-in and superimposing the model is found. The syntactic structure of sentences does not seem to be respected. Primarily functors and grammatical particles are omitted. The resulting agrammatism does not correspond with the verbal production of the same patients.

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The structure of word frequently appears altered. Errors in transcription, most often regarding the categories of functors and verbs, are present. The most frequent types of errors are omissions and additions of mostly consonants and final letters of words. Chedru and Geschwind (1972b) concluded that ACS is characterised by severe compromise of writing with mild disorders of other linguistic functions. This phenomenon is due to the fact that a correct graphic performance requires the integrity of many functions (motor, praxic, visuospatial, linguistic) and usually this involves an activity that only infrequently reaches high levels of habit and automatism. For this reason, in patients with attentional impairment, even though spontaneous verbal production and reading are still almost normal, less automatic tasks, such as writing, are performed poorly.

Other cognitive functions In Chedru and Geschwind’s (1972a) work, the evaluation of right-left orientation does not seem particularly impaired, though digital recognition is more deficient. Performances in copying and drawing tasks are variable, ranging from severe impairment, characterised by the production of scribbles and the appearance of closing-in phenomena, to substantially correct performances, even if they are executed with some uncertainty. In two of the subjects examined by Chedru and Geschwind (1972a), the association of dysgraphia, difficulty in right-left orientation, digital agnosia, and acalculia outline Gerstmann’s syndrome. As for ideative and ideomotor apraxia, symbolic and transitive movements are generally carried out well. However, performance on Head’s test, in which the subject must imitate nonrepresentational gestures carried out by the examiner, is particularly impaired. Visual recognition and abstract reasoning (evaluated using tests of similarity and interpretations of proverbs) did not seem particularly impaired in the patients observed by Chedru and Geschwind (1972a). However, other authors have shown that a deficit in ideation is one of the primary characteristics of ACS (Levin, 1956).

This lack of homogeneity in results is probably due to differences in the selection of patients as well as the use of different methods of evaluation.

CONCLUSIONS A deficit in cognitive functions is the characterising aspect of ACS. Other signs, which can also be part of the syndrome (such as vigilance alterations, psychomotor agitation, modification of vegetative parameters, etc.), are less constant and they vary as a function of etiology. With regard to the basic mechanisms of the cognitive disorder, two main interpretative hypotheses have been proposed. Some authors (Engel & Romano, 1959; Lipowski, 1967; Strub, 1982) have shown that a diffused impairment of cognitive functions involving primarily spatialtemporal orientation, memory, and abstract and conceptual reasoning is found in confused subjects. Toxic and/or metabolic imbalances, which, in the majority of cases, are at the root of the confusional syndrome, provoke a sort of “diffused cerebral failure”, whose consequences at the clinical level are represented by a generalised cognitive impairment and whose electrophysiological correlate is a diffused slowing down of the electroencephalogram (Engel & Romano, 1959). According to this interpretative model, ACS is basically a sort of demential syndrome with characteristics of reversibility. However, the hypothesis of “diffused cerebral failure” does not satisfactorily explain those confusional syndromes that are supported by focal cerebral lesions. A somewhat different interpretative model hypothesises that the behavioural alterations and cognitive deficits characterising the confusional syndrome are the direct consequence of a specific deficit of the attentional function (Chedru & Geschwind, 1972a; Geschwind, 1982; Mesulam, 1985). Attention is a prerequisite for carrying out any cognitive task, whether it requires the acquisition and manipulation of external stimuli or whether it is based on recall and processing of previously learned material. Starting from this

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consideration, Mesulam (1985) points out that the disorder of “global attentional tone is the salient characteristic of ACS” and deficits of other functions (such as disorientation, alteration of critical judgement, and presence of hallucinations) are not constant and, in any case, when present, are secondary. The hypothesis of a basic attentional disorder at the root of the cognitive and behavioural picture of the ACS derives from clinical observations. Alternately, these patients appear abnormally distractable (so that any perceptual stimulus, however irrelevant, attracts their attention) or completely incapable of removing their attentional focus from a target stimulus and shifting it toward new stimuli entering and becoming part of the perceptual field. Coherence in thought flow is often altered because of the frequent intrusion of other thoughts, often released by irrelevant associations. In other cases the processing of concepts seems blocked by the onset of perseverative phenomena (Geschwind, 1982). Very few studies have attempted to outline the qualitative characteristics of cognitive compromise in patients with ACS using neuropsychological methods. One study (Chedru & Geschwind, 1972a) proposed evaluating a wide range of cognitive functions in a relatively high number of confused subjects. Three other works (Chedru & Geschwind, 1972b; Daniel et al., 1987; Wallesch & Hundsalz, 1994) were limited to examining a single cognitive area: writing in the first case, orientation in the second, and naming in the third. Finally, Osmon (1984) reported the profile of a single patient on the Luria-Nebraska Neuropsychological Battery. Some of the data from these studies seem to support the interpretative model of a specific attentional deficit at the root of the ACS. For example, Osmon (1984) reported that the patient he was studying showed inconstancy in performance, a perseverative attitude, with the frequent production of irrelevant associations, all of which seems to suggest an attentional lability that would only secondarily determine a deficit in behavioural responses. Chedru and Geschwind (1972a,b) showed that within a cognitive sphere, those trials in which the attentional request is greater are particularly deficient (for example, writing in the

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area of linguistic functions). Further, it has been suggested that by manipulating the attentional component it is possible to obtain improvement in these patients’ performances on specific tasks (Mesulam, 1985). Even though the hypothesis of an attentional deficit at the root of ACS is very popular among researchers (Geschwind, 1982; Mesulam, 1985), the neuropsychological evidence collected up until now in its support is mostly indirect; in fact, it comes from non “ad hoc ” studies and therefore is not able to outline the qualitative characteristics of the deficit. A specific neuropsychological investigation of the attentional function in confused subjects requires first moving within a defined cognitive model that takes into consideration the various aspects into which this function is presumably broken down. There are many cognitive models for exploring the attentional function (see Mesulam, 1985; Posner, 1980; Shiffrin& Shneider, 1977; Van Zomeren, 1981). All agree in distinguishing a series of discrete subcomponents within that function, each with its own specific competence and all functionally connected. Mesulam (1985) proposed that the attentional system can be differentiated on clinical and neurophysiological terrain into two basic components. The first component, defined as attentional matrix, provides the substrate for the detection of stimuli coming from the entire potentially perceptible field toward which the focus of attention can be shifted. Relevant characteristics of the attentional matrix are the ability to process a great amount of information in parallel, and to be in relationship with shortand long-term memory stores in order to decide about the novelty or repetitiveness of stimuli and the significance to attribute to them. The second basic component of the attentional system is defined as selective attention. The major characteristic of this component is that it permits focusing consciousness for long periods of time on a single or on a few objects of the potentially perceptible field. Thus, the ability to process stimuli is limited, even if it is lasting. A correct functioning of selective attention requires the ability to inhibit sensory or cognitive processing and/or behavioural response to other stimuli present in the perceptual field. It is still

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being debated (Shiffrin & Schneider, 1977; Treisman, 1969) whether this inhibitory function of the processing of irrelevant stimuli operates at a pre-perceptual level (so that these stimuli are not processed perceptually at all) or a post-perceptual one (so that from the perceptual stage they do not enter the cognitive processing stage). Recent PET data (Drevets et al., 1995) documented changes in metabolic parameters in cerebral sensory areas delegated to perceptually process the signal during the preparatory phase of a signal detection task. In particular, when an increase in metabolism occurs in the sensory area that directly processed the stimulus, reduced metabolism (as an expression of functional inhibition) is recorded in the neighbouring or contralateral homologous areas. These data seem to support the hypothesis that the functional inhibition of the processing of irrelevant stimuli occurs in very precocious phases of signal processing. Other aspects that must be taken into consideration to carefully investigate the attentional function are the temporal persistence of selective attention (sustained attention), and the ability to direct attention to more than one cognitive task at the same time (divided attention). Sustained attention is the ability to maintain the focus of consciousness for long periods of time on a specific stimulus. It is generally explored with tasks that require indicating recognition of a target stimulus in a series of irrelevant stimuli administered for a long period of time. Increased fatigability of sustained attention is signalled by a progressive reduction in accuracy and readiness in the detection of the signal with passing time (Greber & Perret, 1985). Divided attention is usually explored by means of tasks requiring the simultaneous processing of two or more perceptual stimuli coming from the same or from different sensory channels. It is hypothesised that two mechanisms (not necessarily alternatives) deal with the surplus of information to be processed. A first mechanism resides in the use of temporary stores that increase the ability to retain information entering when the speed of processing of the cognitive system is saturated. Baddeley’s (1986, 1990) Working Memory model predicts the existence of modality-specific stores for the temporary retention of verbal (Articulatory Loop)

or visual-spatial material (Visual Scratchpad) and of a central processor (Central Executive) involved in storage and information processing activities not linked to a specific perceptual modality. A second system hypothetically able to cope with the requests deriving from the simultaneous execution of more than one cognitive task has been proposed by Shallice (1988). In his model, Shallice hypothesises the existence of a Central Operator (Supervisory Attentional System) that controls the adequacy of behavioural responses to perceptual inputs. In many cases, this behavioural response, as a virtue of hyper-learning, acts in a semi-automatic way (for example, driving a car) so that more attentional resources are made available for carrying out other tasks, which are less, or not at all, automatised (for example, conversing with a person who is sitting beside us in the car). When perceptual inputs signal an unexpected condition (for example, a passerby who crosses the street), the Central Operator inhibits the automatic response and activates response modules adequate for the new situation and more expensive in terms of the attentional resources involved. From what has been said up until now, it can be deduced that the presumed attentional deficit in patients with ACS can be caused by compromise at different levels of the functional system. Mesulam (1985), for example, proposed that the ACS is characterised by an alteration of the basal attentional matrix with a secondary compromise of selective attention. On the other side, Geschwind’s (1982) hypothesis, that the less automatised procedures are more compromised in these subjects, suggests reduced efficiency of the Central Operator in allocating sufficient attentional resources to cognitively more complex tasks. Future studies must examine the many aspects into which the attentional function is broken down. In the next few years, neuropsychological research must tackle the question of whether the cerebral damage that produces ACS impairs all aspects of attentional functioning or whether, instead, it affects more or less selectively specific components (for example, the persistence of attention or the ability to select relevant stimuli and inhibit irrelevant ones or, finally, storing or control functions of the Central Operator).

Part Vili

Special Syndromes

Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

26 Calculation and Number Processing Gabriele Miceli and Rita Capasso

following years (e.g. Berger, 1926; Head, 1926; Henschen, 1920; Krapf, 1937; Peritz, 1918; Poppelreuter, 1917; Singer & Low, 1933; Sittig, 1917; see Boiler & Grafman, 1983 for review), but this area of research was relatively neglected for a long time. Over the past few years, cognitive neuropsychological studies of calculation and number processing disorders have provided a new impulse to this area. Cognitive neuropsychologists deal with the brain lesion responsible for cognitive damage as with an experiment of nature, whose known and unknown parameters must be carefully investigated. The main research goal is to reconstruct the pre-existing cognitive “order”, starting from the disorder caused by the lesion. On the assumption that brain damage can have only “local” consequences on the functioning of the cognitive system, and that pathological data can be transparently related to the underlying cognitive system, analyses of cognitively impaired subjects are brought to bear on issues regarding the normal organisation of mental processes. Investigations on normal and brain-damaged subjects have demonstrated that cognitive processes have a very

INTRODUCTION Each of us has to look up, retrieve, and dial telephone numbers, compare prices, write cheques, verify bank or credit card statements, check the change in department stores, etc. Thus, it is entirely obvious that normal use of calculation and number processing is necessary in order to carry out daily activities, and that damage to these processes is extremely disruptive for everyday life. However, only very recently have neuropsychologists devoted to calculation and number processing an attention comparable to that granted for over a century to language, memory, and spatial cognition. The first report of a subject with a selective disorder of calculation was published by Lewandowski and Stadelman (1908). They described the case of a young man, whose job required normal mathematical skills, who suffered from a severe dyscalculia following left occipital damage, in the presence of essentially normal language abilities. Additional subjects with brain lesions resulting in disorders of calculation and number processing were reported on in the 583

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rich and articulated internal structure. This complex organisation has determined an important methodological choice. As each of many subcomponents of each cognitive system can be damaged selectively or in association with others, damage to a system can take an extreme variety of forms. Thus, to unequivocally identify the cognitive lesion responsible for a pathological behaviour, it is not sufficient to evaluate the subject’s performance, based on a restricted set of tasks, arbitrarily selected a priori. Quite to the contrary, it is necessary to evaluate all the theoretically relevant aspects of the subject’s behaviour, and the inferences on the cognitive impairment can only be made a posteriori. The process that allows identification of the cognitive lesion is lengthy and detailed, and can be successfully completed only if the performance of each subject is carefully analysed. Only the analysis of single cases allows reliable conclusions to be drawn on the structure of the cognitive system (for extensive discussion of these issues, see Badecker & Caramazza, 1985; Caramazza, 1986, 1987; Caramazza & McCloskey, 1988).

FIGURE 26.1

The “modular” model of the calculation and number system (adapted from McCloskey et al., 1985; McCloskey, 1992).

THE NUMBER PROCESSING SYSTEM The general architecture of the number system and its relationships with the calculation system are schematically represented in Fig. 26.1.1 Number comprehension is independent of number production. The components involved in processing the various number codes (spoken and written number words; Arabic numbers) are also independent, both in comprehension and in production. Different input components are involved in processing Arabic numbers (5), visually presented number words (five) and auditorily presented number words (“five”).2 Also the number production system has a complex internal structure, which includes mechanisms responsible for the production of Arabic numbers, of spoken and of written number words. Both in recognition and in production, each subcomponent includes independent lexical and syntactic mechanisms, involved in processing each digit in the number and the relationships among the digits comprising the number, respectively. The

26.

mechanisms involved in processing numbers for input and for output also serve as input and output mechanisms for the calculation system (even though the calculation and the number processing system are independent). Patterns of performance reported for braindamaged subjects, which support the architecture presented in Fig. 26.1, will now be briefly reviewed.

The overall structure of the number processing system Independence o f input and output processing components Benson and Denckla (1969), Singer and Low (1933), and McCloskey, Caramazza, and Basili (1985), described subjects who demonstrated normal comprehension of numbers. Regardless of the code in which numbers were presented (Arabic, spoken and written number words), in the context of multiple-choice tasks these subjects flawlessly recognised numbers presented by the examiner, pointed to the greater of two numbers, or selected the number corresponding to the solution of a problem. By contrast, they performed poorly on tasks that required the ability to produce numbers. They could not solve written and mental calculations, write numbers to dictation, read aloud Arabic numbers, or say the number corresponding to the dots on a piece of paper. These subjects will be reconsidered later. For the time being, suffice it to say that their pattern of performance constitutes a dissociation between spared number comprehension and damaged number production. Independence o f number codes In the schema presented in Fig. 26.1, separate mechanisms are involved in processing Arabic numbers, written number words, and spoken number words. This distinction is also supported by experimental observations. In comprehension, a double dissociation between verbal and Arabic codes has been reported. McCloskey et al. (1985) described the behaviour of two subjects, who had been asked to select the greater of two visually presented numbers. Subject HY performed flawlessly with pairs of Arabic

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numbers (e.g. 8-5, 27,305-27,350, etc.), but performed at random with pairs of written number words (e.g. eight - five; twenty-seven thousand three hundred and five - twenty-seven thousand three hundred and fifty; etc.). Subject K presented with the reverse impairment—flawless performance with pairs of written number words, random responses with pairs of Arabic numbers. More recent reports further support the distinction. Subject SF (Cipolotti, 1995) read aloud correctly 365/385 (95%) numbers presented as written words (length: one to seven digits), but only 173/385 (45%) of the same numbers presented in the Arabic code. A similar dissociation was observed, in the context of a more severe deficit, in BAL (Cipolotti, Warrington, & Butterworth, 1995). This subject flawlessly read aloud isolated letters and 20/20 number words corresponding to single digits. When the same digits were presented in the Arabic code, however, BAL only read aloud correctly 31/60 (52%). The reverse pattern of performance was reported by Anderson, Damasio, and Damasio (1990) in a subject who read aloud Arabic numbers, but was unable to read aloud number words and isolated letters. The results of these subjects are consistent with the hypothesis that independent mechanisms are used to process numbers presented in the Arabic code and in the alphabetic code. Berger (1926) described two subjects with contrasting performance in the production of spoken and written Arabic responses to calculations. In responding to table facts, the first subject produced correct spoken responses, but wrote incorrect Arabic responses (e.g. to the problem 10x5 he would say “fifty” but write 32), whereas the second subject presented with the reverse pattern. A further dissociation between number production mechanisms was observed in JS (Sokol & McCloskey, 1988), who produced digit substitution errors in reading Arabic numbers aloud, but not in writing Arabic numbers to dictation. There have also been reports of dissociations within the number word production domain, resulting in the selective inability to process auditorily or visually presented numbers. For example, in a magnitude judgement task, HY (McCloskey et al., 1985) flawlessly responded to

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stimuli read aloud by the examiner, but performed at random when the stimuli were presented in the form of written number words.

A computational model of number production The independence o f syntactic and lexical number production mechanisms Deloche and Seron (1982a, 1982b) and Seron and Deloche (1983,1984) analysed the corpus of errors produced by an unselected sample of braindamaged subjects in the course of tasks that required the ability to read numbers aloud and to write numbers to dictation. Based on their analysis, they proposed hypotheses on the structure of the lexicon used in the course of number processing, and on the cognitive mechanisms used in number transcoding tasks. According to these authors, the number lexicon consists of primitive numbers and of “miscellaneous” elements. Primitive numbers belong to three distinct classes: units, tens, and teens. The “miscellaneous” set includes, among other items, multipliers like “-hundred”, “thousand”, “-million”, etc. Because many errors apparently result from an incorrect processing of primitives (e.g. 476 read as “four hundred and fifty six”) or of the relationships among digits in a number (e.g. 476 read as “four thousand and seventy six”), Deloche and Seron (1982a, 1982b) and Seron and Deloche (1983,1984) proposed that number comprehension and production requires lexical and syntactic mechanisms, which are involved in processing the individual digits comprising the number and the relationships among them, respectively. Similar conclusions had been reached by Grewel (1952). The independence of lexical and syntactic number processing mechanisms is further supported by the analysis of errors produced by individual subjects in writing Arabic numbers to dictation. The subject described by Benson and Denckla (1969) substituted one or more digits in a number, but in his incorrect responses the order of magnitude of the target number was systematically preserved (“two hundred and twenty-one” —►225). In three other subjects, the opposite disorder was

observed. In the incorrect responses produced by the subject described by Singer and Low (1933), subject VO (McCloskey et al., 1985) and subject DM (Cipolotti, Butterworth, & Warrington, 1994) while writing Arabic numbers to dictation, digits were correct, but the order of magnitude was incorrect (“two hundred and forty-two” —►200A2). In the latter cases, the individual digits were processed flawlessly, but the ability to encode the relationships between digits in the syntactic number structure was impaired. The double dissociation between lexical and syntactic number production mechanisms can only be accounted for by assuming independent mechanisms for the two aspects of the production process. Some aspects o f lexical and syntactic number processing mechanisms Results relevant for the understanding of lexical and syntactic number production mechanisms were obtained by McCloskey et al. (1985), McCloskey, Sokol, and Goodman (1986) and Sokol and McCloskey (1987) from the study of subjects RR, HY, and JG. These results are reported here, and will be discussed in the context of a procedural model of number production later. Subject RR (McCloskey et al., 1985) flawlessly comprehended numbers, but could not produce them. He read aloud incorrectly 62% of the digits comprising the Arabic numbers used as stimuli. In 90% of the cases, the incorrect response consisted of the substitution of the correct digit with another of the same order of magnitude (e.g. 56 —> “fiftynine”). An analysis of the stimulus-error relationship in substitution errors showed that each digit in the stimulus was equally likely to be substituted for by any other element in the same class (e.g. “six” in the response to 56 was equally likely to be substituted for by “one” or by “seven”). Subject HY (McCloskey et al., 1986) demonstrated normal understanding of numbers, but presented with difficulty in all production tasks (writing number facts, like the number of days in the year; reading numbers aloud; and writing numbers to dictation, also in response to problems). In reading aloud 4989 Arabic numbers, HY produced 694 (13.9%) incorrect responses. The number of incorrect responses increased with

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length (from 3.5% with single-digit numbers, to 30.5% with 6-digit numbers). Almost all errors (654/694, or 94.2%) were “lexical”, i.e. the incorrect response was of the same order of magnitude as the target, but one or more number words were substituted for, as in 29 —►“forty-nine”. The distribution of the reading errors produced by HY was far from random; on the contrary, the number words produced incorrectly neatly fell into three categories, depending on the nature of the stimulus. Incorrect responses to stimuli from 1 to 9 resulted in a number from 1 to 9; incorrect responses to stimuli from 10 to 19 resulted in a number from 10 to 19; and, incorrect responses to 20, 30, 40, ..., 90 resulted in the production of another tens number. In other words, whenever a number belonging to a class was read aloud incorrectly, the error resulted in most cases (units: 96%; teens: 96%; tens: 85%) in the production of another element in the same class (e.g. 482 —►‘five hundred and eighty-two”; 615 —►“six hundred and twelve”; 745 —►“seven hundred and sixty-five"). Given a primitive in a position in the stimulus number, any element of the same primitive class was as likely to be produced in error as any other element of the same class. Error occurrence was comparable to digits from 2 to 9 (range: between 4% and 5%), independent of the position that the digit occupied in the stimulus. For example, the probability of incorrectly reproducing digit 4 was the same across the stimuli 42,971; 54,236; 29,415; 83,842; and 93,254. By contrast, performance on digit 1 differed as a function of its position in the stimulus. When 1 was in the positions corresponding to the hundreds of thousands, to the thousands, to the hundreds or to the units (as in 745,936; 547,573; 867,734; and 394,767, respectively), it behaved just like digits 2 to 9 (and in fact, the error occurrence was in the same range in these cases— 31/648, or 4.8%). However, when 1 was in the positions corresponding to the tens or to the tens of thousands (that is, when it was the first digit of a teen element, as in 374,974 o 635,977), the error incidence dropped substantially (6/1777 errors, or 0.4%). The analysis of HY’s performance on teens shows that numbers in this class behave like the other primitives (units and tens). In fact, HY produced an incorrect response

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to approximately 3.8% of the teens (e.g. to 14 in 74,753 or to 17 in 58,977), and his incorrect responses resulted in one of the teens in 96% of the cases. The pattern of performance reported for HY is consistent with the view that units, teens, and tens constitute distinct classes in the number lexicon. Subject JG (McCloskey et al., 1986) was more accurate in reading aloud Arabic numbers than either RR or HY (98/7594 errors, 1.3%). The error distribution in this subject was very different from that observed in the other two cases, as 59/98 incorrect responses (60.2%) resulted in errors like 912 —►“nine hundred and twenty”, or 50,300 —► ‘five thousand three hundred”. In other words, most reading errors resulted in an incorrect number word that belonged to a different primitive class than the target, but occupied the same “position” in another class. In the first example, “twelve” and “twenty” are the second element in the teens and in the tens class, respectively; in the second example, “fifty” and “five” are the fifth element in the tens and in the units class, respectively. The contrast between the error type produced by RR and HY (withinclass, across-position errors, resulting in the substitution of an element belonging to a class for another element belonging to the same class) and those produced by JG (within-position, across-class errors, resulting in the substitution of an element belonging to a class for another occupying the same position in a different class) are consistent with the hypothesis that the two features that characterise each primitive number (the class to which it belongs and the position within the class) are represented independently. Subject JS (Sokol & McCloskey, 1988) presented with difficulties in both spoken and written number production. As in the subject described by Singer and Low (1933) and in subject VO (McCloskey et al., 1985), errors resulted from a difficulty in encoding the relationships among the elements comprising a number (e.g. 146,359 —► “one hundred thousandforty-six, three hundred and fifty-nine; 509,362,490 —►“five million and nine, three thousand and sixty-two, four hundred and ninety”; 799,970 —►“seven ninety-nine thousand, nine hundred and seventy”). The occurrence of these “syntactic” errors was comparable in reading aloud (17.1%) and in writing to dictation (17.8%).

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In addition to these errors, JS also produced errors like those observed in RR, HY, and JG, which result from the inappropriate selection of class or of position within class. Interestingly, these errors occurred only in reading aloud, where they accounted for 13.4% of the total number words produced by JS, but never in writing to dictation. To sum up, the incorrect responses produced by RR (McCloskey et al., 1985) and HY (McCloskey et al., 1986) take the form of “within-class, across-position” errors. In the course of output tasks both subjects access the correct primitive class (units, teens, tens), but at times cannot access the correct element within that class. The errors produced by JG (McCloskey et al., 1986), by contrast, take the form of “across-class, withinposition” errors. This subject accesses the correct position, but in an incorrect lexical class. Overall, these results suggest that spoken number production requires a level of representation in which the number words to be produced are specified in terms of class and of position within class. HY’s results are relevant in order to understand the structure of the number lexicon. They suggest that the number lexicon consists of three distinct classes: units (numbers from 1 to 9), teens (numbers from 10 to 19), and tens (numbers 20, 30, ..., 90), as schematically represented in Table 26.1. Each number is identified by two access codes: the class to which they belong, and the quantity to which it corresponds (which can be roughly equated to the “position” it occupies within that class). Thus, “twenty” is the primitive in the second position in the tens class; “five” is the primitive in the fifth position in the units class; and, “thirteen” is the element in third position in the teens class; and, so on. The role of “zero” in this system is discussed later. The results obtained by JS in writing Arabic numbers support the hypothesis that the mechanisms involved in processing the syntactic number structure are independent from those involved in the insertion of lexical elements in the syntactic frame. Furthermore, they are also consistent with the hypothesis that syntactic number representation is modality-independent, whereas lexical insertion mechanisms use modality- and code-specific information.

TABLE 26.1 The lexicon of numbers. CLASS Quantity (0) (1) (2) (3) (4) (5) (6) (7) (8) (9)

Units -

one two three four five six seven eight nine

Teens ten eleven twelve thirteen fourteen fifteen sixteen seventeen eighteen nineteen

Tens -

twenty thirty forty fifty sixty seventy eighty ninety

Number production processes The results reported thus far (and in particular those obtained from RR, HY, JG, and JS) have been used by McCloskey et al. (1986) to propose computationally explicit hypotheses on the mechanisms involved in number production. Suppose a subject has to produce the number 4527. The first stage of this process results in the generation of a semantic structure, which specifies each quantity of the to-be-produced number, and the base-ten power to which it is associated. The semantic representation corresponding to 4527 can be thus represented: {4} 10EXP3,

{5} 10EXP2,

{2J10EXP1,

{7J10EXP0

Obviously, this has to be intended only as a rather rough device to visually represent the semantic representation. The “real” semantic representation is abstract, and the elements that comprise it are not spatially ordered (i.e. {4} 10EXP3 is neither “to the left o f ’, nor “before” {5J10EXP2). The information in braces denotes the quantity that specifies each of the to-beproduced elements, and the value next to 10EXP is the power of 10 associated to each quantity (e.g. 10EXP3 corresponds to 103, 10EXP2 to 102, and so on). Finally, “null” elements are not included in the semantic representation. The representation of 40 is [{4} 10EXP1], and not [{4J10EXP1,

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{0J10EXP0]: the semantic representation of a number different from 0 does not represent the 0 quantity. According to McCloskey, the semantic number representation is compositional (it comprises several independent bits of information), precise (the stimulus number activates an exact representation of the corresponding quantity), and supramodal (the same semantic representation is activated, independent of whether the subject is engaged in comprehension or in production tasks, and of the code in which the number is presented, or has to be produced). The semantic representation serves as input to the number production system. The information it contains is necessary in order to generate (or to retrieve) the appropriate syntactic structure, and to fill each slot in the syntactic structure with the elements from the number lexicon. The syntactic representation is generated starting from the highest power of ten included in the semantic representation. The syntactic representation of 5427 can be thus schematically represented: [UNITS:__]MULT:T

[UNITS:_]M ULT:H

T E N S :_

U N IT S :_

10EXP3

10EXP2

10EXP1

10EXP0

This representation specifies the overall structure of the number to be produced. It contains information on the class to which each element belongs, and on the multipliers needed for the correct output (MULT:T and MULT:H stand for the information needed to activate, at later stages of the spoken production process, the multipliers “-thousand” and “-hundred”, respectively). For our example, the syntactic representation specifies that 4527 contains four primitives, of which the first belongs to the units class and is followed by the multiplier “-thousand”, the second belongs to the units class and is followed by the multiplier “-hundred”, the third belongs to the tens class, and the fourth to the units class. What is not specified in the syntactic representation is the quantity tied to each slot in the frame (which is assigned by the order of magnitude expressed by 10EXPX). In other words, the syntactic representation specifies that the target

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number contains thousands, hundreds, tens, and units, but not “how many” thousands, hundreds, tens, and units it contains. Three considerations on syntactic representation are in order at this point. First, it is not clear whether the syntactic representation of a number must be computed each time ex novo, or whether it can be retrieved as a complete representation. According to McCloskey et al. (1986) and to Sokol & McCloskey (1988), both hypotheses are plausible; in some cases, the syntactic representation is retrieved; whereas, in other cases it must be assembled. At any rate, it is not clear how numbers of the first and of the second type can be distinguished in a non-arbitrary way. Second, the structure [[UNITS:_]M ULT:H

T E N S :_

U N IT S _ ]

can be considered as some kind of functional unit of the production system, because its periodic repetition allows the production of numbers of all orders of magnitude (e.g. “one hundred and eightyone billion, two hundred and thirty million, seven hundred and twenty-six thousand, eight hundred and sixty-two”—the syntactic structure of the italic portions of the overall number is identical). Third, “-hundred” differs from other multipliers in that it only multiplies the quantity to its immediate left, whereas all the other multipliers apply to the entire three-digit group to their left, included in square brackets: [[UNITS:_]M ULT:H

T E N S :_

U N IT S :_ ]

The information included in the semantic and in the syntactic representation are used in the subsequent stages of the production process. In these stages the information is necessary in order to address the elements in the number lexicon that must be inserted in the slots of the syntactic structure. In our example, when the quantity associated to the element of the order of magnitude 10EXP3 must be accessed, semantic information activates the primitive number of the corresponding quantity {4}, and syntactic information results in the activation of the elements in the units class. Combined semantic and syntactic information unequivocally specifies the

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element that occupies the fourth “position” in the units class. By means of the same procedure, the remaining elements of the number lexicon are also activated, resulting in a representation that can be schematically represented as follows: UNITS:{4} MULT:T

UNITS:{5}MULT:H

TEN S:{2}

U N IT S:{7}

10EXP3

10EXP2

10EXP1

10EXP0

In this representation, the values after the colon are not digits, but quantities. This representation contains all the information needed to access the appropriate primitive numbers, in the appropriate, modality-specific subcomponent of the number lexicon. Thus, the information on the first element will activate the Arabic representation , the phonological representation /faiv/ or the orthographic representation , as need be. Subsequently, more peripheral (articulatory or graphomotor) mechanisms are engaged in the spoken or written production of the target number. Two exceptions to the general mechanisms discussed thus far must be discussed: the production of teens and of zero. The teens production procedure The hypothesis concerning the mechanisms involved in the processing of the primitives that belong to the teens group is largely based on the results obtained by RR and HY (see earlier). The presence of the information TENS: {1} in the representation that serves as input to the number lexicon activates a special procedure. Instead of activating an element in the tens class, the procedure moves to the next element in the syntactic representation, which corresponds to the units class. The representation of the units in this slot is associated to the corresponding teens element. For example, in the case of a number like 417, the representation that is used as input to the number lexicon has the form [UNITS: {4}]MULT:H

TENS: {1}

UNITS: {7}

The presence of the information TENS: {1} activates the teens procedure, which uses the information UNITS: {7} to generate the

representation TEENS: {7}, and to activate the corresponding teens element in the output system. Zero The other special case in production processes involves zero. It has been said already that the semantic representation does not contain elements that correspond to 0, when it occupies a non-initial (305; 6027), or one or more final positions in an Arabic number (20; 300; 8000; etc.). As a consequence, in the syntactic representation the slots to which the quantity 0 is assigned are empty, and are not considered in accessing the number lexicon. To the absence of the representation of the quantity {0} in the semantic representation of complex numbers corresponds the fact that in the spoken and written number production, the words “zero” and zero are never used to denote quantity 0 in the number structure (507 is read as “five hundred and seven”, not as “five hundred zero seven”). The semantic representation only specifies {0} when it denotes the absolute quantity zero— and in fact, in all these cases the zero must be produced, irrespective of whether the Arabic or the linguistic (spoken or written) code is used. In the case of Arabic numbers, however, 0 must also be produced when it occupies a non-initial position or one or more final positions (“five hundred and seven” is written 507; “two thousand” is written 2000). This results from the fact that the Arabic code uses the position of digits in the number in order to denote the power of ten associated to each quantity. Consequently, all the slots corresponding to orders of magnitude smaller than the highest order of magnitude in a number must be filled, even when some of them are associated to the null quantity. That the production of 0 is a consequence of Arabic code-specific rules is demonstrated by the fact that in the format of Roman numbers, which assigns a smaller role to item position in encoding orders of magnitude, there is no symbol for 0 (compare 807 and DCCCVII; or, 1010 and MX). The only exception to this rule applies to the null quantity in the teens class. In producing a number like 310, the semantic representation [UNITS:{3}]MULT: H

TENS:{ 1}

U N IT S:[J

26.

is generated. In this case, the teens production procedure generates the representation TEENS: {0}, that results in the activation of number 10 in the number lexicon for production. Syntactic and lexical representations in number comprehension So far, we have only considered the mechanisms involved in number production. These procedures allow an amodal semantic number representation to be converted into a series of intermediate representations that are increasingly modalityspecific. A reverse sequence of events takes place in the course of number comprehension. The goal of number comprehension processes is the transformation of a number presented in a specific modality (auditory or visual) and in a specific code (verbal or Arabic), into an abstract semantic representation. As in production, so also in comprehension intermediate representations must be computed, which share some basic features with the representations discussed in the previous section. For example, the comprehension of the Arabic number 45 requires that visual recognition processes realise an abstract graphemic representation [], that generates a series of intermediate representations, until the semantic representation [TENS: {4} UNITS: {5} ] is generated.

Semantic information in number processing The role o f semantic information in number processing In the model proposed by McCloskey (1992) and discussed so far, conceptual representations play a central role in number transcoding processes (reading aloud, writing to dictation, repetition). All transcoding tasks require the activation of an abstract semantic representation, independent of input or output modality, and of input or output number format. In fact, in the schematic hypothesis presented in Fig. 26.1 there are no direct links between input and output representations—during transcoding tasks, format-specific input representations must activate semantic representations, which in turn activate formatspecific output representations (see also Macaruso,

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McCloskey, & Aliminosa, 1993). Those who advocate a critical role for the semantic component in the course of number processing tasks argue that conceptual number representations must be computed in the course of everyday activities. Knowing that the external temperature is 37°C has obvious consequences on the kind of clothing one wears; seeing that the same shirt is priced at £100 at one store and at £120 at another store directly affects the decision as to where to buy it; taking half a pill three times per day may influence our wellbeing, and so on. Support for this hypothesis comes from the observation that the semantic system is also activated during tasks that apparently do not require overt conceptual processing. Starkey, Spelke, and Gelman (1980) demonstrated that, when children of 6 to 8 months are shown two visual displays, one with two items, one with three items, and at the same time are shown a two- or three-tap sequence, children preferentially direct their gaze at the visual display that contains the same number of items as the auditory sequence (for further results demonstrating that children at few weeks of age are able to process numbers at the semantic level, see also Antell & Keating, 1983). An additional empirical phenomenon, well documented in adults, confirms semantic processing of numbers: the number distance effect. When they are asked to evaluate which of two numbers is larger, normal subjects react more slowly when the two numbers are very close than when the two numbers are distant (for reviews, see Banks, 1977; Holender & Peereman, 1987; Moyer & Dumais, 1978). This hypothesis is further confirmed by studies that demonstrate semantic processing of numbers also in the course of tasks that do not overtly require the activation of semantic representations. In a recent work on normal subjects, Dehaene and Akhavein (1995) showed that, when asked to say whether or not two Arabic numbers are physically identical or different (e.g. 8-8; 8-5; etc.), reaction times to odd pairs are faster when the two numbers are very different (e.g. 2-8) than when they are very close (e.g. 7-8). A number distance effect in a task that only requires an overt physical similarity judgement can only be accounted for by assuming that semantic representations are activated in the

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course of the task, even though they are not necessary in order to carry out the task. These observations are consistent with the hypothesis that number processing requires the activation of a semantic representation. However, it is not as obvious that a semantic representation is necessarily activated in all number processing tasks, nor that the activation of an abstract semantic representation is the only procedure that allows number processing. In neuropsychological research, this issue has been repeatedly debated. According to some authors (Cipolotti, 1995; Dehaene, 1992; Deloche & Seron, 1987), tasks like reading aloud, writing to dictation, repetition, conversion of a written number word into an Arabic number, do not require the activation of a semantic representation. On the contrary, the target number can be processed via direct connections between input and output representations, without any semantic activation. The performance of some brain-damaged subjects has been presented as support for this hypothesis. Subject YM (Cohen & Dehaene, 1991) could not read aloud Arabic numbers (errors involved mostly the left side of the number in the canonical, left-to-right presentation, but occurred with comparable frequency when the stimulus number was presented vertically); however, this subject correctly pronounced number words in the context of other tasks, and never made errors in identifying the larger of two Arabic numbers. This result cannot be easily accommodated in McCloskey’s model (1992). This model predicts that good comprehension of Arabic numbers and good spoken number production should be associated with good performance in reading aloud Arabic numbers. In order to interpret YM’s behaviour, Cohen and Dehaene propose that reading aloud Arabic numbers does not require the activation of abstract representations, and propose an asemantic reading procedure, which takes as input a visual representation of the number, consisting of spatially ordered digits. This representation serves as input to procedures that compute the syntactic structure of the number and retrieve single-digit identity. This representation in turn serves as input to procedures that activate the phonological representations necessary for the spoken response.

This model (Dehaene, 1992) assumes that format-specific input representations are directly and asemantically transformed into format-specific output representation, but does not specify the nature of these procedures, nor the level at which these procedures interact. Several very diverse alternatives can be entertained. Consider for example reading Arabic numbers aloud. The processing of the written input string requires the activation of a graphemic representation, which is subsequently transformed into a syntactic representation that specifies Arabic digits; the processing of the spoken output requires the assembly (or the retrieval) of a syntactic structure containing number words, which is subsequently used to activate phonological representations. Asemantic transcoding might take place via at least two distinct mechanisms: a direct link between the graphemic digit representation and the phonological, number word representation; or a direct link between the syntactic structure filled with Arabic digits and the syntactic structure filled with number words. The current version of the hypothesis does not specify which possibility is true (or if both mechanisms are active). Subject SF (Cipolotti, 1995) performed reasonably well (although not flawlessly) in Arabic number recognition and comprehension tasks, and in number production in all formats (Arabic numbers, written and spoken number words). In most tasks, errors occurred to 3-6% of the stimuli. SF was also comparably accurate in reading number words aloud, in repeating numbers, and in writing Arabic numbers to dictation. However, he produced 55% incorrect responses (mostly of the syntactic type) when reading Arabic numbers aloud. These results are taken as evidence that, in addition to a semantic procedure, an asemantic procedure is also used in reading Arabic numbers aloud. Although both the hypothesis proposed by Dehaene (1992; see also Cohen & Dehaene, 1991; and Cohen, Dehaene, & Verstichel, 1994) and that proposed by Cipolotti (1995; see also Cipolotti, Warrington, & Butterworth, 1995) assume asemantic number processing mechanisms, the latter assigns a greater weight to the semantic than to the asemantic procedure. According to Cipolotti, asemantic conversion procedures are based on

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Arabic number-to-number name conversion procedures, and contain information regarding units of different sizes (isolated digits, as well as groups of digits), as well as knowledge on number lexicon and syntax. The representation computed by asemantic number conversion procedures directly activates the mechanisms involved in spoken number production, without activating the number lexicon (see earlier). This hypothesis is also rather underspecified. The levels of representation involved in asemantic procedures and the relationships among these levels are not explicitly clarified. In addition, in this hypothesis conversion procedures are extremely powerful, as they include in asemantic conversion procedures ranging from single digits to digit groups (there is no upper limit to the degree of structure that these mechanisms can process); however, the principles governing the activation of the individual conversion rules are not spelled out. The debate on the procedures involved in number processing is still open, and the problem is still unsolved. However, we believe that great caution should be exerted when new components are inserted in models of number processing. Regardless of the objections on the empirical justification that justify the various assumptions (see for example McCloskey’s considerations on YM’s results), there is a more general theoretical problem, which is not restricted to theories of calculation and number processing, but applies to all neuropsychological theories. New procedures can be legitimately included in a model, provided that the computational aspects of these procedures are made explicit. In our case, the assumption that non-lexical conversion procedures operate in number processing is perfectly reasonable, but the content of these mechanisms and the procedures that activate each of them must be specified. For example, the hypothesis that there are mechanisms that convert a number from a format onto another format through an asemantic conversion of the basic elements of the number system (e.g. 6 —► “six”-,five —►5) is not problematic, and could be easily included in all current models. It is very different, however, to assume that there are also mechanisms that can make very complex asemantic conversions like 783,421 —►“seven hundred

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eighty-three thousand four hundred and twentyone”. If such powerful procedures are included in a model, it must also be clearly indicated over which range of phenomena these mechanisms apply, and how they work. For example, do asemantic procedures apply only to reading Arabic numbers aloud, or in all tasks that require the ability to process Arabic numbers (reading number words aloud; writing number words to dictation; repetition; conversion of an Arabic number into written number words)? If the second hypothesis is true, what information is included in which component, and how is it activated? Also, and more in general, which factors result in the activation of the asemantic rather than of the semantic procedure (or vice versa)?3 The nature o f semantic information in number processing According to McCloskey (1992), the abstract representation involved in semantic number processing is supramodal—the same semantic representation is activated in transcoding tasks, irrespective of the stimulus format and of the response format. Input and output formats only affect number processing at very “peripheral” stages (very early or very late, respectively). The hypothesis of a supramodal semantic representation does not rule out the possibility that response modality influences the ways in which the stimulus is processed. In fact, the hypothesis explicitly includes representations that differ as a function of the number format, both in comprehension and in production. In comprehension., for example, visual processing of number words and of Arabic numbers (seven and 7) involve different mechanisms. The processing of written number words requires as an intermediate stage the recognition of the letters that comprise the stimulus [ ], which eventually allows the activation of the orthographic representation , which in turn activates the corresponding semantic representation. Conversely, the Arabic number 7 directly activates the orthographic representation , which in turn activates the semantic representation. Also in the late stages of the production process, format-specific representations are activated. For example, the null quantity is

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realised differently in the verbal and in the Arabic format (see later). In the former, no word corresponding to the quantity zero is produced; whereas, in the second case the digit 0 is always produced.4 A very different hypothesis from McCloskey’s has been proposed by Campbell (Campbell, 1994; Campbell & Clark, 1988,1992; Clark & Campbell, 1991), Dehaene (1992), Deloche and Seron (1987), and Cipolotti et al. (1995), who reject the notion that there is just one supramodal abstract representation. They assume that the number system is built up as the function of the computational demands of each task, and allow many different abstract number representations, each of which is involved in processing numbers in a specific code. The empirical basis of these hypotheses comes from the performance of subjects like BAL (Cipolotti et al., 1995) who perform normally in Arabic number comprehension and in reading aloud number words, whereas they make errors in reading aloud Arabic numbers. This performance is hard to account for in the theoretical framework of the model proposed by McCloskey, according to which sparing of the supramodal semantic number representation should systematically result in similar performance across all production tasks, independent of response format. The pattern of performance observed in BAL is taken to indicate that stimulus format (in this case, an Arabic number) influences the accuracy of spoken responses, in the presence of spared ability to comprehend numbers presented in the same format, and to produce responses in the same modality, but to a different input. It is then concluded that the spoken output system can be activated by format-specific abstract representations. A detailed discussion of each hypothesis would be impossible, as models differ both in the number of abstract representations that they allow, and in the extent to which the various representations are allowed to interact. In an extreme form (Campbell), all input representations and all output representations interact, and the activation of a given format of number representation also results in the activation of the other formats. An obvious corollary of this hypothesis is that the presentation

of a number in a given format also activates representations that are specific for very different formats (i.e. in reading Arabic numbers visual, auditory, articulatory, analogical, and motor representations are also activated). This type of hypothesis, which increases the number of representations involved in each transcoding task without specifying formal properties and activation procedures for each representation, complicates inextricably the interpretation of the mechanisms involved in the tasks under scrutiny. However interesting the theory, the virtually infinite number of degrees of freedom it allows makes it impossible to empirically evaluate its merits. To a lesser degree, less “extreme” theories also suffer from the same type of problems. Providing clear answers to the problems that concern the role and nature of the conceptual information involved in number processing is essential for the development of theories of number processing. In the absence of such answers, however, the proliferation of representations and processes (or of connections between them) disproportionately increases the explanatory power of a model, makes it non-falsifiable and, eventually, prevents its empirical verification. The analysis of asemantic conversion procedures, and of the nature of conceptual representations involved in number processing, are critical issues. It is to be hoped that the hypotheses that advocate multiple (semantic and asemantic) procedures and multiple (formatspecific) conceptual representations, are elaborated in enough detail to allow a cogent empirical evaluation.5

CALCULATION Any cognitively unimpaired subject can quickly and accurately solve the multiplication problem presented in Fig. 26.2. And yet, if we try to describe, even in an unsophisticated way, all the steps that are necessary to achieve the correct solution, it is obvious that even an apparently simple problem requires the normal functioning of many complex cognitive mechanisms. The number processing system must recognise the two

26. CALCULATION AND NUMBER PROCESSING

FIGURE 26.2

A complex multiplication.

operands, and the representation activated by means of the lexicon and the syntax of numbers must be used as input by the calculation system. The operational sign must be recognised, in order to establish that the to-be-solved problem is a multiplication. In carrying out further steps, “arithmetic facts” must be retrieved (in this case, table facts) to obtain the partial products; the specific procedures for multiplication must be applied in order to establish the order in which the partial products must be calculated (3x7, then 3x5, then 4x7, then 4x5), and the manipulation to which they must be submitted (the carrying procedure, the correct alignment of partial products, and the addition procedures that must be applied to the two partial products). As the last step, number production mechanisms are necessary to produce the correct response. In the model proposed by McCloskey et al. (1985), the number system is used as input and as output for the calculation system, but the two systems are functionally independent. In this part of the chapter the neuropsychological studies that offer information relevant to the understanding of calculation processing and of the relationships between calculation and number processing are reviewed. Unless otherwise specified, all the subjects discussed here present with spared number processing, and with impaired calculation. The functional architecture of the calculation system includes at least three independent components: operational signs, “arithmetic facts”, and calculation procedures.

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Operational signs The mechanisms involved in the recognition of operational signs are independent from those involved in accessing “arithmetic facts” and in carrying out calculation procedures. In at least two cases (Ferro & Botelho, 1980; Caramazza & McCloskey, 1987) such dissociation has been empirically documented. When asked to solve visually presented problems, both subjects made several errors of the type 7+3=21, or 5-4=9; in other words, they executed correctly an incorrect problem. Shown with 7+3 or 5-4, they behaved as if the presented stimuli were 7x3 or 5+4, respectively. These two subjects, then, recognise numbers and access “arithmetic facts”, but incorrectly process operational signs (responding 21 to the problem 7+3 results from the incorrect recognition of the + sign as the x sign, but is the correct response to the problem 7x3). In both cases, the administration of complex calculations demonstrated good preservation of the procedures for the four basic operations (the carrying procedure in addition and multiplication, the borrowing procedure in subtraction and division, alignment of partial products in multiplication, etc.). This behaviour can only be accounted for by assuming that number processing, arithmetic facts, and calculation procedures are spared, whereas recognition of operational signs is selectively impaired.

Arithmetic facts and arithmetic rules The term “arithmetic facts” denotes the basic problems that are solved by directly accessing the solution, without the activation of calculation procedures. Multiplication table problems are the typical example of a set of arithmetic facts. The solution of 3x6 is not obtained by using calculation procedures (i.e. by adding 6 times the number 3), but by directly accessing the result (3x6=18). Also the divisions corresponding to the multiplication tables and one-digit additions and subtractions are typically considered to be arithmetic facts. The results obtained by brain-damaged subjects have been used to investigate several aspects of the relationships between arithmetic facts and the other components of the calculation system, and of the internal organisation of the arithmetic fact system.

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The independence o f arithmetic facts from the other components o f the calculation system The mechanisms involved in processing arithmetic facts are independent from the mechanisms involved in calculation procedures and in the recognition of operational signs. Subjects DRC (Warrington, 1982) and MW (Caramazza & McCloskey, 1987) provide clear evidence with this regard. DRC demonstrated normal comprehension of numbers and operational signs, and provided correct definitions of the problems he was asked to solve. However, he produced approximately 10% incorrect responses to arithmetic facts and, even when he managed to produce the correct response, he was extremely slow (it took him up to 14 seconds to solve single-digit problems whose solution was greater than 10). In this subject, the ability to solve arithmetic facts as such seems to be lost, resulting in the need to resort to calculation procedures even when presented with very simple problems. Coherent with this interpretation, the time needed to solve additions and subtractions increased with the magnitude of the second operand. For example, DRC took longer to solve 2+6 than to solve 6+2; as if he solved the former problem by calculating 2+1+1+1+1+1+1, and the second by calculating 6+1+1. This severe deficit with facts notwithstanding, DRC flawlessly applied calculation procedures to solve complex problems. MW processed digits and signs normally, and (contrary to DRC) responded to arithmetic facts very quickly. However, many responses to facts were incorrect, and resulted in numbers included in the table system. For example, on various occasions, MW solved 6x7 as 30, 63, 54, and 36 —that is, he produced an incorrect number that is part of the 6 or of the 7 table. In other instances, unable to respond right away, he arrived at the correct solution by a complex procedure, decomposing the to-be-solved problem into two or more problems whose solution was available to him. For example, unable to respond to 9x4, he solved it as 9x2=18; 18+18=36. The difficulty in this subject does not result from deficits in number recognition, as in a task in which the two operands were presented as sets of tokens (each comprising 1 to 9 tokens), he correctly counted the tokens, and

obtained the correct operands, but produced incorrect responses, just as in the previous task. Also in this subject, damage to arithmetic facts was very selective. In fact, MW correctly applied calculation procedures to complex problems, even though his responses were incorrect, due to the arithmetic fact deficit. To sum up the relevant features of these two subjects: DRC and MW recognised operational signs correctly, and used calculation procedures appropriately; thus, their errors resulted from a selective impairment of arithmetic facts. This pattern of performance supports the notion that arithmetic facts are independent from the other components of the calculation system.6 The independence o f arithmetic rules from arithmetic facts Not all simple problems must be solved like facts: some of them can be solved by rule. The reasons for distinguishing between facts and rules are rather obvious. The results of problems like nx3 or n:2 vary as a function of n\ whereas, the results of problems like nxO, or nxl are highly systematic Cn:0=0, and nxl= n, independent of the magnitude of n). Thus, it is reasonable to assume that problems like 5x0, 0x8, 6:0, 0:3, 6x1, 1x8 are not solved by accessing a different fact for each problem, but by accessing rules, shared by groups of problems. If this hypothesis is true, arithmetic facts and arithmetic rules might also be represented autonomously, and it should be possible to observe cognitively impaired subjects who present with selective impairment or selective sparing of facts over rules, or vice versa. Some subjects demonstrate a selective impairment of the rules for problems with 0, relative to arithmetic facts. In multiplication tables, JB and HM (McCloskey, Aliminosa, & Sokol, 1991b) responded incorrectly to only 3-4% of table problems whose operands ranged from 2 to 9, but systematically responded incorrectly to problems with 0. The reverse pattern was observed in CM and IE (McCloskey et al., 1991b), who produced many incorrect responses on table problems ranging from 2 to 9 (17% and 29%, respectively), but performed normally on problems with 0 (0% and 1% incorrect responses, respectively).

26. CALCULATION AND NUMBER PROCESSING

The contrast between the two patterns of behaviour confirms the hypothesis that problems with 0 and problems with numbers ranging from 2 to 9 are represented independently. Further support to the hypothesis that the 0 table is represented by a single rule, which applies to all facts within the table, comes from the observation that subjects frequently present with extreme behaviours on problems within the 0 table—they either systematically respond correctly, or systematically respond incorrectly. Another example is provided by subject PS (McCloskey et al., 1991b; Sokol et al., 1991). If her performance throughout the experimental study is considered, she produced 41 % incorrect responses on problems of the 0 table. However, this value is the average of two opposite behaviours. At the beginning of the investigation, PS produced 98% incorrect responses to 0 problems; as soon as she realised that she was responding incorrectly, her incorrect response rate fell abruptly to 5%. Another result consistent with the hypothesis has been provided by JG (McCloskey et al., 1991b). This subject, who produced many incorrect responses to all table facts before treatment, was submitted to a remediation programme that included two problems with Os, and some problems with tables from 2 to 9. The outcome of treatment was very different with the two sets of problems: JG responded correctly to 99.3% of all (treated and untreated) problems with 0; to 85% of the problems from 2 to 9 that had been treated; but to only 1.4% of the problems from 2 to 9 that had not been treated. This pattern is consistent with the hypothesis that problems with 0 are rule-governed (if the rule is retrieved, all problems are solved correctly), whereas the other table facts must be solved by access to fact-specific knowledge. The 0 rule is but one of the rules that are possibly used when accessing arithmetic facts. Theoretical considerations and empirical observations on cognitively impaired subjects suggest that a larger number of rules is involved in solving table problems. One of these rules concerns problems with 1 (nxl= n; lxn = n). The observations in this case are less compelling than those obtained for 0 problems, but they still suggest the possibility that

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these problems are also solved by rule. For example, subject MD (McCloskey et al., 1991b) performed rather poorly on facts from 2 to 9 (27% errors), and systematically failed to respond correctly to 0 problems (100% errors), but almost always solved correctly problems with 1 (1% incorrect responses). Other putative rules might apply to problems like 0:n=0, n:0=0, n:l=n, and n :n - l. Subject AB (McCloskey et al., 1991b) produced on average 8% incorrect responses to all divisions within the range of table facts, but produced a much greater number of incorrect responses (22%) to divisions with 0. All the errors resulted from solving problems as if 0:n=n\ in addition, all the problems of the type n:n, with only one exception, were solved as if n:n=0. The representation o f arithmetic facts Most hypotheses on the nature of knowledge about arithmetic facts, and on the mechanisms by which this knowledge is accessed, result from studies on the multiplication tables. They are of two broad types: single-format hypotheses and multipleformat hypotheses. According to single-format hypotheses (Dehaene, 1992; McCloskey, 1992; Sokol et al., 1991), even though the format in which tables are presented may vary (written or oral number and sign words; Arabic numbers, tokens, etc.), the corresponding facts have a single internal representation. According to these hypotheses, problems presented in the formats 5x6, /faiv/ /bai/ /six/, five by six, and ••••• x •••••• are solved by accessing one and the same abstract representation. This hypothesis is supported, among other things, by the observation that children who learn to solve tables from auditory presentation also manage to solve the same problems when they are presented in written form (five by six, or 5x6). Two variants of this hypothesis have been presented. The first variant (Dehaene, 1992) is related to the theory of number processing presented earlier. Arithmetic facts are represented as phonological sequences. Solving a table multiplication entails mapping the stimulus presented in any format onto a phonological representation, which activates the corresponding solution, also represented as a phonological sequence. For example, 5x6 activates

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/faiv/ /bai/ /six/, that in turn activates the sequence /faiv/ /bai/ /six/ /is/ /B^rti/, which subsequently drives the production of the written response ( /0srti/—►30),)- That multilingual subjects who learned table facts in their first language, keep using it when solving arithmetic facts, even when they become proficient in other languages has been considered consistent with the hypothesis. The second version of the single-format hypothesis (McCloskey, 1992) relates to the modular theory sketched in Fig. 26.1. The hypothesis in this case is that multiplication table facts are represented semantically, and not as phonological strings. In this context, solving a multiplication table fact requires that, irrespective of stimulus format (5x6, five by six, /faiv/ /bai/ /six/), one and the same semantic representation is activated. This hypothesis is supported by the observation that incorrect responses produced by normal subjects who are asked to solve multiplication table facts demonstrate the operand effect and the operand distance effect (Campbell & Graham, 1985). Typically, the incorrect numbers produced by normal subjects on these tasks are present in the multiplication tables, and are correct for another problem that contains one of the operands (7x9=56; 8x6=42)—the operand effect. Furthermore, the incorrect operand is usually close in magnitude to the target ( \ and, /faiv/ /bai/ /six/ can activate the phonological number word representation like /faiv/ /by/ /six/ /is/ /Gsrti/. It is also possible that a stimulus presented in one modality activates more than one representational format (5x6 can activate , , and /faiv/ /by/ /six/ /is/ /Gorti/). Some studies on brain-damaged subjects allow us to compare the two single-format hypotheses, and to compare the single- and the multiple-format hypotheses. Subject JM (Whalen, McCloskey, Lindemann, & Bouton, in preparation) was presented with written Arabic additions, which he was asked to read aloud and to which he had to produce a written Arabic response (e.g. 5+6 —►/faiv/ /plas/ /six/ —► 11). According to Dehaene’s hypothesis (1992), solving arithmetic facts requires converting a stimulus into the corresponding phonological sequence, which activates the phonological string corresponding to the solution, and eventually allows the spoken response (5+6 —►/faive/ /plas/ /six/ /is//ilevn/—►/ilevn/—►11). In this framework, the spoken response is constrained by the phonological sequence activated in response to the stimulus, and the written response is determined by the spoken response. Thus, this hypothesis predicts that when the stimulus problem is read incorrectly, the spoken response should be incorrect and should correspond to the just-read phonological sequence; furthermore, the written response should also be incorrect, and should correspond to the spoken response. A subject who misreads 5+6 as /faiv/ /plas/ /nain/ will access the phonological sequence /faiv/ /plas/ /nain/ /is/ /fortin/, and will subsequently write 14. According to McCloskey (1992), solving arithmetic facts does not require the activation of a phonological representation, but rather of a supramodal semantic representation, which activates the response in the required format (in our example: 4+5-^SUM( {4}, {5} )-+SUM({4}, {5})= { 9 }— 9 ).

As written output does not depend on the activation of a phonological representation, and the mechanisms used for spoken and written responses are also independent, the spoken output produced when reading aloud the stimulus and

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when providing the spoken solution will not constrain the selection of the written response. Thus, a subject might solve 5+6 as 11, even though he or she reads the stimulus as /faiv/ /plas/ /nain/, and produces /fortinJ as the spoken solution to the problem. JM’s results are consistent with the latter hypothesis: the subject reads aloud incorrectly more than 50% of the problems (all the errors result in digit substitutions), but solves correctly more than 90% of them. In other words, he produces the correct written response to stimuli that he reads aloud incorrectly. Similar results were obtained by HG (Whalen et al., in preparation) when solving multiplication table facts. The results obtained by subject PS in solving multiplication facts (Sokol et al., 1991) are also consistent with the view that solving arithmetic facts involves the activation of a supramodal semantic representation. Independent of stimulus format, this subject produced a comparable overall number of incorrect responses and the same error types on each problem. Overall, the patterns of performance observed in JM, HG, and PS favour the hypothesis that arithmetic facts are solved by activating formatindependent semantic representations (McCloskey, 1992) over the hypothesis that the same problems are solved by activating phonological representations (Dehaene, 1992). The choice between single- and multiple-format hypothesis (Campbell) is more difficult. The latter hypothesis (arithmetic facts are represented in many formats, each of which can be activated to a different extent as a function of input and format modality) is motivated by the observation that the performance of normal subjects who are asked to solve arithmetic problems presented in various modalities are similar, but not identical (Campbell, 1994), in at least three respects. In the first place, the magnitude of the operand distance effect varies as a function of input modality (as the effect presumably takes place at the semantic level, its magnitude should be modality-independent). Second, error priming does not generalise across formats. In normal subjects asked to solve a series of table facts, the presentation of a problem increases the probability that the correct solution to that problem is produced as the incorrect solution

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to a problem presented later in the series (e.g. presenting 6x8=48 increases the probability that 48 is incorrectly produced if 7x8 is presented subsequently). The single-format hypothesis predicts that the magnitude of the effect should be unaffected by input modality (in the previous example, error priming should occur also when 6x8 is followed by seven times eight). Campbell’s data suggest that transfer of error priming does not occur. A third and final example results from incomplete transfer of learning. The single-format hypothesis predicts that, if a problem is trained in one modality, training should have the same effect across modalities (including those in which no training was provided). The results obtained by MC (Whalen et al., in preparation) are consistent with this hypothesis. This subject, who presented with a severe impairment of arithmetic facts, was submitted to a remediation programme. During treatment, some facts were presented auditorily, some as Arabic numbers, and some as written number words. After treatment, all facts were presented in all modalities. As predicted by the single-format hypothesis, improvement generalised across modalities, for all treated facts. However, reaction times were significantly faster when the problem was presented in the same modality in which it had been trained, than when it was presented in the other modalities. To sum up, at this stage it is difficult to make a clear-cut choice between the single- and the multiple-format hypotheses. One of the reasons for this state of affairs results from the relative underspecification of the multiple-format hypothesis. In fact, under the assumption that there is both a large number of format-specific representations and an extreme individual variation, it is impossible to identify patterns of performance that might disprove the hypothesis, unless each detail of the model is specified in detail. The organisation o f arithmetic facts and the procedures used to access them In the previous sections, some hypotheses concerning the nature of the representations used in solving arithmetic fact problems were reviewed. Other crucial issues of research on this system concern its internal organisation, and the

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procedures used to access knowledge on arithmetic facts. It is obvious that the various aspects of the problem are not independent of each other: hypotheses on the internal organisation of table facts and on the procedures used to access them cannot be articulated without specific assumptions on the nature of the representation of the same facts. To mention but an obvious example, very different access mechanisms will have to be postulated, if it is assumed that table facts are represented in a phonological code, as opposed to a semantic code. Without discussing each model in detail, some hypotheses are reviewed here. The only assumption that is made in this review is that arithmetic facts representations are abstract. Models are of two types: table-search models (e.g. Ashcraft & Battaglia, 1978; Widaman, Geary, Cormier, & Little, 1989) and network retrieval models (e.g. Ashcraft, 1987; Siegler, 1988; Siegler & Schrager, 1984).

FIGURE 26.3

The solution of 8 x 7 in a table search model (Ashcraft & Battaglia, 1987).

Table-search models (schematically represented in Fig. 26.3) assume that the table system is organised like a true multiplication table. In this theoretical framework, individual facts are not represented autonomously. Each fact is connected via associative links to several adjacent facts, and it is solved indirectly, through the propagation of activation in the system. The two operands are the access nodes to the table. From these access nodes, activation proceeds along rows and columns to the intersection, where the solution is represented. For example, when 8x7 is presented, the access nodes corresponding to 8 and 7 are activated. Activation proceeds along the 8 row, spreading through the intersections 8x1, 8x2, 8x3, ..., 8x6, 8x7, 8x8, ..., and along the 7 column, spreading through the intersections 1x7, 2x7, 3x7, ..., 7x7, 8x7, 9x7. As the intersection 8x7 is activated from both rows and columns, the corresponding information (56) is selected for production.

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Network retrieval models assume a direct connection between the operands and the solution, for each problem. Ashcraft’s model (1987), based on the activation of associative networks is schematically represented in Fig. 26.4. Arithmetic multiplication facts are represented in an associative network that has two access nodes, one for each operand. On this account, a problem like 8x7 is solved by directly activating 56 from the access nodes 8 and 7. In addition to maximally activating the access nodes 8 and 7, the problem 8x7 also activates adjacent access nodes, in

FIGURE 26.4

The solution of 8x7 in an associative network model (Ashcraft, 1987).

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proportion to its distance from the activated nodes. In the case of 8x7, the activation of access node 8 also activates to a lesser degree nodes 7 and 9 (and to an even lesser degree node 6); similarly, the activation of access node 7 also activates to a lesser degree nodes 6 and 8 (and to an even lesser degree nodes 5 and 9). Consequently, responses like 42, 49, 63 and 72 are also activated (because they correspond to 7x6,7x7,9x7 and 9x8, respectively). Deciding which of these hypotheses is more likely to be true crucially rests on the possibility of offering reasonable accounts for the patterns of performance (correct and incorrect responses) observed in normals and in cognitively impaired subjects engaged in table-solving tasks. Normals and brain-damaged subjects produce similar errors (e.g. Campbell & Graham, 1985; Sokol et al., 1991), even though with a very different frequency of occurrence. In both groups, operand errors are the most frequent error type. The subject produces an incorrect response that shares one of the operands with the stimulus problem (8x6=56; 7x3=18). Table errors also occur rather frequently. These errors result in incorrect responses that are included in the table system, but do not share operands with the stimulus (3x5=14). Another error type, which occurs less frequently, results from operation errors, in which the subject produces a number that is the correct solution to a problem with the same number, but a different operational sign (e.g. 4x5=9). One last error type, which occurs only exceptionally in normals, results from non-table errors, in which the response is not in the multiplication table (3x5=13). Other behaviours in the solution of number facts are also observed in all experimental groups. For example, children (Miller, Perlmutter, & Keating, 1984), normal adults (Campbell & Graham, 1985), and cognitively impaired subjects (McCloskey et al., 1991b; Sokol et al., 1991) all solve problems with small operands more quickly than problems with larger operands. In addition, in subjects who suffer from brain damage, problems with small operands are usually less impaired than problems with larger operands.8Furthermore, damage across problems is not homogeneous, as different problems may be impaired to a substantially different extent in various subjects. For example,

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one of our subjects, CMI, produced incorrect responses to 17/20 (85%) presentations of 8x7, but never produced incorrect responses to stimuli like 5x9, 6x8, 7x7, etc. These observations seriously undermine tablesearch models. In the framework of these models, errors can result from the incorrect selection of access nodes, from damage to the propagation of activation along rows and columns, or from an impairment of the information stored at the intersection between rows and columns. Tablesearch models allow an appropriate account of operand errors (incorrect selection of an access node), table errors (incorrect selection of both access nodes), and operation errors (access to an incorrect table, or incorrect processing of the operational sign), but cannot account for non-table errors (by definition these numbers are not part of the set within which the response is selected). These models also have problems accounting for the “scattershot” damage to multiplication tables that occurs very frequently in cognitively impaired subjects. CMI produced 85% incorrect responses to 8x7, but only 5% incorrect responses on adjacent problems like 8x8 and 9x7. In a table-search model, activation propagates along rows and columns, from the smallest to the largest problem. As a consequence, damage to 8x7 should impair also the ability to produce the correct solution to 8x8 and 9x7, because the activation of these facts presupposes sparing of 8x7. Models based on the activation of associative networks seem to provide a more adequate explanation of the available data, and in particular of the scattershot damage to table facts observed in cognitively impaired subjects. Because in these models the operands of each problem are directly connected to the solution, 8x7=56 can be impaired independent of adjacent problems. This outcome might result from two mechanisms that are not mutually exclusive. First, operand-solution links can be damaged at random; second, these links might be more or less robust (perhaps depending on familiarity, learning history, etc.), and can be impaired to a different extent as a consequence of a brain lesion. Also this class of models, however, cannot easily account for non-table errors. Siegler and Schrager (1988) proposed a solution within the

framework of a distributed-association model (Fig. 26.5). Also in this model the table system consists of a set of nodes. Each node specifies a problem, and is connected to a set of nodes corresponding to different responses by means of associative links of different strength. For example, in the case of 7x8 the link to 56 is strongest, the links to 48, 64, 49, and 63 are weaker, and those to 40, 35, 72, etc. are weakest. The associative links are built during the learning process, and are strengthened or weakened depending on exposure to the problem —the link is reinforced each time a number is produced in response to the corresponding problem. This mechanism might account for nontable responses produced by cognitively impaired subjects. During development, in addition to the correct connection between a problem and its solution, one or more incorrect connections can also be established, some of which are incorrect (7x8=48) or are not part of the table system (7x8=53). The latter links might develop because one of the ways in which children learn to solve multiplication problems is by means of serial additions—an error-prone procedure. In a system

FIGURE 26.5

Relationships among table nodes in the distributed association model (Siegler & Schrager, 1988).

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like this, when the problem 7x8=56 is damaged, the weakened association between stimulus and response can result in responses like 48 or even 53. The representation o f the various operations in the arithmetic fact system In most brain-damaged subjects, addition is the least impaired of the four basic operations. As a consequence, selective sparing of addition is not considered as evidence for the independent representation of the various operations. However, the possibility that the facts for the four basic operations are indeed represented independently is suggested by the results obtained in cases in whom the spared operation is more “difficult” than the operations that are damaged. Subject SB (McCloskey et al., 1991b) presented with a rather severe multiplication impairment (15% incorrect responses), but performed much more accurately on addition and subtraction (1% and 3% incorrect responses, respectively). Subject RG (Dagenbach & McCloskey, 1992) produced significantly fewer errors to subtractions (46%) than to additions and multiplications (90% and 89%, respectively). A similar dissociation between addition and subtraction has been described by McNeil and Warrington (1994). These results suggest that addition, subtraction, multiplication, and division facts are represented independently. However, as is made clear in the next section, the relationships among operations are probably more complex, especially in the case of multiplications and divisions. The representation o f complementary operations and problems One aspect of the arithmetic fact system is the relationship between complementary operations, like addition and subtraction, and multiplication and division. For each pair of complementary operations, there are problems that share all quantities but, depending on the operation, are operands or results. With addition and subtraction, for example, for given values of a, b , and c, if a+b=c, then c -b -a and c -a -b (e.g. 5+3=8; 8-5=3; 8-3=5). With multiplication and division, for given values of a, b, and c, if axb=c, then c:b=a and c:a=b (e.g. 6x3=18; 18:3=6; 18:6=3). Thus, it is

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reasonable to ask if the four basic operations use fully independent nodes, or whether the same node is shared by addition and subtraction, and by multiplication and division. Available results do not allow firm conclusions. Even though there are no systematic observations for addition and subtraction, the observation that the two operations are often impaired to a disproportionate degree in the same subject (McCloskey et al., 1985, 1991b) suggests that they use independent nodes. Fewer results have been collected on multiplication and division. A systematic analysis in case BE (Hittmair-Delazer, Semenza, & Denes, 1994) showed complementary multiplication and division problems to be damaged to a similar degree. BE was comparably impaired on multiplication and division facts; and divisions were solved like corresponding complementary multiplications. Furthermore, after a treatment programme based only on multiplications, BE’s performance on complementary divisions improved as well. This observation suggests that nodes for complementary multiplications and divisions are unlikely to be represented totally independently, and is more consistent with the alternative possibility that they are either shared, or at least connected in some way. Another relevant problem for the understanding of the internal organisation of the table system concerns the organisation of complementary problems within the same operation (i.e. problems that contain the same operands in the reverse order, like 3x9 and 9x3, or 8x7 and 7x8, etc.). Do these problems share the same node, or are they represented independently? (Or, is the order of presentation of the operands relevant in constraining access to the fact system?) The available results offer a controversial picture. The single-node hypothesis is supported by the observation that some subjects perform at comparable levels on complementary problems within the same operation (Hittmair-Delazer et al., 1994; McCloskey et al., 1991b). However, other results are compatible with the opposite conclusion. Our subject CMI, for example, responded incorrectly to 9/20 (45%) presentations of 8x3 and to 8/20 (40%) presentations of 8x6, but never made errors when responding to the complementary problems 3x8 and 6x8. Also investigations of

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treatment and recovery from damage to multiplication tables are difficult to accommodate within the hypothesis that complementary problems in the same operation share the same node. Before treatment, BE (Hittmair-Delazer et al., 1994) performed similarly on complementary problems within the same operation. In this subject, some problems were treated, but not their complementary problems. After treatment, both treated problems and their complementary problems were administered (result analysis included reaction times). Treated problems improved significantly, whereas untreated, complementary problems did not. This result is all the more compelling because knowledge of the commutative law of multiplication (mxn=nxm) was spared in this subject. To sum up, BE’s performance before treatment is consistent with the shared-node hypothesis, whereas his performance after treatment suggests that complementary problems are represented independently. Another puzzling result on this issue has been reported by Rickard, Healy, and Bourne (1994), who found significant differences between complementary problems during development, but not in adults, and suggested that the effect disappears because of the greater exposure of the adult group to the problems. A similar problem is posed by rule-based table facts. So far, the possibility that complementary problems (3x7 and 7x3) share the same representation and thus result in the activation of the same response node has been considered. A further question can be asked for operations containing 0 and 1. Is the solution to complementary problems like nxO and Oxn, or like nxl and lx n , mediated by the same rule or by independent rules? Also in this case, available results are inconclusive. The results reported for some subjects (JG, FW, and JB, in McCloskey et al., 1991b) suggest that the two types of problems are mediated by independent rules. For example, JG systematically produced incorrect responses to problems of the type Oxn. By contrast, with problems like nxO, his error rate changed from 100% during the first four administrations of the problems to 0% in the following administrations, just as if the rule for problems of the first type were

systematically unavailable, and the rule for problems of the second type, initially unavailable, was selectively recovered during the study. Another observation consistent with the hypothesis of distinct rules has been reported in subject GE (McCloskey et al., 1991b). Before treatment, this subject produced 100% incorrect responses to problems with 0. He responded in error both to problems like nxO and to problems like Oxn, by applying the incorrect rule nx0=0xn=n. GE was trained on the rules nx0=0 and nxm -m xn. After treatment, he always provided the correct response to problems like nxO, but still systematically produced incorrect responses to problems like Oxn. Overall, the results reviewed in this section suggest that problems in which 0 is the first operand and those in which it is the second operand are solved by distinct rules.

Calculation procedures Results relevant to the understanding of the functional architecture of the calculation system have been repeatedly reported in cognitively impaired subjects (Benson & Weir, 1972; Caramazza & McCloskey, 1987; Grewel, 1952). These papers report on subjects who perform normally on number transcoding tasks (reading aloud, writing to dictation, repetition, etc.), but who are severely impaired on calculations. In some cases (e.g. Benson & Weir, 1972), errors in complex calculations resulted from damage to both arithmetic facts and calculation procedures. In other subjects, however, calculation procedures were selectively impaired. Examples of these errors, produced by brain-damaged subjects examined by the authors, are reported in Fig. 26.6. In the two multiplications, subjects had no difficulty producing the solutions to the intermediate problems (3x7, 3x3, 2x7, 2x3), but were unable to apply multiplication procedures. In the first example, the intermediate products were incorrectly aligned; in the second, the carrying procedure was not applied. In the subtraction, our subject was unable to carry out the “borrow” procedure (he correctly subtracted 6 from 12, borrowing 10 from the position to the left of digit 2, but then he incorrectly subtracted 2 from 7); other subjects simply subtract the smaller number from

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FIGURE 26.6

Complex calculations: errors in applying calculation procedures.

the greater number, irrespective of whether the greater number is the first or the second operand. In the addition, instead of writing the quantity corresponding to the units and carrying tens, the subject wrote partial sums fully (9+3=12,7+6=13, 6+5=11). These errors reveal spared processing of operational signs, and spared knowledge of arithmetic facts. In the multiplications reported in Fig. 26.6, all the intermediate steps were correct: the patient used the multiplication table facts to obtain intermediate products and correctly applied addition procedures to the intermediate products. Errors resulted from the inability to apply the problem-specific procedures correctly (or in the correct order). The performance obtained by PS (Sokol et al., 1991; Sokol & McCloskey, 1991) clearly show that arithmetic facts and calculation procedures are represented separately. This subject produced incorrect responses to 20% multiplication facts, and incorrectly solved 66/145 (46%) complex multiplications. All her errors, however, unequivocally resulted from difficulty with table facts, in the presence of a spared ability to apply multiplication-specific procedures. Calculation procedures constitute a very heterogeneous set. Some neuropsychological results suggest that the procedures for the four basic operations are represented independently. The subject described by Benson and Weir (1972) presented with an essentially normal ability to carry out complex additions and subtractions, but with severe difficulty in carrying out even simple multiplications and divisions. By contrast, a subject reported on by Caramazza and McCloskey (1987) correctly solved complex divisions, but had a severe deficit in solving multiplications. Multiplication procedures have attracted the greatest attention. McCloskey et al. (1991b)

analysed the performance of some subjects on three special multiplication procedures involving 0. Here, only one of these procedures is discussed. A multiplication like 274x70 can be solved in two ways. The first possibility (Fig. 26.7a) consists of using the procedures that apply to all multiplications. The digits of the number in the upper position are multiplied, from right to left, by the rightmost digit of the number in the lower position (0 in this case); subsequently, the same sequence is repeated with the number to the left of 0. The second possibility (Fig. 26.7b) is to apply a special procedure—to write 0 as the intermediate product that refers to the entire first intermediate product, and then to write the quantities corresponding to the second intermediate product to the left of 0, on the same row. This is precisely the strategy used by GE (McCloskey et al., 1991b), who applied all 0-specific procedures whenever possible. This behaviour is all the more striking, because he systematically failed in responding to facts in the 0 table. This pattern of performance suggests that 0 is processed by specific rules (in the arithmetic fact domain) and procedures (in the calculation system); and that rules and procedures for 0 are represented independently.

FIGURE 26.7

A special rule for 0 in complex multiplication.

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OTHER COMPONENTS The patterns of performance discussed in the previous sections help identify the basic representations, rules, and procedures used in number processing and in calculation. However, they do not exhaust the varieties of knowledge that are called upon during the tasks described so far. Other, less well defined abilities play a critical role in the use of this cognitive system. Neuropsychological reports have provided helpful information in this domain as well. Of particular relevance have been investigations of the performance of subjects with damage to arithmetic fact and rules. DRC (Warrington, 1982), who suffered from a severe deficit of arithmetic facts, solved very slowly even the simplest table problems (see also earlier). This difficulty notwithstanding, DRC provided very sophisticated descriptions of the operations that she executed so slowly. Subject IE (Sokol et al., 1989; Sokol & McCloskey, 1991) was unable to retrieve the solution to 3x9. He managed to produce the correct response by transforming the problem into 9x3, and by carrying out serial additions (9+9+9). Thus, even though his knowledge of a multiplication table fact was damaged, IE demonstrated spared knowledge of the commutative law of multiplication (axb=bxa) and of the general rule of multiplication (the solution of a multiplication is equivalent to the sum of one operand a number of times equal to the quantity of the other operand). Subject MW (McCloskey et al., 1985; McCloskey & Sokol, 1991), when in trouble responding to multiplication facts, appealed to strategies that show the integrity of sophisticated conceptual knowledge of calculation. Unable to directly retrieve the solution to 7x7, MW solved it by calculating 7x10=70 and 7x3=21, and by subtracting 70-21=49. This behaviour unequivocally shows that this subject retained the knowledge that axb=(axc)-(axd), if b -c -d . In this subject, there is a clear-cut dissociation between sparing of complex conceptual knowledge on the calculation system and severe impairment of the (intuitively much more basic) knowledge of table facts.

A systematic analysis of preserved conceptual arithmetic knowledge in the presence of a severe deficit of arithmetic fact knowledge was carried out by Hittmair-Delazer et al. (1994). Subject BE responded quickly and correctly to 28/64 multiplication table facts (44%). To 90% of the other problems, he responded correctly but very slowly, and by means of strategies. Many of these required relatively few intermediate steps (8x5 was solved via the sequence 8x10=80; 80:2=40; 8CM-0=40), but some were very complex (the same problem was solved on another occasion via the sequence 5x10=50; 50:2=25; 5x2=10; 25+10+5=40). Interestingly, BE never solved multiplications via serial additions—the strategy children use when learning calculations. With divisions, BE ran into greater difficulties, as he took longer and was much less confident than with multiplications. However, he performed with reasonable accuracy (only two incorrect responses). The strategies used to solve divisions were harder to classify than those he used with multiplications, but they were complex nonetheless. A frequently used strategy consisted of applying the cancellation rule (ac:bc = a:b), according to which, for example, 24:4 corresponds to 14:2 and to 7:1. Subject DA (Hittmair-Delazer, Sailer, & Benke, 1995) presented with a clear-cut dissociation between substantial impairment of table facts and sparing of abstract arithmetic principles. DA could not solve many facts (he made errors to 19/36 multiplications without 0; to 32/64 additions; and, to 10/20 subtractions with numbers ranging from 1 to 9), but accurately solved abstract equations like (bxa): (axb)= l, or like (cd+ed):d=c+e, and correctly established that the equation (a+b)xc=(axc)+(bxc) is correct, whereas the equation (d:c)+a=(d+a):(c+a) is incorrect. These observations demonstrate that conceptual arithmetic knowledge can be spared in the presence of severe damage to other aspects of calculation and number processing, and allow the conclusion that these two types of knowledge are represented separately. Consequently, future developments of cognitive models will have to include, in addition to detailed hypotheses on facts, rules and procedures used in calculation and number processing, also explicit hypotheses on conceptual

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arithmetic knowledge, and on how these two strictly interrelated domains interact.

CALCULATION, NUMBER PROCESSING, AND OTHER COGNITIVE SYSTEMS The computational structure of the calculation and number processing system that emerges from neuropsychological analyses has been discussed so far without explicit reference to other cognitive systems (language, memory, visual-spatial analysis, etc.). However, as damage to calculation and number processing is usually associated with damage to other systems, the meaning of this association must be clarified, and it must be established if and when these associations can be used to draw conclusions on the structure of mental processes. In the early literature, the conclusions on these relationships are often implicit. Several classifications of the deficits observed in braindamaged subjects (e.g. Berger, 1926; Cohn, 1961; Collignon, Leclercq & Mahy, 1977; Goldstein, 1919; Krapf, 1937; Grewel, 1969; Henschen, 1920) acknowledge the autonomy of the calculation and number processing system, but distinguish between “primitive” and “secondary” deficits, thus implicitly assuming that in some cases poor performance in tasks that require the ability to perform calculations and to process numbers results from the impairment of other cognitive systems. The conclusions of these papers are usually hard to discuss, because it is not clear which deficits of the system are secondary to which deficits of other systems. In at least two studies, however, poor performance on calculation and number processing tasks has been explicitly considered as the result of damage to other cognitive systems. In the first of these studies, Hecaen, Angelergues, and Houillier (1961) distinguished three main forms of calculation deficits: “alexia/agraphia for numbers”, due to the inability to read/write digits; “anarithmetia”, due to the inability to carry out the appropriate conduct resulting in the correct solution; and “spatial dyscalculia”, which consists

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of a difficulty aligning digits, resulting from poor visual-spatial analysis. In the second study, Dahmen, Hartje, Bussing, and Sturm (1982) attributed poor calculation in Broca’s aphasia to linguistic deficits, and in Wernicke’s aphasia to visual-spatial deficits. Metatheoretical, methodological, and empirical considerations make these conclusions uninterpretable. Empirically, for each of the described associations there are counterexamples, in which one deficit is not accompanied by the other. Far from being functionally necessary, these associations are most likely to result from damage to contiguous anatomical structures, whose integrity is critical for the normal functioning of the systems that are simultaneously impaired. From the metatheoretical and the methodological standpoint, the reported analyses are insufficiently detailed, the criteria on which they are based are intuitive and are not justified by clear hypotheses on the structure of the cognitive system(s) under analysis. Consider for example the notion of “spatial dyscalculia”, and the conclusion that it results from a visual-spatial deficit (Hécaen et al., 1961). In order to license this conclusion, the functioning of “visual-spatial analysis”, and its role in calculation and in other cognitive processes under normal conditions, should be made explicit, so as to generate verifiable predictions on the consequences that disruption of “visual-spatial analysis” should bring about in various tasks. Instead, “spatial dyscalculia” is defined intuitively, based on a criterion (incorrect alignment of intermediate products) identified independently of any theory of calculation; and it is just as intuitively considered to be secondary to a disorder of visual-spatial analysis. This state of affairs does not allow us to clarify the structure of the normal system, nor to characterise its disorders in non-trivial ways. The only possible conclusion is that, in the presence of disorders of calculation and number processing, other cognitive systems are likely to be disrupted as well. Of course, this does not mean that all associations of symptoms are uninterpretable, or useless in order to define the structure of the cognitive system. Quite to the contrary, it has been convincingly demonstrated that symptom associations are as relevant as symptom dissociations to the understanding of the

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functional architecture of cognitive systems (Caramazza, Miceli, & Villa, 1986). Their interpretation, however, is contingent on the availability of an explicit cognitive theory, which in some areas is yet unavailable. Another relevant aspect of the co-occurrence of difficulties with calculations and numbers and of deficits in other cognitive domains results from the observation that the calculation and number system is similar to other cognitive systems, in various respects. In the presence of a calculation and number processing deficit, it would be desirable to establish that the observed impairment results from damage to a component that is specific for this system, or from damage to a component shared by several cognitive systems. Deloche and Seron (1982b), and Seron and Deloche (1983) seem to prefer the second possibility. In their sample of aphasic subjects, they observed that Broca’s aphasics, who present with a syntactic deficit in the verbal domain, also make syntactic errors in number transcoding, and that Wernicke’s aphasics, who present with verbal lexical deficits, also produce lexical errors in number processing. Based on these observations, they concluded that the deficits with words and with numbers in the two types of aphasia are “parallel”, thus implicitly suggesting that the deficits observed in the two domains (language and number processing) result from damage to a shared component. These conclusions are as problematic as those on symptom associations, for the same reasons. From the empirical standpoint, in addition to the reported association, there are also subjects who present with a verbal lexical deficit and a syntactic number processing deficit, and others who show the reverse pattern. A more general drawback to conclusions on shared vs dedicated cognitive mechanisms is that in some domains cognitive theories are not sufficiently developed to warrant firm statements, even when all the methodological precautions are taken. Consider for example the hypothesis that disorders of the number lexicon result from damage to a shared component, used by both the verbal and the number lexicon—this is the hypothesis implicitly proposed by Deloche and Seron (1982b) and Seron and Deloche (1983) to account for the co-occurrence in the same subject of Wernicke’s

aphasia and of lexical errors in number transcoding tasks. It was said earlier in this chapter that each primitive is identified in the number lexicon by the class to which it belongs and by the position it occupies in its class, and that in some subjects the mechanisms that allow access to the appropriate number class or to the appropriate within-class position are selectively impaired (McCloskey et al., 1985, 1986). Even if these subjects presented with a lexical deficit at the level of single-word production, it would still be impossible to establish whether the observed association of deficits results from damage to independent components of the number lexicon and of the word lexicon, or from the impairment of one component that plays a more general role, shared by the word lexicon and the number lexicon. A reliable response to this question would be at hand only in the presence of a lexical theory sufficiently articulated to specify which aspects of the lexicon of words are cognitively analogous to “class” and to “within-class position” in the number lexicon. As lexical theories are not so detailed, for the time being it is not possible to establish if a deficit of the number system results from damage to a number-specific or to a shared lexical component of the cognitive system.

ANATOMO-CLINICAL CORRELATES Anatomo-clinical correlates of calculation and number processing have been studied rather unsystematically. However, as suggested in a recent review (Kahn & Whitaker, 1991), disorders of this cognitive system result from lesions that are ubiquitous in the brain. This view is confirmed by a revision of the available literature Hecaen studied the anatomo-clinical correlates of the three forms of acalculia he had identified. In a first study, which only included subjects with retrorolandic lesions, Hecaen and Angelergues (1961) report that “alexia/agraphia for digits” occurs very frequently (84%) in left brain-damaged subjects, and very infrequently (8%) in right braindamaged subjects; that anarithmetia occurs in up to 62% of patients with left hemisphere damage and in up to 15% of patients with right hemisphere

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damage; and that, by contrast, “spatial dyscalculia” has a greater occurrence in the event of right hemisphere damage (75%) than in the event of damage to the left hemisphere (6.7%). In a second study, which also included subjects with retrorolandic lesions, Hecaen (1962) set the occurrence of “alexia/agraphia for numbers” to 37.1% in left brain damage, and to 2.1% in right brain damage, that of “anarithmetia” to 86.7% in left brain damage, and to 20.2% in right brain damage; and, the occurrence of “spatial dyscalculia” to 31 % in right brain damage and to 2.1% in left brain damage. Even though the quantitative figures reported in the two studies vary (and there are no principled ways of interpreting the observed discrepancy), “alexia/agraphia for numbers” and “anarithmetia” are observed more frequently after damage to the left hemisphere, whereas “spatial dyscalculia” is observed more frequently in the event of right hemisphere lesions. Grewel (1969) tried to characterise the deficits of the calculation and number system observed after lesions to the frontal, temporal, parietal, and occipital lobes. According to this author, frontal lesions result in a greater difficulty in using “abstract” as opposed to “concrete” numbers, a difficulty further increased by disorders of productive thinking and by lack of initiative typical of frontal lesions. Temporal lesions are responsible for a difficulty in processing auditorily presented number words. Occipital lesions prevent the elaboration of a unitary representation of complex numbers, due to visual and perceptual deficits. Finally, parietal lesions result in a wide range of heterogeneous disorders, resulting from the role that parietal structures play in such crucial cognitive domains as language and movement control. Collignon, Leclercq, and Mahy (1977) observed damage to this cognitive system in 34% of the subjects with left hemisphere damage, and to 29.5% of those with right hemisphere damage. Grafman, Passafiume, Faglioni, and Boiler (1982) studied the occurrence of calculation disorders in subjects with anterior and posterior lesions of the left and right hemisphere. The most severe impairment was observed in subjects with left posterior lesions, even when allowance was made for other cognitive disorders (the authors

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claim that the disorder analysed in their study corresponds to Hecaen’s “anarithmetia”). Taken together, these studies suggest that disorders of calculation and number processing occur more frequently as a consequence of left than of right hemispheric lesions. However, the results are far from univocal. For example, in the paper by Grafman et al. (1982), subjects with left posterior damage are the most severely impaired; but the next most impaired group is that of subjects with right posterior damage (instead of the group of subjects with left anterior damage, as would be expected if the left hemisphere were “dominant” for calculation and number processing). Furthermore, the occurrence of impairments due to anterior lesions is still an open question. Grafman et al.’s results (greatest impairment in left posterior damage) are clearly at odds with Hecaen’s observation that the occurrence of anarithmetia after left brain damage rises from 62.7% when only retrorolandic lesions are considered, to 84% when all the subjects with left hemisphere damage are considered. In the event that left posterior regions are specifically involved in calculation processing (as suggested by Grafman et al.), the occurrence of subjects with calculation problems should decrease (not increase) when subjects with anteriorly located lesions are included in the analysis. Case reports discussed in Kahn and Whitaker (1991) demonstrate that damage to either hemisphere, both superficial and deep, can result in disorders of calculation and number processing. These investigations are exposed to the same criticisms as those that dealt with symptom associations. Their explicit goal is to discover systematic relationships between mental processes and neural structures, based on the pathological behaviours observed in groups of brain-damaged subjects, and on lesion site. If these results are to be taken as relevant for a theory of mind-brain relationships, they must obey several constraints, foremost among which is that the cognitive impairment in the subjects experimental groups be homogeneous. Unfortunately, such homogeneity has been assumed a priori, on the basis of arbitrary criteria, and not demonstrated a posteriori, based on the relevant analyses. The pathological behaviours that these studies have sought to

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correlate to brain regions are entities like “alexia/agraphia for numbers”, “anarithmetia”, or “spatial dyscalculia”, which denote ostensibly heterogeneous disorders (for example, the “number alexia/agraphia” category easily accommodates all the disorders discussed earlier in The number processing system). The approach suggested by cognitive neuropsychology (Caramazza, 1986, 1987; Caramazza & McCloskey, 1988) provides a novel perspective for these studies. The identification of the cognitive lesion responsible for the disorder of calculation and number processing observed in each subject allows the identification of cognitively homogeneous subjects, and hence correlation of mental processes and neural structures in a methodologically appropriate way. The accumulation of studies of brain-damaged subjects with carefully studied deficits and precisely identified lesions is, however, difficult and slow, the only safe way to proceed towards a reconsideration of brain-behaviour relationships. It is to be hoped that this methodology will allow us to overcome the current limitations of knowledge on the relationships between calculation and number processing on one hand, and the brain regions involved in this processing on the other. A substantial supplement to these investigations will hopefully come from neuroimaging studies (PET, fMRI) of both normal and brain-damaged subjects. Having said that, it must be stressed that there are no set expectations concerning the type of correlation existing between calculation and number processing on the one hand, and the brain on the other. In particular, assuming that the system is modular does not in any way commit one to the expectation that tight relationships will be found between a “module” and a geographically defined region (independent of whether the latter coincides with a lobe, a circumvolution, or a cytoarchitectonie area). This is just one of the possible outcomes of the investigation, but it is also possible that forthcoming anatomo-clinical studies will demonstrate correlations between specific functional units and a specific anatomical substrate distributed over a large volume in one, or even both hemispheres. Along these lines, at least one recent attempt at providing a comprehensive account of the

anatomical correlates that implement the complex architecture of calculation and number processing must be presented here (Dehaene & Cohen, 1995). The model assumes the functional architecture of Dehaene’s triple-code model (1992). The occipitotemporal regions of both hemispheres (but mostly those on the left) are involved in recognising visually presented numbers, and in constructing an abstract visual representation that includes information on the identity and relative position of each digit in the target number (this component is akin to the “visual word form system” proposed in the context of studies on reading by Warrington & Shallice, 1980). The language areas of the left hemisphere are also involved in processing spoken numbers for input and for output (this seems to imply that this part of the system is not specific to number processing, but is shared by all language tasks). The parieto-temporo-occipital junction of both hemispheres (perhaps mostly that of the right hemisphere) obtains an analogical representation of number magnitude. As concerns the calculation system, simple mental arithmetic requires retrieval of phonological representations, and hence relies heavily on language areas of the left hemisphere; whereas, a more complex interaction between visual-spatial and verbal digit representations (and hence a more bilateral involvement) is probably necessary for complex calculations. Visual, verbal, and magnitude (semantic) representations are largely interconnected within the left hemisphere; the right hemisphere contains connections between visual and semantic representations. Visual and magnitude number representations in the two hemispheres are connected by callosal pathways; there are no right-to-left connections linking visual to verbal number forms.

CONCLUSIONS In recent years, the processes involved in calculation and number processing have been the focus of an increasing number of experimental analyses of brain-damaged subjects. The main results of the cognitive neuropsychological approach to the study of acquired disorders of

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calculation and number processing have been briefly discussed, along with some hypotheses on the correlations between these processes and brain structures. Cognitive models of calculation and number processing are increasingly more detailed and computationally more explicit. Due to these features, they have achieved not only theoretical, but also clinical relevance. For example, analyses of the calculation and number processing system based on the hypotheses discussed in this chapter are now an essential part of the neuropsychological examination of brain-damaged subjects and are systematically used for the remediation of their disorders (Hittmair-Delazer et al., 1994; McCloskey et al., 1991b; Miceli, Capasso, & Temussi, 1987; Seron & Deloche, 1987; Sullivan, Macaruso, & Sokol, 1996).

ACKNOWLEDGEMENTS The preparation of the present chapter was made possible in part by research funds from MURST, CNR, and IRCCS S. Lucia. This support is gratefully acknowledged. The authors wish to thank an anonymous reviewer for helpful suggestions on an earlier version of the manuscript.

NOTES 1. In this chapter, only the adult system is considered. Issues related to the development of calculation and number processing will not be considered. 2. The following notations are used: Arabic numbers are reported in digits (5); numbers presented auditorily or produced verbally are between inverted commas (“five”); number words presented visually or produced in the written modality are in italics (five ). When the code in which the number is presented or produced is not relevant, uppercase numbers are used (FIVE stands for 5, “fiv e ” , and five). Phonological representations of number words are in phonetic notation /faiv/; orthographic representations are between signs (); semantic representations of quantities are between braces, as in {5}. 3. It cannot be ignored that, if the notion of asemantic transcoding is accepted, the behaviour observed in

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YM and SF would receive a paradoxical account: in the presence of a normal functioning of the procedures involved in number recognition, comprehension, and production, which would allow the use of the semantic procedure, these subjects would still be using an alternative, allegedly less efficient procedure, that furthermore is damaged and results in incorrect responses. 4. In other models, number format exerts an even greater influence on the types of representations activated in the course of number processing tasks, to the point that it also influences the more “central” number representations. This is especially true in models like Dehaene’s (1992). For example, Noel, Seron, and B redart (1994) take up the fact that in various languages the same number can be verbally expressed in different ways (e.g. in some French-speaking countries, 73 corresponds to “soixante-treize”, whereas in others it corresponds to “septante-trois”; in English, numbers like 1600 correspond to both “one thousand six hundred” and to “sixteen hundred”), to hypothesise that different, intermediate syntactic representations are realised for the two alternative versions of each number. 5. It will be clear to the reader at this point that the debate on semantic and asemantic number transcoding mechanisms, and the debate on the unique, supramodal as opposed to the multiple, formatspecific conceptual representations in number processing is strongly reminiscent of similar arguments in the context of the neuropsychology of language, as the theoretical arguments discussed in both areas of cognition are structurally similar. Those interested in the discussion on the presence/absence of direct, asemantic connections between input and output lexical representations can also read Coltheart, Patterson, and Marshall (1980), Coslett (1991), Howard and Franklin (1987) and Patterson, Coltheart, and Marshall (1985), who favour Ithe hypothesis of direct, asemantic transcoding, and Hillis and Caramazza (1991,1995), Miceli, Capasso, and Caramazza (1994), and Miceli, Giustolisi, and Caramazza (1991) who favour the notion of semantically mediated connections between input and output word processing mechanisms. Those interested in the debate on unique/multiple semantic representations can read Caramazza, Hillis, Rapp, and Romani (1990), Rapp, Hillis, and Caramazza (1993), and Hillis, Rapp, and Caramazza (1995), who favour the notion of a unitary semantic system, and Shallice (1988a, 1988b; 1993), Warrington &Shallice (1979, 1984), and Warrington and McCarthy (1987),

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who favour multiple semantic representations. It will be seen that, at the moment, it is not likely that the problem can be solved by simply accumulating empirical observations, as in both areas the competing hypotheses allow plausible accounts of the available results. The solution to these problems will be at hand when neuropsychological theories are sufficiently explicit to generate and empirically verify clear predictions, thus allowing choice between competing hypotheses. 6. Note that these two subjects might suffer from different disorders. DRC could not gain access to the fact system, and was forced to solve the problem by activating procedures normally used for more complex calculations; whereas, MW easily accessed the fact system, but frequently activated an incorrect fact.

7. A similar effect (better preservation of multiplication facts with smaller operands) has been reported in brain-damaged subjects by Sokol et al. (1991). 8. This effect, which was originally attributed to the size of the operands (problem-size effect, or operand-size effect), is now considered to result from the difficulty of the problem (problem-difficulty effect). In other words, it is now believed that solving problems with greater operands takes more time not because it is intrinsically more complex, but because these problems are less frequently encountered than those that include smaller operands (Ashcraft, 1992). The greater relative frequency of problems with small operands would result both in shorter reaction times in normals, and in lesser vulnerability of these problems to brain damage.

27 Neuropsychology of Emotions Guido Gainotti

of love inside or outside the area of emotions is much more problematic. A somewhat rough method, which may be effective enough for trying to differentiate more or less similar behavioural schemata, consists of identifying reference axes and, in relation to them, distinguishing the schemata that are part of the area of emotions from those that are not. A first reference axis could be the complexity and level of phylogenetic development of the behavioural schema in question. This axis could extend from the stage of simple reflexes to that of cognitive behaviour. On this axis the emotions are found at an intermediate level of complexity, differentiated on one side by reflex behaviours (such as sneezing or flinching), which are very simple, primitive and innate behavioural schemata; and on the other side by cognitive behaviours, with respect to which the emotions are distinguished by lesser complexity due to their automatic (rather than intentional) nature and because they are anchored to relatively fixed response patterns. A second reference axis might be based on the duration of the behavioural schema in question. This axis could range from very brief reactions (such as the reflex responses we have already mentioned) to long-lasting behavioural schemata,

WHAT ARE EMOTIONS? At first sight it may seem that the meaning of the word “emotions” is as clear as that of words like “perception,” “memory,” “language” and so on. If, however, we try to define the meaning of the word “emotions” precisely, identifying the semantic traits that define it and distinguish it from other rather similar words, we see that the boundaries of the concept of “emotions” are rather vague and indistinct. Most authors, in fact, agree in considering emotions as rather complex and more or less stereotyped behavioural schemata, characterised by a particular type of subjective experience and by a certain level of activation of the vegetative system. However, there is much less agreement over which behavioural schemata to include in this area and how to demarcate emotions from other behavioral schemata belonging to contiguous but different areas. To illustrate this point, we need only point out that two terms such as “anger” and “love,” commonly considered as very typical examples of emotions in the context of the current meaning of this term, have a different status for theorists of emotional behaviour. Anger is commonly considered one of the basic emotions, but the position 613

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which are stable over time. According to Ekman (1984), who attempted to analyse the problem with reference to this axis, emotions are reactions that last several seconds and are thus differentiated by affects (or personality traits) that have a much longer duration. Again according to Ekman (1977), the emotions are also characterised by the fact that they include motor components (such as body movements, facial expressions, or tone of voice), vegetative components (such as breathing or heartbeat frequency), and subjective components, that is, the type of experience that is often difficult to verbalise and constitutes the mark of the emotional experience. Other characteristics typical of emotions are the similarity with which they manifest in individuals of the same species and the possibility that they will be subject to control by phylogenetically more highly evolved systems, such as that responsible for cognitive behaviours which can inhibit, modulate, or simulate the emotional motor response in relation to social-type rules or motivations.

THEORETICAL AND APPLICATIVE ASPECTS The meaning of the emotional changes observed in patients affected by cerebral lesions is not as clear as the meaning of cognitive deficits that can be observed in the same patients. In fact, although a direct relationship is usually hypothesised between a lesion in a certain area of the cortex and onset of a certain type of cognitive deficit, the relationship established between the cerebral lesion and changes in emotional behaviour is generally much less direct. In fact, human emotions are much more complex than those of animals and much more interwoven with cognitive functions and with the personal meaning people attribute to events and situations. Therefore, it is understandable that a dramatic event such as a cerebral lesion can raise problems and trigger emotional reactions that depend more on the personal meaning the patient attributes to the consequences of the lesion than on the involvement of structures selectively implicated in emotionaltype functions.

However, the problem of the significance that must be attributed to an important emotional change cannot be neglected by the clinician, as the rehabilitative process can be markedly influenced by this change. Therefore, both the neurobiological and psychological aspects of the problem must be considered in a chapter dedicated to the neuropsychology of emotions; and even though more space has to be given to the theoreticalneurobiological aspects of cerebral organisation of emotions, it seems opportune to devote some attention also to the more psychological aspects of emotional behaviour in brain-damaged patients. Therefore, in the first part of this presentation the major characteristics of the emotional system will be explained, and considered in partial contrast and in partial integration with the cognitive system. In the second part, the neurobiological bases of emotional behaviour will be described, underlining the subcortical organisation of the mechanisms at the basis of this behaviour. In the third part— also the most extensive—we will see how this basic subcortical organisation is modulated in the human brain by two important aspects of neocortical development: 1. The distinction between anterior and posterior parts of the cortex. 2. The phenomena of hemispheric latéralisation. This aspect of the problem will receive particular attention as it has been the major interest of researchers in recent years, leading to the development of interpretative models, which are not easy to reconcile. Then, in the fourth and final section of this chapter, we will see how the emotional behaviour of brain-damaged patients is influenced by psychological, psychodynamic, and psychosocial factors as well as by neurobiological ones.

CHARACTERISTICS OF THE EMOTIONAL AND COGNITIVE SYSTEMS Many authors (for example Gainotti, 1989a, 1994; Leventhal, 1984; Oatley & Johnson-Laird, 1985,

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1987; Leventhal & Scherer, 1987; Scherer, 1984) have considered the emotional and cognitive systems as phylogenetically advanced adaptive systems based on the integrated work of many components. In fact, both the emotional and the cognitive system, must deal with information coming from the environment, select the most relevant stimuli, provide an appropriate response to these stimuli, and memorise the whole constituted by the stimulus, the response, and the result of this response. However, differences must be added to this structural analogy between the two systems in relation to the specific objectives of each of them and regarding all the components constituting the system. Moreover, these differences cannot be correctly evaluated without referring to the general logic of the corresponding system. Thus, before analysing the details of these differences, a description of the entire organisation and the specific aims of the emotional and cognitive systems seems necessary. The model proposed by Oatley and Johnson-Laird (1985, 1987) seems particularly interesting from this point of view. Starting from a perspective which is at the same time evolutionistic and computational, these authors proposed that to face a partially unexpected environment and to select the most adequate plan of action from among those available, the organism disposes of two operative systems: The emotional system, considered as an emergency system, able to interrupt the action occurring with an urgent procedure in order to be able to rapidly select a new operative scheme. • The cognitive system, considered as a more adaptive and evolved system, able to process much more plastic and varied plans, tending to harmonize the different variables intervening in the environment, but needing much more time to carry out its work.

•

According to Oatley and Johnson-Laird, the elementary and phylogenetically primitive emotional system bases its functioning on a certain number of modules (automata) that rapidly and automatically process a restricted number of signals and trigger an immediate response. The latter is

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selected from a small number of innate operative patterns, corresponding to the basic needs of the species in question. Intervening with an emergency procedure, this system is endowed with high priority, dominating and directing attention, just like executive systems, and making very probable the achievement of plans of action it has selected. The cognitive system, recent from a phylogenetic point of view, is, instead, based on more sophisticated modules and provided with a propositional structure which permits: 1. dealing with information in a thorough, controlled, and conscious way; 2. developing operative strategies which are as appropriate to external conditions as to information stored in memory. A schematic illustration of the major characteristics that associate and differentiate the emotional system from the cognitive one is presented in Table 27.1. The characteristics attributed by most authors to the emotional system, both in dealing with information and in selecting and implementing plans of action, are essentially in agreement with Oatley and Johnson-Laird’s (1985, 1987) interpretation of this system. Thus, with regard to dealing with information, almost all authors recognise that what is required to judge whether an external situation has dangerous or pleasant meaning for the individual can be, at least in some cases, global, rapid, and unconscious. This position is also shared by supporters of “cognitive” theories (such as Frijda, 1986, 1987; Mandler, 1980; Lazarus, 1982; Scherer, 1984); according to these authors, there can be no independence between emotional and cognitive behaviours because a cognitive evaluation is the necessary prerequisite for all forms of emotional experience. Equally general is the agreement about the individualisation of action schemata that should be activated by the evaluation of the emotional value of a stimulus. Authors of different orientations, such as Tomkins (1962), Izard (1971, 1977), Ekman (1977, 1984), Leventhal (1979, 1984), Scherer (1982, 1984), Frijda (1986, 1987), and Oatley and

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Johnson-Laird (1985, 1987) agree in recognising that these schemata: 1. are probably innate; 2. correspond to a small number of basic emotions, such as joy, sadness, fear, anger, surprise, and disgust; 3. reflect the most important interactive schemata of the human species at the communicative level or at that of proneness toward action. Thus, for example, laughter (joy) and crying (sadness) play a basic role in behaviours of attachment and collaboration, while anger and fear are as important in intra-species conflicts (linked to sexual choice, territorial defence, and constitution of social hierarchy) as in inter-species conflicts. Obviously, these considerations about dealing with information and response schemata typical of the emotional system refer above all to the simplest and most elementary emotions as well as to the more precocious phases of child development. Much more elaborated cognitive evaluations and much more flexible and differentiated behavioural schemata must naturally be taken into consideration when referring to complex emotions such as nostalgia, vanity, compassion, or remorse.

However, it should be noted that most authors consider these complex emotions as derived from the primary emotions just mentioned, following blends between more than one of them and interactions with increasingly complex situational schemata and cognitive evaluations. If this interpretation is correct, it becomes necessary to construct ontogenetic models that explain how complex emotions can be formed starting from simple ones and from interactions between the latter and the cognitive system. This type of developmental model was formulated by Leventhal (1979, 1980, 1984), who held that human emotions could derive from the activity of a hierarchical, multicomponent system based on the activity of three functional levels during which the emotional system becomes increasingly interconnected with (and in a certain sense, increasingly dependent on) the cognitive system. These functional levels are: (a) the sensorimotor level, (b) the schematic level, (c) the conceptual level. (a) The sensorimotor level consists of a set of innate and universal expressive-motor programs which include components of motor activation and vegetative activation, whose elicitation threshold depends on changes in the organism’s internal milieu and which are triggered

TABLE 28.1 Characteristics of the emotional and cognitive systems. Common characteristics

Adaptive, phylogenetically advanced systems, based on integrated work of components that must: (a) analyse information; (b) formulate responses; (c) learn and give a subjective (emotional) or objective (cognitive) meaning to stimuli.

Specific characteristics E m o tio n a l s y s te m

Emergency system. Must respond rapidly with a limited number of partially innate operative schemata to relevant stimuli for the basic needs of the individual. Based on conditioned automatic and unconscious learning. C o g n itiv e s y s te m

More complex adaptive system able to analyse situations more thoroughly and to respond to them with more plastic and varied schemata. Requires more time to process responses. Based on conscious, controlled declarative memory systems.

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automatically by a environmental stimuli.

certain

number

of

The basic aims of these programs include the predisposition toward a certain number of actions and interpersonal communication and, thus, the tendency to influence the proneness toward action of the person with whom one is communicating. For example, very precocious child-adult communicative interactions can be stabilised thanks to the expressive-motor reactions automatically triggered by social stimuli, such as the mother’s voice or the production of emotional facial expressions by the examiner (Field et al., 1982). Therefore, thanks to expressive-motor programs the subject is either predisposed toward the necessary action to resolve his or her problem or involves the persons who are meaningful for him or her, who can contribute to that solution. According to Leventhal, these primitive emotional reactions based on simple sensorimotor circuits act in a direct way only in the first stages of development and are successively incorporated, thanks to conditioning mechanisms, into true emotional schemata, typical of the second level of emotional processing. (b) The schematic level is based on the activity of schemata, that is, prototypes of emotional behaviour, formed (on the basis of conditioning processes) by the connection between innate programs, typical of the sensorimotor level and situations associated with these programs in individual experience. These schemata, constructed automatically during emotional situations linked to individual experience, are different for every individual and, thus, differ greatly from the expressive-motor programs typical of the sensorimotor stage, which are, instead, innate and universal. Leventhal conceives of these emotional schemata as syncretic memories containing the situation that sparked the emotion, the emotional response with its expressive, motor, and vegetative components, and the subjective experience during the emotional episode. The generalisation of schemata is due to the repetition of experiences in which more or less similar stimuli produced more or less

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superimposable emotional responses. Finally, the automatic activation of an emotional schema, accompanied by the evocation of all the subjective and expressive-motor components of the emotion, is the basis of what is typically experienced during spontaneous emotions and which constitutes the unmistakable characteristic of the emotion. (c) The conceptual level of emotional processing differs greatly from the schematic level due to a different type of learning (conscious rather than automatic and mediated by cognitive processes rather than by processes of conditioning) of emotional significance. The conceptual processes relative to emotions do not lead to memorisation of the concrete recollection of a situation typically linked to an emotional experience, but to the abstract and propositional notion of what emotions are, of which situations provoke them, and of how to respond correctly to these situations, in agreement with the norms of one’s social group. Therefore, the activation of these propositional representations of emotions does not accompany the experience of the corresponding emotions (as happens during activation of corresponding emotional schemata). Further, when an expressive-motor response is activated intentionally by this level, the aforementioned response is not felt as an authentic emotion by the subject, due to the absence of the subjective experience characterising the spontaneous emotional response. As the schematic and conceptual levels of emotional processing correspond respectively to the prevalence of the emotional system over the cognitive one and of the cognitive one over the emotional one, what we have said up until now regarding the mechanisms of learning at the base of the first and second levels leads us to another important difference between the emotional system and the cognitive one. The typical processes of memorisation of the emotional system are based on automatic and unconscious mechanisms of conditioning, while those typical of the cognitive system are based on conscious and controlled declarative memory processes.

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This also occurs when, as in the case of the conceptual level of emotional processing, the cognitive system takes the emotions themselves as the object of its own activity. We will conclude this section with a brief discussion of another important characteristic of the emotional system, a characteristic we mentioned in passing when speaking about the differences between schematic and conceptual level, that is, the specific quality of the emotional experience. Starting from the discussion of the nature of pleasure and pain initiated by Wundt ( 1896) at the end of the 19th century and more recently taken up by Arnold (1960), most authors currently recognise that pleasure and pain are elementary and irreducible forms of experience. The presence of pleasure or pain is what gives a specifically hedonic character to emotional experience. Further, as pleasure and pain are felt not only as internal sensations, but also as sources of attraction or repulsion respectively of objects or external situations, they are at the basis of that motivational amplification that confers such an important adaptive value to the emotional system.

THE ROLE OF SUBCORTICAL AND CORTICAL STRUCTURES IN THE SPONTANEOUS EXPRESSION AND CONTROL OF EMOTIONS Since the end of the 19th century a certain number of clinical observations and experimental results have demonstrated that several subcortical structures seem to play a basic role in the global evaluation of the emotional value of stimuli and/or in the production of an integrated emotional response; on the other hand, neocortical structures might exercise a tonic activity of modulation and control over these basic emotional mechanisms. For example, Goltz (1892) demonstrated that well integrated responses of anger can also be provoked in a decorticated animal; and Dusser de Barenne (1920) and Rothman (1923) observed that even stimuli with scarce emotional significance can trigger emotional reactions in these animals. In agreement with this experimental research on animals, anatomical-clinical observations carried

out on humans have shown that paroxysmal manifestations of laughter or uncontrollable outbursts of crying can be observed in patients with multiple lesions of the cortical-subcortical pathways. Just as in the manifestations of anger observed in the decorticated animals, these emotional explosions were also considered as being due to decreases in the inhibitory controls the cortex would normally exercise over the subcortical structures. A better definition of the subcortical structures involved in these basic emotional mechanisms was provided by Woodworth and Sherrington (1904) and by Bazett and Penfield (1922), who demonstrated that sections made below the mesencephalon eliminate these emotional reflex responses and that therefore the structures responsible for this emotional processing are located below the cortex and above the brain stem. Integrating these data with the results of Karplus and Kreidl (1909,1927), who showed that electrical stimulation of the hypothalamus produces an important activation of the ortho-sympathetic vegetative system (very greatly involved in aggression/flight behaviours), Bard (1928, 1929) proposed that the hypothalamus is the structure critically involved in the processing of these emotional behaviours. Clinical data supporting this hypothesis were successively reported by Foester and Gagel (1933) and by Alpers (1937), who showed that lesions limited to the hypothalamus can provoke emotional disorders and personality changes in humans. All these conceptions, although interesting and supported by clinical and experimental data, considered emotional behaviour as a unitary phenomenon, localised in well defined portions of the encephalon. A much more articulated hypothesis, compatible with contemporary models, which considers emotions as evolved adaptive systems based on the integrated work of various components, was advanced several years later by Papez (1937). The latter incorporated the preceding observations into an anatomical model of emotions which hypothesised that different components of human emotions may depend on different parts of the brain. According to this model, the hypothalamus, the anterior nuclei of the thalamus,

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the cingulate gyrus, the hippocampus and their interconnections constitute a harmonious and well defined anatomical circuit; their various components could serve to evaluate the emotional value of stimuli, to evoke the subjective experience of emotions, and to generate the corresponding expressive-motor responses. More precisely, Papez hypothesised that the hypothalamus might serve to attribute emotional value to sensory stimuli and to provoke the corresponding vegetative and expressive-motor responses, while the cingulate cortex (which constitutes the cortical component of the circuit) might be involved in processing the subjective experience of emotions. Papez also proposed that sensory information coming from the external environment might follow two different routes to reach the hypothalamic structures, where it might receive its emotional significance. The first route could originate in the cortical association areas, where the information undergoes complex and elaborate perceptual and cognitive processing. Instead, the second route might send directly to the hypothalamus raw and poorly processed data coming from the relay nuclei of the thalamus, which skip the stage of cortical processing (Fig. 27.1). From the anatomical point of view, by shunting the projection and association cortical areas, this second route could account for the qualitative

FIGURE 27.1

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characteristics of speed, automaticity, and holistic processing we considered as typical of the emotional treatment of information. In spite of the merits of this model, a great deal of research conducted successively on the neurobiological aspects of emotions has pointed out the need to introduce important changes; in particular (on the basis of both anatomical and experimental-type considerations) the preeminent role played by the amygdala in emotional behaviour. The anatomical considerations derive from the thorough analysis of circuits existing within the limbic system and, in particular, from the distinction, proposed by Yakovlev (1948) and developed by Livingston and Escobar (1971) between a medio-dorsal circuit and a baso-lateral circuit. The medio-dorsal circuit, corresponding to the circuit originally described by Papez, is centred on the hippocampus and is currently considered as particularly involved in memory (mnesic)- type functions, and not in emotional ones (in this regard see Chapter 15 of this volume). On the contrary, the baso-lateral circuit, centred on the amygdaloid nucleus and including the connections of this nucleus with the ventro-medial hypothalamus, the dorso-medial thalamus, the frontal-orbital cortex, and the temporal anterior cortex, is much more involved in emotional-type functions. Schematic representation of the Papez circuit and of the cortical and subcortical routes (represented by arrows) which might be used by visual information to reach the hypothalamic structures where they could acquire emotional significance. C.C.: Corpus callosum; Cing.G. = Cingulate gyrus; Fo.=Fornix; M.B.=Mammillary bodies; A.Th.=Anterior thalamus; E.C.=Entorinal Cortex; Hipp.=Hippocampus; Vis.Th.=Visual thalamus; Vis.C.=Visual cortex; Hy.=Hypothalamus.

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Experimental considerations, instead, are based on the observation that stimulations of the amygdaloid nucleus provoke manifestations of anger or fear in the animal, while the destruction of these same structures leads to a clear-cut decrease in aggressive tendencies (see LeDoux, 1987 and Doty, 1989b for critical reviews of the problem). Finally, a certain amount of clinical and experimental data seem to indicate that the amygdala (and not the hypothalamus, as Papez suggested) is the structure where information coming from the outside world acquires emotional significance. The most clear-cut clinical finding in favour of this hypothesis is the report of people suffering from bilateral amygdala damage, who have lost the capacity to recognise emotions from facial expressions, though remaining able to recognise the identity of previously familiar faces (Adolphs, etal., 1994; Calderetal., 1996; Young et al., 1995). Even if in these patients only the recognition of some emotions (in particular fear) was severely affected, and even if Hamann et al. (1966) failed to confirm these observations in two more cases of bilateral amygdala damage, these results suggest that the amygdala could play a critical role in recognising the facial expression of basic emotions. The anatomical and experimental data consistent with the hypothesis that the amygdala may be crucially involved in tasks of crude emotional recognition are more numerous and perhaps more interesting because they provide convincing empirical support for Papez’s purely speculative hypothesis, according to which the evaluation of the emotional value of a stimulus could be made both by a cortical route and a purely subcortical one. From an anatomical point of view, the existence of

Schematic illustration of the fibre bundles composing the baso-lateral circuit of the limbic system and of the cortical and subcortical routes through which visual information could reach the amygdaloid nucleus, where it might receive emotional meaning. F.P.=Frontal pole; O.P.=Occipital pole; T.L=Temporal lobe; O.F.C.=Orbito-frontal cortex; T.R=Temporal pole; S.T.=Stria Terminalis; V.M.Hy.=Ventromedial hypothalamus; D.M.Th.=Dorso-Medial thalamus; Vis.Th.=Visual thalamus; Vis.C.=Visual cortex; Am.=Amygdala.

subcortical routes able to directly reach the amygdala (or the hypothalamus) without preliminary processing of sensory data at the cortical level was confirmed by Ebner (1969), Veening (1978), Russchen (1982), and LeDoux et al. (1984, 1985). These authors showed that relay nuclei in the thalamus and metathalamus project not only on primary cortical areas (visual, auditory, and somesthetic) but also on the hypothalamus and on the amygdaloid nucleus. A schematic illustration of the fibre bundles composing the baso-lateral circuit of the limbic system and the cortical and subcortical routes through which visual information could reach the amygdala (where it would acquire emotional meaning) is presented in Fig. 27.2. From the experimental point of view, LeDoux et al. (1984, 1985, 1986), using a classical conditioning method to associate auditory stimuli with a fear response, showed that this conditioned emotional response is linked more to the direct

FIGURE 27.2

27.

thalamo-limbic projections than to the integrity of the thalamo-cortical pathway. The bilateral destruction of the most important subcortical nuclei of acoustic relays (medial geniculate body and inferior colliculum) was in fact able to interrupt emotional conditioning, while the bilateral destruction of cortical auditory areas did not have the same effect. According to these authors, the establishment of a conditioned emotional response to auditory stimuli depends on the connections existing between the medial geniculate body and the amygdaloid nucleus and not on the cortical processing of auditory data. Besides confirming the existence of a subcortical route through which sensory data can acquire emotional value, Le Doux et al.’s (1984, 1985,1986) results strongly agree with Leventhal’s (1979, 1980, 1984) hypothesis that a conditioning mechanism plays a basic role in the constitution of the schematic level of emotional processing. Anatomical data, experimental results, and theoretical models agree, therefore, in recognising that the most elementary and spontaneous components of emotional behaviour are initially inscribed in subcortical structures and that they use primarily subcortical structures and routes to progressively create a spontaneous system of emotional processing. On the other hand, the cortical structures surely become increasingly more important during the individual’s cognitive and social development, as this development is incompatible with an automatic and uncontrolled activation of basic emotional programs and tends to substitute responses based on simple conditioning with responses based on thorough, conscious, and controlled evaluations. Cortical structure supervision of subcortical structures of emotional processing regards both the treatment of information with potential emotional value and the control of basic expressive-motor programs. Considering the social efficacy of these programs and therefore their potential constructive and destructive value, it is logical that access to them is subordinate to a cognitive analysis, which is much more subtle and thorough than that allowed by the subcortical pathways. On the other hand, the cortical control structures, besides inhibiting emotional responses that tend to

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emerge outside an appropriate social context, also tend to use expressive emotional programs to communicate by including them in the set of communicative abilities which can be used in different situations involving social interaction.

CORTICAL REGULATION OF THE BASIC MECHANISMS OF EMOTIONS The development of the process of telencephalisation, that is, of migration toward the cortex of functions which prior to cortical development had their operative vertexes at the diencephalic level, leads to a profound reorganisation of the emotional system. This functional reorganisation includes the following: 1. Increasing integration of the emotional system with the cognitive one. 2. Representation at the cortical level of the functional system reorganised in this way. 3. Development of functions of control so that systems of voluntary movement inhibit (or intentionally use) the expressive motor programs of the emotional system. Following this overall transformation, the small number of automatic and primitive reactions that constituted the operative nucleus of the basic emotions are integrated into a complex set of values and norms, giving rise to the rich and varied repertoire of human emotions. Not all of the neocortical structures seem to be involved equally in this process of reorganisation, as some types of cerebral lesions seem to disturb emotional behaviour more than others. In particular, the neuropsychology of emotions has suggested the usefulness of distinguishing two major axes in the study of the cortical organisation of emotions: • An anterior-posterior axis, as the frontal lobes seem to play a much more important role than the posterior parts of the encephalon in the functions of emotional control. • A transverse axis, as many clinical and experimental data seem to show a different

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involvement of the two cerebral hemispheres in the processing of emotional behaviour. The first of these dichotomies is the most classical and the most easily explicable in terms of the anatomical connections between the limbic system and the frontal lobes; but it is the second one that has held the attention of neuropsychologists most in recent years. Therefore, we will first deal briefly with the problem of the relationships between emotions and frontal lobes and then, more thoroughly, with the relationships between emotions and hemispheric latéralisation.

Emotions and the frontal lobes The hypothesis that assumes that the frontal lobes play a critical role in the control of emotional behaviour and that frontal lesions can give rise to major emotional disorders or to obvious personality changes probably goes back to Harlow’s (1868) classical description of the changes observed in his patient, Phineas Gage, following a serious traumatic lesion of the frontal lobes. According to Harlow, this patient, who was described as a balanced and dynamic man before the trauma, primarily interested in work and family, “was no longer Gage” after the frontal lesion: “The balance between his intellectual faculties and his animal propensities seems to have been destroyed. He has become inconstant, irreverent, unable to accept advice or restrictions that contrast with his desires. A child in his manifestations and intellectual abilities, he has the animal passions of a vigorous man.” (Harlow, 1868, p.335) Although many authors later doubted the specificity of this description (which emphasises the difficulties of emotional control in patients with frontal lesions), the link between frontal lesions and emotional disorders has been confirmed by both clinical studies and anatomical and experimental research. From the structural point of view, Nauta (1971) pointed out two characteristics of the anatomical connections of the frontal lobes which could explain their importance in the modulation and control of emotional behaviour. The first consists of the importance of the reciprocal connections linking the frontal lobes to the

structures of the limbic system; the second of the convergence in the frontal lobes of information coming from the external environment (through pathways of association with the visual, auditory, and somesthetic areas) and from the internal environment (through connections with the hypothalamus and with various structures of the limbic system). Precisely because of the importance of the connections linking the limbic system with the frontal lobes, Nauta considered the latter as “neo-cortical representatives of the limbic system” and proposed that their function is the modulation and control of emotional mechanisms supported by the limbic system. On the other side, the convergence of information in the frontal lobes coming from both outside and inside the organism leads one to think that a lesion in this area could dissociate the cognitive evaluation of environmental situations from the concomitant emotional experience. This lack of integration could explain not only the development of inappropriate social and emotional behaviour, but also the inability to foresee, which is so typical of frontal lesions. In order to foresee the consequences of one’s actions it is, in fact, necessary to link external changes with the internal ones provoked by one’s own actions at the representative level; but this synthesis could be made impossible by a frontal lobe lesion. Very relevant experimental research regarding the problem of relationships between frontal lesions and social and emotional behaviour disorders was carried out at the beginning of the 1970s by Myers et al. (Frazen & Myers, 1973; Myers, 1972; Myers et al., 1973). In natural observation conditions, these authors studied the behaviour of monkeys (macaques) that had been captured, submitted to a frontal or parietal-occipital lobectomy, and then rapidly reintroduced into their social group of origin. Various aspects of their social behaviour (communicative and interactive), including maternal behaviour, were seriously altered by the frontal lobectomy, although analogous perturbations were not caused by a parieto-occipital lobectomy. For example, almost all animals that had undergone the frontal lobectomy showed a great reduction of threatening gestures, submissive behaviour, or facial emotional

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expressions or vocalisations with emotional significance in a social context. Some animals did not even try to re-establish contact with the social group they belonged to and remained alone or disappeared into the forest. Finally, females with young offspring ignored them in the laboratory or abandoned them after returning to their natural environment. Comparing the results of this experimental research with results of clinical studies regarding emotional, social, and behavioural disorders in patients with frontal lesions, important analogies (and also differences) can be noted due to the greater variety and heterogeneity of the disorders presented by these patients. Some patients are striking, in fact, because of their absence of tact and inhibitions, which manifests with a tendency toward inappropriate familiarity, peppered with coarse puns, often with sexual content. Other patients primarily show a lack of initiative and spontaneity, with apathy, abulia, and bradypsychism on the action plane, and poverty of emotional expressions at the mimicry or vocal level on the social interaction plane. Still other patients appear capricious, unstable, and egocentric, showing indifference toward the problems and difficulties of persons they interact with. A part of this heterogeneity is probably due to the patient’s pre-morbid personality and to the diversity of etiologies (traumatic, tumoral, vascular, etc.) giving rise to a lesion in the pre-frontal areas. On the other hand, a significant part of this variability is probably due to the intra-lobar position of the lesion, as the frontal lobes constitute a large portion of the whole cerebral cortex and as it is possible to distinguish well defined areas in them in terms of connections and, thus, functional specialisation. A clinical distinction proposed originally by Kleist (1934a) and Kretschmer (1956) and taken up more recently by Blumer and Benson (1975) contrasts, for example, emotional disorders and behaviours produced by extensive lesions of the dorso-lateral areas (hemispheric convexity) with those provoked by lesions of the fronto-orbital cortex. In the first case apathy, abulia, lack of motivation, and the inability to foresee are most prominent, whereas in the second case, the symptomatology is characterised above all by the tendency toward puns

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(Witzelsucht), infantilism, disinhibition, and by lack of interest in others. Blumer and Benson (1975) proposed calling the first type of functional disorders “pseudo-depression” and the behaviour of patients with lesions of the frontal-orbital areas, “pseudo-psychopathic”. In recent years, Damasioetal. (1990,1991)have more thoroughly investigated the behavioural consequences of damage to the fronto-orbital areas (or, more in general, to the ventro-medial parts of the frontal lobes). These authors have shown that patients with lesions of the fronto-orbital region acquired in adulthood can develop a striking change in social behaviour, apparent in conditions of daily living but contrasting with apparently intact cognitive functions and even with a good capacity to give verbally appropriate evaluations of emotional, social, and ethical problems. According to Price et al. (1990) and to Eslinger et al. (1992) a similar kind of developmental social learning disability can occur when the same type of lesion is acquired in childhood. According to Damasio et al. (1990, 1991), the mechanism underlying the socially abnormal behaviour of patients with ventral frontal lobe damage could consist of a defect in the activation of the “somatic markers” (i.e. of the vegetative afferences) which provide the individual with a conscious “gut feeling” of the merits of a given response. Recently, more specifically neuropsychological research aimed at evaluating the influence of frontal lesions on well defined components of emotional behaviour has supported these clinical studies which have primarily analysed behaviour disorders and personality changes resulting from frontal lesions. Almost all of this research has studied the ability of patients affected by lesions localised in the anterior or posterior portions of the brain to produce or to understand emotional facial expressions. For example, some authors have studied the facial expressions produced spontaneously by patients during neuropsychological trials (Kolb & Taylor, 1981; Weddel et al., 1988) or in response to emotional stimuli (Borod et al., 1985; Mammucari et al., 1988). Other authors have studied the ability of these patients to intentionally produce emotional facial expressions (Caltagirone et al., 1989b; Weddel et al., 1990). Still others have examined the

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ability to understand the emotion expressed on a face (Borod et al., 1986; Prigatano & Pribram, 1982). Overall, this research has confirmed the role played by the frontal lobes in the spontaneous or intentional production of emotional expressions (Borod et a l, 1985; Kolb & Taylor, 1981; Weddel et al., 1988, 1990) and has provided contrasting results regarding the comprehension of emotional facial expressions. According to several authors (for example, Kolb & Taylor, 1981; Prigatano & Pribram, 1982) a lesion of the frontal lobes does not significantly influence the ability to understand emotional expressions, but according to others (for example, Hornaketal., 1994; Weddel, 1989,1994) frontal lesions affect not only the production but also the comprehension of emotional expressions. It must also be said that the greatest disorders of emotional comprehension have been observed in patients with extensive bilateral frontal lesions (Prigatano & Pribram, 1982; Weddel, 1989, 1994) and that the influence of frontal lesions becomes much less significant when these patients are excluded from surveys. However, the problem is still open because, according to Rolls et al. (1994), the inability to understand emotions expressed by others plays an important role in the origin of emotional disorders in patients with lesions of the orbital frontal cortex.

Emotions and hemispheric latéralisation The first clinical observations suggesting the existence of a relationship between emotions and hemispheric latéralisation were made by chance at the end of the 1950s by Italian authors during trials of pharmacological inactivation of one of the two cerebral hemispheres; a quick-acting barbiturate (sodium amytal) was injected into the right or left carotid. First Terzian and Cecotto (1959) and then Alemà and Donini (1960) and Perria et al. (1961) noted that the pharmacological inactivation of the left hemisphere is often followed by a “depressivecatastrophic” reaction, while inactivation of the right hemisphere can give rise to “euphoric or hypomaniacal” reactions. These authors attributed the “depressive-catastrophic” reactions to the inactivation of a “centre for positive emotions” located in the left hemisphere and the euphoric reactions to the inactivation of an analogous “centre

for negative emotions” located in the right hemisphere. This general interpretation, postulating the existence of two neuronal structures responsible for the negative and positive aspects of the hedonic experience, in dynamic equilibrium and located respectively in the right and left hemispheres, was successively taken up again and developed by other authors. Data supporting this interpretative model were obtained by Dimond and Farrington (1977), Sackheim and Gur (1978), Ahern and Schwartz (1979), Reuter-Lorenz and Davidson (1981), Natale et al. (1983), Reuter-Lorenz et al. (1983), and Davidson and Tomarken (1989) in research carried out on normal subjects; and by Sackheim et al. (1982) in a retrospective study of the relationships existing between hemispheric latéralisation of an irritative or destructive lesion and positive or negative tonality of paroxysmal emotional manifestations observable in these patients. However, most of the authors who have tested this hypothesis experimentally in both normal subjects and brain-damaged patients have obtained data that contrast the basic assumptions of this interpretative model. As it is easier to contrast the positive and negative components of the emotional experience at the level of mimicry (or vocal) expression of emotions, most of this research has studied the problem using methodologies that tend to evaluate the comprehension or production of positive or negative expressions (vocal or facial mimicry). In research conducted on normal subjects by Suberi and McKeever (1977), Campbell (1978), Ladavas et al., (1980), Strauss and Kaplan (1980), Strauss and Moscovitch (1981), Heller and Levy (1981), Hirschmann and Safer (1982), Moscovitch and Olds ( 1982), Duda and Brown ( 1984), Gage and Safer (1985), Wylie and Goodale (1988), Moreno et al. (1990), and Wittling (1990), the monohemispheric treatment of emotional information was studied both in the visual modality (lateralised tachistoscopic presentation) and in the auditory modality (dichotic listening or lateralised auditory presentation) and the hemispheric asymmetries on the executive side were studied primarily by comparing the emotional expressiveness of the two halves of the face.

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On the other hand, in research conducted on brain-damaged patients the influence of unilateral hemispheric lesions on comprehension and expression of positive and negative emotions was evaluated, comparing the ability of patients with right and left cerebral lesions to recognise or express emotions both with voice (emotional prosody) and with facial expressions (Borod et al., 1986; Bowers et a l, 1985; Etcoff, 1984; Gainotti, 1989b; Kolb & Milner, 1981a; Mammucari et al., 1988). Overall, the results obtained with these lines of research, rather than confirming the hypothesis of a different specialisation of one of the cerebral hemispheres for the positive and negative aspects of the hedonic experience, seem to indicate a general superiority of the right hemisphere for both comprehension and expression of emotions. Although these conclusions do not confirm the hypothesis of different hemispheric latéralisation for positive and negative emotions, they are in agreement with another general interpretation of the relationships between emotions and hemispheric latéralisation proposed by Gainotti (1969, 1972b, 1983a) following analyses of emotional behaviour of patients affected by unilateral hemispheric lesions. First, this author underlined the analogies existing between his clinical observations and the description of emotional behaviours observed after the injection of amytal in the right and left carotid; however, after a finer-grained analysis he noted that the differences between right and left brain-damaged patients seem more traceable to the distinction between “catastrophic reaction” and inappropriately “indifferent” behaviour than to the opposition between euphoria and depression. Patients with left hemispheric lesions, and in particular those with serious Broca’s aphasia, often showed increasing manifestations of anxious disorganisation with frequent crying spells during neuropsychological examination; but these “catastrophic reactions” were almost always triggered by serious difficulties with verbal expression or by the impossibility of making use of the right hand in graphic or praxic-type trials. Therefore, it seems more reasonable to consider these manifestations as dramatic, but psychologically appropriate, forms of reaction to a

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catastrophic situation than to attribute them to a shift in mood tone toward depression for purely biological reasons. On the other hand, patients with right hemispheric lesions did not seem truly excited or euphoric, but rather indifferent to their illness and to the frustrating situations caused by the neuropsychological examination. Furthermore, these patients showed other paradoxical or contradictory behaviours such as the tendency to make jokes or puns, coexisting at times with exaggerated or caricatural expressions of hostility or rejection of paralysed limbs. Overall these behaviours, rather than suggesting a shift toward euphoria in mood tone, seem to indicate an abnormal and inappropriate emotional reaction to the personal consequences of the cerebral lesion. To explain the contrast between the dramatic but psychologically appropriate reaction of patients with left hemisphere lesions and the paradoxical indifference of patients affected by right lesions, Gainotti (1972b) advanced the hypothesis that the right hemisphere may play a critical role in the processing of emotional behaviours. According to this hypothesis, the emotional reaction is appropriate when the right hemisphere is intact; while it may be absent or inappropriate when a serious lesion of the right hemisphere inactivates the portions of this hemisphere involved in the processing of emotional behaviours. Components o f emotional behaviour that seem more closely connected with the functional organisation o f the right hemisphere In the preceding section we saw that most research that has studied hemispheric asymmetries in the comprehension and expression of emotions has revealed a general superiority of the right hemisphere for both positive and negative emotions. Overall these results have led several authors to hypothesise that the functional specialisation of the right hemisphere concerns the communicative aspects of emotions (or perhaps all nonverbal communicative activities) more than the processing of emotional behaviours. Following this line of thought, Ross (1981, 1984) and RuckdeschelHibbard et al. (1984) proposed that in the area of

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nonverbal communication the right hemisphere may have a superiority analogous to that shown by the left hemisphere for linguistic-type tasks. Data obtained by Blonder et al. (1991, 1993) on braindamaged patients seem to confirm this hypothesis, which gives a different interpretation to the indifference of right brain-damaged patients than the one proposed by Gainotti. According to this interpretation, the manifestations of indifference of patients affected by right hemispheric lesions should not be considered as inappropriate forms of reaction to illness, but as the consequence of an inability to correctly express and communicate an otherwise intact emotional reaction. The impression of indifference given by these patients could therefore be due to an inability to express anguish and apprehension, and not to an inappropriate emotional reaction to a dramatic event they recognise. If this interpretation is correct, the emotional experience and the vegetative components associated with it should be adequate to the event in these patients, as their apparent indifference would essentially be due to an inability to express emotion. However, in recent years, a series of studies carried out on patients with unilateral hemispheric lesions has seriously invalidated the hypothesis that the right hemisphere is critically involved in nonverbal communication tasks rather than in the spontaneous processing of emotions. This research can be subdivided into three relatively homogeneous groups: 1. The results of research that seem to indicate that the superiority of the right hemisphere in tests of comprehension and expression of emotions has probably been overestimated in preceding investigations, belong to the first group. Gainotti (1989b), Weddel (1989), and Young et al. (1993), for example, did not obtain significant differences between right and left braindamaged patients in recognition of emotional facial expression tasks, and analogous results were obtained by Bradvick et al. (1990) in an emotional tone recognition task where several verbal expressions were uttered with different emotional prosody. Similar results were obtained on the expressive side by Mammucari

et al. (1988) studying the spontaneous facial expressions provoked by the presentation of films with high emotional valence; by Caltagirone et al. (1989b) and by Weddel et al. (1990) studying the voluntary production of emotional facial expressions; by Bradvick et al. (1990) studying the ability to intentionally express emotions by means of vocal emotional prosody. 2. Instead, research studying the vegetative response (psycho-galvanic reflex, heart rate, etc.) to emotional stimuli in patients with lateral hemispheric lesions (Caltagirone et al., 1989c; Heilman et., 1978; Meadows & Kaplan, 1994; Morrow et al., 1981; Yokoyama et al., 1987; Zoccolotti et al., 1982, 1986) belongs to the second group. All of this research has systematically shown a decrease in psychophysiological responses to emotional stimuli in patients with right hemispheric lesions, in agreement with the results obtained in normal subjects by Wittling (1990) using a technique of lateralised projection of films with high emotional valence. In this research, the blood pressure changes induced by the emotional stimulus were greater during the presentation of the film to the right hemisphere than during lateralised projection to the left hemisphere. All of these data obtained in normal and brain-damaged subjects lead one to think that the interhemispheric differences are not located only (or primarily) at the level of cognitive and communicative components of emotional behaviour, but also at a much more elementary level, such as that of vegetative response and probably also at the level of the concomitant subjective experience (Hohmann, 1966; Schachter, 1975). 3. Research carried out with normal subjects or brain-damaged patients suggesting that the concomitant subjective experience to the presentation of emotional stimuli is linked more to the right than to the left hemisphere, belong to the third group. Evidence gathered in brain-damaged subjects is indirect and (besides indifference to illness

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and to frustrating situations, which we have already mentioned) consists of an unexpected observation made by Mammucari et al. (1988) in their study on expressive facial reactions to the presentations of films with high emotional tonality. These authors noted that during the projection of a very unpleasant film (of a rather bloody surgical scene) the normal subjects and the patients with left hemispheric lesions generally tended to look away from the screen, while subjects with right hemispheric lesions did not feel the need to look away. Mammucari et al. (1988) hypothesised that left braindamaged and control subjects tend to look away from the screen because the crude scene makes them anxious, while patients with right hemispheric lesions do not show analogous behaviour because they are less emotionally involved and thus more indifferent to the emotional situation. Caltagirone et al. (1989c) checked this hypothesis, studying the relations between presence of avoidance eye movements and changes in heart rate, both in normal subjects and in patients with unilateral brain lesions. The hypothesis was confirmed because in control subjects and in patients with left lesions the decrease in heart rate was significantly linked to the presence of avoidance eye movements, while in patients with right lesions the changes were very slight and were not linked to the presence of avoidance movements. The evidence obtained in normal subjects by Wittling and Roscmann (1993) is more direct; these authors showed films with emotional content to the right and left hemisphere, evaluating the concomitant subjective experience both during and at the end of the projection of the films. With both modalities of evaluation the authors documented a more intense emotional experience during presentation of films to the right hemisphere than during lateralised projection to the left hemisphere. Therefore, in conclusion, the results of research conducted with both brain-damaged patients and normal subjects have indicated that the right hemisphere is critically involved not only in tasks of emotional communication, but also (and

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probably above all) in the generation of the vegetative components of the emotional response and of the concomitant subjective experience of emotions. The left hemisphere and functions o f control o f emotions Up until now in our discussion of the relationships between emotions and hemispheric specialisation we have focused our attention on the right hemisphere and on the components of emotional behaviour that may depend primarily on this half of the brain. However, it should not be thought that the left hemisphere plays a marginal role in emotional behaviour or that only a quantitative difference exists between a “more emotional” right hemisphere and a “less emotional” left hemisphere. Actually, some data seem to indicate that the two halves of the brain play a complementary role in emotional behaviour, the right hemisphere being involved primarily in basic vegetative components and the left hemisphere in functions of emotional control. Making reference to Leventhal’s (1979, 1980, 1984) conceptualisation and terminology, it can be hypothesised that the right hemisphere preferentially subserves the “schematic level” and the left hemisphere the “conceptual level” of emotional processing. Three groups of apparently independent data seem to support the hypothesis of a critical role of the left hemisphere in functions of emotional control. First, the observation that patients with lesions of the anterior parts of the left hemisphere at times show an excessive level of emotional reactivity which renders them at least in part similar to patients with multiple lesions of the cortical-subcortical pathways. This analogy has already been pointed out by Gainotti (1972b, 1983a), who noted that the sudden crying spells of patients with Broca’s aphasia in some ways resemble (for example, in their low triggering threshold and their dramatic, but transitory aspect) the paroxysmal outbursts of crying in patients with a pseudo-bulbar syndrome. Recently, this clinical impression was checked more thoroughly by House et al. (1989) who studied the manifestations of hyperemotivity in a group of stroke patients. These authors showed that sudden episodes of unpredictable and uncontrollable

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outbursts of crying were often observed in patients with anterior left lesions, suggesting that the anterior parts of the left hemisphere may play a critical role in functions of control of emotions. Second, results of research studying the vegetative response and in particular the electrodermal response (psycho-galvanic reflex), to emotional stimuli in brain-damaged patients have sometimes (for example, Heilman et al., 1978; Meadows & Kaplan, 1994) shown increased vegetative reactivity in left brain damaged compared with controls. Even if these data have not been confirmed by other authors (for example, Caltagirone et al., 1989c; Morrow et al., 1981; Zoccolotti et al., 1986) they may suggest that at least in certain groups of patients with left hemispheric lesions, the decrease in cortical controls is manifested not only by an accentuation of the expressive behavioural response, but also by an increase in the vegetative response to emotional stimuli. Finally, a third group of data, which may be compatible with the hypothesis of left hemisphere dominance in the voluntary control of emotional facial expressions, regards the difference between the right and left halves of the face in the production of positive and negative emotional expressions. In the neuropsychological literature dealing with this problem, there is a contrast between a majority of research showing greater expressivity of the left hemiface for all types of emotions and a minority of research showing greater expressivity of the left hemiface for negative but not for positive emotions. Results in favour of the latter point of view have been reported, for example, by Sackheim and Gur (1978), G.E. Schwartz et al. (1979), and Borod and Caron (1980) who showed greater expressivity of the left hemiface (with respect to the right) only for negative emotions, but not for smiling or other positive emotions. These data have generally been discussed in the context of a hypothesis assuming a different functional specialisation of the two cerebral hemispheres for positive and negative emotions, but Etcoff (1986) rightly noted that there are other possible interpretative contexts. In fact, smiling differs from other emotional facial expressions not only because of the positive

polarity of the emotion it usually expresses, but also because it represents the most easy “emotional” facial expression to reproduce voluntarily, and the most currently used for approach and for social communication. A dominance of the left hemisphere in the intentional control of expressive facial apparatus could therefore counterbalance the greater “natural” expressivity of the left hemiface which is due, as we have seen, to a general superiority of the right hemisphere in the spontaneous expression of emotions. This same difference between right and left half-face in the expression of positive and negative emotions was interpreted by Buck (1984) and Rinn (1984) in a model that underlines even more than we have the possible dominance of the left hemisphere for functions of control of emotional expressivity. According to these authors the greater asymmetry between the left and right half-face in the expression of negative emotions could be due to the greater inhibition exerted by the left hemisphere on the right hemiface in the clear expression of these emotions, which are not socially communicable. Instead, smiling presents a lesser degree of asymmetry because it is not subject to this inhibition by the left hemisphere. Therefore, both our interpretation and the one proposed by Buck (1984) and by Rinn (1984) recognise that a superiority of the left hemisphere in the control of structures involved in the facial expression of emotions could explain the difference between the levels of facial asymmetry revealed in the expression of positive and negative emotions. Factors that might explain the complementary role o f the two cerebral hemispheres in emotional behaviour Results of research conducted on both normal subjects and brain-damaged patients suggest that the two halves of the brain play a complementary role in emotional behaviour. The right hemisphere seems to be involved primarily in the functions of spontaneous processing of emotions, corresponding to Leventhal’s schematic level of emotional processing, in which subjective experience and vegetative components of the emotional response play an important role;

27. NEUROPSYCHOLOGY OF EMOTIONS

the left hemisphere seems to play a critical role in the intentional control of the structures involved in emotional expression. It might be tempting to look for analogies between the role played by the two halves of the brain in the processing of emotional behaviours, the hierarchical organisation of the functional levels classically attributed to the cortex and the subcortical structures, and the distinction between emotional system and cognitive system. From this point of view it could be said that the right hemisphere is involved primarily in the basic aspects of emotional behaviours (classically attributed to the subcortical formations of the limbic system), while the left hemisphere plays a prominent role in the functions of regulation and control of emotional response, typical of the more phylogenetically evolved neocortical structures. Naturally this does not mean that the anatomical organisation of emotional behaviour is different in the two halves of the brain, with a primarily subcortical representation in the right hemisphere and a primarily cortical one in the left hemisphere. A more plausible interpretation might be to suppose that in the right hemisphere the processing of emotional behaviour maintains the characteristics of immediate and spontaneous reactivity typical of the subcortical structures of the limbic system. On the contrary, the type of emotional processing observed in the left hemisphere (where the functions of control of emotional expression seem to play the major role) could be due to the emergence of a propositional language in this hemisphere and of changes produced by language in other important functional control systems, such as the functions of intentional orientation of attention or the functions of voluntary programming of behaviour. Given that many authors (for example Bear, 1983; Buck, 1984; Gainotti, 1972b, 1983a) have already speculated over this topic, it does not seem useful to dwell further on it here. However, it should be noted that from this point of view the different roles played by the two halves of the brain in emotional behaviour could be considered a consequence of the profound reorganisations provoked by the progressive emergence of language in the human brain.

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EMOTIONAL DISORDERS IN BRAIN-DAMAGED PATIENTS The main factors responsible for the emotional and behavioural disorders of brain-damaged patients can be schematically subdivided into three categories: 1. Specifically neurological factors. 2. Psychological or psychodynamic factors. 3. Psychosocial factors. Included in the first category are those disorders that depend directly on the disorganisation of the structures underlying cerebral representation and mechanisms of emotional control. In the second category are those attitudes (more or less adaptive) the patient assumes about his/her own disability; they depend on awareness of the deficit and consequences in relation to psychological well being of the patient with a cerebral lesion. Finally, in the third category are all the problems created by the disability in the patient’s work activity and social relations; problems also involving family members (or the persons caring for the patient).

Neurological factors The emotional and behavioural disorders included in this category depend on the disorganisation of the limbic system or systems linked to it. Clinical and neuropathological data suggest that of the various categories of patients subjected to neuropsychological examination, the ones with closed head injuries show the most direct relationship between anatomical site of the lesion and emergence of emotional and behavioural disorders. In these patients, and in particular in those who have had a typical acceleration-deceleration type of road accident, the lesion primarily involves the axial structures of the brain and the medio-basal portions of the frontal and temporal lobes (Grcevic, 1988; Langfittetal., 1986). The clinical equivalent of this lesional localisation, primarily in the limbic system, consists of a clear prevalence of emotional disorders and personality

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changes with respect to sensorimotor deficits in long-term sequelae of head injury patients (Brooks & McKinlay, 1983; Thomsen, 1984). The direct dependence of these disorders on the limbic structure lesion, rather than on psychological factors linked to the brutality of the trauma and to the awareness of the disability that might possibly remain, is demonstrated by studies comparing long-term sequelae of serious head injuries with those of serious spinal cord injuries. Personality changes and psychosocial problems are, in fact, much greater in head injury patients than in patients with spinal cord lesions, in spite of the analogies between the two groups regarding the epidemiology and dynamics of the trauma and the much greater degree of physical disability shown by patients with spinal cord lesions (Stambrooketal., 1991). A second morbid condition in which a direct relationship between emotional disorder and damage to specific cerebral structures has been hypothesised is the so-called “post-stroke depression”. This clinical entity refers back at least in part to the depressive-catastrophic reactions we mentioned in the previous discussion of relationships between emotions and hemispheric latéralisation. In fact, we noted in the previous section that: 1. Severe depressive-catastrophic reactions are often presented by patients with left hemispheric lesions, and in particular by patients with Broca’s aphasia. 2. The significance of these manifestations is not uni vocal. The authors who observed them in patients who had received an injection of a barbiturate in the left carotid attributed them to the inactivation of a centre for positive emotions situated in the left hemisphere (see Rossi & Rosadini, 1967, for a detailed presentation of this hypothesis); but Gainotti (1969, 1972b) considered them a dramatic, but psychologically appropriate, form of reaction to a catastrophic event for the patient. Referring back in part to the first interpretation, Robinson et al. (Robinson et al., 1984; Starkstein & Robinson, 1989) affirmed that the depressive syndromes observed in patients suffering from

strokes located in the anterior parts of the left hemisphere may be due to purely biological causes. These authors distinguished between two forms of post-stroke depression; 1. A “major” depression (i.e. a psychotic form of depression) generally associated with a lesion in the anterior parts of the left hemisphere and due to an interruption of mono-aminergic pathways coming from the brain stem and directed toward the cerebral cortex. 2. A “minor” depression (i.e. a reactive form of depression) having no localising value and due to the patient’s psychological reaction to the disability caused by the lesion. In spite of the importance of this conceptualisation, which tends to propose a “neurological model” for interpreting the major depression, the equivalence proposed by Robinson et al., between post-stroke depression and endogenous depression, does not seem very convincing. Some of the symptoms most typical of major depression, such as the tendency toward guilt feelings, suicidal ideas, expressions of selfaccusation, and the prevalence of negative ideas upon awaking in the early morning are, in fact, generally absent in post-stroke depression. Further, the relationships among seriousness of the depression, degree of disability, and loss of social relationships are not very significant in the initial phases of the illness but tend to become much more so in successive phases, probably in relation to the patient’s increasing awareness of the consequences the cerebral damage will have on the quality of his/her future life. Finally, the “neurochemical” hypothesis, which attributes post-stroke depression to an interruption of mono-aminergic afferences to the cerebral cortex, presupposes on one side a left latéralisation of mono-aminergic pathways and on the other, a coincidence between the portions of the frontal lobes usually damaged by stroke and those crossed by the mono-aminergic pathways. Neither of these hypotheses seems very plausible (see Gainotti, 1992 for a discussion of the problem). An alternative and certainly more traditional interpretation could be to suppose that psychological factors, rather than neurochemical

27. NEUROPSYCHOLOGY OF EMOTIONS

changes, are at the root of the depressive disorders of patients who have had a stroke. A critical role in the development of depressive symptomatology could be played, in this case, by full awareness of the deficit and its personal and social implications. Probably both neurophysiological and psychodynamic mechanisms interact in this process of increasing awareness of the deficit. A missing or partial recognition may in fact depend on bad functioning of control mechanisms intrinsically connected with the cerebral organisation of a given function (see McGlynn & Schächter, 1989, for a critical summary) and on the intervention of psychodynamic defence mechanisms that tend to protect the patient from the impact of events that are too disorganising for his/her psychological equilibrium. The prevalence of post-stroke depression in patients with left anterior lesions could be due to the fact that the deficits resulting from this lesion are acutely present in the patient’s awareness, provoking feelings of depression and anguish.

Psychological and psychodynamic factors In the preceding section we briefly mentioned the fact that the awareness of illness depends on both neurobiological and psychodynamic factors. Among the latter, “denial of illness” mechanisms are extremely important; they are interpreted as defence mechanisms tending to protect the patient from impact with aspects of reality he or she is not yet able to face. The importance of motivational factors in the missing recognition of relevant aspects of the illness is demonstrated by observations incompatible with the hypothesis that only cognitive factors or neurobiological mechanisms are responsible for a lack of awareness of the illness: 1. Phenomena of denial have frequently also been observed in illnesses such as cancer or myocardial infarctions, which are not usually accompanied by a state of cerebral impairment but which are full of dramatic significance for the patient. 2. Not only the patient but also family members often deny important aspects of their relative’s illness. For example, family members of serious

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head-injured patients often recognise only the most obvious and acceptable disorders of the sensorimotor sphere and refuse to recognise cognitive deficits and personality changes resulting from the head injury (McKinlay et al., 1981). 3. According to Weinstein and Kahn (1955), who studied the factors at the base of the “Denial of Illness” syndrome extensively, personality factors usually play an important role in the onset of denial phenomena. 4. The study of the temporal evolution of anosognosia (Gainotti, 1968a) showed that after the initial phase of complete denial (or, in any case, of missing awareness) of the deficit, a phase of minimisation (or rationalisation) of the disability occurs, before complete recognition is achieved. At this point the patient often appears frustrated and depressed. In agreement with these empirical observations on the temporal evolution of manifestations of anosognosia, several authors consider the denial syndrome as the first phase of a process of emotional adjustment to loss of functions and abilities that were part of the patient’s “self’. Tanner and Gerstenberg (1988), for example, affirm that the loss of important aspects of personal integrity (just as the loss of a loved person) usually gives rise to a reaction of mourning which may successively include manifestations of denial, frustration, depression, and acceptance. Within this conceptual model, denial is considered as the only solution that permits the patient to delay confrontation with a situation he/she was totally unprepared for and allows for the development of more realistic defences and putting into action of more acceptable adaptive mechanisms. Frustration, instead, originates primarily from the sense of impotence the patient experiences toward his/her disability due to the impossibility of carrying out acts (such as interpersonal communication or the manipulation of objects), that were completely normal before the morbid event. Just as in other situations of frustration, so also in this one, irritation and anger are the most frequent modalities of reaction but, primarily in cases in which the disability is more severe and irreversible, frustration

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rapidly tends to give way to apathy and withdrawal from social relationships. Depression is obviously the most common form of emotional reaction to an event the patient has become completely aware of; therefore, the greater the importance the lost function played in the patient’s psychic economy, the greater the seriousness of the depression. Even though it must be judged as pathological when its seriousness and length extend beyond normal limits, depression must be considered in many cases as the final part of the long tunnel represented by the “mourning” resulting from functional loss and the necessity of reorganising the self-image. When this process of modification has completed its course, the patient enters into a condition of acceptance of the disability or, at least, of resignation toward his/her destiny.

Psychosocial factors In recent years, increasing attention has also been dedicated to the psychosocial aspects of organic cerebral damage because of the problems emerging due to the survival of patients with serious head injuries and to their resumption of social activities after long periods in intensive care structures. From the epidemiological point of view, these patients are often young, even very young, and their handicaps (just as their personality changes and the behaviour disorders deriving from them) often create difficulties for their families and for rehabilitative structures. Therefore, these psychosocial problems not only regard the patients’ social activities (work, relational, recreative) but also the great emotional, social, and financial burden their physical, cognitive, and behavioural disorders create for the family. Therefore, many studies have taken into consideration not only the presence and the type of remaining disability in these patients, but also the influence of these outcomes on the resumption of work and social activity, and on the functioning of the family system. The changes that seem to have the worst influence on the resumption of work activity and on family equilibrium regard the affective-emotional sphere (and in part cognitive capacities) more than the sensorimotor deficits, and primarily consist of a dependent and egocentric attitude on the part of the patient, with a decrease in initiative and programming abilities, difficulty with

emotional control (with impulsivity and irritability), and inability to be aware of others’ problems. The major consequence of the patients’ dependent and egocentric attitude, reduced work capacity, and reduced interest in social or leisure activities is their progressive isolation together with that of the family. Kozloff (1987) described two main changes in the network of social relationships of the patient surviving a serious head injury: 1. A reduction in the number of people interacting with the patient. 2. An increase in the intensity of relationships with the few persons remaining in contact with him/her, that is, members of the family group. As a result of this decrease in the variety of social relationships and the emotional burden represented by having to sacrifice oneself daily for a person who has been profoundly changed by a head injury from the physical, cognitive and affective point of view, growing tensions often develop within the family; latent conflicts re-emerge, brothers and sisters often become jealous of time dedicated to the braindamaged patient; they stop visiting and thus increase the social isolation of family members actively caring for the patient. But the problems of the families of these patients are not limited to social isolation and financial difficulties deriving both from expenses and reduction of an important income. They also regard the role changes taking place within the family system, because of the changes in a member of that system. For example, consider a young couple with a good affectivesexual relationship and traditional role separation, with the husband more involved in external work activity and the wife more in home work activities and in caring for children. A serious head injury to the husband could make it necessary for the wife to assume roles that were not hers, and for which she feels unprepared (the male roles formerly carried out by her husband), and to assume different roles than those on which their relationship as a couple was based. For example, the infantilisation of the patient could change the relationship of the couple from a symmetrical one between partners (wife-husband) to an asymmetrical one between a dependent person and one who cares for the

27. NEUROPSYCHOLOGY OF EMOTIONS

dependent person (child-mother). Many couples are not able to resolve these financial, psychological, and psychosocial problems and this explains the high incidence of separations or divorces observed in families of head-injured patients (Thomsen, 1984). But all the difficulties and emotional and psychosocial problems of the families of these patients are not only important for the other members of the family; they have a great influence on the motivation and emotional behaviour of brain-damaged patients, changing their attitude positively or negatively. In this way a circular process is created between patient and family, which may assume the characteristics of both the vicious circle and the virtuous circle, and in which the attitude of the family plays an extremely important role. If family members are not able to tolerate the emotional and behavioural disorders of patients, and assume a negative attitude toward them, this attitude will probably increase the patients’ apathy, depression, and sense of frustration, further reducing their motivation toward the rehabilitative process. If, instead, family members manage to assume an open and realistically positive attitude toward the patient, this attitude may contribute toward increasing the brain-damaged patient’s motivation and efforts in the rehabilitative process, thus making possible a partial recovery of selfesteem and an improvement in his/her emotional and behavioural condition.

CONCLUSIONS In the introduction to this chapter on the neuropsychology of emotions I said that the relationship between a lesion in a particular area of the cerebral cortex and onset of an emotionalbehavioural disorder is much more complex than what is usually hypothesised regarding the relationships between cerebral lesion and deficit of a specific component of the cognitive system. Developing this initial statement, we have seen in the final part of this chapter that the emotional and behavioural disorders of brain-damaged

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patients depend only partly on specifically neurological factors. In fact, they depend even more on psychological factors (linked to the patients’ pre-morbid personality and system of values) or on psychosocial factors (linked to the type of interpersonal relationships the patient had with the persons most significant for them and the changes produced in this set of relationships by the illness). Therefore, I believe that the study of the neuropsychology of emotions should follow two very different lines of research: 1. A theoretical-neurobiological one oriented toward a better understanding of what human emotions are and how the various components of the emotional system are mapped on different parts of the cortex and the subcortical structures. 2. A practical-rehabilitative line, oriented toward a better understanding of the significance of the dramatic consequences of a cerebral lesion on the individual’s psychological equilibrium or on the microsystem to which the individual belongs. The second line of research has up until now received too little attention, considering the impact of the patient’s personal problems (emotional, psychodynamic, and psychosocial) on the rehabilitative process. Obviously, this unsatisfactory state of affairs is not due to the shortsightedness of researchers or to their greater propensity to face relevant problems primarily from a theoretical-doctrinal point of view. Above all it is due to the extreme complexity of the problems in question and to the methodological difficulties their study involves. Perhaps, just as substantial advances have been made in other sectors of neuropsychology by interacting with different disciplines such as linguistics, neurophysiology, or the cognitive sciences, so also in this area of research closer interaction with social psychology or with other disciplines of the family and the social sciences would be useful. After all, the emotional schemata are primarily interactive and the human emotions find their sense in the vast and articulated world of interpersonal relationships, and in the way in which these schemata are experienced, represented, and communicated.

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28 Interhemispheric Disconnection Syndromes Giovanni Berlucchi and Salvatore Aglioti

centres in different hemispheres. The latter syndromes, called interhemispheric disconnection syndromes, are typically due to selective alterations of the forebrain commissures (Bogen, 1985, 1987, 1993; Sperry et al., 1969). The forebrain commissures are fibre bundles that connect cortical areas of the two hemispheres in a reciprocal fashion. Very few of these fibres originate from or terminate in subcortical structures. In placental mammals the forebrain commissures are the corpus callosum, the anterior commissure, and the hippocampal commissure. The corpus callosum is by far the largest fibre tract of the central nervous system. It is made up of fibres of different sizes, both myelinated and unmyelinated, whose number can be estimated to be a few hundred million, corresponding to 2-8% of all cortical neurones. All cytoarchitectonic areas of the cortex, which to some extent can be regarded as functional units of the brain, contain neurones projecting to or receiving from the corpus callosum, though usually these neurones are restricted to limited portions of each area. The majority of callosal connections are termed homotopic because they interconnect corresponding points of the neocortex of the two hemispheres. The far less

INTRODUCTION The concept of disconnection symptoms presupposes that neural functions are localised and that neural connections are specific. If function x is subserved by neural substratum A and function y is subserved by neural substratum B, functions x and y can only be integrated into a conjoint function xy if a specific anatomo-functional connection between A and B is activated. In theory, a lesion interrupting such connection without disturbing A and B should produce a disconnection symptom consisting in the disappearance of integrated function xy while leaving functions x and y intact. In practice it is quite unlikely that a lesion can be so selective as to disconnect two single neural centres. Typical brain lesions interrupt connections between multiple functional substrates, bringing about constellations of symptoms which constitute disconnection syndromes (Geschwind, 1965a,b). One can distinguish syndromes caused by a disconnection between centres in one hemisphere (intrahemispheric disconnection syndromes) from syndromes caused by a disconnection between 635

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numerous heterotopic callosal connections link up non-corresponding neocortical regions of the two hemispheres which however share some functional properties, as attested by their common allegiance to a specific sense modality, or by the existence of intrahemispheric connections with an organisation matching that of the interhemispheric connections. There exist, for example, direct callosal connections between visual occipital areas of one hemisphere with visual temporal areas of the other hemisphere, but there are no direct callosal connections between visual areas of one side with auditory areas of the other side, or vice versa. Sperry’s principle of supplemental complementarity (see Sperry, 1962; see also Berlucchi et al., 1986) states that callosal connections function to ensure the anatomical and functional continuity between motor and sensory maps of the two hemispheres. For example, the tactile representation of each hand generated by the specific afferent pathways in the contralateral somatosensory cortex overlays the representation

of the other hand generated in the same cortex by the corpus callosum. This organisation is supplemental because of the juxtaposition of the representations of the two hands in each somatosensory cortex, and complementary because this bimanual representation in each hemisphere provides a unified substratum for tactile bimanual perception. To study interhemispheric disconnection syndromes in humans it is important to know the intracallosal position of the fibres interconnecting different cortical areas. Fig. 28.1 illustrates the subdivisions of the corpus callosum in humans and provides their denominations; in addition, it presents a map of the intracallosal distribution of the interhemispheric connections of various cortical areas, largely based on the extrapolation of the topography of the macaque’s corpus callosum to that of humans (Pandya & Rosene, 1985 ; Pandya & Seltzer, 1986). The few data obtained in studies on human corpus callosum using Wallerian

FIGURE 28.1

C a llo s a l

A n a to m ic a l

P r o je c tin g a n d /o r

R e g io n N.

D e n o m in a to n

R e c e iv in g C o r tic a l A r e a s

1

R o stru m

C a u d o -o rb ita l P re fro n ta l C o r te x ; In fe rio r P re m o to r C o rte x

2

G enu

P re fro n ta l C o rte x

3

R o stra l B o d y

P re m o to r an d S u p p le m e n ta r y M o to r C o r te x

4

M id d le P art o f B o d y

M o to r C o rte x

5

C audal B od y

A n te rio r an d P o ste rio r P a rie ta l C o r te x

6

Isth m u s

S u p e r io r T e m p o ra l an d P o ste r io r P a rie ta l C o r te x

7

S p le n iu m

O c c ip ita l an d In fe rio r P a rie ta l C o r te x

Schematic representation of a midsagittal section of the corpus callosum in adult humans, and general summary of the ascertained or suspected topography within the corpus callosum of fibres originating from and projecting to different cortical areas. AP = anterior pole PP = posterior pole; M = midpoint. (Adapted from Witelson, 1989, with the permission of Oxford University Press.)

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degeneration (De Lacoste et al., 1985) or stereotaxic stimulation of callosal connections (Schaltenbrand et al., 1970; Schaltenbrand, 1975) suggest a fair similarity between humans and macaques in the topographic organisation of the corpus callosum. Modern post-mortem investigations and in vivo magnetic resonance studies have provided many data on the morphometry of corpus callosum and anterior commissure in humans (Byne et al., 1988; Clarke et al., 1989; De Lacoste & Holloway, 1982; Demeter etal., 1988;Foxmanetal., 1986; Holloway & De Lacoste, 1986; Witelson, 1989). Of considerable interest are recent studies addressing the issue of whether the anatomical structure of the corpus callosum varies as a function of gender (Aboitizetal., 1992 a, b; Allen etal., 1991; Cowell et al., 1992; Steimetz et al., 1992,1995; Weis et al., 1989; Witelson, 1991) and manual preference (Witelson, 1985; Witelson & Goldsmith, 1991). Possible structural differences in the corpus callosum between males and females, or between right-handers and left-handers, might underlie differences in interhemispheric transfer and coordination, and even in general cognitive style, between those groups. While some studies report a complete absence of differences in callosal morphology between the genders (Aboitiz et al., 1992 a, b; Pozzilli et al., 1994; Rauch and Jinkins, 1994; Weis et al., 1989) and the manual dominance groups (Steinmetz, 1992, 1995), other studies indicate that the corpus callosum or some parts of it, such as the splenium, are comparatively larger in females (Allenetal., 1991; Steinmetz, 1992,1995) and in ambidextrous subjects (Witelson, 1985). Further, it has been suggested that a gender-related callosal dimorphism is more apparent during development or ageing. The maximal size of some callosal portions such as the splenium is attained in females at or after the age of 50 years, while in males the maximal development of the corresponding callosal portions is reached at about 20-30 years of age, and there are already signs of atrophy after age 50 (Cowell etal., 1992; Witelson, 1991). Finally, no difference in callosal morphology has been found between right-handed and left-handed females, whereas Witelson and Goldsmith (1991) report that the isthmus of the corpus callosum is larger in lefthanded and ambidextrous males compared to

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right-handed males. In addition to the evidently inconclusive nature of the available anatomical data, one has to keep in mind that there is no consensus about the relation between efficiency of interhemispheric transfer on one side, and gender or manual preference on the other. The relation is significant according to some authors (Potter & Graves, 1988) but not according to others (Burton et al., 1991; Piccirilli et al., 1989; Savage and Thomas, 1993). Be it as it may, the bearing of callosal morphology on the mechanisms for interhemispheric coordination as well as on the disconnection syndromes is to be considered as yet largely controversial. The anterior commissure is the commissure of the paleocortex, the amygdalae, and the olfactory bulbs, but it also contains fibres, that originate from and terminate in neocortical areas. In macaque monkeys the neocortical fibres of the anterior commissure interconnect relatively broad portions of the frontal and temporal lobes, whereas in humans the neocortical regions giving rise to or receiving anterior commissure fibres are less well known and certainly less extensive than in other mammals, including non-human primates (Gazzaniga, 1988). The anterior commissure is much smaller than the corpus callosum: the ratio between the areas of the midsagittal sections of the two structures is 1/100 in humans (Demeter et al., 1988; Foxman et al., 1986), and 5/100 in macaque (Foxman etal., 1986). The hippocampal commissure, divided into an anterior or ventral portion and a posterior or dorsal portion, is a predominantly archicortical commissure which courses underneath and in close contiguity with the corpus callosum. Few data are available on the structure and organisation of the hippocampal commissure in primates and especially in humans. It is not known whether the ascertained links between the hippocampal commissure and the hippocampal formation and the peri- and para-hippocampal structures in macaques (Demeter et al., 1985) are also present in humans. Gloor et al. (1993) have reported that whereas the ventral hippocampal commissure of man is a vestigial structure, the dorsal hippocampal commissure is far more developed and could be involved in the generalisation of temporal epileptic seizures.

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The forebrain commissures can be damaged in their intra- or interhemispheric course, or at their regions of origin or destination, because of traumatic, vascular, tumoral, or degenerative processes. Alternatively, they can be surgically sectioned for the treatment of epilepsy or for gaining access to underlying pathologic formations, or can be absent at birth because of congenital cerebral malformations. The existence of cases with a complete agenesis of all forebrain commissures cannot be excluded, but usually agenesis is limited to parts or the totality of the corpus callosum. Acquired lesions of the corpus callosum and probably of the other forebrain commissures are as a rule incomplete. As a consequence, the possibility of studying the effects of the complete absence of the forebrain commissures has been limited so far to epileptic patients treated with surgical section of all these commissures.

HISTORICAL DEVELOPMENT The contributions from clinical research in human and animal experimental studies to the historical evolution of the concept of the interhemispheric disconnection syndrome are strictly connected. The two approaches start from different premises but converge on common theoretical and practical objectives, bearing on the physiological significance of the activities of the forebrain commissures and their physiopathologie role in epilepsy (review in Berlucchi, 1990). In the first decades of the twentieth century the attempts of animal experimenters to identify a pattern of deficits specific to section of the forebrain commissures had little if any success (reviews in Mingazzini, 1922; Bremer et al., 1956). In brief, these attempts failed to reveal any constant and consistent difference between the preoperatory and postoperatory behaviours of commissurotomised animals. Only nonsystematic, unspecific, and usually temporary disturbances, variably defined as apathy, inertia, sleepiness, loss of interest, lack of initiative, ataxia, were reported after commissurotomy. Current knowledge indicates that such disturbances can be attributed at least in part to nonintended lesions of

noncommissural structures of the midline, especially of the cingulate cortex. But the inconclusive character of these first attempts is explained above all by the inadequacy of the methods employed to disclose the effects of interhemispheric disconnection. The first to take the right path to success were Bykov and Speranski (1924), two pupils of Pavlov, who are credited with the pioneering demonstration of a genuine effect of interhemispheric disconnection in callosotomised dogs, i.e. the suppression of the normal ability to transfer from one body side to the other a conditioned salivary response to a tactile stimulus. But this path was soon abandoned, and almost 30 years elapsed before Myers and Sperry (1953) followed a similar approach to the problem. After an equally unsuccessful start, investigations on the role of the forebrain commissures in experimentally induced epilepsy in laboratory animals started to be more productive when the technical aid provided by electroencephalography became available. At first, Gozzano (1935) and Moruzzi (1939) showed in rabbits that callosotomy could prevent the transhemispheric spread of an electrically or chemically induced seizure of the masticatory cortex in one hemisphere; and subsequently Erickson (1940) and McCulloch and his colleagues (Bailey et al., 1941, 1943; Garol, 1942; McCulloch & Garol, 1941) were able to confirm in various species of nonhuman primates that the corpus callosum and the other forebrain commissure constitute the primary routes for the propagation of epileptic discharges throughout the cortex, thus starting a fruitful line of research endeavour which has been actively pursued for many years (review in Berlucchi, 1990). In the field of clinical studies, descriptions and interpretations of neural disturbances as due to interhemispheric disconnection can be traced back to the dawn of scientific neurology. The initially prevailing opinion was that such disturbances were specific enough to allow one to draw reasonable inferences about the normal functions of the commissures. Among the deficits classically attributed to interhemispheric disconnection, whether isolated or associated with symptoms of intrahemispheric disconnection, were Freund’s

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(1889) optic aphasia, i.e. a selective incapacity to name visually perceived objects, Déjerine’s (1892) alexia without agraphia, and Liepmann’s (1900; Liepmann & Maas, 1907) unilateral apraxia and agraphia. Freund and Déjerine attributed their patients’ disturbances to vascular lesions interrupting the specific connections between the visual centres of both hemispheres and a hierarchically higher unilateral visuo-verbal centre in the left hemisphere; and Liepmann explained unilateral apraxia of the nondominant hand in terms of a callosal disconnection of the motor centres of this hand from a single eupraxic centre in the left hemisphere. By summarising clinical, anatomical, and philogenetic data, Mingazzini’s monograph (1922) presented a specifically connectionistic view of callosal functions in humans. He subdivided the corpus callosum into an anterior portion, portio verbalis et praxica, primarily involved in the coordination of verbomotor centres in the two hemispheres; a middle portion, portio praxica, necessary for the eupraxia and eutaxia of synergic movements of the limbs of the two sides; and a posterior portion, portio sensorialis, subserving the unification of the visual and auditory fields of the two hemispheres and the transmission of perceptual information from the nondominant hemisphere to interpretative centres restricted to the dominant hemisphere. However, this interpretation of the functional significance of the corpus callosum, reasonably predicated on the indisputable anatomical specificity of the callosal connections between functionally specialised centres, was soon supplanted by the fuzzy hypothesis according to which the corpus callosum must be considered the seat of the highest psychical functions because of its alleged ill defined associative activities. Throughout the first half of the twentieth century, the way of thinking implicit in this hypothesis, undoubtedly reminiscent of the Cartesian pineal gland, and hence far from being novel or original or productive, succeeded in exerting a weighty influence on neurology’s theoretical approach to the issue of the functional significance of the interhemispheric connections. In the 1930s the result of the efforts aimed at systematising a “corpus callosum syndrome” was a mixture of predominantly “psychical” symptoms,

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so poorly defined as to be unsuitable for any serious anatomo-functional analysis: apathy, akinesia without paralysis, “imperviousness” to external solicitations in spite of preserved consciousness, amnesia, and altered personality (see e.g. Alpers, 1936; Alpers & Grant, 1931). Out of patience with so vague and generic a terminology, the American neurosurgeon Dandy (1936) hastily convinced himself that the callosal sections he made to approach underlying pathological formations of the midline produced no symptoms whatsoever, and branded as “extravagant” all extant statements about the possible functional significance of the corpus callosum. On the other hand clinical experience continued to agree with animal studies in identifying the forebrain commissures, and especially the corpus callosum, as the main avenues for the interhemispheric propagation of epileptic discharges. At the beginning of the 1940s another American neurosurgeon, Van Wagenen, probably though not explicitly influenced by the clear results obtained at that time in animals with experimental epilepsy, decided to perform partial or total sections of the forebrain commissures in an extreme attempt to treat patients with drug-refractory forms of epilepsy. The explicit justification of his decision was based on precise clinical observations: 1. Unilateral seizures usually do not cause a loss of consciousness and therefore are less severe than bilateral seizures, which in most cases depend on propagation of discharges through the forebrain commissures. 2. The frequency of epileptic seizures caused by space-occupying lesions decreases significantly when such growths invade the corpus callosum. 3. The same phenomenon occurs in chronic epileptics after an acute vascular lesion affecting the forebrain commissures (Van Wagenen & Herren, 1940). The consequence of this clinical decision for the scientific analysis of the alterations of the normal cerebral functions by interhemispheric disconnection was that about 30 cases, submitted with uncertain therapeutic effects to total or partial section of the forebrain commissures, could be studied before and after the operation with

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apparently well controlled psychological techniques by Akelaitis and his co-workers (Akelaitis, 1941a, b, 1942 a, b, 1943,1944,1944-45; Akelaitis et al., 1942; Bridgman & Smith, 1945; Parsons, 1943; Smith, 1947; 1951; 1952; Smith & Akelaitis, 1942). The results of these studies are as surprising as easy to summarise: suffice it to say that they did not bear out any systematic effect that could be specifically attributed to interhemispheric disconnection, whether partial or total. The prompt repercussion of these negative results on neurological theorising resulted in a further support to holistic concepts of the nervous system which were then prevailing in the scientific community because of other historical reasons (e.g. Lashley, 1951). Holistic concepts ascribing nervous integration to effects of electrical fields or diffuse connection systems, hence totally overlooking the orthodox anatomy of specific connections between neural centres, seemed to be most convincingly upheld by the absence of any apparent change in the behaviour of persons submitted to the section of some of the most conspicuous connection tracts of the brain. At the end of the 1940s the “state of art” was such as to justify the not so openly jocular statement by McCulloch (1949) that the only function of the forebrain commissures is that of transmitting epileptic seizures from one side of the brain to the other. For some time, neither the ascertained notion of a physiological callosal facilitation between the masticatory cortices of the rabbit, possibly subserving the bilateral coordination of chewing movements (Moruzzi, 1939), nor the sporadic reports in the neurological literature of interhemispheric disconnection symptoms resulting from pathological or surgical lesions of corpus callosum (e.g. Maspes, 1948; Sweet, 1941; Trescher & Ford, 1937) were considered serious enough challenges to undermine the paradoxical attribution of exclusively pathological functions to the forebrain commissures. Ironically, the case with interhemispheric disconnection symptoms reported by Trescher and Ford (1937) was a patient with a cyst of the third ventricle operated with a transcallosal approach by the same Dandy who had claimed that corpus callosum sections can be asymptomatic.

The scientific revolution needed to revitalise the field broke out in 1953, when Roger Sperry, a staunch advocate of the connectionistic theory, i.e. functional specificity of neural centres and selectivity of their interconnections (Sperry, 1951), and his student Ronald Myers applied to the analysis of the normal functions of interhemispheric connections in animals an experimental paradigm that was at last appropriate to that purpose. The paradigm was based on the perceptual equivalence principle whereby objects maintain their identity in time and space regardless of the sensory channel through which they are perceived. If a sensory channel is directed to a cerebral hemisphere and another sensory channel is directed to the other hemisphere, perceptual equivalence across the two channels is bound to require an interaction between the hemispheres, and according to the connectionistic theory this interaction can only occur by way of specific interhemispheric connections. In full accord with the connectionistic theory, Myers and Sperry (1953) showed that whereas in intact cats visual stimuli projected to a single hemisphere were promptly recognised when projected to the other hemisphere, this interhemispheric transfer was impossible in cats with the corpus callosum sectioned. Subsequently Sperry and his co-workers demonstrated that the abolition of perceptual equivalence across the hemispheres was a systematic consequence of the section of the forebrain commissures in other animal species as well, in the visual modality as well as in nonvisual sensory modalities allowing the separate stimulation of either hemisphere (Sperry, 1961). The notion that the forebrain commissures are the indispensable substrate for the interhemispheric transfer of information, as well as for the unification of cognitive activities of the two hemispheres in experimental animals, thus became one of the keystones of neuroscientific knowledge, and the starting point of a vast series of commissurotomy experiments which have continued to provide fresh information (review in Berlucchi, 1990). If the studies of Akelaitis and his colleagues on commissurotomised patients might still justify some scepticism concerning the generalizability to the human brain of the conclusions reached in Sperry’s studies on animals, this scepticism was laid

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to rest in 1962, a year that saw the publication of two pioneering papers. The first paper by Geschwind and Kaplan reported a case with tumoral and vascular lesions of the anterior two thirds of the corpus callosum, who showed tactile anomia and agraphia of the left hand and absence of intermanual transfer of somatosensory information. Explicitly inspired by Sperry’s research in animals (Geschwind, 1965a, b), the authors ascribed such symptoms to the disconnection of motor and somatosensory areas of the right hemisphere from speech centres in the left hemisphere. In the second paper, Sperry and his co-workers (Gazzaniga et al., 1962) described various conspicuous signs of interhemispheric disconnection in an epileptic patient with complete forebrain commissurotomy. This was the first case in a series of Californian patients operated by the neurosurgeons Bogen and Vogel (1962), who reintroduced cerebral commissurotomy for the treatment of forms of epilepsy totally refractory to pharmacological therapy. It is in this series of patients that Sperry and his co-workers (1969) had the opportunity to examine in depth the effects of the anatomofunctional separation of the cerebral hemispheres, thus defining a pattern of symptoms of interhemispheric disconnection that has served as a frame of reference for all subsequent investigations and systematisations. In synthesis, the lack of hemispheric interactions found in commissurotomised animals proved typical of commissurotomised patients as well, with the fundamental difference that contrary to the disconnected hemispheres of experimental animals, the disconnected hemispheres of the human brain exhibit quite different functional abilities. The finding by Sperry et al. (1969) of such a rich and varied pattern of symptoms in a series of patients similar to the apparently asymptomatic patients of Akelaitis et al. (1944) can be accounted for by Sperry et al.’s rigorous application to the testing of their patients of principles and expedients derived from animal experimentation. The techniques that allowed Sperry and his colleagues to lateralise stimuli to a single hemisphere, while relatively simple, were definitely more efficacious than those used by Akelaitis et al. (1944), thus proving decisive for demonstrating the loss of various

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interhemispheric transfers and interactions in commissurotomised patients. Some of Akelaitis’s patients, retested many decades after the operation with techniques similar to those of Sperry, showed typical symptoms of interhemispheric disconnection which had escaped the attention of previous investigators because of the inadequacy of their testing methods (Goldstein & Joynt, 1969; Goldstein et al., 1975). These findings have definitely disproved Geschwind’s hypothesis (1965 a, b) of a fundamental difference in cerebral organisation between the patients of the Akelaitis series and those of the Sperry series, tentatively attributed to a putative difference in onset time of epilepsy between the two series. From the 1960s to the present time, clinical and experimental knowledge about the effects of interhemispheric disconnections has continued to grow as a result of investigations on four groups of patients: 1. Patients with commissural agenesis (reviews in Ettlinger, 1977; Ettlinger et al., 1972, 1974; Jeeves, 1990; Lassonde & Jeeves, 1994). 2. Patients who have suffered pathological lesions of the commissures, either vascular or tumoral (see e.g. Brion & Jedynak, 1975; Deloche et al., 1993; Geschwind, 1985) or traumatic (Boldrini etal., 1992; Brion & Jedynak, 1975; Levin etal., 1990; Strich, 1976) or degenerative (Bereket al., 1994; Brion, 1976; Lindeboom & Ter Horst, 1988). The latter subgroups include multiple sclerosis patients with corpus callosum demyelinisation and the attendant disconnection symptoms (Pelletier et al., 1992, 1993; Rao et al., 1989; Schinderetal., 1993). 3. Non-epileptic patients submitted to operations for the removal of intraventricular tumours and cysts using the transcallosal approach (see e.g. Damasio et al., 1980; Jeeves et al., 1979; Levin et al., 1993; Oepen et al., 1988; Petrucci et al., 1987). 4. Epileptic patients submitted to therapeutic commissurotomies. This group, which is by far the largest, is the only one to include subjects with complete commissurotomies. Surgical commissurotomy for the treatment of epilepsy is now practised on a relatively large scale in

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various countries (Garcia-Flores, 1987; Gates et al., 1984, 1987; Gazzaniga et al., 1975; Geoffroy et al., 1983; Harbaugh et al., 1983; Luessenhop et al., 1970; Olivier et al., 1988; Pallinietal., 1995; PapoetaL, 1989; Pro vinciali et al., 1988; Roberts & Reeves, 1987; Reeves, 1985; Sass et al., 1988; Spencer, 1988; Spencer et al., 1988, 1993; Wilson et al., 1975, 1977, 1978, 1982). In a significant number of cases, the in vivo use of the modern noninvasive brain imaging techniques allows one to interpret clinical and experimental data in the light of precise assessments of the extent and location of commissural lesions or sections (see e.g. Bogen etal., 1988; Gates etal., 1986; Gazzaniga, 1988; Sussman et al., 1987). In recognition of his contributions to the understanding of interhemispheric differences and interactions, Roger Sperry (1913-1994) was awarded the Nobel prize for physiology or medicine in 1981.

SYMPTOMATOLOGY Symptoms of interhemispheric disconnection may be subdivided into symptoms of deficiency, which result directly from the loss of interactions between functional centres in the two hemispheres, and symptoms of dissociation, which express the differential styles with which the two hemispheres control behaviour after acquiring a partial functional autonomy because of their separation. The main aim of this chapter is to analyse symptoms of deficiency as relatively permanent results of interhemispheric disconnection, and to infer from them as much as possible the physiological role of forebrain commissures in the interactions between functional centres in the two hemispheres. Symptoms of dissociation providing crucial evidence for the theory of hemispheric asymmetry and functional specialisation are described in detail in many reviews (e.g. Bogen, 1993; Hoptman & Davidson, 1994; Gazzaniga, 1995; Nass & Gazzaniga, 1987;Trevarthen, 1984). In this chapter they will be considered only in as much as they aid the understanding of symptoms of deficiency. Our description will be focused on the interhemispheric

disconnection pattern typical of total commissurotomy patients with right manual dominance and language represented in the left hemisphere, as well as on the most systematic symptoms of this pattern.

Vision Unihemispheric visual stimulation The image inversion by the eye dioptrics results in the projection of the right half of the visual field onto the left hemiretinae (temporal hemiretina of the left eye and nasal hemiretina of the right eye), and, conversely, the projection of the left half of the visual field onto the right hemiretinae (temporal hemiretina of the right eye and nasal hemiretina of the left eye). The left hemiretinae projects to the left lateral geniculate nucleus, and the right hemiretinae project to the right lateral geniculate nucleus; in turn, each lateral geniculate nucleus project to the ipsilateral primary visual cortex. The optic inputs to each hemisphere are therefore such that the primary visual cortex of each side contains a binocular representation of the contralateral half field. This representation is then transmitted through intrahemispheric connection to other cortical areas with visual functions in the occipital, temporal, parietal, and frontal lobes of the same hemisphere. Finally the representations of the two half fields in the two hemispheres are reciprocally linked across the midline by homotopic and heterotopic connections which course in the corpus callosum and perhaps also in the anterior commissure. The crossed relation between visual half fields and cerebral hemispheres allows one to restrict the visual input to a single hemisphere, at least as far as the initial stages of information processing are concerned. This aim can usually be achieved with tachistoscopic lateralised stimulation, a technique first used by Maspes (1948), perhaps with exposure times that today may be considered somewhat too long, who was looking for interhemispheric disconnection symptoms in two nonepileptic patients operated for the removal of a third ventricle cyst through a transplenial approach. Lateralised tachistoscopic stimulation involves the presentation of a visual stimulus in the half field contralateral

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to the hemisphere to be stimulated. Latéralisation of the stimulus by even less than a degree with respect to the fixation point is a necessary but insufficient condition for ensuring a strictly unihemispheric stimulation (Fendrich & Gazzaniga, 1989; Sperry, 1968a). The additional requirement is that stimulus duration is shorter than saccadic reaction time (about 200msec.), so that there is no time for any ocular movement toward the stimulus to bring the stimulus itself into the other half field. It seems certain that the apparent absence of visual symptoms of interhemispheric disconnection in Akelaitis’s (1944) commissurotomy patients is to be attributed to the failure to use the lateralised tachistoscopic technique for unihemispheric stimulation (Goldstein et al., 1975; Goldstein & Joynt, 1969; Sperry et al., 1969). In addition to lateralised tachistoscopic stimulation, commissurotomy patients have been less frequently tested with techniques that allow the prolonged presentation of stimuli to a half field, hence to a single hemisphere, even in the presence of eye movements (Butler & Norsell, 1968; Myers & Sperry, 1982; Zaidel, 1975). These techniques, even if basically different, are all directed at maintaining an unvarying spatial relation between the position of the stimulus and that of its image on the retina. Left hemianomia and hemialexia Normal subjects have no difficulty in naming visual stimuli—colours, common objects, digits, letters, syllables, words, sentences—presented tachistoscopically in either half field. After commissurotomy, patients with complete interhemispheric disconnection perform normally in naming tasks with stimuli presented in the right half field, but not with stimuli presented in the left half field. Although they detect the occurrence of left field stimuli, the patients admit their failure to recognise them, or produce random and inappropriate naming responses, or do not respond at all. This behaviour might at first suggest that they are affected by left hemianopsia or hemiagnosia, but simple tests of nonverbal recognition make it clear that the condition is best characterised as a left visual hemianomia, due to a disconnection between vision in the right hemisphere and speech in the left

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hemisphere. When the commissurotomy patients are allowed to identify stimuli in the left field by means of nonverbal responses, they prove quite able to recognise those stimuli whose names they cannot say or write. For instance they can successfully choose an object or a drawing corresponding to the left field stimulus in a series of disparate foils or, given the appropriate instructions, they can pick up other objects endowed with physical or semantic associations with that stimulus. All this shows that after its disconnection from the left hemisphere, the right hemisphere maintains a normal capacity for visual recognition, at least as far as objects are concerned, but has lost its access to the contralateral speech controlling centres (Gazzaniga et al., 1965; Sperry etal., 1969). The ability of the disconnected right hemisphere to understand written words varies significantly from case to case. In this relation it is important to distinguish between type 1 alexia, the inability to grasp the meaning of written words, from type 2 alexia, the inability to read aloud words in spite of having perceived their meaning (Sugishita et al., 1985). As commissurotomy patients as a rule cannot read aloud words presented to their left half field, one must determine the reasons for their failure. There are very few commissurotomy patients who are demonstrably capable of understanding the meaning of words presented in their left half field (Gazzaniga, 1983a). Therefore the great majority of commissurotomy patients are affected by a type 1 left hemialexia, which means that their right hemisphere can visually recognise objects but not written material. The implications of this dissociation for the understanding of the normal linguistic functions of the right hemisphere have been the object of a heated debate which will be mentioned further on. Loss ofvisuoperceptual equivalence between hemifields and hemispheres In commissurotomy patients, vision is characterised by a surprising independence of the perceptual domains of the two hemispheres. Objects presented in one visual hemifield are subsequently recognised only if they are presented in the same hemifield. If an object is presented first in one hemifield and then in the other, upon the second presentation patients

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behave as if they are seeing the object for the first time; nor can they say or otherwise indicate whether two simultaneously presented stimuli, one in each field, are the same or different, even though they can be shown to have perceived both stimuli. Patients who can read words in both fields find it impossible to perceive a compounded word presented across the midline, as each hemisphere perceives solely the contralateral component word. The loss of visuoperceptual equivalence between the hemispheres of commissurotomy patients is undoubtedly the counterpart of the loss of interhemispheric transfer of visually guided behaviours by commissurotomy animals (Gazzaniga et al., 1965; Sperry etal., 1969). A striking demonstration of the independence of the two hemispheres of commissurotomy patients in visual perception has been obtained using chimeric stimuli. An example of a chimeric stimulus is the photograph of a face constructed by joining the photographs of two different half faces. Such stimuli are presented tachistoscopically to commissurotomy patients in such a way that the two half faces fall in different half fields (Levy et al., 1972). In these conditions each disconnected hemisphere “completes” the half face projected to it, so that two complete different faces are perceived altogether across the vertical midline, one by each hemisphere. This double perception is demonstrated by the fact that if patients have to name or verbally describe what has been presented, they report the face corresponding to the right field stimulus; but if they have to select among different photographic foils a face matching the tachistoscopic stimulus, they choose the face corresponding to the left field stimulus. In both cases patients deny having seen half faces; each half face gives rise to a complete face percept, but the reported percept depends on response instructions. Levy and Trevarthen (1974) believe that in these conflictual conditions the modality of the response determines which hemisphere prevails on the other by means of a choice function termed metacontrol: the verbal response modality would favour the linguistically competent left hemisphere, whereas the nonverbal modality would allow the expression of the superior visuospatial abilities of the right hemisphere.

Callosal agenesis and partial commissural lesions or sections Left hemialexia and visual hemianomia and the loss of visuoperceptual equivalence between the hemispheres have been repeatedly observed in patients with complete commissurotomy (e.g. Gazzaniga, 1975), so that these symptoms are regarded as pathognomonic of the total interhemispheric disconnection syndrome (Bogen, 1985, 1987, 1993). They are usually not found, at least to the extent that commissurotomy patients exhibit them, in subjects with complete callosal agenesis (Ettlingeretal., 1972,1974; Jeeves, 1990; Lassonde et al., 1988). However the performance of these subjects in tasks that require visual hemispheric interactions, such as the matching of visual stimuli across the vertical meridian, may be subnormal even though it is never at chance (Kamath et al., 1991). The lack or limited severity of disconnection symptoms in callosal agenesis compared to commissurotomy is commonly attributed to the vicariating action of noncallosal interhemispheric connections. The obvious candidate for this role in interhemispheric extracallosal interactions is the anterior commissure in view of its size and its contingent of neocortical commissural fibres (Jeeves, 1990). In nonhuman primates, including chimpanzees (Black & Myers, 1964), the anterior commissure contributes significantly to the interhemispheric transfer of visuognosic information, such that it can in some sense be regarded as sharing common functions with the splenium of the corpus callosum (Doty et al., 1994; Gross & Mishkin, 1977; Hamilton, 1982). The hypothesis that the anterior commissure may similarly mediate visuognosic interactions between the hemispheres of the human brain is countered by the fact that, like commissurotomy patients, callosotomized patients with spared anterior commissure are affected by left hemianomia and loss of visuoperceptual equivalence between the hemispheres (Gazzaniga, 1988; Lassonde et al., 1988; McKeever et al., 1981). The anterior commissure of subjects with callosal agenesis may perhaps contain fibres that in the normal brain run in the corpus callosum, and thus it might possess greater functional potentialities compared to the anterior commissure of

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commissurotomy cases (Jeeves, 1990). More recent findings suggest that the interhemispheric connections that partially compensate for the lack of the corpus callosum in callosal agenesis run in the brain stem rather than in the anterior commissure (Jeeves, 1994; Milner, 1994). In callosal agenesis there might also be a potentiation or supernormal development of uncrossed components of the sensory pathways that would allow a projection of lateralised information to both hemispheres. However at least for the somatosensory modality this hypothesis is contradicted by electrophysiological findings (Vanasse et al., 1994). It is of interest to consider the cognitive nature of exchanges of information presumably occurring by way of brain stem connections between the hemispheres of the genetically acallosal brain. As a rule, these exchanges concern declarative or explicit knowledge, i.e. conscious factual knowledge that can be expressed in words. By contrast, deficits found in subjects with callosal agenesis suggest that defective interhemispheric communication concerns procedural or implicit knowledge, i.e. knowledge that subserves action but is not usually represented in consciousness and cannot be easily verbalised. Interhemispheric transfer of implicit information is needed for binocular stereopsis and fusion across the midline, for simple rapid visuomotor integration, for bimanual coordination in complex motor activities, and for some marginal aspects of auditory memory, language and space cognition. In tasks tapping these abilities, callosal agenetics exhibit deficits comparable in kind, if not in degree, to those observable in commissurotomy patients (see reviews in the book edited by Las sonde & Jeeves, 1994). Compensatory mechanisms activated in callosal agenesis may be regarded as being mainly directed at unifying conscious processes of the two hemispheres. Milner (1994) believes that information transmitted between the hemispheres at brain stem levels can access consciousness in the genetically acallosal brain but not in the callosotomised brain, probably because in the former brain compensatory processes are already active at birth, and thus can benefit from a long time at their disposal and the greater plasticity of the developing brain. In partial accord with this hypothesis, Lassonde et al. (1991) have found that

the interhemispheric disconnection symptoms following callosal section are much less severe if the operation is performed in infancy rather than in adulthood. Patients with callosal agenesis prove inferior to normal controls in the precision of their visual reaching for objects in the hemispace contralateral to the performing hand, and their deficit affects both distal and proximal limb muscles (Jakobson et al., 1994). This finding confirms that compensatory mechanisms in callosal agenesis are far from perfect, and that their effectiveness varies from task to task. Finally, it must be mentioned that the interhemispheric transfer of perceptual visual learning, a typical procedural task, has been found to be normal in a subject with complete callosal agenesis who exhibited electrophysiological signs of interhemispheric disconnection (Fiorentini et al., 1992). In accord with the fact that the splenium of the corpus callosum contains the interhemispheric connections of most cortical visual areas, lesions or surgical sections restricted to the posterior part of the corpus callosum suffice to cause left hemianomia and loss of visuoperceptual equivalence between the hemisphere (see e.g. Brion & Jedynak, 1975; Damasio et al., 1980; Ford, 1937; Gazzaniga, 1988; Gazzaniga & Freedman, 1973; Poeck, 1984; Trescher & Maspes, 1948). Conversely, these visual symptoms are absent following sections or lesions of the anterior and/or middle parts of the corpus callosum sparing the splenium, regardless of whether the anterior commissure is intact or lesioned (Brion & Jedynak, 1975; Gazzaniga, 1988; Gordon et al., 1971). It is possible that the splenium contains contingents of fibres with different roles in interhemispheric visual communication in both macaque (Hamilton & Vermeire, 1986) and humans (Greenblatt et al., 1980). Relevant to neuropsychology is the possible separation between splenial fibres involved in the interhemispheric transfer of visual verbal information and those subserving the transfer of nonverbal visual information. In the normal brain, the transfer of both types of information from the right hemisphere to the left is required for the naming of left field stimuli, and transfers in both senses obviously subserve visuoperceptual equivalence between the

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hemispheres. Pathologic investigations (Damasio & Damasio, 1983) suggest the existence of separate splenial connections for the transfer of the two types of information. For a more extensive treatment of this problem the reader is referred to the discussion of pure alexia in Chapter 14. Visual extracommis sural interhemispheric interactions The independence of the visuoperceptual domains of the two hemispheres of commissurotomy patients is not complete. The initial experiments disclosed the appearance in the speech of commissurotomy patients of emotional intonations which could be explained by exhilarating or terrifying stimuli just presented to the right hemisphere. As the patients were unable to give a verbal description of those stimuli, the finding suggests that unlike the identity of the stimuli, their emotional content can be communicated from the right hemisphere to the left via extracommissural pathways (Gazzaniga, 1970). Subsequent studies have revealed further possibilities for the interhemispheric transfer of visual information in commissurotomy patients, some of which are independent of the emotional content of the stimuli. For example, the commissurotomy patients in the study by Trevarthen and Sperry (1973) were able to provide an accurate verbal description of the orientation, position, and direction of large rectangular segments presented in the periphery of the left visual field. Further, they could also describe the spatial relations between these stimuli and similar stimuli simultaneously presented in the right field. Other experiments have shown that some commissurotomy patients can sometimes name stimuli in both hemifields, or perform a fairly efficient cross integration even of relatively complex stimuli, such as digits, letters, words, faces, moving objects, targets for ocular movements etc. especially when the sample of potential stimuli is small and known in advance (CroninGolomb, 1986; Holtzman, 1984; Johnson, 1984a, b; Myers & Sperry, 1985; Sergent, 1986, 1987, 1990; Teng & Sperry, 1973). These results can be accounted for by various, not necessarily alternative hypotheses. According to one hypothesis, unlike denotative information, con-

notative and contextual cues about a lateralised stimulus can be transmitted between the hemispheres by extant subcortical connections, and the receiving hemisphere can infer from them the identity of the object (see e.g. Myers & Sperry, 1985). Recent experiments indicate that commissurotomy patients can indeed transfer subcortically between the hemispheres information about elementary features of visual stimuli, such as location and orientation, but not more complex information about the identity of, for example, words or digits (Corballis, 1994, 1995; Corballis & Trudel, 1993; Seymour et al., 1994). Another hypothesis emphasises strategic cooperations between the hemispheres such as those named “cross-cueing” by Gazzaniga (1970) and wittily renamed “external commissure” by Brion and Jedynak (1975). These strategies do not involve exchanges of neural signals along the extant interhemispheric connections, but rather the emission by either hemisphere of behavioural outputs which can be perceived by the other hemisphere and thus guide its responses. For example, a commissurotomy patient studied by Gazzaniga and Hillyard (1971) was able to name digits presented to his left hemifield by counting subvocally, presumably with his left hemisphere, until his right hemisphere could detect and signal the correspondence between the subvocal digit and the digit in the left field. The third hypothesis postulates an anatomo-functional brain reorganisation following commissurotomy (Campbell et al., 1981), especially in patients operated on as children (Lassonde et al., 1988). According to Gazzaniga (1987, 1988, 1995) interhemispheric transfer of visual inputs in commissurotomy patients is limited to rather crude information, and thus the evidence for complex interhemispheric interactions in vision should in all cases be attributed to cross-cueing strategies. For instance he denies that commissurotomy patients can perceive apparent movements across the midline when two stimuli are flashed in succession at brief intervals, one on the right and the other on the left, contrary to what had been reported by Bridgman and Smith (1945) and rediscovered by Ramachandran et al. (1986). Gazzaniga (1987) believes that if cross-cueing strategies are

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accurately impeded, commissurotomy patients can perceive apparent movement within but not across visual hemifields. Naikar and Corballis (1996) have recently reanalysed the capacity of callosotomised subjects to perceive apparent movement across the midline. The results in a patient with total callosotomy suggest that perception of apparent movement requires (1) the capacity to discriminate simultaneous light stimuli from successive light stimuli, (2) the capacity to shift attention from one stimulus to the other, and (3) the capacity to experience the illusion of a continuous movement of the stimulus from one location to the other. When these capacities were tested across the visual field midline in the total callosotomy patient, the first two were as good as in normal subjects, presumably due to subcortical integration of the stimuli. By contrast, the third capacity was found to be considerably reduced compared to the normal standard. The finding that visual interactions between the hemispheres of commissurotomy patients may be absent soon after the operation and appear some time later (e.g. Trope et al., 1988) suggests that adaptation and learning processes may come into play. Estimates o f interhemispheric transmission time based on visuomotor and visuovocal RTs and visual ERPs Poffenberger (1912) was the first to exploit simple reaction time measures for assessing the participation of interhemispheric connections to visuomotor control in normal humans. In a task requiring subjects to press a key with the right or left hand in response to a light stimulus in the right or left visual field, he observed that direct responses, made with the hand ipsilateral to the stimulated field, were faster than crossed responses, made with the hand contralateral to the stimulated field. Knowing that each hemisphere receives inputs from the contralateral visual field and controls movements of the contralateral hand, he reasoned that the neural pathway for direct responses, arguably contained within one hemisphere, should be shorter than the neural pathway for crossed responses, which should include a passage from the hemisphere receiving the light stimulus to the hemisphere controlling the responding hand. He

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therefore concluded that the mean difference between crossed and direct responses, which he assessed to be 6 msec, is a measure of interhemispheric transmission time. Poffenberger’s (1912) results and conclusions have been substantially confirmed in many modem reaction-time (Agliotietal., 1991;Bashore, 1981;Berlucchietal., 1971; Di Stefanoetal., 1980; Jeeves, 1969; Levy & Wagner, 1984; Marzi et al., 1991; St.John et al., 1987) and event-related potential studies (Brown & Jeeves, 1993; Lines et al., 1984; Rugg et al., 1984; Saron & Davidson, 1989). In the conditions of these studies interhemispheric transfer time has been estimated to last 2-3msec. As there are no direct callosal connections between cortical visual areas on one side and cortical motor areas on the other, the interhemispheric transfer subserving crossed responses can be postulated to occur between corresponding visual or motor areas of the two sides, or between corresponding areas of the two sides which are interposed between visual and motor areas. In normal subjects interhemispheric transfer time does not vary in relation to such parameters of the visual stimulus as intensity and eccentricity, thus it seems likely that the transfer occurs beyond the visual cortical areas, possibly at a premotor stage of the response (Berlucchi, 1978; Rizzolatti, 1979). If crossed reactions are mediated by callosal connections, they should become slower, if not impossible, following a callosal section which destroys the most direct pathway between the hemispheres. Smith (1947) reported that in the commissurotomy patients operated on by Van Wagenen the difference between direct and crossed responses was the same before and after the operation, but he used a choice reaction-time paradigm, different from the Poffenberger paradigm, which was unsuitable for studying interhemispheric transfer (Berlucchi, 1978). Using Poffenberger’s simple reaction-time paradigm, the difference between crossed and direct responses was found to be much longer in subjects with callosal agenesis (Jeeves, 1969,1990; Milner, 1982) or section of the cerebral commissures (Aglioti et al., 1993; Clarke &Zaidel, 1989; Sergent& Myers, 1985) than in normal controls. In two complete commissurotomy patients of the California series,

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Sergent and Myers (1985) found interhemispheric transmission times of 30 and 50msec respectively, and Clarke and Zaidel (1989) reported interhemispheric transfer times varying from 35 to 96msec in four patients of the same series, including the two used in the Sergent and Myers study. Aglioti et al. (1993), estimated the interhemispheric transfer time to be as long as 130msec in a subject with a complete callosotomy. This huge difference between crossed and uncrossed responses could not be attributed to, and in fact was greater than, any possible spatial compatibility effect between stimulus and response (Aglioti et al., 1996). From the fact that in the callosotomy patient of Aglioti et al. (1993, 1996) the anterior commissure was intact it can be argued that this commissure can by no means compensate for the absence of the corpus callosum in the interhemispheric integration of fast crossed responses. In another patient with complete callosotomy but intact anterior commissure, a prolonged interhemispheric transfer time was assessed on the basis of motor asynchronies between the two corners of the mouth during posed smiles, in which each hemisphere controls movements of the contralateral half lips (Gazzaniga & Smylie, 1990). These authors found that in response to a lateralised visual command to pose a smile, the mouth corner ipsilateral to the command moved before the contralateral mouth corner, and the inferred interhemispheric transfer time was comparable to that estimated with manual responses in other commissurotomy patients (Aglioti et al., 1993; Clarke & Zaidel, 1989; Sergent & Myers, 1985). There were no buccal asymmetries in spontaneous smiling responses to lateralised visual stimuli, most probably because unlike posed facial expressions, emotional expressions engage motor pathways projecting from each hemisphere to both halves of the mouth (Gazzaniga & Smylie, 1990). Similarly, in agreement with previous findings by Di Stefano et al. (1980) in normal subjects, Aglioti et al. (1993) concluded from data from a callosotomy subject that crossed responses made with proximal and para-axial muscles of the upper limb do not need an interhemispheric integration. Unlike distal hand movements, these movements can be executed through bilaterally distributed

motor systems which allow each hemisphere to exert a direct control on the appropriate motoneurones of both sides (Brinkman & Kuypers, 1973; Kuypers, 1981), hence no interhemispheric transfer is required in the crossed response condition (Berlucchi et al., 1995). In the absence of the corpus callosum, interhemispheric transfers required for crossed responses probably occur by way of brainstem pathways. In subjects with callosal agenesis, interhemispheric transfer by these putative brainstem pathways differs from that subserved by the corpus callosum because it is sensitive to parameters of the visual stimulation, varying directly with the eccentricity of the stimulus and inversely with its intensity (Milner, 1982; Milner & Lines, 1982; Milner et al., 1985). Attempts to test for similar relations between interhemispheric transfer time and parameters of visual stimulus in commissurotomy patients have yielded controversial and not easily interpretable results (Clarke & Zaidel, 1989; Sergent & Myers, 1985). In normal subjects interhemispheric transfer time is somewhat faster from the right hemisphere to the left than vice versa, as shown by both reaction times (Bisiacchietal., 1994; M arzietal., 1991)and event-related potentials (Brown et al., 1994), but this asymmetry is not apparent in extracallosal interhemispheric transfer. With regard to topographic specificity of the callosal transfer subserving crossed responses, studies of cases with unilateral cortical lesions suggest that the transfer uses predominantly the anterior part of the corpus callosum (Arutiunova & Blinkov, 1962; Lines etal., 1984;Ruggetal., 1984; Tassinari, 1981; Vallar et al., 1988c). In agreement with this, Di Stefano et al. (1992) found an abnormally prolonged interhemispheric transfer time in a patient with an anterior callosotomy which presumably spared the splenium. By contrast, Tassinari et al. (1994) found that interhemispheric transfer time was normal in patients with extensive anterior callosotomies which spared the isthmus and the splenium. Similarly, Iacoboni et al. (1994) found a normal interhemispheric transmission time in an anterior callosotomy patient sparing the splenium, at least when the light stimuli were presented within four degrees of the vertical meridian. A normal interhemispheric transmission time in subjects with

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anterior callosotomies is not necessarily incompatible with the hypothesis that the interhemispheric transfer required for crossed responses is premotor rather than visual in nature. Indeed the splenium and isthmus of the corpus callosum contain not only fibres originating from purely visual cortical areas, but also fibres running between posterior parietal cortical areas which are known to transduce visual inputs into motor responses (Tassinari et al., 1994). The discrepancies between the findings of Di Stefano et al. (1992), Tassinari et al. (1994), and Iacoboni et al. (1994) can be explained by assuming that such callosal fibres between posterior parietal cortices were totally severed in the case of Di Stefano et al., totally spared in the case of Tassinari et al., and partially spared in the case of Iacoboni et al. On the other hand, one cannot exclude some kind of functional equivalence between different callosal portions in the interhemispheric transfer mediating crossed responses. It might be supposed that the emission of a nondiscriminative verbal response to a lateralised light stimulus should be faster if the stimulus is presented in the right field, hence directly to the left hemisphere. While it cannot be doubted that the left hemisphere is responsible for the organisation of verbal responses, simple visuomotor reaction times of such responses are not suitable for seeking symptoms of interhemispheric disconnection. Tassinari et al. (1983) showed in normal subjects that the speed of emission of monosyllabic (“si” [yes], “no” [not]) orbisyllabic words (“otto” [eight], “nove” [nine]) in response to a lateralised light flash did not vary with the side of the stimulus. But when the task was changed from a simple to a choice reaction time task by requiring subjects to use those verbal responses for discriminating structured lateralised stimuli (for example by saying “otto” when seeing the digit 8), then the response speed was significantly greater with right than left field stimuli. Tassinari et al. (1983) believe that though verbal responses are articulated by the left hemisphere, they are initiated by centrencephalic structures which can be activated by either hemisphere. When lateralised visual verbal stimuli are to be discriminated, verbal response initiation must be preceded by a stimulus recognition which is faster in the right field because it is effected more

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efficiently by the left hemisphere than by the right. In the case of a nondiscriminative task, the speed of initiation of a verbal response to a lateralised stimulus is the same for right and left stimuli because both hemispheres can activate the centrencephalic command system in an equally fast manner. In accord with this concept, a study by Sergent and Myers (1985) reported that in three commissurotomy patients the latency of the verbal response “cat” to lateralised light flashes was the same for right and left stimuli. Recent experiments on another callosotomy patient have confirmed that both hemispheres have access to a centralised mechanism for vocal control, and therefore simple vocal reaction times cannot provide a reliable measure of interhemispheric transmission time (Reuter-Lorenz et al., 1995). Binocular stereopsis The basic mechanism for binocular depth perception, as well as for the perception of egocentric distance and tridimensionality of an object, is provided by populations of special neurones of visual cortical areas which receive binocular information. Each of these neurones codes for a specific horizontal disparity between the two retinal images of a target lying at a certain distance from the observer, so that the disparity coded by each neurone corresponds to a given distance between target and observer (Bishop, 1981; Rizzo, 1989). The neural coding of the distances of targets on the midsagittal plane in front of or behind the fixation point presents some peculiarities, as the two images of each of these targets lie on heteronymous retinal halves, both nasal or both temporal (Hubei, 1988). Most of the central projections of heteronymous retinae go to different cerebral hemispheres; only in a narrow strip of each retina, less than one degree across and lying along the vertical meridian, is there an overlap between ganglion cells projecting to one or the other hemispheres (nasotemporal overlap). Information from the two eyes, which is needed for coding the distances of targets lying on the midsagittal plane, can converge onto single neurones in two ways: 1. Intrahemispherically, if the interocular disparity corresponding to the distance of the target is so

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small that the target’s two monocular images lie in the strip of nasotemporal overlap that projects to both hemispheres. 2. Interhemispherically, if the disparity for the target distance is such that its two images in heteronymous retinal halves lie outside the strip of nasotemporal overlap, so that they are projected to different hemispheres. In the second case, the coding of target distance is effected by neurones that receive binocular information about the target via intrahemispheric visual projections from one eye and interhemispheric callosal visual projections from the other eye (Blakemore, 1969). A removal of the latter projections by a callosal section should render the aforementioned neurones monocular, such that they would lose the ability to code for disparity. The images of targets lying to the right or left of the midsagittal plane, whatever their distance from the observer, are always formed on homonymous hemiretinae, and therefore in no case does binocular convergence onto single neurones require an interhemispheric transfer of information. In agreement with the results of experiments on callosotomised macaques (Cowey, 1982; Cowey & Wilkinson, 1991)andcats (Timney etal., 1985),the threshold for stereoptic acuity has been found to be normal across the entire visual field of total commissurotomy patients (Bridgman and Smith, 1945; Gazzaniga et al., 1965), probably because the disparities tested were sufficiently small to allow processing by a single hemisphere in all cases. When stimuli with larger disparities are used, the binocular performance of commissurotomy patients is quite normal if the targets are presented off the midsagittal plane, but fails when the targets are presented on the midsagittal plane, so that cooperation between the hemispheres is required for binocular disparity coding. A visuomotor correlate of this astereoptic deficit consists in the inability of the same patients to produce appropriate convergent or divergent eye movements for fixating targets on the midsagittal planes. This inability is in contrast with the patients’ normal ability to produce appropriate vergence eye movements for fixating targets off the midsagittal plane (Westheimer & Mitchell, 1969).

More recently Lassonde (1986) has described a deficient performance of commissurotomy patients or genetically acallosal subjects in depth perception over the entire visual field. This deficit could be observed only when targets were presented tachistoscopically, as performance was normal when stimulus exposure was not limited in time. Lassonde (1986) has ascribed these findings to the lack of a callosal unspecific and diffuse facilitatory action which is necessary for the optimal functioning of visual centres, especially during tachistoscopic vision. Other researchers have instead reiterated that deficits in binocular stereopsis due to corpus callosum section (Hamilton & Vermeire, 1986; Hamilton et al., 1987; Jeeves, 1990) or agenesis (Jeeves, 1990) are selectively limited to the vertical meridian region of the visual field. In partial contrast with previous work, a recent study by Lassonde and her co-workers (Rivest et al., 1994) has reported that subjects with callosal agenesis can compare binocular depth cues across the hemispheres. However they are unable to use monocular cues, such as parallax, in the same kind of task. Visual imagery Zaidel and Sperry (1974) postulated that in commissurotomy patients verbal processes in the left hemisphere lack the usual support from visual images presumably generated in the right hemisphere. In a test of this assumption, Milner et al. (1990) compared commissurotomy patients and control brain-damaged patients with at least partly intact commissures in tasks involving the recall of word associations. Sometimes the recall was cued with visual images, sometimes it was not. Normally the recall of an association between two semantically unrelated words, such as elephant and flower, can be facilitated by generating a visual image linking the two words, for example a trunk holding a rose. Milner et al. (1990) found that the recall performance of commissurotomy patients was significantly inferior to that of control patients in the facilitated and non-facilitated conditions alike, but in both groups recall was clearly facilitated by visual imagery. While one can thus agree with Zaidel and Sperry (1974) that commissurotomy reduces general memory functions,

28. INTERHEMISPHERIC DISCONNECTION 651

their hypothesis that the effect is exerted by interfering with visuoverbal associations is not supported. As mentioned by Milner et al. (1990), the basic assumption that visual images are generated in the right hemisphere is not proven. If visual image generation occurs in the left hemisphere as well, obviously the recall of words association could be cued by visual imagery within the same hemisphere independent of the cerebral commissures. Only relatively recently attempts have been made to look for differences in visual imagery processes between the two hemispheres, and to analyse how the two disconnected hemispheres of commissurotomy patients generate visual images and utilise them for cognitive purposes (Corballis & Sergent, 1988, 1989; Farah et al., 1985; Kosslyn, 1987; Kosslyn et al., 1985). Relevant for the interpretation of the results of Milner et al. (1990) is the hypothesis that the left hemisphere has a primary role in the generation of visual images (Trojano & Grossi, 1994), at least when the imaged objects or symbols are divided into their component parts (Farah et al., 1985; Kosslyn, 1987; Kosslyn et al., 1985). Arguably, visual images generated for facilitating the association between semantically unrelated words are indeed composite images.

Audition Dichotic listening test Auditory deficits in commissurotomy patients have been reported for the first time by Milner et al. (1968) and by Sparks and Geschwind (1968). In the Milner et al. study (1968), series of three pairs of digits were delivered dichotically. For each pair, the number presented to the right ear (e.g. three) was different from that presented to the left ear (e.g. six). Subjects were instructed to report in a free order all the digits they remembered for each series. In tasks of dichotic presentation of digits, right-handed normal subjects perform slightly but significantly better with the right ear than the left ear (Kimura 1961; 1967). Milner et al. (1968) found that commissurotomised subjects tested with dichotic stimuli, though able to perform within the normal range with the right ear, were severely impaired in reporting digits presented to the left ear. No digits

presented to the left ear were reported by five out of seven patients; and the left ear performance was very poor in the two remaining patients. As the same patients made no errors in reporting digits presented monoaurally to either ear, their left ear impairment under dichotic listening conditions could not be attributed to a primary auditory deficit. In a simultaneous but independent study on another commissurotomy patient tested with a similar method, Sparks and Geschwind (1968) found a comparable pattern of deficits that they called “left ear extinction”. As shown by Milner et al. (1968) the term is inappropriate if it is taken to mean that left ear messages are consistently suppressed by concurrent right ear messages. When instructed to execute with the left hand and while blindfolded different orders that were dichotically delivered (for example, “take the clip” to the left ear and “find the eraser” to the right ear), their commissurotomy patients typically executed the order delivered to the left ear and ignored the order received by the right ear. They could, however, repeat the right ear order but not the left ear order, suggesting that though their right hemisphere could understand the left ear order and carry it out with the left hand, it did not have the ability to express itself through the vocal apparatus. In summary, both studies suggest that in commissurotomy patients, dichotically delivered auditory stimuli are processed separately in the two hemispheres: the left hemisphere processes right ear stimuli for both verbal and nonverbal responses, whereas the right hemisphere processes left ear stimuli only for nonverbal responses. Several subsequent studies have confirmed that under dichotic listening conditions the left ear (or the ear ipsilateral to the hemisphere dominant for language) of commissurotomy patients is less competent than the opposite ear in tasks requiring the written or oral recognition of linguistic stimuli, like digits, or monosyllabic or bisillabic words (Corballis & Ogden, 1988; Efron et al., 1977; Milner etal., 1990;Musiek&Kibbe, 1985;Musiek & Reeves, 1986; Sidtis et al., 1981; Springer etal., 1978; Springer & Gazzaniga, 1975; Tweedy et al., 1980; Wale and Geffen, 1986). The basic mechanisms underlying this effect are not completely understood. The auditory pathways are distributed bilaterally, so that each cochlea sends

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information to both hemispheres and each hemisphere receives information from both cochleae, independently of the cerebral commissures. The performance of commissurotomy patients in dichotic listening tests can be accounted for only by complex interactions between the two cochlear-cortical channels. Studies in intact subjects and patients with unilateral temporal lesions suggested that the neural pathway from each cochlea to the ipsilateral hemisphere is at least partially “occluded” under dichotic listening conditions (Kimura, 1961, 1967). According to this hypothesis, when there is a competition between signals from the two ears, the functionally predominant crossed pathway would tend to silence the uncrossed pathway. Sparks and Geschwind (1968) attempted to explain the different performance of normal and commissurotomy subjects in dichotic listening tests by combining the hypothesis of the occlusion of the uncrossed auditory pathway with the hypothesis of an interhemispheric callosal transfer of auditory information. Based on the notion that the verbal report of linguistic stimuli depends on the left hemisphere, these authors postulated that in normal subjects performing dichotic listening tasks the language-dominant hemisphere receives direct information from the right ear and indirect, callosally transmitted information from the left ear and the right hemisphere. After commissurotomy, the left hemisphere can normally receive dichotic stimuli from the right ear but not from the left ear. Verbal reports of stimuli monaurally delivered to the left ear would be possible because in the absence of competing signals from the right ear the uncrossed auditory input to the left hemisphere would not be occluded. This model cannot be entirely accepted for several reasons. First, in dichotic listening commissurotomy patients can verbally report not only stimuli delivered to the right ear but also some of the stimuli delivered to the left ear (Milner et al., 1968; Springer & Gazzaniga, 1975; Springer et al., 1978, Tweedy et al., 1980). The commissurotomy patient studied by Sparks and Geschwind (1968) showed a total left ear “extinction” in the first sessions, but after several additional trials he was able to report some left ear stimuli, particularly

when attention was focused on that ear. The importance of attentional factors has been confirmed in dichotic listening studies in which commissurotomy patients showed an increased ability verbally to report left ear stimuli when attention was focused on that ear compared to when it was allocated to both ears (Corballis & Ogden, 1988; Wale & Geffen, 1986). Finally, commissurotomy patients can equal the performance of normal subjects in tasks requiring the fusion into a single percept of phonologically complementary dichotic stimuli, such as “back” to the left ear and “lack” to the right ear, to be fused into the single word “black” (Geffen, 1980; Springer etal., 1978). If one also considers that unilateral hemispherectomy reduces, but by no means suppresses, the capability to process information from the contralateral ear under dichotic listening conditions (Corballis & Ogden, 1988; Lassonde et al., 1990; Nebes et al., 1981; Wale & Geffen, 1986), it is evident that the hypothesis of a complete occlusion of the uncrossed pathway by the crossed pathway during dichotic listening becomes indefensible, and the participation of the forebrain commissure to auditory information processing must be redefined. A different model has been proposed by Kinsbourne (1975, 1980) who posited that the selective activation of one hemisphere induces a shift of attention towards the contralateral hemispace, thus facilitating the processing of information from that hemispace at the expense of the information from the ipsilateral hemispace. Tasks involving verbal responses to verbal dichotic stimuli would selectively activate the left hemisphere, thus causing a shift of attention towards the right acoustic hemispace; and as dichotic signals from each ear are localised to the corresponding acoustic hemispace, such attentional shift would result in a processing bias in favour of the right ear. In normals, this bias effect would be considerably limited by callosally transmitted inhibitory influences of the right hemisphere onto the left hemisphere, but in commissurotomy patients the attention-related interaural imbalance in information processing would be much greater. This theory is also open to substantial criticisms. In commissurotomy patients, dichotic information from each ear can produce independent responses

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in parallel (e.g. verbal responses to right ear stimuli and pointing responses to left ear stimuli), thus suggesting that the postulated attentional imbalance is absent, or at best not sufficient for totally suppressing the processing of information from the ear ipsilateral to the activated hemisphere. In addition, dichotic tests using nonverbal stimuli such as melodies, which are supposed to activate the right hemisphere, do not suppress the right ear-left hemisphere channel (Milner et ah, 1990). Finally, hemispherectomy patients can perceive dichotic stimuli delivered to either ear (Corballis & Ogden, 1988; Lassonde et al., 1990; Nebes et al., 1981; Wale & Geffen, 1986), and shift their attention between ears (Wale & Geffen, 1986). To the extent that Kinsbourne’s hypothesis predicts that hemispherectomy should abolish the capability to pay attention to and even perceive stimuli from the contralateral ear (Kinsboume, 1975), the prediction is directly undermined by these results. But the strongest evidence against Kinsboume’s hypothesis is the “paradoxical extinction of the left ear” that can be observed in left brain-damaged patients in verbal dichotic listening tests (Damasio & Damasio, 1979). This phenomenon can only be accounted for by assuming that the lesion interrupts callosal fibres carrying left ear auditory information from the right hemisphere to the left hemisphere (Damasio & Damasio, 1979). Other studies suggest that the auditory callosal connections can transmit perceptual information while a stimulus is on, and mnestic information after the stimulus has disappeared. Verbal stimuli presented to the left ear can be temporarily stored in the right hemisphere and sent to the left hemisphere as soon as it has completed the processing of verbal stimuli presented to the right ear (Corballis & Odgen, 1988). Perception o f tonal sequences and rhythms Another symptom of interhemispheric disconnection in the auditory domain has been reported in commissurotomy patients by Musiek and Kibbe (1985) and Musiek and Reeves (1986) in tasks requiring verbal reports of tone sequences monaurally presented to each ear in turn. Each sequence consisted of three pure tones, two of which had identical frequencies. Patients were instructed

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to verbalise the temporal succession of the tone’s frequencies (for example, by saying high-low-low, or low-high-low). Patients who were able to perform the task before commissurotomy, responded after the operation at chance regardless of the ear that was stimulated. The presence of peripheral auditory disturbances was ruled out by the correct shadowing by the same patients of words presented to each ear, even when the word stimuli were distorted by a low-pass filter. Musiek and Kibbe (1985) and Musiek and Reeves (1986) postulated that the tonal sequence discrimination task relies on first, the identification of the “musical” configuration of each sequence, probably carried out in the right hemisphere, and second, its verbal description, probably performed by the left hemisphere. In intact subjects, the corpus callosum seems indeed involved in the interhemispheric cooperation assumed to subserve the perception of tonal sequences as well as the discrimination of rhythms, as suggested by a specific impairment of patients with lesions to the anterior part of the corpus callosum in related tasks (Nakamura et al., 1984). In addition, patients with agenesis of the corpus callosum showed a clear impairment in tasks requiring the localisation of tones delivered to different points of the extrapersonal space (Poirier et al., 1994).

Somaesthetic functions An analogy with the visual system would suggest that the main signs of interhemispheric disconnection in the tactile domain should be the following: (1) inability to use verbal responses for identifying somaesthetic stimuli felt by the right hemisphere, and (2) inability to combine somaesthetic information delivered to, and match tactile stimuli felt by, different hemispheres. It is worth remembering, however, that the anatomic organisation of the somaesthetic system makes it difficult to channel stimuli into a single hemisphere. Indeed, the medial lemniscus system, mainly involved in the transmission of tactile and proprioceptive inputs, and even more the spinothalamic system, mainly transmitting thermic and pain sensations, project not only contralaterally but also ipsilaterally. While the ipsilateral connections from distal body parts are almost

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absent, those from axial and proximal body parts are dense. Moreover, somaesthetic afferents from the face go to both ipsi- and contralateral cortical areas. Thus, it is not surprising that commissurotomy patients do not show striking disconnection deficits when requested to detect single somaesthetic stimuli (for review see Bogen, 1985, 1987, 1993; Gazzaniga, 1970; Sperry et al., 1969). Commissurotomy patients are typically able to indicate, both verbally and nonverbally, the onset and end of tactile, pressure, thermic, or pain stimuli, no matter if these are delivered to a left or right body part (Sperry et al., 1969; Bogen, 1985, 1987, 1993). In both agenetic and commissurotomy patients an increase of the threshold for tactile acuity is observed only when stimuli are delivered to body parts densely connected through the corpus callosum, for example the trunk but not the hands (Schiavetto et al., 1993). More complex discrimination tasks are required for disclosing additional signs of interhemispheric disconnection in the somaesthetic domain. Tactile localisation The capability of split brain patients to name the locus of stimulation is normal for stimuli delivered to virtually any point of right hemibody. A different pattern emerges when stimuli are delivered to the left side of the body. Stimuli delivered to the left face, neck, and trunk are localised correctly even with a verbal response; by contrast, the capability to report stimuli delivered to the left distal extremities, for example the tips of the fingers, is not perfect. Verbal localisation reports of commissurotomy patients are correct when they are touched on the left wrist, palm, or thumb, but they perform poorly when they have to discriminate verbally whether or not two stimuli are applied to contiguous left fingers. Nonetheless these patients perform accurately when they are asked to localise a touched point on a given finger by using a nonverbal, pointing response. The poor naming performance with stimuli to the left fingers can be attributed to: (1) too coarse a representation of the left hand in the left hemisphere; and/or (2) a disconnection of the presumably accurate representation of the left hand in the right hemisphere from the linguistic centres in the left hemisphere.

Another disconnection sign has been detected by assessing the capability to localise touches on fingers by means of intramanual or intermanual nonverbal, pointing responses. In the intramanual task, patients are asked to touch with the thumb a finger of the same hand after it has been touched by the examiner. In the intermanual task, the examiner touches points on the fingers of one hand and patients are requested to touch with the opposite thumb the corresponding points of the fingers of the nonstimulated hand. Commissurotomy patients perform well in the intramanual task, but poorly in the intermanual task, in which, however, they score better than chance. In Geffen et al.’s (1985) study, for example, correct intramanual localisations were nearly 100% in both commissurotomy and control subjects, while the percentages of correct intermanual localisations were 18% in commissurotomy patients and 95% in controls. In tasks requiring the replication of sequences of touches delivered to the fingers, commissurotomy patients make several mistakes no matter whether touches are given to a single or both hands (Bentin et al., 1984; Geffen et al., 1985). This impairment is likely to be due to difficulties in perceiving and memorising the sequences of stimuli, and in planning and executing the corresponding sequences of actions, rather than to an altered tactile perception per se. This hypothesis is supported by the fact that commissurotomy patients also perform poorly in tasks requiring the imitation of visually perceived sequential movements executed by the examiner (Milner & Kolb, 1985). Stereognosic anomia o f the left hand The most evident sign of interhemispheric disconnection in the somaesthetic domain is a stereognosic anomia that can be erroneously considered as a unilateral astereognosis. This sign consists in an inability to use tactile and proprioceptive information (and sometimes even thermic and pain information) for naming objects palpated with the left hand. A blindfolded commissurotomy patient is typically able to name objects felt with the right hand but cannot name objects palpated with the left hand. This inability cannot be accounted for by a deficit in object recognition (tactile agnosia), because even minutes

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after palpating an object with the left hand, commissurotomy patients can use the same hand for the blind retrieval of the same object, or another object semantically associated to it, from among a number of distractors. In spite of these normal stereognosic capabilities, commissurotomy patients perform poorly in tasks requiring the integration of stereognosic information across the two hands. For example, they are unable to use one hand for the blind retrieval of an object identical to that held in the other hand; similarly, they cannot judge correctly whether an object held in one hand is the same as or different from the object held in the other hand. Thus, a complete commissurotomy abolishes perceptual equivalence between the hands as well as between the visual fields, and agrees with the lack of intermanual transfer of stereognosic discriminations of commissurotomised animals. Proprioception McCloskey (1973) found no impairment in the capability to match proprioceptive information from the two sides of the body in two complete commissurotomy patients of the California series. When blindfolded, these patients were able to reproduce with one forearm postures imposed by the experimenter to the other forearm, suggesting a normal capability to match muscle and joint information from the two sides. They were also able to cross-integrate vibratory stimuli applied to the brachial biceps and triceps muscles of the two sides, giving rise to illusory perceptions of forearm movements, or to respond accurately to selective activations of the distal interphalangeal joint of either middle fingers. The fact that they could use words accurately to describe the illusory or veridical perception arising from stimulations of either upper limb attested that the speaking hemisphere could receive proprioceptive information from both sides. These data stand in contrast to Gazzaniga’s (1970) suggestion that commissurotomy patients can give a verbal description of postures imposed to the left limbs only by means of “cross-cueing” strategies based on changes in the tone of represented trunk muscles specifically associated with specific limb postures, which by being represented bilaterally can provide the relevant information to either hemisphere. Moreover, the two commissurotomy

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patients studied by McCloskey matched weights held in the two hands in a normal fashion (Gandevia, 1978), possibly because they could make a cross comparison of the motor efforts necessary to support the weights. In sum, the projection of proprioceptive information to either hemisphere from the limbs of each side, even from their distal joints, seems sufficient to explain the persistence of interlimb perceptual equivalence in the proprioceptive modality in commissurotomy patients, as well as their ability verbally to describe both right and left proprioceptive stimuli. Nevertheless, commissurotomy patients were found to be unable, when blindfolded, to copy with one hand complex postures of the fingers imposed to the other hand (Bogen 1985,1987,1993; Sperry et al., 1969), possibly because the reproduction of postures involving multiple joints in many fingers requires an interhemispheric integration of proprioceptive and motor information much more complex than that involved in the reproduction of postures involving a single joint. Impairment o f nonverbal stereognosic memory Milner and Taylor (1972) asked seven commissurotomy patients to feel abstract structures made out of wire with one hand and then match those stimuli using the same or the other hand, either immediately or after a delay. In addition to the expected inability of all patients to perform intermanual comparisons, in six of them there was a striking superiority of the left hand over the right in the intramanual condition, supporting the predominance of the right hemisphere in perceiving and memorising complex stimuli that are difficult to label verbally. The intramanual performance of either hands of the commissurotomy patients was significantly inferior to that of both hands of control subjects with noncommissural brain damage who could also correctly perform intermanual comparisons. This suggests that an interhemispheric cooperation through the forebrain commissures is involved not only in intermanual, but also in intramanual comparisons of abstract, nonverbalisable stimuli. The difference between the intramanual performances of commissurotomy and control patients became particularly marked with long delays, where the former patients performed at

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chance while the latter did not. This may mean that the contribution of the forebrain commissures to a successful performance in this task has mostly to do with memory processes (Milner et ah, 1990).

Olfaction Latéralisation o f the olfactory pathways Unlike other sensory pathways, the olfactory pathways are almost exclusively uncrossed. Information from primary sensory neurones in the olfactory epithelium of each nostril is transmitted to the olfactory bulb of the same side. The axons of the projection neurones of the olfactory bulb form the lateral olfactory tract that reaches the ipsilateral olfactory cortex, consisting of paleocortical (prepiriform and periamigdaloid areas) and mesocortical components (entorhinal area). The interhemispheric transmission of olfactory information does not involve the corpus callosum and relies upon the anterior and hippocampal commissures. Anomiafor olfactory stimuli presented to the right nostril and loss o f perceptual equivalence between the nostrils. Gordon and Sperry (1969) described in complete commissurotomy patients an olfactory anomia that was confined to the right nostril and was probably due to an olfacto-verbal interhemispheric disconnection. These patients were perfect in naming odourants (perfumes, mint essence, coffee powder, and so on) presented to the left nostril but failed badly in the same task when stimuli were presented to the right nostril. However, odourants presented to the right nostril were recognised correctly by using nonverbal responses. For example, lemon essence presented to the right nostril was not sufficient for these patients to say “lemon” but allowed them to select a lemon from among other objects by palpation with the left hand. Analogous results have been obtained in another complete commissurotomy patient by Gazzaniga et al. (1975). This behaviour of commissurotomy patients is likely to depend on the absence of interhemispheric connections between the right olfactory cortices, receiving information from the right nostril, and the language centres in the left hemisphere. Another consequence of the olfactoverbal disconnection is the inability of complete

commissurotomy patients to categorise as same or different odourants presented separately to each nostril (Gordon & Sperry, 1969). A role for the anterior commissure. Experimental research in rats has shown that this commissure is crucial for the internostril transfer of conditioned responses to olfactory stimulation (Teitelbaum, 1971). The anterior commissure appears to have a similar role in humans, as patients with section of the callosum and the hippocampal commissure, but an intact anterior commissure, can name odourants presented to the right nostril (Risse et al., 1978). Patients with callosal agenesis, who have normal or larger than normal anterior commissures, are typically able to name odourants no matter if presented to the left or the right nostril (Jeeves, 1990). Other pathways, however, may under some circumstances mediate the interhemispheric transfer of olfactory information, as a patient with a section of the anterior part of the corpus callosum, of the ventral hippocampal commissure, and the anterior commissure was able to name odorants presented to the right nostril (Gordon et al., 1971). This capability might depend on a transfer from the right hemisphere to the left, via the posterior part of the corpus callosum, of a visual transform of the olfactory stimulus. An alternative explanation is that Gordon et al.’s patient was able to transfer olfactory information between the hemispheres through the dorsal hippocampal commissure. However mediated, the interhemispheric transfer of olfactory information was far from perfect in both the Gordon et al. ’s patient (1971) and Gazzaniga et al.’s patient (1975).

Motor control Praxis A sign commonly observed after a complete commissurotomy, particularly in the acute stage, is the so-called callosal ideomotor dyspraxia of the left limbs consisting in an impaired ability to use those limbs for executing movements verbally described by the experimenter (Bogen, 1985,1987, 1993; Gazzaniga et al., 1967; Sperry et al., 1969). At variance with the classical bilateral ideomotor apraxia following lesions of the left hemisphere (see

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Chapter 18), patients with callosal dyspraxia have no difficulties in performing appropriate movements with the right limbs to oral or written commands, and can perfectly imitate with either right or left limb movements performed by the experimenter. It is worth noting that in contrast with their left ideomotor dyspraxia, commissurotomy patients do not display any deficit in the use of the left hand in typical tests of ideational and constructional apraxia, and their praxic control of the orofacial and trunk musculature is fully normal (Bogen, 1969; Gazzaniga et ah, 1967; Zaidel & Sperry, 1977). Soon after the operation, commissurotomy patients may not even try to execute very simple verbal orders like “move the fingers of your left foot” or “make a fist with your left hand”, but the suspicion of a severe paresis is ruled out by the spontaneous occurrence of the very same motor acts that cannot be carried out on verbal command (Bogen, 1985, 1987, 1993). As time elapses, callosal dyspraxia is less evident although disorganisation, slowness, or imprecision of left hand movements to verbal command may be detected months or even years after the operation, especially by comparison with the perfect praxis of the right limbs. The residual dyspraxic deficits mostly affect distal movements and are particularly evident during actions requiring compounded postural adjustments and movements of hand and fingers, such as those, for example, involved in making the “hitchhike” sign (Zaidel & Sperry, 1977). Signs of callosal apraxia have been described after a posterior callosotomy (Volpe et al., 1982) but were found to be absent following an anterior commissurotomy sparing the splenium (Gordon et al., 1971), indicating that callosal dyspraxia is selectively caused by the interruption of posterior callosal connections. Commissurotomy patients with callosal dyspraxia can correctly imitate drawings of hand and finger postures presented in either visual hemifield, but only when they use the hand ipsilateral to the stimulation side, in which case the accuracy of the two hands is comparable. By contrast, these patients are clearly impaired if they have to imitate with either hand drawings of hand and finger postures presented in the contralateral visual hemifield (Gazzaniga et al., 1967). This impairment can

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be entirely accounted for by the disconnection between the hemisphere receiving the visual stimulus and the hemisphere controlling the motor response. Zaidel and Sperry (1977) examined eight complete commissurotomy patients from the California series and found a 100% accuracy in the ipsilateral visual hemifield-hand combinations. In the contralateral combinations, performance was much better in the right hemifield-left hand combination (80-90%) than in the left hemifield-right hand combination (25%), suggesting a possible control of the motility of the left upper limb by the left hemisphere. In three patients of another series who had a complete section of the corpus callosum but an intact anterior commissure, Volpe et al. (1982) found the following percentages of correct responses: ipsilateral left hemifield-hand combination 75-90%; ipsilateral right hemifield-hand combination 80-90%; left hemifield-right hand combination 10-19%; right hemifield-left hand combination 0-10%. The partial difference between these results and those of Gazzaniga et al. (1967) and Zaidel and Sperry (1977) lies in a comparatively much lower percentage of successes in the contralateral combinations, and a comparatively smaller superiority of the right hemifield-left hand combination over the left hemifield-right hand combination in the Volpe et al.’s study (1982). Gazzaniga et al. (1967) reported that commissurotomy patients were able to carry out instructions consisting of written verbs (e.g. “smile” or “tap”) presented tachistoscopically to the right hemifield and thus to the left hemisphere. The appropriate movements were made by using effectors of the right side of the body or axial muscles. The same patients systematically failed the task when the written orders were presented in the left hemifield, no matter whether the appropriate motor responses had to be performed with axial muscles (e.g. “stand up”) or with the left hand (e.g. “knock”). However they could perform the act of “knocking on a door” in response to a graphic representation of the act which was tachistoscopically projected to the left hemifield and the right hemisphere. These patients were also unable to choose from among different distractors the graphic representations of actions that corresponded to written verbs presented in the left hemifield (Gazzaniga et al., 1967), suggesting that the

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verbal orders could not be performed simply because of the right hemisphere’s inability to understand them. This consideration underlines the difficulty of separating truly dyspraxic disorders from comprehension defects in commissurotomy patients. The possible role of comprehension defects in bringing about a seemingly dyspraxic behaviour was tested by Zaidel and Sperry (1977) in two commissurotomy patients who in the Gazzaniga et al. study (1967) had proven unable to carry out written orders presented in the left hemifield. They were now presented with groups of four graphic representations of actions in the left hemifield, and were asked to point with the left hand to the one in each group that fulfilled an order read aloud by the examiner. From the finding that the patients’ choices were correct on 80% of the trials, Zaidel and Sperry (1977) inferred that the previous failure of the same patients to carry out written commands presented to the right hemisphere was not due to a failure of this hemisphere to understand verbal commands, but rather to its inability to translate the commands into appropriate motor acts. In a subsequent study employing a technique that allowed a prolonged stimulation of the right hemisphere, Zaidel (1978) observed in the same two commissurotomy patients that their right hemisphere was partially able to understand visually presented action verbs, though not as well as when the same stimuli were acoustically presented. Gazzaniga (1983a) has argued that whereas all commissurotomy patients can correctly perform movements in response to nonverbal commands delivered to their right hemisphere, they can be divided into three categories on the basis of the differential efficiency of their right hemispheres in fulfilling verbal commands. The great majority of commissurotomy patients cannot execute any type of oral or written commands presented to their right hemisphere because of this hemisphere’s total inability to understand language. In a second category, comprising a minority of commissurotomy patients who can be considered as genuinely dyspraxic, the right hemisphere can understand some verbal orders but cannot generate appropriate motor responses to them. Even less numerous are the commissurotomy patients of the

third category, whose right hemispheres can understand and execute written or oral commands with an efficiency comparable to that of the left hemisphere. Three patients with this ability have been extensively studied by Gazzaniga and coworkers (Baynes et al., 1992; Gazzaniga, 1983a; Gazzaniga etal., 1977; Gazzaniga &Ledoux, 1978; Nass & Gazzaniga, 1987; Sidtis et al., 1981; Volpe et al., 1982). The only dyspraxic behaviour observed in these patients was the inability to imitate with one hand postures presented in the opposite visual hemifield (Volpe et al., 1982). Taken together, the results suggest the following: 1. Whereas classic (Liepmann, 1900; Liepmann & Maas, 1907) and modern studies (Geschwind, 1965a, b, 1975; Kimura & Archibald, 1974) in brain-damaged patients emphasised the role of a praxic centre lateralised to the left hemisphere, evidence from commissurotomy patients shows that both hemispheres can independently exert a praxic control on the contralateral limbs. 2. The left hand dyspraxia on verbal commands of commissurotomy patients is mainly due to the inability of the right hemisphere to understand the commands and translate them into motor acts, rather than to the disconnection of the left hand representation in the right hemisphere from a unilateral “praxic centre” in the left hemisphere. 3. In some patients, each hemisphere can exert a variable, but generally rudimentary, control on praxic and motor functions of the ipsilateral limbs. 4. In many severe apraxic patients with pathologic brain damage involving the cerebral commissures (see Brion & Jedynak, 1975; Geschwind & Kaplan, 1962; Graff-Radford et al., 1987; Watson & Heilman, 1983) apraxia is probably due to summation or interaction effects between the commissural lesions and the noncommissural lesions associated with them. This may also be true of the severe left limb apraxia observed in the acute post-operative stage of commissurotomy surgery which must inevitably involve some unintended damage to extracommissural brain structures (Bogen, 1985, 1987,1993; Sperry etal., 1969).

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Copy o f complex motor sequences A severe impairment in copying complex sequences of limb or orofacial movements has been reported in complete commissurotomy patients. These deficits were bilateral and even more severe than those observed in patients with left parietal and frontal lesions. As no impairment was observed in the copying of single movements, it is plausible that commissurotomy causes deficits in the memorisation or retrieval of the order of single movements in the sequence (Milner & Kolb, 1985). Manual dexterity and bilateral motor co-ordination Routine clinical examinations do not reveal any clear-cut deficit in bilateral motor co-ordination in commissurotomy patients (Akelaitis et al., 1942; Bogen, 1985, 1987, 1993; Sperry et al., 1969). Usual bimanual movements like, for example, tying one’s shoe-laces, lighting a cigarette, shuffling cards, and so on, are typically performed with the same dexterity before and after the operation. In new and thus unfamiliar tasks, however, commissurotomy patients show notable impairments in bilateral co-ordination. Preilowski (1972, 1975) tested anterior and complete commissurotomy patients in a task where each hand rotated a knob with the aim of moving the cursor of a pantograph along a diagonal line. Patients performed under visual control and then while blindfolded. In the absence of vision they could not perform the task even after repeated attempts, because they were unable to learn to make differentiated but cooperative movements of the two hands. Zaidel and Sperry (1977) examined the same patients with a series of tests aimed at assessing unimanual and bimanual motor dexterity. Patients were slow but accurate in executing left and right unimanual movements and bilateral synchronous and symmetric movements of the two hands. All of them performed very poorly in bimanual co-ordination tasks that required asynchronous and asymmetric movements of the two hands, like the Preilowski test and an asynchronous bilateral tapping test (Zaidel & Sperry, 1977). Tuller and Kelso (1989) asked two commissurotomy patients to tap with each hand in response to a stroboscopic light presented in the

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respective ipsilateral visual fields. Control subjects were able to maintain a stable pace in this task only when the timing of the light stimuli was compatible with in-phase or in-antiphase movements of the two hands. Their performance became unstable when the timing of the light stimuli required bilateral movements with intermediate phase relationships that could only be maintained with strictly controlled dissociations between the responses of the two sides. This pattern of behaviour was even more evident in commissurotomy patients, thus supporting the hypothesis that the cerebral commissures are crucial for maintaining precise asynchronies between symmetric or asymmetric movements of the two sides, rather than for synchronising bilateral movements, as indirectly suggested by a study on macaques (Brinkman, 1984). The hypothesis of a callosum mediated asynchrony of movements is also supported by data from subjects with callosal agenesis (Jeeves et al., 1988; Jeeves, 1990) and patients with nonsurgical commissural lesions (Nakamura et al., 1984), but not by recent findings by Franz et al. (1995) who asked commissurotomy patients to copy with the right hand a drawing presented tachistoscopically in the right field, and simultaneously with the left hand a drawing presented tachistoscopically in the left field. The two drawings could be the same or different. Commissurotomy patients showed a synchrony of the two hands that did not differ from that of normal controls, thus suggesting, at variance with Preilowsky (1972, 1974), that the timing of bilateral motor co-ordination does not heavily rely on the cerebral commissures. An interesting finding of Franz et al. (1995) is that the analysis of spatial aspects of bimanual co-ordination showed a lesser degree of intermanual interference in commissurotomy patients than in normals, as if the corpus callosum were involved in the spatial coupling of bilateral movements. The good bimanual coordination shown by commissurotomy patients in well rehearsed daily-life actions can be explained by a practice-dependent subcorticalisation or latéralisation to one hemisphere of the underlying neural mechanisms (Ellenberg & Sperry, 1980; Jeeves, 1990; Trevarthen, 1987). For example, overlearned bilateral visuomotor responses could

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be subserved by cerebellar circuits (Glickstein, 1990; Glickstein & May, 1982; Stein & Glickstein, 1992). Writing abilities and constructional praxis Some commissurotomy patients can write disgraphically but legibly with the left hand both by copying and from dictation (Bogen, 1969, 1985, 1987, 1993; Gazzaniga & Sperry, 1967; Sperry et al., 1969). As the right hemisphere is typically unable to translate verbal commands into motor actions, it is likely that in writing, the left hand is controlled by the left hemisphere, as indicated by the fact that the left hand of commissurotomy patients could copy words presented in the right field but not in the left field (Gazzaniga et al., 1967). An exception to this is constituted by three commissurotomy patients with a bilateral representation of language whose right and left hands are controlled during writing by the respective contralateral hemispheres (Gazzaniga, 1983a; Gazzaniga etal., 1977: Gazzaniga & Ledoux, 1978; Nass & Gazzaniga, 1987). The commissurotomy patients of the California series presented different degrees of constructional apraxia and a difficulty in copying complex geometric shapes with the right hand which in these tasks proved inferior to the left hand (Bogen, 1969; Kumar, 1977). This result is in line with the notion of the complementary specialisations of the two hemispheres, the left hemisphere being dominant for language functions and the right hemisphere being dominant for graphic and constructional functions (Zaidel & Sperry, 1977).

Language The first studies on the linguistic capabilities of each cerebral hemisphere were conducted on two complete commissurotomy patients from the California series. Results showed that the left hemisphere was completely dominant for linguistic expression, but also that the right hemisphere was not totally inept at language, for it was able to comprehend common words, to put appropriate verbal labels to common objects or drawings, and to comprehend whether a given sentence was negative (Gazzaniga & Hillyard, 1971; Gazzaniga & Sperry, 1967). However the right hemisphere was

unable to join subject and object by an appropriate verb and to perform actions instigated by written commands consisting of verbs (Gazzaniga & Hilly ard, 1971; Gazzaniga & Sperry, 1967). Subsequent studies on the same patients showed that the right hemisphere, unlike the left hemisphere, cannot judge whether words presented orally rhymed with written words presented tachistoscopically in the left hemifield (Levy & Trevarthen, 1977). From extensive studies of the linguistic competence of the right hemisphere in two complete commissurotomy patients Zaidel (1978, 1986, 1988), concluded the following: 1. The right hemisphere can have a surprisingly complex lexicon, given that in a patient with a high IQ it equalled the capability of an average 18-year-old normal subject. Although this lexical competence involved different semantic structures, the representation of the words in the right hemisphere was only connotative and not denotative as in the left hemisphere. 2. The right hemisphere is able to comprehend short sentences and simple syntactic constructions, including passive and negative constructions. 3. The verbal short-term memory of the right hemisphere is limited to 3 ±1 elements, while that of the left hemisphere can contain 7 ±2 elements. 4. The right hemisphere cannot evoke the phonologic image of an object’s or a drawing’s name, and cannot judge whether or not written words or pseudowords rhyme with one another. 5. The linguistic performance of the right hemisphere is less stable and less open to corrections than that of the left hemisphere. To sum up, according to Zaidel (1986, 1988), the linguistic repertoire of the isolated right hemisphere has a rich semantic-lexical organisation but a poor phonology and no syntax. In line with this profile is the recent report of a patient with a lesion of the posterior half of the corpus callosum in whom the right hemisphere showed some semantic processing capabilities but a profound inability to manage phonological coding (Michel

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et al., 1996). This language profile of the right hemisphere does not correspond to any known aphasic syndrome, but from the fact that the linguistic abilities of the isolated right hemisphere may exceed those of patients with severe aphasia, one can nonetheless infer how interhemispheric interactions contribute to verbal functions. If after disconnection from left hemisphere the right hemisphere exhibits greater language capacities than found in severe aphasic patients with left hemisphere lesions, it may be that in the latter patients the linguistic competence of the intact right hemisphere is inhibited and disorganised by abnormal cross-midline signals received from the damaged left hemisphere via the corpus callosum (Gazzaniga & Sperry, 1967; Zaidel, 1986, 1988). According to Moscovitch (1976) even in the intact brain callosally transmitted influences from the left hemisphere may repress linguistic competences inherent in the right hemisphere, which could thus become expressed only after a callosal section. The hypothesis that language functions of the right hemisphere may be inhibited or interfered with by commissural influences from the left hemispheres rests on the assumption that the language-proficient right hemisphere of a few commissurotomy patients is representative of the linguistic functions of the “normal” right hemisphere. If normal means more frequent, Gazzaniga’s (1983a, 1995) observations on the largest commissurotomy series ever studied do not assign significant linguistic competences to the right hemisphere. He claims that in about the 90% of commissurotomy patients the right hemisphere’s mental processes do not enjoy any support from language, are limited to the performance of simple perceptual and mnemonic comparisons between nonverbal stimuli, and are clearly exceeded in efficiency by the cognitive abilities of a chimpanzee. According to Gazzaniga (1983a, 1995) only a very small minority of commissurotomy patients shows some evidence for linguistic capabilities in the right hemisphere; moreover, patients whose right hemisphere shows lexical, semantic, and syntactic competences are exceptional (Gazzaniga, 1983a; Sidtis et al., 1981). Even in these patients, however, the right

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hemisphere is inept at mathematics and deductive reasoning, and its cognitive capacities are much inferior to those of the left hemisphere (Gazzaniga & Smylie, 1984). In contrast to Gazzaniga (1983a), other authors maintain that linguistic abilities may be absent in the right hemisphere of commissurotomy patients because of an abnormal or aberrant cerebral organization, and that there is enough evidence to believe that the linguistically competent right hemisphere found in some commissurotomy patients has a functional organisation similar to that of a normal right hemisphere (Levy, 1983; Myers, 1983; Zaidel, 1983). Gazzaniga’s rebuke to these criticisms is that only two commissurotomy patients with a linguistically competent right hemisphere have been described by his opponents, and that there is no evidence of right hemisphere damage in the history of other commissurotomy patients which can account for the proven absence of language in that hemisphere. More recently Gazzaniga and his co-workers (Baynes et al., 1992), described a third commissurotomy patient in whom the right hemisphere was clearly competent in visual and auditory lexical tasks. Moreover, linguistic capabilities of this patient increased over time, thus suggesting that the isolated right hemisphere’s language potential is not fixed but can be improved (Baynes et al., 1995; Gazzaniga et al., 1996). It appears, therefore, that the extent to which the right hemisphere of commissurotomy patients can possess or develop linguistic capabilities is still an open issue.

Memory Although studies on macaque monkeys suggest that the cerebral commissures contribute significantly to the interhemispheric integration of memory processes (Lewine et al., 1994), a complete commissurotomy in humans does not usually result in dramatic and persistent memory deficits. Trescher and Ford (1937) and Ferguson et al. (1985) described single commissurotomy cases with severe amnesia but the deficit was most likely caused by the presence of extracommissural brain lesions. Huppert (1981) reported that three commissurotomy patients from the California series showed a normal retention capability in a task that

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required the delayed recognition of pictures of landscapes and animals one week after learning. That the patients were slower in learning than the control group is no surprise, given that the latter group consisted of Caltech students with notoriously high IQs. Anyhow, the picture recognition task was suitable for contrasting the good performance of commissurotomy patients with the very poor performance of patients with organic amnesia. There are few studies in which relatively subtle memory deficits were assessed in commissurotomy patients with standard psychometric tests, such as the digit span or the difference between the IQ score and the memory score of the Wechsler scale (Lezak, 1983). Parsons (1943) tested eight commissurotomy patients from the Akelaitis series before and after the operation and found only a small and nonsystematic post-operatory deficit in the forward and backward digit span test. Zaidel and Sperry (1974) examined eight complete commissurotomy patients and two patients with an anterior commissurotomy that spared the splenium in six standard memory tests from the Wechsler scale. In all tests, the performance of both complete and partial commissurotomy patients was significantly worse than that of healthy subjects matched for age and IQ. The difference between the IQ score and the memory score was 18 points in the total commissurotomy patients and 19.5 points in the partial commissurotomy patients, supporting the assumption of a selective post-commissurotomy memory impairment. In the verbal association subtest of the Wechsler scale, commissurotomy patients and controls alike found unusual associations more difficult than usual associations, but the relative drop in performance was 41 times greater in patients than controls. According to Zaidel and Sperry (1974) memory may be impaired in commissurotomy patients because it is not aided by interhemispheric visuo-verbal associations effected by the corpus callosum, but this suggestion is made implausible by the findings of Milner et al. (1990) mentioned earlier. More pertinent to the interpretation of the memory deficits in their commissurotomy patients is Zaidel and Sperry’s mention of the fact that in addition to the callosal sections their patients

also had sections of one fornix and the hippocampal and anterior commissures. Memory deficits have also been reported in commissurotomy patients of the California series by Milner and Taylor (1972), Campbell et al. (1981), and Milner et al. (1990). On the contrary, Ledoux et al. (1977) did not find any memory deficit in a commissurotomy patient from another series who was tested before and after the operation. They speculate that as memory had not been tested in the commissurotomy patients of Zaidel and Sperry (1974) before the operation, the memory deficits found after it might have been preoperatory. An alternative explanation of the discrepancy between Zaidel and Sperry’s (1974) results and those of Ledoux et al. (1977) is that the patient in the latter study had intact anterior and hippocampal commissures, while the patients in the former study did not. In agreement with this explanation is the study by Phelps et al. (1991) who found visual and verbal memory deficits in patients with complete section of the callosum and the hippocampal commissure, but not in partial callosotomy patients. This is not surprising in view of the fact that the hippocampal and anterior commissures interconnect brain regions heavily involved in memory functions, such as the peri- and parahippocampal cortex and the medial temporal cortex. In an extensive review of complete and partial commissurotomy patients, Clark and Geffen (1989) report that persistent memory deficits are mostly evident when there is associated extracallosal damage involving the fornix (see also BotezMarquez & Botez, 1992; Rudge & Warrington, 1991) and the hippocampal commissure (see also Phelps et al., 1991). While it is generally believed that subjects with callosal agenesis have a normal memory (Chiarello, 1980), it is still unclear whether at least some of the memory deficits observed in commissurotomy patients (Zaidel & Sperry, 1974) can be attributed to the section of the corpus callosum. In any case, memory deficits caused by interhemispheric disconnection are best explained by a disruption of interhemispheric co-operations necessary for the formation of complex engrams (Campbell etal., 1981; Gazzaniga&Smy lie, 1984; Trevarthen, 1974).

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Vigilance and selective attention In the acute post-operatory stage commissurotomy patients may often appear torpid, apathic, abulic, and incapable of concentration, but soon thereafter routine clinical examination fails to reveal any particular alteration of vigilance and reactivity to the environment (Bogen, 1985, 1987, 1993). The sleep-wake cycle is within normal limits, and there are no temporal uncouplings between the electroencephalographic indexes of sleep onset and arousal in the two hemispheres (Sperry, 1974). An apparently normal capacity for recalling dreams has been reported in callosotomy patients (Greenberg et al., 1977) and subjects with callosal agenesis (Nielsen et al., 1994). There is much anatomical and physiological evidence that the fundamental neural substrates for vigilance and intensive attention are located in the ascending brainstem systems which project diffusely to both hemispheres (Bloom, 1988; Robbins & Everitt, 1995). The bilaterality of their projections, which is unaffected by forebrain commissurotomy, ensures the synchronous occurrence of sleep and waking in the two disconnected hemispheres (Sperry, 1974). The minimal but systematic asynchronies in the electroencephalographic activity of the two hemispheres that can be recorded during sleeping and waking states, but not in the transitions between states, attest the importance of the corpus callosum in the fine regulation of the bilateral coherence of electrocortical activities (Kuks & Vos, 1994; Nielsen et al., 1994). According to Singer (1995) the representation of objects in the brain would occur by way of assemblies of widely distributed, selectively connected neurons. The presence of a particular object in conscious experience would entail the synchronous firing of the neurones that make up the assembly representing that object, and the corpus callosum would provide the functionally indispensable connections between neurones belonging to the same assembly but located in different hemispheres (Engel et al., 1991). Some cognitive deficits occurring in long-term commissurotomy patients may be ascribed to impaired vigilance. In detecting monotonous stimuli presented at irregular intervals these patients tend to go through periods of areactivity that Dimond has termed “black holes of consciousness”

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(Dimond, 1976, 1979a, b). Ellenberg and Sperry (1979) maintain that commissurotomy patients become temporarily areactive when they function as passive receivers of stimuli, but not when they must act on the stimuli in order to perform tasks that are more demanding than mere stimulus detection. Based on clinical suggestions that the right hemisphere is dominant for the detection of external stimuli, Dimond (1976,1979a, b) has attributed the areactivity periods of commissurotomy patients to the absence of an alerting influence of the right hemisphere on the left hemisphere, normally transmitted via the corpus callosum. Given that the vigilance impairments observed by Dimond in commissurotomy patients were assessed by comparison with healthy control subjects in their twenties, there is no compelling reason why such impairments should be regarded as genuine interhemispheric disconnection signs rather than effects on vigilance of age, epilepsy, or chronic antiepileptic medication (Ellenberg & Sperry, 1979). A role for the corpus callosum in the maintenance of vigilance has been suggested by a study in normal children by Rueckert et al. (1994) who found a significant positive correlation between a measure of efficiency of interhemispheric transfer, i.e. speed of matching visual stimuli across the midline, and the efficiency of detection of visual targets presented at irregular intervals at the fixation point. More extensive and articulate is the literature on visual selective attention and the capacity for visual information processing in commissurotomy patients. Surprising as it may seem, these patients may outperform normal controls in visual discrimination tasks, perhaps because they benefit from a reduction or lack of interferences between the visual hemifields (Gazzaniga, 1987,1995). In a test of this possibility, subjects saw two sample targets moving simultaneously along different trajectories, one in each hemifield, followed by a single test target moving in one hemifield, and had to decide whether or not the trajectory of the test target matched that of the sample target previously presented in that same hemifield. The presentation side of the test target was not known in advance, and therefore a correct judgement required the memorisation of the trajectories of both sample

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targets. Compared to normal subjects, who have a unified perception of the double sample stimulus, commissurotomy patients may be less prone to confusion, as each hemisphere can separately perceive and memorise its half of the sample stimulus and then, if presented with the target, compare the latter solely with its memory. Results showed that commissurotomy patients did indeed outperform normal controls, supporting the hypothesis that in this task they benefit from a convenient division of labour between the hemispheres and from the attendant reduction of interferences between the visual fields (Holtzman and Gazzaniga, 1985; Gazzaniga, 1987). Studies in normal subjects have shown that interference effects deriving from aunihemispheric informational overload are greater than those deriving from a comparable load divided between the hemispheres (Kreuter et al., 1972; Rizzolatti et al., 1972). In commissurotomy patients, interferences between competing inputs to the same hemisphere are comparable in magnitude to those seen in normal controls; but interferences between competing inputs channelled into different hemispheres, if present, are smaller than in normals (Kreuter et al., 1972; Levy et al., 1972; Teng & Sperry, 1973). Holtzman and Gazzaniga (1982), however, found an inverse correlation between the accuracy of a cognitive performance by one hemisphere and the degree of difficulty of another cognitive task performed simultaneously by the other hemisphere. This clear demonstration of an interference between concurrent cognitive activities in the two disconnected hemispheres strongly suggests that after commissurotomy the two hemispheres continue to draw from a common, capacity-limited pool of attentional resources (Gazzaniga, 1987,1995). A similar conclusion has been arrived at in studies of memory performed on macaque monkeys with splitting of the optic chiasm and the forebrain commissures (Lewine et al., 1994). A probable neural site for the sharing of attentional resources by the disconnected hemispheres is the aforementioned complex of ascending brain-stem systems which are reciprocally interconnected with both brain sides and are thus in a position to ensure a unified bilateral control of cerebral functioning independent from

commissural activity (Berlucchi, 1997; Trevarthen, 1987). The forebrain commissures may however interact with the brain stem ascending systems at the cortex for the fine regulation of vigilance and attentional processes (Ellenberg & Sperry, 1980). The two hemispheres may compete for attentional resources either in the analysis of sensory inputs or in the selection and execution of the responses called for by the inputs. In most cases where different and complex stimuli are presented in parallel for analysis to the two disconnected hemispheres, patients often tend to respond to inputs from one hemifield and ignore inputs from the other hemifield (Levy & Trevarthen, 1976; ReuterLorenzetal., 1995; Teng & Sperry, 1973,1974). But as usually in these tasks different responses must be made to stimuli in different hemifields, interhemispheric interferences may mostly occur at the response selection or execution stage because of an incompatibility between different responses required from different hemispheres. The latter possibility is supported by the results of Luck et al. (1989, 1994) who tested normal and commissurotomy subjects in search tasks requiring the detection of a target (a red square above a blue square) among a variable number of distractors, each consisting of a red square below a blue square. Target and distractors were presented in one or both visual hemifields, and subjects had to press a key with the hand ipsilateral to the hemifield containing the target. In normal subjects response speed and accuracy decreased as a function of the number of distractors, suggesting the occurrence of a typical serial search over the entire stimulus array, whether unilateral or bilateral. Callosotomised patients behaved like normal subjects when the stimulus array was unilateral, but performed better than normals on bilateral presentations, as if serial search by each hemisphere was limited to the corresponding half field and the response was emitted by the hemisphere that found the target. In each case there was no room for response interferences between the two hemispheres, because response mechanisms were not activated in the hemisphere unexposed to the target. Normal subjects do not seem to be ordinarily able to perform two concurrent serial searches, one in each visual hemifield, probably because the corpus callosum forces the two

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hemispheres to work together and to make a joint search over the entire array, thus probabilistically slowing down the detection of the target. ReuterLorenz et al. (1995) have provided further evidence that in normal subjects response competition limits the benefits that may accrue to commissurotomy patients from the more efficient stimulus analysis predicated on a division of labour between the two disconnected hemispheres. However the parallel execution of different cognitive tasks by the disconnected hemispheres may be the exception rather than the rule (Sperry, 1974). Further, well practised normal subjects may come to equal commissurotomy patients in the performance of split field tasks where the latter group is expected to excel because of hemispheric independence, suggesting that by strategic learning one can achieve a parallel independent processing by the two hemispheres even when the corpus callosum is intact (Ellenberg & Sperry, 1980). In summary, there is evidence, on one hand, that the cerebral hemispheres of commissurotomy patients must share common attentional resources; and on the other hand, that each disconnected hemisphere can, under some circumstances, work as an independent channel for information processing, endowed with its own attentional resources which are inaccessible to the other hemisphere. Further instances in which the two disconnected hemispheres appear to be forced to use common attentional resources are provided by tasks in which attention must be voluntarily allocated to a point in the visual field. As in normal subjects, each hemisphere of commissurotomy patients can direct saccadic eye movements towards points in both ipsilateral and contralateral visual hemifield (Hughes et al., 1992). Similarly, each disconnected hemisphere can direct attention voluntarily to ipsilateral and contralateral locations in a covert fashion, that is without moving the eyes. In this task of covert attention, commissurotomy patients behave like normal subjects in so far as they cannot attend to two locations at the same time, no matter if the two locations to be heeded are in the same or opposite hemifields (Holtzman et al., 1981,1984). Obviously both hemispheres of commissurotomy patients utilise common mechanisms for the voluntary allocation of attention to spatial

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regions (Gazzaniga, 1987,1995 ;Plourde& Sperry, 1985), and both hemispheres can deploy attention in space within a framework of either egocentric or environmental co-ordinates (Ládavas et al., 1994). Thus, the voluntary control of spatial attention does not appear to be modified substantially by commissurotomy, except for the fact that while the isolated right hemisphere controls shifts of attention with comparable efficiency in the two visual hemifields, the left hemisphere seems more efficient in controlling attention in the right visual field (Berlucchi et al., 1997a; Mangun et al., 1995; Proverbio et al:, 1994). According to a recent attempt at synthesising the patterns of attentional regulation in commissurotomy patients (Gazzaniga, 1995), the two disconnected hemispheres must utilise common indivisible attentional resources when attention is voluntarily allocated to a specific information-processing task, with control preferentially lateralised to the left hemisphere in some experimental conditions. It is only when attention is automatically controlled by external events that appropriate stimulation can automatically elicit from the two separated hemispheres independent attentional reactions which occur in parallel and without reciprocal interferences (see also Berlucchi et al., 1997b). The findings by Luck et al. (1994) with the trajectory matching task described previously are a good example of this possibility for parallel behavioural performance, with externally controlled attention being divided between the hemispheres. In a different perspective, Corballis (1995) has posited that the voluntary control of selective visuo-spatial attention cannot be divided between the hemispheres by forebrain commissurotomy because the subcortical mechanisms for this control are unaffected by the operation. By contrast, the control of selective attention for objects relies on cortical structures and therefore can be duplicated following section of the cortical commissures.

TEMPORARY UNRELATED SYMPTOMS Several conspicuous but usually promptly reversible signs can be observed following a single

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stage complete commissurotomy (Bogen, 1987; Spencer, 1988) or after vascular or traumatic accidents involving the cerebral commissures (Brion & Jedynak, 1975). They include grasping, paresis of the leg opposite the dominant hand, a bilateral Babinski sign, akinesia, and psychic areactivity and stupor, all of which may be accounted for by unintended extracommissural damage to the nondominant hemisphere, which is usually retracted during the operation to gain access to the corpus callosum, or to cortical diaschisis caused by commissural sections or lesions. Other temporary signs of neuropsychological interest, such as dyspraxia of the nondominant hand (discussed earlier), mutism, diagonistic dyspraxia and the alien hand phenomenon, might be related in a more direct way to interhemispheric disconnection. According to Bogen (1987) a transitory mutism is almost always present in the acute stage after a complete callosotomy. Acutely callosotomised patients tend to produce no utterances in spite of being awake, cooperative, and free from specific aphasic symptoms. Mutism usually clears off in days or weeks (mean 35 days, range 2-90 days in 10 patients of the California series) although it may persist in an attenuated form for years in a few exceptional patients (Bogen, 1987) . A transitory mutism has also been reported following a two-stage callosotomy in 3 out of 12 cases by Wilson et al. (1975, 1978) and in 2 out of 6 cases by Ferguson et al. (1985). More recently mutism has been observed in 15% of complete commissurotomy cases and in 6% of partial commissurotomy cases (Sass et al., 1988; Spencer, 1988) . A frequently expressed interpretation of post-commissurotomy mutism attributes it to an intraoperatory damage of non-commissural brain structures involved in phonation, like the walls of the anterior part of the third ventricle, the anterior part of the cingulate cortex or the supplementary motor areas (Bogen, 1987; Novelly & Deinzer Lifrak, 1985). However, mutism may be directly caused by commissurotomy at least in those cases whose neural control of phonation seems to require an interhemispheric co-operation (Bogen, 1987; Sussman et al., 1983). Finally, some authors postulate that mutism is best accounted for by a summation or an interaction between the effects of

total commissurotomy and those of pre- or intraoperatory extracommissural brain damage (Nakasu et al., 1991; Novelly & Deinzer Lifrak, 1985). Indeed mutism was absent in two partial commissurotomy cases whose splenium was left intact, even though extracommissural brain structures involved in phonation presumably were exposed to the same intraoperatory traumatism as occurs in complete commissurotomy (Bogen, 1987; Gordon et al., 1971). Given that postcommissurotomy mutism is transitory and fully reversible in most cases, one must conclude that normally the cerebral commissures are not indispensable for the control of phonation. The term diagonistic dyspraxia was introduced by Akelaitis (1944-45) to indicate a behavioural pattern of involuntary competition between the two hands which occasionally appeared to interfere with the correct execution of unimanual or coordinated bimanual actions in commissurotomy patients. He described a patient with a section of the anterior two-thirds of the corpus callosum who sometimes could not drink because one hand emptied the glass that the other hand had just filled, and a total callosotomy patient who with one hand returned to the baker the bread he had just bought with the other hand. Similar observations have been made in some of the epileptic commissurotomy patients of the California series (Bogen, 1987) who could occasionally display conflicting movements of the two hands during common daily life actions like dressing (e.g. one hand undoing the button just fastened by the other hand), or interfering intrusions of one hand during the execution of praxic or writing tests with the other hand. The incidental occurrence of intermanual conflicts has also been described in commissurotomy patients of other series (e.g. Wilson et al., 1997), for example in a patient of Ferguson et al. (1985) who spent an enormous amount of time in dressing, cooking, and shopping because of between-hand competitions, such as the clutching by the left hand of a piece of clothing that the right hand had already discarded. Signs of diagonistic dyspraxia have also been reported in nonepileptic patients with vascular or tumoral lesions of the corpus callosum (Watson & Heilman, 1983). Brion and Jedynak (1975) described a patient who, after an acute rupture of a left

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pericallosal artery aneurysm and the surgical evacuation of a hematoma infiltrating the anterior part of the corpus callosum, complained that in reading she often tore the book pages because the left hand blocked the turning over of pages by the right hand. In the physiopathologie interpretation of diagonistic dyspraxia one must consider that this sign, though so conspicuous that it cannot go unnoticed, is quite uncommon even in the cases with the most extensive commissurotomies (Wilson et ah, 1977). Moreover, even when present, diagonistic dyspraxia occurs sporadically and eventually is fully regressive (Bogen, 1985, 1987, 1993), so that most of the time the patients who suffer from it can cope well with demands for simple forms of bimanual motor cooperation in everyday life (e.g. Preilowski, 1972). It thus seems inappropriate to consider diagonistic dyspraxia as a marker of interhemispheric disconnection, or attribute it to a clash between conflicting intentions of the disconnected hemispheres. Perhaps diagonistic dyspraxia can be attributed to the same extracommissural alterations that are thought to cause occasional and temporary Korsakovian and attentional disturbances in commissurotomy patients (see Brion & Jedynak, 1975; Ferguson et al., 1985). A more mundane interpretation is that this deceptive appearance of a highly complex disruption of voluntary motor control is nothing more than a disorganised coordination of simple reflex actions (Zaidel & Sperry, 1974). The alien hand phenomenon, probably a special form of intermanual conflict, was described by Brion and Jedynak (1975) in three patients with tumours invading the corpus callosum. Though free from somatosensory or body schema disturbances, these patients were unable, when blindfolded, to recognise as their own a hand or finger, whether right or left, held in the other hand. The feeling of non-belonging disappeared immediately upon opening the eyes. These patients, however, showed a clinical picture reminiscent of a Korsakov syndrome. Goldberg et al. (1981) and Della Sala et al. ( 1991 ) maintain that the alien hand phenomenon is caused by lesions of the frontal mesial cortex rather than by commissural lesions. A contrary opinion has been expressed by Papagno and Marsile

(1995) who believe that the co-occurrence of commissural and extracommissural lesions is necessary for the emergence of the alien hand phenomenon. However, a patient with a lesion of the body of the corpus callosum has been recently reported by Geschwind et al. (1995) who posit that an interhemispheric motor disconnection is crucial for the occurrence of the alien hand syndrome of the non-dominant hand.

MIND AND CONSCIOUSNESS IN THE SPLIT BRAIN The idea that the forebrain commissures confer unitarity not only to physiological cortical activities on the two sides, but also to mental processes was already entrenched in the philosophical and scientific mentality of the 19th century. Instances of this naive way of thinking are the assertions of the philosopher Hartman (1871) who believed that two men with their brains united by a callosum-like fibre tract would share the same consciousness, and the psychophysicist Fechner (1889), who maintained that each half of a bisected brain would keep its own consciousness. Even today it is easy to succumb to the temptation of describing forebrain commissurotomy as an operation that gives rise to two independent psychic entities, and there is a distinct tendency to ascribe various symptoms of mental dissociation to putative disruptions of the normal cross-talk between the hemispheres. For example, some believe that the “voices” heard by patients suffering from chronic hallucinatory psychoses are in effect normal messages from the right hemisphere which the left hemisphere fails to recognise and attributes to external sources (review in Doty, 1989). With due respect for all attempts to understand the brain mechanisms of mental illness, it must be recognised that many of these speculations belong in psychiatric folklore more than in the neurosciences. From the side of the neurosciences, Sperry has repeatedly claimed that commissurotomy patients live with two widely separated conscious spheres, that the sensations, perceptions, thoughts, and memories of each of their hemispheres are

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inaccessible to the consciousness of the other hemisphere, and even that the cranium of these patients harbours two free wills. On the other hand he has always counterbalanced these bold claims with the unconditional recognition that in everyday life the behaviour of commissurotomy patients is wholly unitary and coherent, and such as to convince their relatives and family doctor that the operation has not changed the fundamental structure of their personality. Duplication of consciousness, if any, occurs only in the artificial conditions of the neuropsychological testing room, where sensory input or motor output can be restricted to a single hemisphere (Sperry, 1966, 1968, 1974, 1982,1984). As there are no universally accepted definitions of mind and consciousness, every attempt to answer the question of whether commissurotomy can duplicate these entities is bound to meet sooner or later with nearly unsolvable semantic puzzles. But before we arrive at these almost insurmountable obstacles we must ask ourselves if and to what extent the duplicated consciousness hypothesis can be a product of a deception engendered by the anatomical duality of the brain and its presumptive enhancement by brain bisection. Are we prepared to attribute a double consciousness or a double mind to a person with an intact brain, or at least with intact interhemispheric connections, who exhibits patterns of behaviour similar to those found experimentally in commissurotomy patients? Let us look at the facts. 1. The post-commissurotomy abolition of perceptual equivalence across sensory channels going to different hemispheres is spectacular, but equally spectacular are similar effects of intrahemispheric disconnections on sensory channels directed to a single hemisphere, not to mention the conflicts between sensory modalities (e.g. Rock, 1983) or between perception and action (e.g. Aglioti et al., 1995) which can be observed in normal subjects as well. If subjects showing these phenomena are not commissurotomised, hardly anyone thinks that they have more than one consciousness. 2. It is true that commissurotomy patients cannot express in speech and writing bits of knowledge

that they certainly possess and use in nonverbal behaviour, but this is equally true in patients with blindsight or organic amnesia, and at least some of the so-called procedural memories cannot be expressed verbally even in normal people. Yet we do not assume that blindsight, organic amnesia, and procedural memory can be accounted for by the existence of a second mind, detached from the speaking mind. 3. It is a fact that the disconnected right and left hemispheres of the split brain differ at least partly in the ways and cognitive styles with which they process information and generate actions, but adequate testing methods can disclose this hemispheric differentiation in the normal brain as well. Shall we then conclude that even the intact brain houses two separate minds, and that commissurotomy enhances an already existing separation? Some say yes (e.g. Bogen, 1986), but then why not three, four, n minds? (Nagel, 1993). Certainly the cognitive styles and the modes of information processing of every single brain are more than two, and many more than two are the putative modular components of mental processes and behavioural control that are presented to us with ever increasing vigour, sometimes quite convincingly, by contemporary neuropsychological speculation (e.g. Gazzaniga & LeDoux, 1978; Shallice, 1988). 4. Occasional support for the double consciousness hypothesis is sought in rather erratic phenomena which are purported to reveal psychological conflicts between the intentions, opinions and even passions of the two hemispheres. Instances of these phenomena are diagonistic dyspraxia and the so-called interhemispheric self-critique (Brion & Jedynak, 1975), consisting in expressions by one hemisphere of dissatisfaction with the behaviour controlled by the other hemisphere. As rightly argued by Zaidel and Sperry (1977), it is very likely that diagonistic dyspraxia can be parsimoniously accounted for by simple forced reflex responses or other largely involuntary reactions which have nothing to do with cognition and emotion. With regard to interhemispheric self-critique, nobody ascribes two minds or two consciousnesses to patients with prefrontal lesions who criticise

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their own perseverative errors but cannot refrain from making them (Milner, 1964). 5. If it were true that the two disconnected hemispheres can simultaneously give rise to two parallel streams of consciousness, then commissurotomy patients should enjoy a supernormal capacity to carry out a mental task with one hemisphere and another concurrent mental task with the other hemisphere, being freed from the costs that interhemispheric interferences impose on normal subjects in similar conditions. The control of selective attention in the split brain differs only partly from that in the intact brain. As mentioned earlier, the parallel performance of different tasks by the disconnected hemispheres, though possible under appropriate circumstances, is the exception rather than the rule, and in general commissurotomy does not seem to alter attentional regulation of cognitive processes to a significant degree. It is especially the voluntary control of attentional processes that does not seem to be open to parallel, independent, and different commands from the two disconnected hemispheres, given that both of them cooperate for the attainment of the same aim or, in some special conditions, attentional control is committed to the sole left hemisphere (Berlucchi et al., 1997a; Gazzaniga, 1995). 6. Even if behavioural control were systematically duplicated in commissurotomy patients, such duplication need not be conflictual and might be restricted to the executive level under the control of an undivided normative level where evaluation criteria and priorities for action are established. The results of a complex experiment designed to address this issue in a commissurotomy patient have allowed MacKay and MacKay (1982) to argue that his highest level of evaluative supervision of action is by no means divided into two separated half systems or “free wills”, but rather consists of an undivided whole system, presumably localised in deep brain stem structures left untouched by the operation. After commissurotomy, the patients’ evaluative and emotional responses to questions concerning family, work, politics, religion, hobbies, com-

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mitments, and hopes for the future remain coherent, regardless of whether the questions are addressed to the left, the right, or both hemispheres, and are consistent with the patients’ preoperatory personality (Sperry, 1984). The occasional small discrepancies between reactions to the same question presented to different hemispheres can be accounted for by changes in mood or differential effects of fatigue (Gazzaniga & LeDoux, 1978). Obviously these interhemispheric comparisons can be tested in those patients whose right hemisphere has some comprehension of language, but not in those patients with a right hemisphere totally inept at language processing (Gazzaniga, 1983b). Although it can be suggested that the latter patients conform with Eccles’ (1973) general hypothesis that the conscious self resides only in the left hemisphere, another possibility is that information channelled into their right hemisphere is not elaborated enough to activate the evaluation system which according to MacKay and MacKay (1982) presides over both hemispheres. In conclusion, the overall unitarity and consistency of the behaviour of commissurotomised patients is a fact, whereas inferences that conceive the split brain as a two-channel processor, or the organ of a double consciousness are not supported by sufficiently convincing evidence. The following have been listed by Sperry (1984) as possible factors that can maintain unitarity in the control of the behaviour of commissurotomy patients: 1. The anatomical organisations which ensure that both hemispheres are endowed with representations of right and left fields in most sensory modalities, independent of the forebrain commissures. 2. The motor adjustments of exploratory organs, such as the eyes and the hands, and the behavioural strategies that make exogenous and endogenous information initially restricted to one hemisphere promptly available to the other hemisphere.

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3. The cognitive structures presumably lying in the undivided depth of the forebrain and in the brain stem, which allow evaluative, attitudinal, orientational, emotional, and contextual components of cognitive processes of the two hemispheres to converge into a single unified conscious experience. In agreement with the last point of this analysis, several recent experimental findings and theoretical considerations, while upholding the dissociative effects of commissurotomy, provide concrete grounds for beginning to explore in depth the

possible contributions of the brain stem to those aspects of interhemispheric cooperation that are not affected by commissurotomy (Corballis, 1994, 1995; Doty, 1989a; Gazzaniga, 1987, 1995; Kutasetal., 1988; Sergent, 1987,1990;Trevarthen, 1987). No major developments in our understanding of interhemispheric interactions will be possible without paying heed to the physiological complementarity between commissural cortical components and subcortical noncommissural components of the systems that control the exchanges of information between the hemispheres.

29 The Neuropsychological Approach to Consciousness Edoardo Bisiach

dismaying intricacy of the matter and the almost ubiquitous danger of confusion. The content of the chapter, therefore, can only be regarded as an introduction to further readings, left to individal choice among the wealth of contributions that in a few years have enriched the literature to such an extent as to frustrate any attempt to provide an unbiased compendium. In addition to the two aforesaid volumes, helpful suggestions are Consciousness in contemporary science (Marcel & Bisiach, eds., 1988) and Experimental and theoretical studies o f consciousness (Marsh, ed., 1993). The BBS target articles and commentaries on consciousness cited in this chapter are also highly recommended not only because of their instructive and provocative contents, but also because of the valuable lists of references they always provide.

This chapter is not intended to recapitulate the contribution of neuropsychology to the study of consciousness. Accounts of the different aspects of this contribution are distributed throughout this volume. Interested readers can find wider and more specific treatment in The neuropsychology o f consciousness, edited by Milner and Rugg in 1992, as well as in the last section of The cognitive neurosciences, edited by Gazzaniga in 1995. The main purpose of this chapter, in fact, is to offer the non-expert reader tentative guidelines in approaching a subject that has so far proved to be much more open to brilliant, witty, vivaciously contentious, and usually prolix essay-writing and fanciful speculation than to rigorous and co-ordinated assessment and ground breaking. Definitional issues will first be considered, as well as the limits and gaps with regard to which our efforts towards an explanation of consciousness will be oriented. Then the issues of the spatial and chronological structure of consciousness will be raised. Finally, some suggestions about the causal role and the neural mechanisms of consciousness will be briefly examined, with the intent to show the

PRELIMINARY DEFINITIONS The best way— actually, the only way—to start talking coherently about consciousness is implied 671

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in Marcel’s (1988, p. 128) felicitous claim: if we did not have phenomenal experience we would have no concept of consciousness at all.” This immediately evinces the unique status of consciousness in the domain of natural sciences. Phenomenal experience, indeed, does not belong to either of the two cornerstones of regular scientific knowledge: it is neither something subject to public observation, nor a theoretical construct. None the less, the difficulties we encounter in trying to frame phenomenal experience in our language and make it a putative matter of scientific inquiry have led to unsatisfactory (more or less explicit) proposals such as denial, dismissal, or substitution. As we shall see, the last one is particularly troublesome, because it may engender confusion and groundless disagreement. Most commonly and indiscriminately, consciousness in information-processing terms is more or less clandestinely substituted for phenomenal experience. Block (1995, pp.236-239) gives instructive examples of this mistake. Derivative confusions are those between consciousness (in either of the aforementioned two senses) and attention or knowledge. The latter is often mediated by the ambiguous concept of awareness and instantiated by infelicitous terms such as “conscious awareness”, implying existence of nonconscious awareness (possibly held to be synonymous with so-called “implicit knowledge”). In order to proceed in the study of consciousness, we shall negotiate between two opposing attitudes. On the one hand we might wish to stipulate from the outset exact definitions of our terms. On the other hand, we might prefer to take care of the empirical findings and burgeoning theories on the assumption that scientific definitions will take care of themselves (e.g. Farber & Churchland, 1995; Weiskrantz, 1988). A good many would agree that the second, laissez-faire, resolution has much to recommend itself. Others, none the less, could easily retort that it is indeed this resolution that is largely responsible for the undisciplined growth of the juniper thicket in which debates on consciousness have got entangled and where people often seem to talk past each other, as witnessed, for example, by articles and discussions in Dennett and Kinsbourne (1992), Marsh (1993), Block (1995), and Gray (1995). They could also rightly point out

that one of the terms at issue, namely phenomenal experience, is not a construct such as “impetus” or “phlogiston”, subject to being worked out and replaced through progress in science. Regarding phenomenal experience, actually, problems of definition should not even arise, unless we mistake that experience for the inner thirdperson perspective, as it were, of introspection, and engage in describing, taxonomising and hierarchising its contents. Such a mistake would reify qualia as something given to phenomenal experience, rather than identify them with its intrinsic qualitative aspects, thus running into the fallacy exposed by Dennett (1988). It would insinuate the abstruse idea of consciousness as an inner spectator watching the play performed on the stage of what has been aptly caricatured by Dennett and Kinsbourne (1992) as the Cartesian theatre. Being endowed with phenomenal experience is only subject to self-ostensive definition. However, a tentative outline of the contents of phenomenal experience would have to make important discriminations among a huddle of heterogeneous and yet interlacing and intersecting constituents. In addition to the relatively pregnant and often stationary outside-driven contents of merely perceptual activity, that outline would normally have to include more fuzzy and unstable, or quite fleeting, inside-driven contents: namely, more or less sensorily vivid mental images and more or less articulated inner speech (as they unroll in thought processes such as remembering, surveying, evaluating, anticipating, planning, and entertaining “propositional attitudes” like fears, desires, beliefs, etc.). It would also have to include coenaesthesis and the manifold of moods. Particularly troublesome, in this context, is the frequent use of terms such as “self-consciousness” and “reflexive consciousness” without clear indication of what these terms are exactly meant to designate: a special higher-order (though in any case fairly enigmatic) consciousness, or, much more plainly, one among the extreme variety of the contents of consciousness, a content arising from the mind’s faculty to bring itself into its focus through introspection. Barring pathological states, it is usually stated or tacitly assumed that intrinsic in phenomenal

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experience are the feelings of exclusive ownership and of unitary and continuous personal identity. The term “consciousness” may indeed be viewed as capturing the unitary selfhood of phenomenal experience. Still in agreement with its etymon, the same term may otherwise be taken to designate the coherent, actual or possible, monitoring of any mental content throughout the whole spectrum of available behaviour open to public observation. Without regard to the extent to which notions such as “mental content” and “behaviour” will have to be worked out as we proceed, this would transact a working definition by which at least some aspects of consciousness can be dealt with in informationprocessing terms, without breaking away from the scope of traditional scientific inquiry and, hopefully, without being bogged down from the beginning in a series of misunderstandings and idle controversies. This definition looks at least suitable to turn disputes about true versus purported unawareness of, say, a masked or “neglected” prime — see findings by Marcel (1983) and Berti and Rizzolatti (1992), respectively, as well as Driver’s (1996) critique of the latter—into an effort to understand what leads to consciousness in the normal brain and to its breakdown following brain injury. According to this definition, both a patient who verbally acknowledges being hemiplegic, but engages in activities requiring use of both upper (and/or lower) limbs, and a patient who wrongly denies hemiplegia, but entirely abstains from engaging in such activities, are partly nonconscious of illness, though in interestingly different ways (in that awareness of illness is monitored in verbal but not in nonverbal behaviour in the first patient, but vice versa in the second). This definition, in fact, lays special stress on dissociations of consciousness. Far from underestimating the importance of quantitative aspects such as those defined by Merikle and Cheesman’s (1986) “subjective” and “objective” thresholds of discriminative responding1, it simply avoids setting any sharp criterion as to whether a certain input-output channel participates in consciousness at any given time, being instead mainly concerned with interchannel differences. What is retained and what is lost in this definition of consciousness is a separate (though intimately

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connected) issue that will to some extent be dealt with in the next section. In order to avoid confusion, however, the term “consciousness” will arbitrarily be used in this chapter when the working definition just described is implied, while the term “phenomenal experience” will be used when reference is specifically made to the subjective aspects of consciousness that are not directly accessible to public observation. The problem of defining consciousness, of course, cannot be settled by working definitions whose limitations are obvious. It will come out again and again in what follows, especially when the danger of confusion is to be feared. There is one point, however, on which we should not compromise. Farber and Churchland (1995) recommend resisting the “powerful” temptation to “set aside empirical enquiry and theory building until we have determined quite precisely the proper definition and the scope of the concept” of consciousness. Fortunately, nobody so far seems to have yielded to this temptation. The lapse to which we are instead much more susceptible is the attempt to discuss consciousness with no clear, albeit provisional, definition of what we are talking about. This is where confusion arises. Clarity is especially required in theoretical debates. In the pretheoretical assessment of empirical data, implicit operational definitions of consciousness may be sufficiently unambiguous. Such is the case, for example, of blindsight and amnesia. The opposite is likely to be true of disorders such as unilateral neglect, with respect to which (as will be suggested in the concluding remarks of this chapter) an explicit working definition of consciousness such as that given in this section is needed both as a means to avoid direct misunderstanding and, above all, as something to be improved upon or, at least, enriched by uncovering the different ways in which it may apply.

EXPLANATORY PRACTICABILITY Within the limits of the operational definition just outlined there seem to be no principled vetoes to explanations of some aspects of consciousness in

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neuroscientific or functionalist terms. Both approaches can deal with the main problems at issue, such as the kind of information processing that is required in order to achieve consciousness, the way(s) in which that processing is implemented in the nervous system, or could be implemented in artificial intelligence systems, the distinctiveness, peculiarities, and interactivity of conscious and nonconscious processes, the reasons why and the ways in which consciousness may dissociate, the function(s) of consciousness, and, thereby, the framing of consciousness in an evolutionary perspective. The reasons for italicising “implemented in artificial intelligence systems” are clear. Even if an operational definition could be worked out such as to satisfactorily cover all information-processing aspects of consciousness, it would, in any case, hopelessly miss phenomenal experience: it would miss, to use Nagel’s (1974) catching phrase, what it is like to be a conscious being. In order to avoid misunderstandings and pitfalls, and even if it seems obviously true (except perhaps to some radical behaviourists), it must firmly be kept in mind that having phenomenal experience x is not the same as claiming to have that phenomenal experience. This distinction between phenomenal experience and phenomenal reports is of essence in view of determining the extent to which and the way in which the former is amenable, through the latter, to scientific scrutiny. Even though some writers (e.g. Searle, 1993) may be read as being of a different opinion, there seems to be no room for scientific conjectures about the presence of phenomenal experience anywhere in the world, in the same sense that there is no room for scientific conjectures about the existence of any world whatsoever. Likewise, there seems to be no room for scientific speculation as to whether phenomenal experience is only a property of the natural nervous systems with which we are so far acquainted, and how such a property might inhere in these or any other (including artificial or fictional) systems. Were this actually the claim (see McGinn, 1991, for expanded argument) against which the accusation of “New Mysterianism” has been levelled (Flanagan, 1992), the latter would appear

to be a blunt dart thrown in a vein of exuberant New Enlightenment. By contrast, the charge would be fully deserved if, proceeding from this claim, one went so far as to entirely ostracise phenomenal experience from cognitive sciences, including cognitive neuroscience. As noted earlier, claims about one’s own phenomenal experience should not be mistaken for that which they are about. None the less, they offer clues the outright dismissal of which would be unreasonable, notwithstanding any legitimate suspicions we might have inherited regarding introspective reports. Taken for granted that they are not incorrigible (unlike phenomenal experience per se, with respect to which the issue of corrigibility does not make any sense) and are therefore unreliable as self-interpretations, introspective reports are nevertheless data, i.e. legitimate candidates for explanations in their own right or as independent variables in psychological or neuropsychological research (see e.g. Shallice, 1988). This claim does not entail breaking any bonds of official science. A quite different conjuncture arises as soon as we acknowledge that studying other people’s “consciousness” has obvious implications for the understanding of our own phenomenal experience. Subjectivity would ipso facto be taken into partnership in an unprecedented game raising foundational issues vis-à-vis the current paradigm of science. Indeed, the move by which such implications are made explicit is the hypothetical ascription of phenomenal experience to an observed entity by analogy with the phenomenal experience of the observer. It might be objected that this move would incur the fatal mistake of ascribing phenomenal experience to fictional zombies, or people who might have been turned into real zombies as a consequence of brain damage (a possibility hinted at by Gray, 1995), or even pave the way toward panpsychism. Pending clarification, however, one may not be discouraged from guardedly exploring the practicability of this kind of “heterophenomenology” (borrowing the term from Dennett, 1991). To the same end, and with the same amount of caution, auto-phenomenology might also be

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assayed, if not fully licensed, as a source of information or, at the very least, inspiration. This would not only encompass (more or less ironically hypothesised) correlations of one’s own phenomenal experience with data provided by (more or less science-fictional) cerebral autoscopy. More practically, one could engage as subject in experiments such as those run by Marcel (1983) on nonconscious priming or by Libet (1985) on the timing of conscious initiation of voluntary acts, and capitalise on direct experience with them. The risks inherent in intracarotid barbiturate injection prevent experiencing in propria persona what it is like to be transitorily deprived of part of one’s own brain, but much safer procedures might soon be at hand for similar purposes (see e.g. the inducement of visual extinction through transcranial magnetic stimulation in normal volunteers by Pascual-Leone etal., 1994).

THE MAPPING OF CONSCIOUSNESS IN THE BRAIN Neural circuits subserving conscious perception and imagination are spatially articulated in the brain. Most of what is consciously perceived or sensory-wise imagined is referred to a definite location of somatic and extrasomatic environment. Furthermore, “panoramic” consciousness (Kinsbourne, 1988) comprehends all loci of the space spanned at any given time in any sensory domain, and something similar is suggested by introspection to be true of imagery. It therefore makes sense to raise the question of the spatial structure of consciousness. Any spatial structure would of course be incompatible with the conjecture that consciousness is achieved in a certain focal point, a phrenological module reminiscent of the Cartesian pineal gland and endowed with the unique and exclusive function to get mental contents alight. As nowadays such a conjecture does not seem to be seriously entertained and defended in neurophysiological terms by anybody, we can safely dismiss it. The problem itself might otherwise be denied by claiming that asking the question of the spatial structure of

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consciousness implies a confusion between content and vehicle (i.e. nervous system) of representation (see e.g. Dennett & Kinsbourne, 1992). This is a potentially contentious philosophical issue that can hardly be treated here in a cursory way. A possible reply, however, could be that if no enigmatically immaterial go-between is posited, relating the represented (i.e. something existing or imagined to exist in the somatic or extrasomatic environment) and the representing (i.e. the mind, i.e. according to the genuinely non-dualist stance most neuroscientists are likely to endorse, the nervous system), the question of the spatial structure of consciousness is perfectly legitimate in so far as consciousness is held to be ingrained in (rather than bestowed upon) mental representation. Otherwise stated, it seems perfectly legitimate to ask not only whether and how consciousness is distributed over an extended circuitry in the nervous system but also whether and how the spatial properties of what is consciously represented are preserved by spatial properties of the representing system. Regarding the first of these two points, the neural articulation of consciousness shows through the results obtained by requiring different types of conscious responses to identical stimuli with normal people or brain-damaged patients. Examples are the dissociation of awareness of painful stimuli in spoken vs. written reports during hypnosis (Hilgard, 1973), and the decreasing rate of correct responses reported by Zihl and von Cramon (1980) and Marcel (1993) by asking blindsight patients to indicate whether they had “felt” a visual stimulus addressed to their blind field by blinking, pressing a button or uttering “yes”. Other dramatic dissociations of perceptual awareness or conscious intention have been revealed by callosal section or brain lesions causing disorders such as anosognosia and unilateral neglect. A great variety of examples are reported in other chapters of this volume or can be found in neuropsychological literature. One of them is particularly worth being mentioned here in that it is quite recent and appropriate. As already remarked, there are hemiplegic patients who assert being aware of their paralysis, and none the less intend and unhesitatingly try to carry out activities that are obviously and totally precluded by their

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disability. Conversely, patients who bluntly deny their own hemiplegia may behave as if they were in fact hemiplegic: they do not at all remonstrate against being confined to bed or wheelchair; indeed, they peacefully abstain from venturing any action requiring use of the paralysed limb(s). The apparent dissociation of beliefs underlying this condition has been systematically investigated by Marcel and Tegnér (unpublished), who showed that patients who deny hemiplegia may nevertheless disclose their dim knowledge (dunkle Kenntniss, Anton, 1899) of it by correctly rating motor abilities of a person supposed to be in exactly the same condition as theirs. As for the second point, the préservai of the spatial properties of what is consciously perceived or imagined in the spatial properties of the nervous system is suggested by the analogue character of space representation, hypothesised on the basis of results from psychological investigation (Kosslyn, 1980; Shepard, 1975) and demonstrated by the study of unilateral neglect and related disorders (see Chapter 21 in this volume and the papers to which it refers on this subject). Note that, on the one hand, the objections that can be raised against a very naively conceived analogue representation of time by neural processes (Dennett & Kinsbourne, 1992) do not necessarily imply wholesale rejection of any hypothesis based on analogue representation in general and that, on the other hand, the notion of analogue representation should itself be laboriously worked out in order, for example, to account for the ability to conceive a sidereal or a Lobachevskian space. The problem is further complicated by the fact that it should also take into account the brain processes involved in the generation of conscious contents, such as inner speech or moods, that seem to have no intrinsic spatial properties. Further evidence concerning the mapping of conscious representation over the pattern of brain activities is the reversible double dissociation of awareness of one side of ophthalmokinetic and melokinetic spaces suggested by the performance of patients suffering from unilateral neglect on Tegnér and Levander’s (1991) mirror-reversed version of Albert’s (1973) line cancellation task (see Chapter 21). By means of this version of the task, patients may be observed to neglect the

contralesional side of visuo-ophthalmokinetic space, i.e. the ipsilesional side of melokinetic space, or vice versa, possibly depending on whether the brain lesion is more posteriorly or more anteriorly located, respectively. More precisely, they may only cross out on the contralesional side of the stimulus array lines that, due to mirror-reversal of the visual appearance of that array, are seen to lie on the ipsilesional side of their field of gaze (contralesional visuo-ophthalmokinetic neglect), or vice versa (contralesional melokinetic neglect, i.e. apparent unawareness of the contralesional side of their limb’s workspace). Note that the contralesional neglect thus individuated in either exploratory modality entails paradoxical ipsilesional neglect in the other (contextually involved) modality. Furthermore, forcing patients to start cancellation from the side they had (visually or manually) neglected in the condition in which no such constraint was set, was found in some instances to cause a reversal of one type of contralesional neglect (visuo-ophthalmokinetic or melokinetic) into the other2 To summarise and conclude, psychological and, much more conclusively, neuropsychological research supports the contention that full consciousness in information-processing terms is indeed the result of a decomposable complex of devices monitoring mental contents with no common terminal. In so far as such devices are held to be identical with a distributed circuitry of the nervous system, consciousness can be said to have spatial extent and articulate distribution. Furthermore, in so far as brain activity, rather than being materialistically downgraded to a brute vehicle of immaterial contents loaded upon it by some sort of “élan mentale”, is held to be itself instantiating representation and consciousness, it may be argued that part of the spatial structure of consciousness depends on the way the brain has been ecologically shaped in order to represent somatic and extrasomatic space (see Braitenberg, 1979, pp. 100ff.). Finally, to admit the implausibility of a common monitoring terminal as the locus of consciousness in the brain would imply disposal of any overarching and indifferentiated “module” in trying to explain how and why mental contents may become conscious.

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THE DIACHRONIC ARTICULATION OF CONSCIOUSNESS Dismissing the notion of a common terminal where ongoing mental activities come to a finish that makes them conscious, and are ultimately posted up in a showcase where conscious content may be inspected in order to drive further activities, opens the question of the timing of consciousness. This question has already roused lively debate (see e.g. the following papers and appended commentaries: Dennett & Kinsbourne, 1992; Libet, 1993, 1985). It will only be introduced here through a few examples of pertinent empirical findings from neuropsychological and psychological investigation. Libet and his co-workers (Libet et al., 1979) made an experiment, destined to be subject to longlasting discussion, in patients to whom electrodes had been implanted for therapeutical purposes in subcortical structures—thalamus and medial lemniscus—and in the cortical somatosensory area. Three types of electrical stimuli were employed: cutaneous single-pulse stimuli and trains of pulses delivered by cortical or subcortical electrodes, where intensity was calibrated in such a way that equal duration (hundreds of milliseconds) was required in order to reach the threshold for verbal reportability for the two kinds of intracerebral stimulation. Cutaneous stimuli were paired with subcortical or cortical stimuli. The two stimuli of each pair had identical onset, and cerebral stimuli (either subcortical or cortical) were such as to produce a cutaneous sensation on the side opposite to that on which direct cutaneous stimulation was applied. The two stimuli of cutaneous-subcortical pairs were judged to be synchronous. With cutaneous-cortical pairs, by contrast, stimuli were judged by patients to be asynchronous, the sensation due to direct cutaneous stimulation being felt as the leading one. The following paradox seems therefore to arise: experimental conditions were such that identical minimal duration of subcortical and cortical stimulation were required to ensure conscious sensation and, nevertheless, in the case of subcortical stimulation the sensation was felt to be simultaneous with that arising from synchronous

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cutaneous stimulation, whereas in the case of cortical stimulation it was delayed. It is important to note that the application of cutaneous and subcortical stimuli was followed by an almost immediate primary evoked potential in the cortex that did not occur following direct cortical stimulation. This neuronal response, therefore, seemed to be the time-marker on the basis of which the subjects’ introspective reports were determined. However, the cortical primary evoked potential per se was not sufficient for introspective report of sensation, as demonstrated by the fact that, after it, more protracted stimulation of subcortical structures was needed to reach detection threshold. Libet and his co-workers (1979, p.217) concluded that their findings supported the hypothesis that the timing of sensory experience was “retroactively antedated” to the time of the (non-conscious) cortical primary evoked potential. A similar paradox was taken up by Dennett and Kinsbourne (1992) in their critical essay on the spatio-temporal structure of consciousness, namely the phenomenon of apparent motion in the “phi phenomenon”, where the illusion of motion is created by flashing two asynchronous and spatially separated dots. With only dot 1, the subject perceives the offset of that dot. With dot 1 offset followed after a temporal gap by the onset of dot 2, the subject perceives no offset of dot 1, but, rather, dot 1 moving to the position of dot 2. As in the case of the experiment by Libet et al., the phenomenon might dangerously (see later) be described as a backward referral in time of a conscious sensation: the sensation of movement, though caused by the flashing of dot 2 is consciously perceived as preceding it. Opposite, in a sense, is the paradox found in the behaviour of left neglect patients required to react to red or green, and left or right, flashing spots of light by pressing a response key of the same colour simultaneously but permanently lighting up on the same or the opposite side (see Bisiach, Berti, & Vallar, 1985, for details). The paradox was particularly striking with patient FS. He gave 100% correct responses to right stimuli requiring right responses. On trials on which those same stimuli had to be responded to by pressing the key on the left (neglected) side, detection fell to 50%. Omissions were sometimes accompanied by

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the patient’s spontaneous remark that no stimulus had occurred. Note that the patient did not know beforehand the side of the required response: this was dictated, on each trial, by the colour of the flashing dot and the variable location of the appropriate response key. Therefore, the patient had first to discriminate the colour of the stimulus and then to look for the appropriate key on either side of the working space delimited by the experimental apparatus. This means that denial of right stimuli only occurred after he had ascertained the absence of the appropriate response key on the right side and failed to look for it on the left. Unlike the two previous examples, in which a conscious content might appear to arise before its time, i.e. before the events on which it is causally dependent, this might suggest that a content can be prevented from becoming conscious by events occurring after the time by which it should have become conscious, despite the fact that it had guided the preparation for a conscious conventional response having the same cognitive status as a speech act (which makes quite implausible an interpretation in terms of instantaneous retrograde amnesia). It has been argued that findings such as those illustrated by these three examples can only be regarded as puzzling paradoxes, and even suggest the bizarre idea of backward causation, in so far as (1) any proposition about consciousness is indiscriminately implied to refer to phenomenal experience as well as to consciousness in information-processing terms (Bisiach, 1988), and (2) contents of consciousness are held to be those that appear at any given time on the stage of the Cartesian theatre (Dennett & Kinsbourne, 1992). Each of us could be the subject in a phi phenomenon experiment and be directly acquainted with the corresponding phenomenal experience. Due to practical reasons the same is hardly true of the chronometric experiments devised by Libet et al., but we can easily, and probably veridically, imagine what it would be like to have the phenomenal experience reported by their patients. None the less, we would never achieve a point-to-point mapping of the information-processing chronometry of our mental processes on the chronometry of our phenomenal experience simply because, introspectively, the temporal grain of phenomenal

experience is too coarse for that and the qualities of that experience are in many instances quite fuzzy. Much more problematic are cases such as those instantiated by the behaviour of patient FS in the aforementioned experiment. We could only make very arbitrary conjectures about the phenomenal experience underlying his expressed denial of a number of suprathreshold stimuli appearing on the side unaffected by neglect (see Bisiach, 1988, pp. 111-112). By contrast, we could envisage, in information-processing terms, alternative explanations prompting further experimental tests. In any case, assuming for the sake of the argument that FS was not lying, his behaviour would appear to be indicative of how conscious processes may organise and disorganise through a short interval of time. Envisaging that he was deliberately lying, on the other hand, would beg the questions of which mental processes had caused him to lie in the face of evidence and of the level of consciousness of such processes—processes that would be unlikely to constitute a serially ordered set of microscenes on the stage of the Cartesian theatre in the very narrow window of the infested experimental trial. Marcel (1993, p. 174) has envisaged two ways in which perceptual awareness depends on the type of report. On the one hand, we may hypothesise that different kinds of prearranged response influence beforehand the processing of perceptual information to the extent of predetermining whether or not it will become conscious. This mechanism is likely to account for the fact that awareness of a stimulus in unilateral neglect may depend, for example, on which hand is used for the response (Joanette et al., 1986), or the direction in which the responding hand has to move (Tegner & Levander, 1991), or the action the hand has to perform: e.g. crossing out vs. numbering targets over a stimulus array (Ishiai et al., 1990). On the other hand, different ways of reporting may be hypothesised to have differential monitoring effectiveness: “differential access to an experience”, in Marcel’s words. This is especially the case when the required type of response is fully specified only after the disappearance of the stimulus, as in the experiment with patient FS. In this case, however, the locution “differential access to an experience” may easily be mistaken both in phenomenological and information-processing

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terms as implying the possibility of a dissociation between consciousness and response. As a matter of fact, if a stimulus is given that causes a certain mental state at time tg and awareness of that stimulus is probed at time tj, all we can get at is a different mental state at tj at the tip of the particular probe we have chosen to use. The two mental states are likely to differ from one another as a consequence of the time lag and the interference from response-related processes.

THE CAUSAL ROLE OF CONSCIOUSNESS This is another point where a great deal of confusion may arise if no clear distinction is made between phenomenal experience and consciousness in information-processing terms. The issue of the causal role of consciousness is particularly pressing vis-à-vis functionalism, to which it constitutes a most serious challenge. Criticism may go as far as claiming that failure to meet this challenge is the main flaw of functionalism. This doctrine eschews the physicalist straightforward identification of brain and mind; it is based on the tenet that a given type of mental state (e.g. a belief) needn’t be embodied in any definite neuropsychological mechanism, as apparently demonstrated by many instances of functional recovery following irreversible brain damage. Leaving aside the crucial question of the extent to which what is “recovered” is functionally identical with what had been lost, as well as any suspicions about the motives for the emphasis on types, rather than on tokens of mental activity, functionalism may be viewed as paving the way to “strong” artificial intelligence theorists ascribing mental attributes, including consciousness, to man-made systems such as more and more complex computational robots. This ascription may be impugned, as in fact it has been—even if not always unambiguously—by Searle (e.g. 1980, 1993). However, it is difficult, on the one hand, to conceive of any reasons why consciousness in information-processing terms might not be ascribed to artificial brains. On the other hand, if such are the terms in which consciousness is conceived, the functionalist claim that it must have a causal role is

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nothing to be quibbled about: whatever the information-processing criterion on the basis of which a mental content is defined as being conscious, it would be absurd to deny that meeting that criterion entails ipso facto acquiring causative roles of which nonconscious mental states are deprived. Open to question instead are individual proposals about the criteria for the ascription of consciousness in information-processing terms to anybody or anything, and the individuation of the function(s) entailed by that very ascription. Assessments of such proposals— repetita juvant— ought to be undertaken under strict watchfulness against covert diversion of reference towards phenomenal experience; false steps would immediately lead to unproductive confusion. Proposals about the causal role of consciousness may range from generic to specific. The weakness of the former lies in their relative shallowness and lack of articulation. For example, the working definition given of consciousness earlier as “coherent actual or possible monitoring of any mental content throughout the whole spectrum of available behaviour” has obvious functional implications regarding the conscious being’s social adaptation. Functional implications are much less obvious as regards an individual’s mental activity. It might however be reasonably hypothesised that mental contents satisfying this definition are much better qualified for reciprocal inside monitoring and dissemination than those that fail to satisfy it, and therefore more suitable, among other things, to ensure the degree of mental coherence required for survival. This all-embracing, undetailed outlook may be set against more specific suggestions such as those of Shallice (1972,1978) and Johnson-Laird (1983). According to Shallice (1972, p.390), competition among mutually exclusive action plans is resolved by the prominence of a single competitor, strongly activated by perceptual and motivational input, through inhibition of the others. Consciousness is identified with the input to the dominant action system; it would therefore have “the dual function of (a) providing the activation that enables the action-system to become dominant and of (b) setting its goal”. Likewise, Johnson-Laird envisages a competition among parallel, nonconscious, mental processes preluding possibly

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conflicting outcomes. Order is held to be imposed by a superordinate operating system preventing incoherence or stalemate by selecting and sustaining one among the possible courses of events. This operating system is where consciousness comes in. There are problems, however, with these proposals. In both cases, functionally significant consciousness should be regarded as the prerequisite, rather than the consequence, of selection. Indeed, if consciousness were achieved (as some authors seem to be inclined to think) by reverberation from the dominant action system or the operating system upon their input, it is then unclear which functional role it might have. On the other hand, if consciousness were a prerequisite for the selection of the dominant action system or the verdict from the operating system, proposals such as those of Shallice and Johnson-Laird would be no less generic than the proposal implicit in the earlier restated working definition of consciousness. In fact, they would have to include the whole panoramic consciousness as a relevant background both for the selection of the dominant action systems in Shallice’s model and the decisions taken by the operating system in Johnson-Laird’s model. Their apparent specificity would not concern consciousness but only types of hypothesised mechanisms for selective attention and intention (which would, among other things, beg the question as to the existence and differential characteristics of other types, driven by nonconscious mental processes, as in the case of coherent and highly proficient mental activity such as out-of-the-blue problem solving). Surreptitious referential substitution of the concept of consciousness with that of attention is one of the dangers that we are most prone to incur. “Any scientific theory of the mind has to treat it as an automaton” (Johnson-Laird, 1983, p.477). Unless explicitly and convincingly proved to be conceptually wrong, trenchant statements like this would seem to definitively rule out phenomenal experience as causative property. Regrettably, equivocation on this point seems to be very hard to kill, because often people start talking of

phenomenal experience but one soon notices that they are probably substituting that referent with the concept of consciousness in informationprocessing terms (see e.g., Van Gulick, 1993, p. 28, and Searle, 1993, p.39). A causal role of phenomenal experience per se, indeed, could be envisaged within the present paradigm of natural science only by demonstrating that mental activities endowed with phenomenal qualities do not also differ in other respects from activities devoid of such qualities. Such a demonstration has never been given and it even seems impossible to conceive how it could be. A paradox arises at this point, which looks fairly intractable in neurological terms. It arises from what is efficaciously expressed in Marcel’s statement, quoted at the beginning of this chapter. We are extremely far from having a complete neurophysiological description of how, in fact, higher nervous processes corresponding e.g. to the perception and representation of states of affairs in the world predispose or give rise to further nervous processes corresponding in turn to what the mentalistic vocabulary designates as beliefs, action plans, etc.; neural models such as cell assemblies and their dynamics may however be elaborated upon in order to formalise plausible conjectures. Models of this kind may also be envisaged to sustain informational consciousness as defined earlier, but when we entertain a concept of consciousness originating from, and comprising, phenomenal experience, we are apparently forced to admit that the latter is in its own right conducive to the neural processes instantiating such a concept. If this were true, we would be left with the hard problem to find how this causal link might be conceived to be realised in the brain.

NEURAL MECHANISMS OF CONSCIOUSNESS An idea of the prospects and difficulties facing any neurological theory of consciousness may be given by briefly reviewing a few alternative proposals and the lively discussion stirred by the most recent one.

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In Kinsbourne’s view (1993, p.56), “awareness is an irreducible property of the activity of functionally entrained neuronal assemblies and therefore is amenable to no further explanation”. It is important to note, although he is not explicit on this point, that Kinsbourne precisely refers to phenomenal experience; in fact, he invites abandonment of the belief that consciousness evolved for a specific adaptive purpose, a solicitation that would sound preposterous if referred to consciousness in informationprocessing terms. Kinsbourne (plausibly) claims that there is no module in the brain bestowing consciousness upon a privileged élite of products of mental activity accessing it in their definitive make-up; consciousness is simply a property of cell assemblies that due to intrinsic impetus generalise across a wide circuitry to form a “dominant neuronal action pattern”, or, in different words, a “dominant focus”. A very similar proposal has been made (Bisiach, 1992), without explicitly restricting it to phenomenal experience—that is, implying its applicability to a functionally significant, adaptive consciousness in information-processing terms— and with special reference to internally driven mental contents. This prevents the ever-impending danger of confusing the concepts of consciousness and stimulus-driven attention, a danger that becomes particularly acute if terms such as “dominant focus” are used. It also avoids the highly questionable extension of this term to the extremely articulate expanse of panoramic consciousness resulting from parallel processing of information simultaneously fed through all sensory modalities. More specifically, two features have been suggested in that proposal to characterise (predominantly) endogenous cell assemblies (Hebb, 1949; see also Amit, 1995, and commentators) achieving consciousness, namely their being enthymematic and fuzzy-jittery. The first term means that conscious contents corresponding to these cell assemblies leave out a great deal of the antecedents and background from which they are generated and given meaning (cf. the concept of “fringe of consciousness” as reconsidered by Galin, 1993). The second, adumbrates and consociates four additional notions:

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1. The huge expanse of the busy neural network in which representational activity is implemented and which is beyond any realistic hope of panoramic assessment by neurophysiological means. 2. The imprecise correspondence of a cell assembly involved in thinking about a certain object to the cell assembly activated during perception of that object. 3. The co-occurrence of different cell assemblies, some of which may have segments of relevant circuitry in common. 4. The instability of endogenous clusters of neural representational activity. As rightly noted by Kinsbourne (1993, p.46), holistic hypotheses of this kind do not lend themselves to clear-cut confirmation or falsification. Their main force, indeed, lies (for all we know) in their neural plausibility, as well as in their aptitude to account for the spatio-temporal structure of consciousness and, above all, in the absence of more convincing alternatives. Their vagueness, to some extent conceded by the vagueness and elusiveness of phenomenal experience related to mental activities unanchored to input from the external world, is a main shortcoming vis-à-vis the relative preciseness, firmness, and relative veridicality of ordinary sensory-driven phenomenal experience. An alternative conjecture has more recently been worked out by Gray (1995). Drawing from studies on anxiety and schizophrenia, this author outlined a neural model intended to explain how phenomenal experience—with explicit reference to qualial—arises out of brain events and has functional significance. According to this model, phenomenal experience is the output of a comparator system generating immediate predictions about forthcoming perceptions of any kind and assessing the extent to which they match or mismatch really occurring perceptions. The comparator is the septohippocampal complex constituted by septal area, entorhinal cortex, dentate gyrus, hippocampus, and subiculum. The latter is its core, which is held (a) to be fed with perceptual information about the current state of the environment from all cortical association areas and

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about current motor programmes from prefrontal cortex via entorhinal and cingulate cortex; (b) to ask and receive perceptual predictions from Papez circuit; and (c) to control the premotor system, either licensing or stopping its programmes. The timing of match/mismatch operations is set by the hippocampal theta rhythm, with a resolution of one-tenth of a second. “Match” outputs sustain current motor programmes by allowing the nucleus accumbens to accept and respond to input from the amygdala. “Mismatch” outputs are sent to the cingulate cortex, where they interrupt ongoing motor programmes, and to the nucleus accumbens that initiates exploratory behaviour. Phenomenal experience, according to this hour-glass model of mental activity, might be locally sustained at its neck: the subicular area. Alternatively, it might be the result of feedback from this area to those areas on the activity of which the subiculum bases its match/mismatch decisions. Gray favours the second alternative because, despite sharing obvious shortcomings with the first, it affords a more plausible account of the richness, modalityspecificity and, above all, cohesion of the contents of sensory-driven phenomenal experience. Making this option, however, makes Gray’s conjecture itself into an holistic one. Furthermore, unless proved that distributed cell assemblies alone cannot sustain consciousness, or that consciousness is abolished by bilateral lesion of the subicular area, the conjecture may be regarded as being gratuitously unparsimonious. In fact, as repeatedly pointed out in the Commentary following Gray’s target article, there is no reason whatsoever to believe that amnesic patients suffering from bilateral destruction of the septohippocampal system are also deprived of phenomenal experience of their pastless present. Other difficulties have been set up against Gray’s conjecture, such as the dubious role of the subicular comparator in emblazoning with phenomenal experience any kind of contents flowing in the stream of thought and the unargued ascription of functional significance to phenomenal experience. None the less, his daring proposal has surely contributed and stimulated progress in reducing vagueness and ambiguity in the field and laying bare some of the problems and pseudoproblems with which the latter is fraught.

CONCLUSIONS Waiting for more satisfactory definitions issuing from further empirical and speculative work, it has been suggested in this chapter that discussions about consciousness should be explicit as to whether they refer to phenomenal experience or to consciousness in information-processing terms. Furthermore, in order to avoid confusion, the concept of consciousness in information-processing terms should not merge with concepts such as attention, i.e. selection of contents for conscious representation (either from the sensory array or from memory), and knowledge. It has been claimed that there is no scientifically explicable reason why part of the brain’s activity should be endowed with phenomenal qualities. Any explanation of the ways in which consciousness in information-processing terms, and to some extent phenomenal experience itself, are realised in a system such as the brain only concerns the pattern of neural events leading to conscious mental contents. Given that there seems to be no reason to believe either in the existence of a neuroanatomical “centre” of consciousness or in the necessity, or convenience, to posit a functionalist “module” where no less (and no more) a quality than that of being conscious is conferred upon mental contents, consciousness cannot be factored away from mental contents in which it inheres. It is therefore itself characterised by their spatiotemporal structure. In a weaker sense, this only relates to the spatiotemporal structure of those neural processes that in physiological (as opposed to mentalist) description are nothing less than those contents. In a stronger sense—pending however the question of the distinctiveness of content and vehicle of representation—this also relates to the issue of analogue representation of external world. As to the causal role of consciousness, it has been argued that there seems to be no fact of the matter with respect to phenomenal experience, except for the mechanisms giving rise to the concept of consciousness itself. By contrast, it has been claimed that if consciousness is instead conceived in information-processing terms, its causal role is

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fairly obvious. This is one of the reasons why we must be absolutely clear about what we mean by “consciousness” in any particular context. Finally, two contrasting leanings have been outlined and exemplified regarding conjectures about the neural mechanisms of consciousness: one relatively holistic and the other relatively localisationist. Given the present state of the art, this is an issue where it is extremely hard, so far, to form and defend a confident opinion. On either line, general explanatory attempts have shortcomings of their own. On the other hand, they provide inspiration and constraints for further speculation and empirical investigation. A particularly arduous, though very intriguing, aspect of the issue is the assembling of the results of parallel processing streams, notably the ventral and dorsal streams of visual processing suggested by Ungerleider and Mishkin (1982), in phenomenally unitary representations: the so-called binding problem (see Kinsbourne, 1995, p.1324, for possible solutions). This point has more general implications as regards the unity of the phenomenal self. While general explanatory attempts pursue the main goal of unitarily elucidating the neural mechanisms of consciousness, we can capitalise on piecemeal progress so far achieved and guide neuropsychological investigation in search for further pieces of the jigsaw puzzle. No matter how partial, these results are hoped not only (i) to nourish current general approaches to the neurology of consciousness and tie up loose ends, but also (ii) to contribute to a comprehensive theory of consciousness by answering some of the basic questions it is expected to settle, and (iii) to achieve more precise and articulate parsing and identification of the factors involved in the definition of consciousness. Here are a few examples: 1. Recent data suggest that one aspect of the dysfunction responsible for unilateral neglect of visual space is a left-right anisometry of the representational medium, such that the grain of the latter is relatively tightened towards the ipsilesional and progressively relaxed towards the contralesional side (see Chapter 21). This

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dysfunction must have definite correlates in changes induced by the brain lesion in the activity of neurones encoding spatial relationships, such as, for example, the neurones found in Area 6 by Rizzolatti and his co-workers (e.g. Fogassi et al., 1992), in Area V6 by Galletti and his co-workers (Galletti et al., 1993, 1995) and in Area 6 and the putamen by Graziano and Gross (see review in Graziano & Gross, 1994, 1995). Besides affecting the metrics of space representation, these changes might be responsible for the still ill-defined disorders of spatial consciousness shown by neglect patients. 2. A very hard question concerns the differential structure of conscious and nonconscious components of the cognitive machinery. Are there nonconscious perceptions, representations, propositional attitudes, thoughts, and action plans? Some of these mental types may be not envisaged to occur at a nonconscious level as events, but deemed to draw from nonconscious neural dispositions like the “body schema”, held to give shape, according to circumstances, to conscious events such as body percepts, images, and actions. The temporary conversion of a somatoparaphrenic belief into a true belief about body parts under the effect of vestibular stimulation (see Chapter 21), for example, does not imply that the true belief was prefabricated but occluded, as it were, by the false one. This cannot be the case with putative “nonconscious” perceptions. So, what could be the structural difference between, say, the neural code of a conscious and a nonconscious prime? Would that difference be the same in Marcel’s (1983) experiments on normal people as in Berti and Rizzolatti’s (1992) experiment on neglect patients? Although it is so far impossible to answer these questions, further neuropsychological investigation may give us valuable clues. A conjugate question regards the minimal level of sensory processing required for a neural process to be endowed with consciousness. Normally, the product of early processing stages is superseded, at the conscious level, by that of final stages. If the latter is prevented, e.g. by brain lesions causing

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BISIACH

“apperceptive” forms of agnosia, the former may however become conscious in some instances; the colour of an object may thus be consciously perceived even if the patient is unaware of the object’s shape and location (Warrington, 1985). If processing fails at a lower or different level, as happens with blindsight or total cortical blindness, it remains nonconscious. One of the tasks facing neuroscience is therefore to precisely define the configuration required for sensory-driven brain activities to be conscious. Regarding the output side of mental activity, the experience of voluntary movement of a phantom limb might, as piercingly remarked by Kinsbourne (1995, p. 1322), correspond to early phases of premotor activity that are normally supplanted in consciousness by the experience of real movement. 3. Based on the working definition of consciousness in information-processing terms given earlier, most manifestations of unilateral neglect may be described as follows: patients are not conscious o f what lies on the contralesional side of space (according to one or more egocentric spatial frames of references, as discussed in Chapter 21). Yet, nobody sufficiently acquainted with that complex of symptoms would be really satisfied with this description. Indeed, depending on (often hard to define) nuances relative to the way a particular patient behaves in response to a particular task, one would be tempted to fill the slot filled in the above sentence by the phrase “are not conscious o f ’ with alternatives such as: “fail to pay attention to”; “refuse to pay attention to”; “do not bother with”; “shun”; “dislike”; “despise”; “misconstrue”; “deny”; “fear”; etc. Unfortunately, only anecdotal observations are so far on record or have circulated as personal communications pertinent to this point. One example is the left neglect patient who, when requested to pick up a number of small objects aligned left-to-right in front of her, collected those lying on the right and then pushed away the remainder saying: “There aren’t any more” (Bisiach & Geminiani, 1991). Another example is Marcel and Tegner’s (unpublished) patients who denied left hemiplegia, though admitting

that something was wrong with their left limbs when confidentially asked whether those limbs were “naughty”. Explaining away these kinds of behaviour on exclusively “psychodynamic” principles would arguably be wrong (Bisiach & Geminiani, 1991) and, at any rate, questionbegging. Finally, any attempt to understand and define consciousnes will have to take into account the modulation of perceptual awareness of “neglected” space through manipulation of experimental conditions, of which well known examples are the improvement of line bisection errors by contralesional attentional cueing (Riddoch & Humphreys, 1983) and the results obtained by means of Tegnér and Levander’s (1991) mirror-reversed cancellation task and reported earlier in this chapter. The latter could be indicative of the dynamic balance between two interconnected neural nets, one input, and the other output-related, participating in the generation of patterns of conscious activity. At the end of this chapter, the reader may rightly claim that the informational approach with which it is largely concerned misses the meaning of the term “consciousness” altogether. Impetus for such a claim may partly come from the fact that dealing with details in later sections may have effaced the comprehensive intent of the working definition given in the first section. It is therefore worth remembering that by focusing on the “coherent, actual or possible, monitoring of any mental content throughout the whole spectrum of available behaviour accessible to public observation” that definition was only meant to come as close as possible to phenomenal consciousness as experienced in propria persona or inferred from other people’s behaviour. More specifically, it was meant to provide tentative means for a neuropsychological approach to consciousness that could indirectly account for at least some features of phenomenal experience itself and, hopefully, contribute to the clarification and enrichment of the concept of consciousness—a concept that, as is evident from recent debates, is still very far from being unanimously settled.

29. CONSCIOUSNESS

ACKNOWLEDGEMENTS I am greatly indebted to Marcel Kinsboume, Tony Marcel, and Luigi Pizzamiglio for their critical reading of the first draft of this chapter. Their remarks have hopefully led to some improvement of the final version. Most importantly, their remarks made me fully aware of problematic points that I still feel unable to deal with in a satisfactory way.

NOTES 1. According to Merikle and Cheesman (1986, p.42), the su b jec tive th re s h o ld is “the level of discriminative responding at which observers claim not to be able to

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detect perceptual information at better than a chance level of performance”. The objective threshold is “the level of discriminative responding corresponding to chance-level performance”. Merikle and Cheesman suggest that “the subjective threshold, or the threshold for claimed awareness, better captures the phenomenological distinction between conscious and unconscious perceptual experiences and [...] provides a better definition of the boundary between conscious and unconscious perceptual processes than is provided by the objective threshold”. 2. Against an interpretation of the reversal of one type of neglect into the other in terms of inability to disengage attention from the cued side and fatigue, is the fact that no reversal was ever found in the canonical (i.e. nonspecular) version of the cancellation task when patients were required to start cancellation from the contralesional side (see Table 2 in Bisiach et al., 1995).

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Part IX

Dementia

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30 Dementia: Definition and Diagnostic Approach Hans Spinnler and Sergio Della Sala

which is impossible to differentiate from that characterising Alzheimer’s Disease (see Chapter 31). Dementia also differs from the acute confusional state, known also as delirium, which identifies an episode (or episodes) of neuropsychological disorder of acute onset and short duration, mainly characterised by disorientation in various domains (time, space, family, self). This distinction is not so much related to aetiology (e.g. metabolic, traumatic) as it is to the transience of the symptoms (hours, days) and to their progression (cloudy state, stupor) towards coma (see Chapters 25 and 31). Summing up, dementia refers to an acquired, progressive, and chronic clinical and behavioural picture. In the era of early neuropsychiatry, in the wake of Kraepelin (1909, 1910), dementia denoted the behavioural derangement of “symbolic funtions”; therefore its definition was centred on the deficits of semantic knowledge. The “symbolic functions” were conceived as the core of “intelligence”. The recent development of neuropsychology added to our understanding of normal and pathological cognition and behaviour, thus refining the concept of dementia. The current definition of dementia is

This is the first of five chapters focusing on the neuropsychology of the dementias. It is mainly aimed at establishing definitions and terminology to ease the reading of the following chapters.

THE MEANING OF THE TERM “DEMENTIA” The term chronic progressive cognitive deterioration (CPCD), which has been suggested recently (Spinnler & Della Sala, 1988), describes the neuropsychological core of the disease better than the more widely used dementia. CPCD and dementia define the neuropsychological and behavioural consequences of an acquired pathology of the brain in previously normal individuals. Therefore, dementia is distinguished from learning disabilities which characterise pre-, peri-, or immediately post-natal pathologies. However, in particular conditions the two diseases are present in the same person. For instance, 20-, 30-year old subjects with Down’s syndrome may develop dementia, the neuropsychological and histopathological picture of 689

690 SPINNLER AND DELLA SALA

strongly influenced by the clinical picture of Alzheimer’s Disease (AD; see Chapter 31), which is widely accepted as the prototype of most dementias. AD encompasses most of the deficits shown by patients with focal lesions (strokes, head injuries, tumours), such as aphasia, apraxia, agnosia, and, most importantly, amnesia. It follows that it is now common to conceive of dementia as the sum of various neuropsychological deficits, yoking its clinical phenomenology to the well known models of cognitive derangement derived from the studies on stroke patients. However, this notion overlooks the possibility that at least some of the behavioural deficits shown by dements in their everyday lives may derive from the neurological defects responsible for dementia. It might also be postulated that in some instances the cognitive incompetence of the dements can be interpreted in terms of reduced efficacy of the control (executive) functions (attention and motivation), rather than attributing it entirely to their “instrumental” (aphasic, agnosic, apraxic) deficits.

NEUROPSYCHOLOGICAL TAXONOMY OF THE DEMENTIAS In this section we will attempt to frame the diagnostic flow-chart of the dementias within the proposed taxonomy. To this end we will avail ourselves of both conceptual and nominalistic cogencies. Neurological dementias, labelled “organic” by early neuropsychiatrists, are characterised by the presence of structural damage to the neuronal network, detected either in vivo or post-mortem. This strictly morphological definition has now spread to encompass biochemical and neurophysiological evidence of damage to the central nervous system (e.g. metabolic dementias). The classic distinction between “organic” and “functional” (or “psychogenic”) stems from the likelihood of detecting structural damage in the organic forms, therefore defining functional dementias by default. Such a distinction, of course,

rests entirely on the resolution power of the available technology. The ephemeral respective bailiwicks of these two forms are therefore bound to be transient. It is perhaps more appropriate to conceive as “functional” a behavioural derangement of the organic pathology which has yet to be identified. Pure psychogenic aetiologies would give rise to behavioural deficits solely on the basis of “intra-psychic” conflicts, without any detectable damage to the brain. It is likely that the organic/ functional dichotomy (including that relevant for the taxonomy of dementias) will fade away as we probe more and more into the neurobiological and neuropsychological working of the central nervous system. For example, it is known that anxiety (a behavioural manifestation without ascertained neurostructural substrate) may alter the attentional resources available, weighing heavily on the cognitive (psychometric) competence of the patient. In certain neuropsychological domains, e.g. retrograde amnesia (Della Sala et al., 1996) the phenomenology of organic and functional deficits significantly overlaps. This correspondence is less overt in the multifarious cognitive derangement of dementia, the differential diagnosis being limited to the relatively uncommon “pseudo-dementias” due to severe anxiety or depression, which are often liable to pharmacological treatment. We propose to classify neurological dementias in two forms: (i) instrumental (AD-like) dementias (Spinnler, 1991), due to the pathology of the associative (retrorolandic) cortex, and (ii) dysexecutive dementias, caused by dysfunction of the prefrontal cortex and, presumably, by subcortical areas linked with it (see Chapter 32). It is our opinion that dementia develops only if the pathological process encroaches upon the cortex (with or without a subcortical involvement). The instrumental/dysexecutive dichotomy is itself provisional, still awaiting an interpretative model of control functions deficits to substitute the current descriptive one (see Table 30.1 for a model of instrumental deficits in dementia). Within the dysexecutive dementias, some authors prefer to differentiate the so-called subcortical dementias. The term “subcortical dementia” sprang from one of the first reports of the cognitive deficits observed in progressive supranuclear palsy (Albert et al.

30. DEMENTIA

691

TABLE 30.1 Summarised taxonomy of the chronic progressive cognitive deteriorations, or dementias. Neurological Dementias

• Instrumental cortical (retrorolandic) dementias (e.g. Alzheimer Disease) • Dysexecutive cortical (prefrontal) dementias, with (e.g. Huntington Chorea) or without (e.g. Pick Disease) subcortical damage.

Psychiatric Dementias

• Anxiety or Depression pseudo-dementia • Psychotic dementia

1974). The raison d ’être of the term is clearly descriptive (Della Sala, 1988), and it is still in want of unitary pathogenetic specifications (e.g. given neurotransmitter or histopathological systems). When its behavioural phenomenology is purely dysexecutive, it is often hard to distinguish dementia from chronic psychiatric clinical pictures, such as schizophrenia or manic-depressive psychosis. The patient (PG) reported by Brazzelli et al. (1994a) is a good example of this overlap. PG was a teenager with a massive bilateral lesion in her frontal lobes following herpetic encephalopathy. She showed only marginal deficits in her instrumental abilities, therefore the descriptive label of AD-like dementia was inappropriate. However, her dysexecutive derangement was paramount, and, except for the absence of hallucinations, the pattern of her behavioural abnormalities was extraordinarily akin to that of schizophrenia. Dysexecutive profiles in dements with a history of psychosis, or showing a clear psychotic behaviour, lead to the descriptive label “psychiatric dementia”, whereby symptoms and nosography merge. It is foreseeable that the current active research into the neuropsychology of schizophrenia will soon produce a sounder neuropsychological classification of these dementias as well. In Chapter 33 we will discuss the neuropsychological consequences of relatively isolated slowly progressive degenerative processes —histopathologically dishomogeneous—of different cortical associative areas. A few years after onset, the outcome of most of these slowly progressive cognitive deficits is a full-blown global dementia, much the same as the more common

instrumental or dysexecutive form. Therefore, the slowly progressive isolated neuropsychological deficits could be conceived as plodding neurological dementias. Their classification, however, is still a matter of debate (see Chapter 33). To summarise (Table 30.1), dementia, which typically refers to deficits in everyday cognitive competence or behaviour, results from the disorder of cortical neuropsychological functions. In some instances they stem from retrorolandic pathologies (instrumental dementias), in others they stem from prefrontal involvement (dysexecutive dementias). These latter might also encompass subcortical damage and symptoms. The concept of dementia thought to be due solely to subcortical damage (e.g. some of the so-called vascular dementias) is being isolated because of a lack of neuropsychological support.

DESCRIPTIVE DEFINITION OF DEMENTIA The term “dementia” was introduced into the scientific literature at the beginning of the nineteenth century by Pinel (1809) and Esquirol (1814), although its phenomenology had been known for centuries (see Berrios & Freeman, 1991). However, the notion of dementia is still rather loose, especially when it is compared with that of diseases the aetiology (or at least the pathogenesis) of which is better understood. In fact, the clinical picture of dementia lacks both an aetiological specificity and a pathognomic pattern, either biological or behavioural, to which one could anchor the diagnosis.

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A tentative descriptive definition of dementia could be summarised in the following two points (Spinnler, 1985): 1. Dementia defines a complex set of modifications in behaviour; these modifications are, for the most part “losses”, to which heterogeneous neuropsychological deficits combine, giving rise to the picture of cognitive incompetence. 2. The main feature of dementia is its slow, steady deterioration, the progression of which should be detectable within a 6-12 month follow-up. Some general considerations are worth prior discussion of the operational definition of dementia. One of the key functions of the central nervous system is its role of “interface” between the milieu intérieur (in this contex to be understood as general cognition), which has to be preserved and continually updated, and the milieu extérieur, which has to be thoroughly examined, so as to fit in it as well and thriftily as possible. In essence, this is the interaction between oneself and the stimuli of the external world. The Darwinian management of this interaction is linked to the good functioning of neocortical supratentorial cerebral structures (the associative areas damaged by the dementing process). This interaction goes to rack and ruin in demented patients. To this end it is worth remembering that the forensic medicine definition of “death” is no longer determined by the clinical arrest of different vital processes (e.g. the cessation of heart beat), but by the cessation of brain function—the body is then declared “brain dead”. The attention of the lawgivers and the physicians, and possibly soon of the public consciousness, is more and more driven toward the ascertainment of the loss of cortical functions: the bio-ethical idea of “cognitive death” is not that far away. Therefore, dementia should be defined as the progressive behavioural and clinical picture associated with the chronic advancing failure of the cortical associative areas, both those linked with instrumental input (e.g. perception) or output (e.g. apraxia) and those connected with information processing (e.g. memory) or management (e.g. attention).

The chronic-progressive cerebral failure, in analogy with the failure of other organs, such as the liver, the heart, or the lungs, has to be interpreted as the overstepping of the minimal threshold for basic functioning. It corresponds to a many-sided set of losses, which manifest themselves through a ceaselessly progressive behavioural derangement entirely disrupting one’s social life. Ecological multifarious cognitive incompetence characterises the clinical picture of each individual demented patient, although, as stated earlier, this cognitive incompetence can scarcely be framed into a predetermined scheme. We would like to stress that the definition we propose only accounts for ecological deficits, which manifest themselves in the patients’ everyday life. This definition of dementia does not encompass the deficits demonstrated only psychometrically, no matter how thorough the assessment has been. The common belief that psychometric tests are more sensitive to dementia than everyday life tasks is far from ascertained. The availability of sound off-the-shelf tests should not exempt the skilled clinician from learned, accurate, history taking, which should include a behavioural anamnesis fuelled by neuropsychological knowledge. In short, the diagnosis of dementia is syndromic; its first step (see later) must be the observation of behavioural and cognitive deficits in everyday life, which often can be scored and monitored by means of psychometric tests. If the findings from these two sources are discrepant, it is wise to reconsider the diagnosis. The main features of dementia, better CPCD, can be summarised as follows: • It is a heterogeneous behavioural syndrome. Patients’ vigilance is normal. Its neuropsychological counterpart is abridged in the classic “amnesic, apraxic, agnosic, aphasic” plus the “alogic” syndromes. This devising mirrors the instrumental/dysexecutive dichotomy, to which we have alluded earlier. • Sooner or later, in the course of the dementing process, the brain shrinks, giving rise to the macroscopic anatomical picture of the cerebral atrophy, which can be detected by neuroradiological techniques (CT scan or MRI). At

30.

•

•

•

• •

onset however, the neuroradiological picture of the demented patient compared to age-matched controls may be normal. In our own series of patients affected by AD (Della Sala et al., 1986) this was true for 20% of the patients whose approximate duration of disease ranged from two to three years. In some instances characteristic neuroradiological abnormalities might precede the clinical picture of dementia. It is the case, for example, of the selective atrophy of the head of the caudate nuclei in the early stage of Huntington’s chorea. Neurological signs are aspecific and occur rather late in most cortical dementias; their role is paramount in addressing the diagnosis of the underlying subcortical disease. In the last stage of dementia a general, rapidly progressive cachexia intervenes, forcing the patient to be bedridden until death. The correspondent psychiatric symptomatology is initially reactive: anxiety or depression might occur, due to the self-awareness of the impending cognitive ineptitude. Hallucinations, delusions and misperceptions might also be observed (Absher & Cummings, 1993). The psychiatric symptoms are rarer in instrumental than in dysexecutive dementias, where they might be the core of the clinical profile (e.g. Pick’s disease, frontal lobe degeneration). The social counterpart is the leeway from everyday activities and family business coupled with the progressive loss of autonomy. CPCD is a nonspecific picture of behavioural derangement resulting from heterogeneous neurological pathologies.

OPERATIONAL DEFINITION OF CPCD CPCD has to be conceived of as a slowly progressive polymorphous syndrome due to the derangement of the associative and hippocampal neuronal networks of both hemispheres. The neuronal damage can spread to most of these cerebral structures, as in AD, or encroach upon only some of them, as in the selective frontal lobe degeneration. The anatomical locus of this

DEMENTIA

693

neuronal degeneration, inferred from the behavioural characteristics of the patients, is irrelevant in the general definition of CPCD. The associated subcortical damage is likely to affect the neurological, and possibly the neuropsychological, picture of the underlying disease, but it does not play any role in its subsumption among the CPCDs. Moreover, the CPCD should not be defined in terms of poor performance on any given test battery. It should instead refer to the everyday progressive cognitive incompetence. From this definition derives the complexity of ascertaining it. In fact, contrary to the measures considered in all other organ failures, the patients’ performances relevant to posit the diagnosis of CPCD are influenced by myriad variables, including the demographic ones. So, for instance, the clinician should be alerted to the possibility of labelling as dement an illiterate old person (false positive), and overlook the diagnosis when the patient is young and well read. The turn towards a more ecologically minded operational definition was marked in 1981 by the British Royal College of Physicians Committee of Geriatrics. Although it is not theoretically grounded, their definition of dementia is worth being reported in full: Dementia is a global impairment of higher cortical functions, including memory, the capacity to solve the problems of day-to-day living, the performance of learned perceptuomotor skills, the correct use of social skills and control of emotional reactions, in absence of gross clouding of consciousness. The condition is often irreversible and progressive, (p.142) Most of the Committee’s remarks are still up-todate. In particular, the reference to the memory deficits, to the preservation of vigilance, and to the patients’ social incompetence are still key points in the diagnosis of CPCD. The definition of CPCD we are proposing deliberately excludes the vaguely defined “minor forms” of dementia (also referred to as “preclinical” or subliminal”). These (e.g. the Age Associated Memory Impairment; AAMI) are often associated

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with ageing, and are more or less explicitly conceived as foreshadowings of a full-blown dementia. They allude to a blurred taxonomic frame, lacking serious methodological constraints, rapidly aiming at establishing a new profitable pharmaceutical pabulum.

DIAGNOSTIC APPROACH The diagnostic approach to dementia varies according to its main aim: clinical or researchlinked. Here we will consider only the clinical approach. However, it is worthwhile reminding ourselves that the heuristic approach is nothing other than a step forward, and it is entirely based on the clinical. Suspecting dementia, the diagnostic hypothesis relies on two basic concepts (Spinnler & Della Sala, 1988): (i) it should be step-wise, that is the diagnosis of CPCD comes first, followed by its nosographie attribution (e.g. AD); (ii) it should follow a cascade algorithm encompassing the history taking, which should allow the clinician to gather both behavioural hints and neurologically relevant information, and psychometrics. This type of algorithm is common to most of the hierarchical diagnostic procedures. Generally the relatives should be trusted with the ability to recognise “pathological behaviour” of the patient in terms of clear modifications with respect to the patient’s previous bearing. Most often, the suspicion of dementia arises from the gap between the patient’s observed misbehaviour and the expected age-linked modifications, which are influenced by culture, economic status, and locus of residence. Given as a first approximation that the difference between ageing and dementia is mainly quantitative, the differential diagnosis between normal ageing and incipient dementia still relies on the definition of normality by means of age-related psychometric norms. The use of rating scales or a battery of age and education-adjusted tests is one of the best by-products of Italian clinical neuropsychology of the dementias (e.g. Allamano et al., 1987; Borrini et al., 1989; Brazzelli et al., 1994b; Capitani et al., 1988, 1992,1994; Della Sala et al.,

1992, 1995a, b, 1996; Novelli et al., 1986a, b; Spinnler & Tognoni, 1987). In the last eight years in our outpatient Dementia Unit, in Milan, we employed the aforementioned diagnostic algorithm with 737 patients admitted to our ward up to 1994. The diagnosis reported in Table 30.2 is the most recent for each patient. However, in almost 5% of the cases we have changed the initial provisional diagnosis in the course of the follow-up. Instances of diagnostic errors were: overlooking AD onset within clinical pictures of apparently benign memory impairments or depression, or, on the contrary, labelling as AD patients who eventually proved to be affected by global amnesia (Korsakov syndrome) or pseudodementia. Additionally common errors included the wrong nosographic attributions: the clinical boundaries between different dementias (e.g. AD and frontal lobe degeneration) are sometimes blurred (see Chapter 32). The steps of the cascade diagnosis can be summarised as follows: Step 1. Behavioural anamnesis. This consists of a preliminary interview with the patients and their relatives. Given the heterogeneity of the patients, we deem these interviews not to be too rigidly linked to established schemes, such as the NINCDS-ADRDA (McKhann et al., 1984) or the DSM-IV (APA, 1994). The aim of this first diagnostic step is to ascertain whether or not the alleged behavioural modifications have taken place. In this phase of the diagnostic procedure, the patients act as their own control. The delicacy of this situation is paramount, and its outcome is strongly related to the skills of the interviewer. Therefore, this diagnostic step should ideally always be carried out by a neurologist or a psychiatrist with neuropsychological expertise; or subdivided between the consultant and a psychologist, working together, both with neuropsychology training. This diagnostic step is not only guided by neuropsychological knowledge, but also by knowledge deriving from clinical neurology (e.g. extrapyramidal symptoms), old age psychiatry (e.g. senile depression), general medicine (e.g. organ failures, such as kidney or lung; metabolic or endocrinological deficits; drugs effects),

30.

neurosurgery (e.g. normal pressure hydrocephalus), infective medicine (e.g. lues, AIDS). The diagnosis of possible CPCD leads to the next step. Step 2. This second step is merely psychometric. Its purpose is to confirm (or deny) the diagnosis raised in step 1. The instruments often used in this step are ad hoc rating scales or neuropsychological test batteries. Among the rating scales it is worth reminding readers of the widely employed MiniMental State Examination (MMSE, Folstein et al., 1975, see Table 30.3) and the more recent Milan Overall Dementia Assessment (MODA, Brazzelli et al., 1994b, see Table 30.4), the scores of which can be age- and education-adjusted. For this latter test, inner and outer tolerance limits have been calculated to decrease the number of false positives and false negatives (Brazzelli et al., 1994b). Both these instruments have been devised as AD severity

DEMENTIA

rating scales, and therefore their use with other forms of dementia remains to be validated. Moreover, they have not been designed to test very severe patients. To this end the reader will find useful the instrument proposed by Panisset et al. (1994), the Severe Impairment Battery (SIB), specifically devised to assess advanced dements. The use of sound psychometric instruments is a clear improvement in the description of the patients with respect to the more traditional labelling “mild”, “moderate”, and “severe”, based purely on clinical grounds. However, the clinician should be aware of the pitfalls in using the rating scales acritically. For instance the performance of aphasie patients on verbal items might be poorer than their global cognitive deterioration would forecast. Moreover, it is the task of the neuropsychologist to implement the results of the rating scales with analytical test batteries, aimed at investigating the cognitive profile of the patients, when doubt arises

TABLE 30.2 Nosographie classification of 737 patients attending the S.Paolo Hospital (Milan) outpatients surgery in the last eight years because of suspected dementia. The duration of disease in most of these patients is less than three years. The diagnosis reported is the most recently advanced. Demented patients

695

Non demented patients

N=456 (61.9%)

N=281 (38.1%)

Alzheimer Disease (AD) N=394 (86.2%)

Normal ageing N=85 (30.2%)

Non-AD dements N=62 (13.6%)

Psychiatric disease N=29 (10.3%) Pseudo-dementia -Depression: N=33 (11.7%) - Metabolic disease: N=9 (3.2%) Focal non degenerative brain lesions - Global amnesia (including 4 Korsakov syndromes): N=25 (8.9%) - Pure retrograde amnesia: N=4 (1.4%) - Frontal (traumatic) syndrome: N=13 (4.6%) - Left hemisphere lesions: N=8 (2.8%) - Right hemisphere lesions: N=2 (0.7%) Focal degenerative neuropsychological deficits - Benign senile forgetfulness: N=29 (10.3%) - Isolated slowly progressive cognitive deficits (e.g. aphasia, apraxia, agnosia, simultaneoagnosia, etc.): N=21 (7.5%) Other or doubtful diagnosis N=23 (8.2%)

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TABLE 30.3

TABLE 30.4

Items of the Mini-Mental State Examination (MMSE, Folstein, et al., 1975).

Items Included in the Milan Overall Dementia Assessment (MODA, Brazzelli et al., 1994b).

1.

2. 3. 4. 5. 6. 7. 8. 9. 10.

Orientation Registration Attention and Calculation Recall Naming Repetition 3-stage command Reading Writing Copying

concerning a focal progressive deterioration (see Chapter 33).

— — —

no

/3 /5

— 13

— 12 — 11 —

I Orientation Enquiry Temporal Orientation Spatial Orientation Personal Orientation Family Orientation

Total

/3

— 11

—n — zi

II Everyday Life Autonomy Autonomy Scale

Total

— — — —

no 13 no m

—/35

—715

III Neuropsychological Tests

cognitive

Step 3. This is the neurological part of the diagnostic algorithm. Having suspected the presence of CPCD with the first step, confirmed and measured it psychometrically with the second, the clinician is left with the problem of attempting to label it nosographically. Adding to the behavioural and neuropsychological information, the results of the clinical and neurological examination as well as the outcome of neuroradiology and laboratory analyses, the neurologist (psychiatrist) expert in neuropsychology will try to identify the cause of the CPCD, the nosography of the patient’s dementia. Often, it is necessary to ask for further analyses or for the opinion of a different consultant. Sometimes, the diagnosis will remain that of CPCD of undetermined origins. Table 30.5 reports a nosography of dementias according to the patient’s age of onset. When the diagnostic question is raised very early in the dementing process, a follow-up of the patient is necessary in order to be sufficiently confident. This is especially true in the case of elderly patients or patients showing “focal” onsets. A deterioration is foreseen in 6-12 months. However this is not the rule in all CPCD. Exceptions are the forms of dementia that can be treated, with either surgery, such as normal pressure hydrocephalus, or with drugs, such as cerebral

Reversal learning Digit Cancellation Test Logical Reasoning Prose Memory Semantic Word Fluency Token Test Finger Agnosia Construction Apraxia Street Completion Test

MODA

— 15 — no

—/6 —/8 —/5 —/5 —15

Total

— 13 —ß — ISO

Total Score

—/100

syphilis or AIDS encephalitis. In these latter instances, the follow-up aims at demonstrating the expected improvement.

CONCLUSIONS The last shards of information that we deem necessary to provide in this preliminary chapter are listed in Table 30.6. Although they are not strictly speaking neuropsychological, given the social, economic, and epidemiological impact of these figures, they should be part of the background knowledge of clinicians and researchers interested in the neuropsychology of the dementias. The next three chapters will discuss in more detail the neuropsychology of AD, non-AD dementias, and slowly progressive isolated cognitive deficits, while the last chapter of this group, dedicated to the neuropsychology of the dementias, will be devoted to the language deficits of all of them.

30.

DEMENTIA

TABLE 30.5 Nosography of the dementias according to age of onset (modified from Spinnler, 1985). Onset before 45 years of age

-

Post-traumatic dementias (most frequent cause of dementia before age 35) Huntington Chorea (about 1% of all dementias) Dementia associated with hereditary degenerative neurologic abnormalities, especially those associated with degeneration of neuronal philogenetically recent neuronal networks (e.g. olivopontocerebellar degeneration) Post-encephalitis dementias (e.g. subacute sclerosing panencephalitis— SSPE of Van Bogaert)

Onset after 45 years of age

-

Alzheimer Disease (about 60% of all dementias) and other cortical atrophies (e.g. Pick’s Disease, Frontal Lobe Degeneration) - Vascular (multi-infarct) dementia (about 10%) - Mixed vascular + AD forms (uncertain diagnosis in vitam) - Dementia associated with Parkinson Disease (using the ecological and not the psychometric definition, no more than 3-4% of all dementia) - Prolonged cerebral hypoxia (respiratory, hemodynamic, CO intoxication) - Paraneoplastic limbic encephalitis and other paracarcinomatous cerebral atrophies - Pseudo-dementia (at least 10% of all senile dementias)

Onset non related to age

-

Endocrine failures (e.g. hypothyroidism, 1% of all dementias) Multisystem immunological disease (e.g. cerebral involvement in the systemic lupus erythematosus—LES) Alcoholic dementias (in some countries up to 1-5%) Dementia due to disturbances of cerebrospinal fluid circulation (normal-pressure, tension and secondary hydrocephalus: together about 4% of all dementias) - Dementia secondary to infections of the central nervous system (e.g. syphilis, Creutzfeld-Jacob Disease, AIDS dementia complex, herpes simplex encephalitis) The percentages given in the table are drawn from different sources and therefore their total does not add up to 100%. Moreover, given the lack of comparability between these different sources, these figures have to be taken as indicative.

TABLE 30.6 Descriptive statistics of dementia. Figures vary from one source to another; the table reports rough averages from different sources, unless otherwise specified. Life expectancy at birth:

1900 1991

47-55 (figures vary according to country). 76 (males), 80.8 (females) (source: OPCS, 1991).

Percentage of elderly in western societies:

Today: Year 2000: Year 2030:

12% 15% 20%

Prevalence of dementia in the UK: about 10% of population over 65 (more than 20% in people aged 80 years and over).

Approximate duration of disease: 10-14 years. Incidence of dementia in the UK: About 5 new cases per 1000 per year. Economic costs: (NHS only, not considering private costs): About $36 billions in USA per year (Congress

of the United States Office of Technology Assessment, 1987); approximately £900 million per year in Wales only (Hart and Semple, 1990)

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Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

31 Alzheimer’s Disease Hans Spinnler

model, even if they currently allude to psychiatrically or socially disturbing traits. Behavioural aspects can be collaterally described as arising during the course of performance testing (e.g. the propensity of patients with frontal lesions not to respect the test rules, irrespective of what is going to be tested). “Neuropsychological” features has been used to refer to the observation and the description of behavioural disorders in the everyday activities and psychometric testing of functionrelated performances, whenever they are explicitly framed within the taxonomy of psychological functions. Neuropsychological assessments nearly always entail the achievement of test measures. Moreover, a neuropsychological description entails the correlative perspective of the functional architecture of the brain (e.g. language, aphasia, and Wernicke’s area in the left temporal lobe, or memory, amnesia, and the hippocampus, and so forth). “Cognitive” has been used to qualify the understanding of behavioural and neuropsychological aspects whenever there is one or more clear-cut processing model of normal psychological functioning available to interpret them. Interpretation relies on the identification of a precise locus (or more than one) of a functional lesion within the reference model, to which the observed deficit is cogently traced back.

INTRODUCTION This chapter delineates the clinical and neuropsychological issues raised by Alzheimer’s Disease (AD). Hence, it is essentially a balance between clinical-diagnostic and cognitiveexperimental neuropsychology. It is not intended to be an encyclopedic work of reference, but rather an overview of our present experience with 709 demented persons assessed in an outpatient service over an eight-year period. In all, 616 of them were eventually diagnosed as suffering from “probable”, or “possible”, AD. Following a definitional and nosological framework of AD, emphasis is placed on the neuropsychological traits of the patients. The last part of the chapter offers some general professional guidelines on giving diagnostic information and suggestions to the relatives of a patient with AD. Before proceeding further, we should clarify some of the terminology that is frequently used in this chapter. The term “behavioural” patterns has been used herein to denote the observation and description of face-value abnormal activities of the patients in ecological settings. Such descriptions do not necessarily draw back to a psychiatric, neurological, or neuropsychological interpretative 699

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From an epidemiological perspective, AD is the most important of the “cortical” degenerative dementias (see Chapter 30). There are other instances (making up about 10-14%) of “cortical” dementias, known as “non-AD dementias”. Some of them are characterised by predominantly dysexecutive impairment (“Dementia of the Frontal Type”; Neary et al., 1988), while others by a predominantly lexico-semantic impairment (“Semantic Dementia”; Snowden et al., 1989, or “Primary Progressive Aphasia”; Mesulam & Weintraub, 1992). Dysexecutive and semantic dementia are known together as “Fronto-Temporal Dementias” (FTD) (Neary & Snowden, 1996). The label of AD comprises both the clinical (behavioural and neuropsychological) and the histopathological (and histochemical) implications of the disease as far as they may be reciprocally predicted given the high clinical diagnostic accuracy. This is not the case with the cortical non-AD dementias. In fact, FTD can be the outcome of different histopathologically defined diseases, such as Pick’s Disease and Frontal Lobe Degeneration, and others (e.g. Diffuse Lewy Bodies Disease; Salmon et al., 1996). AD is the longest and best studied representative of cortical dementias (formally since Alzheimer, 1907, but informally since Galen). Besides being the most prevalent of all dementias, two general characteristics affirm AD as the prototype of “cortical” dementias. The first is of a neuropathological nature (review in Kemper, 1994), and refers to the predominantly neo- and archicortical location of the intra- and extraneuronal degenerative lesions as compared to the scanty involvement of the subcortical nervous structures. The second is of a neuropsychological nature, and refers to evidence of defects of language, praxia, perception, spatial cognition, and attention whose discrete nervous substrates are essentially cortical. Memory (and to a lesser extent also attention) disorders are common to both cortical and subcortical dementias. The general aim of this chapter is to integrate the neurostructural evolution of the Alzheimer degeneration of neurones and the main conclusions of over a century of clinical neuropsychology. More precisely, in a “reductionistic” attempt to delineate

AD, emphasis is placed on correlational assumptions between lesional sites in the cortex and the psychological deficits emerging in ecological and psychometrical settings. Given the nature of the phenomenology of AD, we regard it as the prototype of all the neuropsychologically hallmarked diseases which in essence can be conceived, as the coping consequences of damage to the associative and limbic cortices. AD is the disease (together with aphasias from focal left hemisphere damage) that adds most to the current diagnostic work of the clinical neuropsychologist.

Definition of AD in view of its clinical diagnosis Under this heading the different ways of defining and diagnosing AD and of differentiating it from other cortical dementias will be outlined. The term “AD” is intended to encompass senile and pre-senile onsetforms (Katzman, 1976), which were once distinguished by Kraepelin in the 1909-1913 8th edition of his Handbook o f psychiatry, according to a cut-off age of 65, at a time when the demographical and social implications of this age were quite different from those of today, at least in developed countries. This is not to deny that there may be some genetic trait (e.g. homozygoty of the alleles 4 of apolipoprotein E; Strittmatter et al., 1993) underlying the early or late occurrence of AD as is the case for any other degenerative disease. However, for the clinical definition and the neuropsychological study of AD, Kraepelin’s distinction is simply irrelevant. The many clinically oriented endeavours that aim to define as a nosological entity what, together with Redlich (1898), Fischer (1907), Perusini (1910) and others, Alois Alzheimer in 1907 and 1911 highlighted neuropathologically with the discovery of the neurofibrillary tangles, reflect the pragmatic goal of early diagnosis, that is, to grasp the few essential traits that support the suspicion that someone is in the early throes of AD. The concept of “definition” in the present case as well as in all of the other clinical and biological conditions which lack a precise aetiology or, at least, pathogenesis, is tantamount to that of possibly the most parsimonious “description”. Because they are essentially check-lists of phenomena, descriptions need to be updated periodically, so as to

31.

accommodate new empirical data as well as keep track of the evolving Zeitgeist. The latter, in the case of AD, has gradually shifted from the behavioural and psychiatric emphasis towards the molecular and cognitive imprinting of today. The many tools aiming at portraying the ecological failures of AD patients and providing measures of severity are in line with the claim that what matters in AD is the AD patients’ coping defect in the natural environment. This is probably appropriate for a geriatric or forensic assessment of an AD patient. In our opinion, however, a neuropsychologically and correlatively directed longitudinal description of AD works better for every use of the diagnostic statement given its underlying rational basis. Unfortunately, we tend to lose sight of these rational bases in the face of the more or less exhaustive lists of possible breakdowns in everyday life and more or less extensive scaling enterprises. At present, the assessment of ADlinked deficits hovers between purely phenomenological descriptions (the policy of the check-lists) and the still outstanding biological specific marker. Currently, the correlative and neuropsychological approach, with its neurological and cognitive imprinting, is probably the best compromise because it provides both description and understanding (i.e. interpretation) of what goes awry during the course of the disease. The claim that AD is a unitary entity in the lexicon of the human diseases is not as widely accepted as it once was (Ajuriaguerra et al., 1960; Sjogren et al., 1952). In fact, it is likely that the nosological status of AD will change radically, either by being dispersed into different molecular nosologies of cortical diseases (St. George-Hyslop et al., 1990) or else by acquiring a greater individuality as a result of the discovery of an aetiologically important neurobiological clue. In our opinion, the considerable effort being directed towards characterising cortical degenerative dementias in terms of the topographical spreading of the degenerative processes parallels the endeavours made to achieve the classical settlement of aphasia. It is the search towards a consistent link, intricate as it may be, between the cognitive characteristics and the topography of the damage. For dementias, the issue is rather more complicated

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than for aphasias, given the progressive nature of the underlying process, and hence the accumulation and transformation of the neuropsychological symptoms in everyday life and profiles in psychometric values. The study of the relationship between brain and behaviour in patients with cognitive deterioration, which is the focus of this chapter, still hinges on a well defined nosological diagnosis. In principle, the diagnosis of AD derives from the concurrence of heterogeneous information possibly collected in a thorough and uniform way against comparable healthy norms. At present, there is little understanding of the hierarchy of such information in terms of diagnostic value. The sources of such information are the cortical topography of the histopathological lesions in a cerebral dimension, the morphology and biochemistry of the damage in a neuronal dimension, the behavioural and neuropsychological syndrome in the coping dimension of a living individual. At present the preliminary diagnosis is based on informal behavioural observation, later backed up by formal assessments. How well this preliminary but crucial task is done, depends on clinical knowledge and skill. The site(s) of the predominant neuronal encroachment of the underlying pathological process is (are) usually inferred from the neuropsychological findings. In the near future, neuroimaging studies (first and foremost functional) may permit far greater confidence in the diagnosis by adding the critical topographical landmark(s) to the neuropsychological observations. In fact, the current morphology-directed routine CT and MRI assessments have failed to adequately serve this purpose. Direct examination of the nervous tissue (both by means of in vivo biopsies and extensive post mortem studies of the brain) is still not common practice because of ethical and technical problems. Enquiries into the possible genetic determinants of the pathological process are in their early stages and as yet poorly validated in diagnostic practice. More accessible diagnostic evidence for AD may be gleaned from longitudinal assessments of behavioural and neuropsychological features, at least for what concerns the slope and the cognitive quality of progression. Presently, this latter point can almost

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be held as the realistic gold-standard of the in vivo diagnosis of AD. The general hallmark of AD is the “progressive multi-focal cognitive deterioration” set forth in Chapter 30, with three further qualifications: (i) a particularly insidious onset, which is almost impossible to date retrospectively without at least a 3-6 month range of error, (ii) The absence of specific neurological signs. Actually, in most AD patients the neurological examination proves negative or yields, at best, scattered signs (such as tonic grasping and snout reflex), which are inconsistent in the single patient and frequently observed in the normal elderly. This negative feature often makes it easy to distinguish AD from many instances of subcortical “non-AD dementias” (see Chapter 32). There is an important exception to the neurological negativity of typical AD patients, namely the rare presence of extrapyramidal signs (first of all, rigidity and braykinesia) in patients in the mid-late stage of the disease (Merello et al., 1994). Myoclonus and generalised seizures (present, respectively, in 21% and 10% of the patients; Foerstl et al., 1992) are either an early hallmark of questionable subtypes of AD patients (Mayeux et al., 1992) or a common, diagnostically irrelevant, late-stage sign, (iii) The crucial hallmark of AD is its neuropsychological onset feature with memory disorders. In any case, the nosological diagnosis of AD, even if bolstered by checklists of worldwide repute, such as the DSMIV or NINCDS-ADRDA criteria, remains in the methodologically wry state of a “diagnosis by exclusion”. This implies that the confidence in an AD diagnosis depends entirely on the certainity of having excluded other diseases which could potentially cause comparable cognitive deterioration or behavioural disorders. Non-AD cortical degenerative dementias are best candidates to be mismatched with AD. CT and MRI findings vary from uninformative data when they are appropriately compared with findings in healthy people (e.g. 20% of the patients with a short length of disease entering Baddeley et al.’s, 1991a, study had a normal CT) to those showing a brain atrophy (above the age-adjusted planimetric average reductions of 10-15%, particularly at the expense of the temporal and

parietal lobes). Routine neuroradiological findings provide a means to rule out the presence of spaceoccupying lesions, normotensive hydrocephalus, and widespread vascular lesions in both hemispheres. The latter evidence might support a diagnosis of “vascular” dementia. Finally, there is a neuropsychological operational definition (Spinnler, 1985) grounded on the traditional brain-behaviour relationship. We trust in its diagnostic efficacy more than in that of the current check-lists of disorders. Its foundations owe much to Arnold Pick’s (1908, pp.20 and 29) general views on “senile dementia”. One such view was eloquently expressed at the International Congress of Psychology, Psychiatry and Neurology held in Amsterdam in September 1907: ... daß die senile Hirnatrophie nicht, wie man früeher geglaubt, ganz gleichmässig das Gehirn, insbesondere seine Rinde beschlägt, vielmehr nicht selten elekitiv oft ganz bestimmte Territorien und stärker als das Übrige betrifft ... Es wäre dadurch zu ... funktionell umschriebene Ausschaltungen... gekommen ” (i.e.,... that senile brain atrophy does not encroach, as was once believed, evenly upon the brain, in particular its cortical aspects, but in frequent instances selectively involves particular areas far more than the remaining ones ... In this way ... one could end up ... with functionally circumscribed defects”). As we are of the opinion that by far the best descriptors of the Alzheimerian phenomenology are of a neuropsychological nature, an appropriate operational definition of AD may be built up by following Pick’s lines. In our view, such a definition is of paramount importance for the early diagnosis of AD, and our confidence in it is supported by the neuropsychological patterns that are found 6-12 months later on reassessing patients’ cognitive characteristics. In fact, whenever we have encountered typical AD patients they have conformed to the cognitive general pattern predicted by means of our longitudinal neuropsychological framing of AD. Neuropsychologically typical AD patients are the great majority of those sent to our

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observation. The simplified neuropsychological framework of AD is set out in Table 31.1. Operational definitions of cortical dementias based on a neuropsychological framework are slow to win support (Neary and Snowden, 1996) as was the ever more neuropsychologically oriented outline of the DSM dementia and AD check-lists from 1980 (DSM III) to 1994 (DSM IV). Two assumptions underlie the cognitive framework (Spinnler, 1985) set forth in Table 31.1, namely (i) that AD is a temporally extended pathological and behavioural process, and as such entails a longitudinal accumulation of cognitive defects, and (ii) that the underlying degeneration moves from the hippocampus and amygdala to the retro-rolandic associative neocortices (temporal, parietal, and posterior cingulate), and eventually to the prefrontal and anterior cingulate areas. The evidence for this postero-anterior (from retro- to pre-rolandic) degenerative progress is scattered across many histopathological reports in the literature (e.g. Kemper, 1994). They were verified in detail in Brun and Englund’s (1981) seminal survey, which was more recently confirmed by Braak and Braak’s (1991) and Bouras et al.’s (1994) study on the topographical distribution of tangles and plaques. There are numerous neuroimaging studies that parallel the histopathological direction of the AD process mentioned earlier (e.g. reviews in Jagust et al., 1989, for functional imaging, and in Scheltens, 1993, for the morphological aspects of atrophy). In accordance with the two general claims stated earlier, the three sections of Table 31.1 depict the longitudinal landmarks of the neuropsychological progression of AD. Akin to other degenerative diseases of the nervous system (such as motor neurone disease), the functional defects that become increasingly evident during the early stages of AD are considered isolated defects (e.g. anterograde amnesia, aphasia, and so on), and they only marginally interfere with subsequent defects. At a later stage, the isolated neuropsychological disorders merge together and give rise to multifactorial syndromes (e.g. dressing and constructional apraxia), often with new traits (e.g. supramodal semantic disorders in place of visual object agnosia). Finally, the impairment of “control functions” render the isolated and multifactorial

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defects less and less recognisable, the scenario now being ruled by worsening confusion and inertia with poor attention and even psychotic outbursts. Following the framework set forth in Table 31.1, AD must be suspected whenever a subject over the age of 40 or so, with unclouded alertness (i) presents with a memory impairment for every kind of content of insidious onset (Section 1 of Table 31.1), which worsens to the point that it interferes consistently with the everyday management of his or her social and working life, and (ii) whenever within six months or so, the subject’s coping skills are also marred by one or more distinct neuropsychological defects (Section 2 of Table 31.1) pointing to the involvement of retro-rolandic associative areas of one or both hemispheres (e.g. language or/and space cognition). Such an event signals the beginning of impairment of the “instrumentalfunctions”. (iii) In the years to come, disorders in the realm of the “control functions” (Section 3 of Table 31.1), including steady confusion and inertia, will become more and more apparent. The “attentional strain” (see “Control functions”) should not be confused with the steady attentional insufficiency meant here. The occurrence of isolated progressive memory disorders in a neurologically negative patient might raise the suspicion of impending AD as well as of Benign Senile Forgetfulness (Krai, 1978; “slowly progressive amnesia,” see Chapter 33). In our view, the subsequent association with one or more instrumental defects warrants the hypothesis of “possible” AD. In our opinion, an assessed worsening along the predicted lines after six months allows the formal diagnosis of “probable” AD. The later association of impaired control functions (Section 3 of Table 31.1) is not an important diagnostic requirement, but rather a predictable outcome. The neuropsychological framework of AD (Table 31.1) makes it possible to systematically record the ecological aspects of the disease and to perform analytical assessments. This means using psychometric measures to support the suspected decline of one (or more) psychological functions, whose impairment is supposed to underly a registered coping defect in everyday life. In a neuropsychological perspective, such defects are most frequently multi-componential by nature. The

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TABLE 31.1 Neuropsychological framework of Alzheimer’s disease. The three sections may be considered as longitudinal steps of the natural history of Alzheimer’s disease.

Section 1: Disorders of Memory Hingeing on the encroachment of the degenerative process on limbic and other structures involved in memory processings.

Disorders of explicit (declarative) memory (i) Deficit of s h o rt-te rm m em ory •

Early impairment of the “central executive” component of the “working memory” with relative sparing of the “slave systems”

(ii) Deficits of lo n g -te rm m em ory • •

Anterograde amnesia: early onset of learning impairment of verbal and nonverbal new information (episodic amnesia) Retrograde amnesia: recollection defect from remote memory of autobiographical (autobiographical amnesia), media-mediated, lexical and (visuo)-structural semantic (semantic amnesia), educationmediated (viz., encyclopedic) knowledge

Disorders of implicit memory • •

Anterograde implicit amnesia: some implicit learning impairment for verbal and nonverbal information Retrograde implicit amnesia: none or mild impairment of retrieval of procedures (procedural amnesia) and “memory organised packets”(MOPs)

Section 2: Disorders of “Instrumental” Functions Hingeing on the encroachment of the degenerative process upon the retro-rolandic associative areas of the temporal and parietal lobe.

Disorders due predominantly to the involvement of the left (i.e. dominant) hemisphere Deficits of oral and written verbal communication • Early onset of anomias of aphasic and lexico-semantic origin • Discourse planning defects and “empty speech” Deficits in number processing and calculations: Apraxias • Ideational apraxia • Ideo-motor apraxia

Disorders due predominantly to the involvement of the right hemisphere Deficits of spatial processing • Early onset of topographical disorientation • Spatial perception and exploration deficits (e.g. simultanagnosia, Balint-Holmes syndrome) Deficits in visuo-perceptual contour processing • • •

Deficit in achieving a stable form representation (apperceptive deficits) Deficit in recognising familiar faces (associative prosopagnosia) and persons Deficit in visual imagary

Disorders due to involvement of both hemispheres’ retro-rolandic associative areas • •

Associative agnosias and deficit in categorical decisions for common objects Constructional apraxia, freehand drawing and dressing apraxia

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TABLE 31.1 continued Section 3: Disorders of the “ControP’Functions Hinging on the encroachment of the degenerative process on the prefrontal and cingulo-anterior associative areas.

Attentional deficits • • • •

Deficits in selective divided attention Deficits in selective sustained attention Deficits in action planning and coordinating (“dysexecutive syndrome”) Deficits in “problem solving” (i.e. also intelligence deficits)

Chronic confusion

• •

Disorientation in multifarious contents (particularly in those calling for continuous updating) Diachronic transposition of dwelling

Defects in motivation •

•

Inertia (i.e. abulic-apathic-akinetic or adynamic syndrome; “A n trie b s m a n g e r pseudo-depressive syndrome) inclusive of “dynamic aphasia” Moriatic (i.e. pseudo-manic disinhibition syndrome)

Neurological disorders • • • •

Tonic grasping and magnetic apraxia Environmental dependency syndrome: echolalia, imitation and utilisation behaviour Oral grasping and Klliver and Bucy syndrome Bilateral melokinetic apraxia

Psychiatric disorders • •

Depression and anxiety Psychotic traits, such as hallucinations, misperceptions (particularly with TV and mirror), manic beliefs, dromomania, para-amnesic reduplications and Capgras’ syndrome

temporally ordered correlative framework set forth in Table 31.1 allows us to make predictions, which may be checked in forthcoming assessments in order to reinforce (or to cast doubts on) the initial hypothesis. It also consitutes a frame against which to compare behavioural and neuropsychological patterns of suspected “non-AD” degenerative cortical dementias (see Chapter 32). When considering the longitudinal aspects of this descriptive framework, one often tries to qualify given defects as hallmarks of a particular stage of the AD process. We do not entirely agree with the usefulness of the formal staging of AD proposed in the past (e.g. Reisberg, 1983) and currently used, particularly by gerontologists. In fact, the interpatient variability of the worsening speed of the natural history of AD and even of the pattern of deterioration within the same patient is so great that such stagings are little better than a standardised global deterioration score. However, there is ample

and universally agreed evidence that some defects of AD arise earlier than others (see the three sections in Table 31.1). Accordingly, one is forced to suggest tentative limits of stages hallmarking the neuropsychological state of an AD patient. In clinical parlance, when one refers to an “early” stage of AD this grossly means that that patient’s behavioural history is no longer than three years; the “mid stage” is between three to eight years, and the “late” stage is all that comprises the remaining years of survival. However, one has to bear in mind that the length of each “stage” can be considerably shortened or lengthened according to the slope of decline. This variability of decline raises many methodological problems in designing longitudinal studies of AD patients: they are cogently reviewed in Gray and Della Sala (1996). At this point it seems worthwhile to make a brief mention of the differential diagnosis. No mention will be made of Lewy Body Disease, whenever it

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presents without extrapyramidal signs and psychotic outbursts, as its clinico-behavioural features cannot be reliably differentiated from AD. Mention is made herein only with reference to the alternative diagnoses that are clinically feasible within the realm of degenerative (chronically progressive after an insidious onset) and cortical (without neurological and neuroradiological hints suggesting a subcortical involvement) diseases likely to entail dementia or similar conditions. Reference is made to the already mentioned nonAD dementias (i.e. FTD; Snowden & Neary, 1996) and to the conditions characterized by a slow progression of circumscribed (“focal”) neuropsychological deficits, with or without neuroimaging evidence of regional atrophy, metabolic or flussometric reductions. For at least a conventional span of three years (see Chapter 33) patients with focal neuropsychological defects of degenerative nature are exempt of general deterioration (i.e. dementia). In provisional neuropsychological terms, FTD can be split into (a) Frontal Lobe Dementia (that one may call “behavioural dementia” as opposed to an AD equivalent label of “cognitive dementia”; Galante, Muggia, Spinnler, & Zuffi, in press) hallmarked by onset features of personality, mood, and social behaviour disorders (see Chapter 32), and (b) possibly more circumscribed neuropsychological defects, that in some ill-defined ways are believed to be linked to temporal and/or frontal lobe selective encroachment, such as, respectively, Primary Progressive Aphasia and Semantic Dementia. Slowly progressive neuropsychological deficits, first recognised nearly a century ago, encompass several long-standing isolated neuropsychological deficits (see Chapter 33) which eventually culminate in global deterioration, often indistinguishable from AD. Important items on this list are (a) slowly progressive apraxia, with either preeminent limb and torso apraxia or apraxic aphemia suggesting a frontal bilateral involvement; (b) slowly progressive Balint-Holmes syndrome (normally with early evidence of associated simultanagnosia, Della Sala et al., 1996) suggesting a bi-parietal involvement of both hemispheres; (c) slowly progressive amnesia (labelled by Krai, 1978, “Benign Senile Forgetfulness” Della Sala et al.,

1995; other labels also have been proposed) pointing to a temporo-mesial involvement. In our experience, benign forgetfulness very often results in AD. Moreover, there is a welter of isolated reports indicating the possibility of very marginal involvements of nervous networks dedicated to isolated cognitive activities (such as progressive amusia, progressive prosopagnosia (Gentileschi, Sperber, & Spinnler, submitted) and so on; see Chapter 33). In any case it is worth bearing in mind that every alternative diagnosis to less usual onset types of AD has to arise from clinico-behavioural and neuropsychological evidence. In absence of histopathological data no inference should be made in the single cases on the traditional nosology stemming from histopathological evidences (e.g. Pick’s Disease, Frontal Lobe Degeneration, etc.). In fact, at present it is possible to predict from behaviour the nature of the underlying degenerative process only in AD.

Neurobiological features of AD Neurobiological features will be briefly outlined in order to underscore the close association between the behavioural and cognitive evolution of AD and the degenerative encroachment upon an increasing number of neurones in the associative cortices of both hemispheres and in some very circumscribed subcortical regions. In fact, the numerous neuropsychological features of dementia are the strict expression of the cortical topography of degenerations. Redlich’s (1898) and Fischer’s (1907) senile extra-neuronal plaques and Alzheimer’s (1907) intra-neuronal neurofibrillary tangles are still considered sufficient (even if far from specific; Bouras et al., 1994; Buee-Scherrer et al., 1995) histopathological evidence to raise the suspicion of an AD degenerative process. Nowadays, granulovacuolar degenerations of the ammonic neurones and amyloid (congophilic) angiopathy are held to be rather too marginal findings to warrant alone the suspicion of AD on purely histomorphological grounds. Neuronal thinning out, particularly of the large neurones of the third and fifth cortical layer (up to global atrophy of the supra-tentorial brain) and progressive dendritic atrophy (Alford et al., 1994; Scheibel, 1983) are crucial findings in AD,

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and they help to reduce the pool of intra-associative synapses. This impoverishment (linked with the amount of tangles; Arrigada et al., 1992) is now thought to be the best correlate of the degree of cognitive impairment. There is a general consensus that the degenerative modifications begin in the neuronal cytoskeleton (review in Selkoe, 1988). Cholinergic cortical impoverishment is a recurrent finding of biochemical surveys of AD brains (review in Bowen et al., 1988), but other transmitters are reduced. Genetic abnormalities on chromosomes at least 1,12, 14, 19, and 21 and the presence of one or both alleles of apolipoprotein E4 (Corder et al., 1993) are likely to play an important (but far from specific) role in the amyloid production and deposition, and in the overall development of the AD process. Bridging the gap between genetic and molecular data and the clinical features of AD still remains the major challenge of modern neurobiological AD research. The spreading neuronal degeneration in the archicortex of the hippocampus and amygdala, and in the associative neocortices of the temporal, parietal, and frontal lobes entails a progressive decrease in synapses. In circumscribed subcortical structures—such as cholinergic nuclei of the basal forebrain (i.e. nucleus basalis Meynert, nucleus of the diagonal band, and medial septum) and locus ceruleus and others—the degeneration gives rise to a progressive thinning out of even those neurones that are devoted to producing specific neurotransmitters essential for the synaptic functioning of the cortical neurones. Such transmitters (e.g. first of all acetylcholine and noradrenaline) cannot be produced in the cortex itself. The gradual decrease in the number of interlocutors (let’s say, neurones because of loss of synapses) and in their ability to communicate (let’s say, reduction of neurotransmitter availability to the surviving synapses) are the interacting aspects of the progressive decrease of the inter-neuronal interview. Such an interview is conceived as the basic condition for the functioning of every neuronal network. The cooperation of the networks of the associative cortices underlies the generation of psychological activities: accordingly, the progressive degenerative encroachment upon different neuronal systems with different

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psychological roles generates the longitudinal evolution of the Alzheimerian cognitive onslaught. Neurologists and clinical neuropsychologists continue to view histopathology as the ultimate gold-standard o f diagnosis: it is claimed that only this information permits one to formally change the qualification of “probable” to that of “definite” in a diagnostic statement of AD. This is an ungrounded traditional belief. In fact, not only is there a great uncertainity about the specificity of the histopathological findings and, most of all, of the corresponding normative criteria of AD (see, for instance, Khachaturian, 1985; Mirra et al., 1991, with reference to CERAD), but one also has to consider that the histopathology and clinical diagnosis (consider for example two different observational achievements concerning interconnected phenomena, such as tangles and anomias) often run in distinctly different directions. For instance, no less than a tenth of clinical Parkinsonians present with sufficient AD features at histopathology to support a diagnosis of “definite” AD, and cognitively normal elderly subjects show a clear-cut AD pattern (Crystal et al., 1988; Katzman et al., 1988). Despite the AD histopathological gold-standard neither the Parkinsonians nor the normal elderly would be labelled as “definite” AD patients, and as such be enrolled in experiments directed at the study of AD. Moreover, of the 119 histopathologically “definite” AD patients of the CERAD study, 82 also presented with other pathological findings that could well have accounted for their cognitive deterioration (Mirra et al., 1991) without referring to AD. Instead of following the outmoded tradition of giving more credit to histopathology than to the clinical constraints of a diagnosis, it would be better policy to take both as parallel observational approaches. Although heterogeneous, they often tie in, but in any case neither can be held to be “better” than the other. Hence, the “definite” nosological diagnosis of AD corresponds to the concordance of the outcome of a well-documented, possibly longitudinal, neurological and neuropsychological study in life and of a thorough morphological and neurochemical assessment after death. It is extremely rare for this to happen, at least in clinical practice. For this reason, AD research is centred on AD patients

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whose formal nosological qualification is that of “probable” (sometimes, merely “possible”) AD without any histopathological information. Of course, the diagnosis of AD also remains “probable” whenever it is grounded on only histopathological data without any behavioural or neuropsychological counterpart. Actually, one has to consider that the histopathological criteria, especially when employed for brains of very old people, are by no means strictly specific to AD. This chapter deals with findings gleaned mostly from “probable” AD patients; that is, without histopathological evidence of signs suggesting AD, but with a confident, possibly longitudinal, neuropsychological diagnosis of dementia and a clinical diagnosis of AD.

Epidemiology, diagnostic accuracy, and survival Epidemiology Old age is the crucial risk factor for all degenerative dementias, AD in particular. The life-expectancy in Western countries is still increasing. By the year 2020 between 16 and 20% (or slightly more in some European countries) of the population will live to over 65 (Jorm, 1990; Schoenberg, 1986). The counterpart of such Western long life-expectancies is that in the Third World people over 65 make up only 3 to 4% of the population. There are an estimated 3.74 million demented patients worldwide: this number is likely to have increased to 9.0 million by 2040 (Stuss & Levine, 1996). AD ranks between 45% (Cummings & Benson, 1992) and 60-85% of all dementias (Evans et al., 1989). The prevalence of “probable” AD in our outpatient sample of demented patients is 86%. AD results in huge health care costs: for instance, by 1992, AD had cost the Italian Public Health Service roughly 11 billion lire: approximately 4 billion of which was spent on formal care and 7 billion on informal care (CRES A, 1993). By 1993 the figure per the USA was 58 billion dollars, that is 20 billion on formal and 38 on informal care (Max, 1993). Comparable data are now available also in Sweden, Greece and Finland. To make matters worse, AD is currently one of the diseases with the least expectancy of prevention and

of pharmacological or rehabilitative amelioration. These variables make AD one of the leading bioethical problems of our time. The incidence o f AD (i.e. new cases per year) varies between 2.5 and 5.0 per thousand of the entire population with a clear link with ageing: it reaches an incidence rate of 1% in people over 65 and of 3.5% in the over 85. In Italy, people over age 85 represent nearly 2% of the population: it is estimated that this age group will most increase its proportion in the population and that it is in this same group that the incidence rate of AD will increase most. Given its starting point, Italy is one of the Western countries with the largest expected overall increase in life-expectancy. The incidence rates of AD for the same age groups are almost identical to those of myocardial infarction and twice those of stroke (Katzman et al., 1989). There are no census, race, or geographical AD risk differences, and even general pre-onset health appears to have no influence on risk of AD. In the literature, there are hints that pre-onset depression may act as a risk factor for AD (see review and prospective data in Alexopolous et al., 1993). Old age, a family history of AD or Down’s syndrome (trisomy 21) appear to be true risk factors (review in Jorm, 1990). The familial risk of AD appears to be a genuine effect (Fitch et al., 1988) even if its real dimension is a matter of great debate (reviews in Breitner, 1990; Shalat et al., 1987) which has been complicated by the finding (Strittmatter et al., 1993) of a genetic association between apolipoprotein E (particularly for allele 4 homozygoty) and AD-risk as well as onsets at advanced ages. Moreover, links have been found between the genetic determinants in chromosomes 14, 19, 21 (reviews in St.GeorgeHyslop et al., 1990; Schellenberg et al., 1992) and rate of progression of AD. Genetic studies of AD incidence date back less than 10 years and, as for the century-old histopathological research, how specific to AD the corresponding findings really are, remains greatly questionable. It now appears to be a consolidate notion that there is slightly less risk of AD in cultured people than in impoverished samples of the population (Black et al., 1994). It might well be that this small difference, coupled with the censorial effect of death in the elderly, merely reflects a later onset of

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cognitive deterioration in the cultured group. One might speculate that prevenient exposure to culture allows a greater pool of synapses in the associative cortical areas of the brain to become active early in life. The AD process will push the pool of active synapses below an hypothetical threshold later on. If this is the case, a later behavioural onset of AD might be concealed by an extra-AD pre-onset death, thus generating a slightly lower AD incidence rate in cultured people than in uncultured samples. There is is a vast body of literature on the prevalence of AD: to date, the best review is by Jorm (1990). There is a growing consensus that the prevalence of AD in people over 65 years is 8-10% (Galasko et al., 1991), and 47% in people over 85 years (Evans et al., 1989). It is worth mentioning that AD may begin between the age of 40 and 50 years; our youngest case of probable AD was 40 when the disease arguably started (Della Sala et al, 1995). Diagnostic accuracy As a consistently credited biological marker supporting the diagnosis of AD is still outstanding, the diagnosis of AD remains a clinical problem with neuropsychology as its most important component. This is particularly true in the case of early diagnoses. Admittedly, from time to time biological predictors (e.g. peripheral tissues, in vitro cultivated non-nervous cells, sensorial receptors, and so on) of AD are reported. However, they always fail to become an important element in the current diagnostic approach. This is the case of Scinto et al.’s (1994) recently reported pupillary test demonstrating in 19 AD patients a post-synaptic hypersensitivity to a cholino-mimetic eyewash, suspected to follow a receptorial denervation, possibly specific to AD patients; the test, however, still requires further sensitivity and specificity assessments. There are several reasons for needing to reach a reliable AD diagnosis as early as possible, the first of which is ethical. To be diagnosed as “demented” or as an “AD patient” in the very early stages of the disease means to have plenty of time to make lucid personal decisions. To do that, of course the patient has to be aware of what to expect, a matter of careful neurological and neuropsychological investigation,

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essentially resulting in a unambiguous diagnostic statement. Second, only well assessed AD patients can give real (non bureaucratic) “informed” consent and thereafter be given the rational opportunity to enter a clinical trial of drugs potentially able to reduce the rapidity of cognitive deterioration. The third is a scientific argument. For most purposes, only early diagnosed AD patients ought to become experimental (i.e. really collaborating) subjects in a research project aiming to add to our basic understanding of AD irrespective of the therapeutic returns. Finally, there may be a fourth argument: to result from an early assessment not to be an AD patient (or still, not even a demented patient) even if initially suspected to be so, is very likely to change one’s way of coping with life. In the nosological disaggregation set forth in Chapter 30, 281 out of the 737 subjects sent to us by that time as outpatients with the suspicion of impending dementia turned out not to be demented; 85 of them were cognitively normal. We consider this an extremely important achievement of our outpatient diagnostic efforts. Lastly, of interest is the chronic-progressive deterioration of elderly subjects that is not psychiatric, or degenerative, or vascular in orgin. For instance, Walstra et al. (1997) picked out 1% out o f200 referred patients, whose dementing progress was traceable back to a fully treatable cause, such as hypovitaminosis B 12 or hypothyroidism. In the early stages of AD, a methodologically agreed “cascade” diagnostic procedure (an example of which is given in Chapter 30) gives rise (Boiler et al., 1989; Joachim et al., 1988; Sulkava et al., 1983) to an 85-90% degree of accuracy (as compared with histopathology). This accuracy may be improved upon if the diagnostic statement is backed up by a two-assessment longitudinal diagnostic schedule. In subsequent stages of the disease, this degree of accuracy is likely to improve further. It is hard to improve upon this 90% or so degree of early diagnostic accuracy, as Stuss and Levin (1996) pointed out, the histopathological, cultural, and genetical variability of ageing and dementing undermine the reliability of any nosological result. This 10% or so of misdiagnoses of AD ought to be considered when discussing the findings of current clinical trials with new potential anti-AD drugs. Therapeutic implications of brain

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biopsies in demented patients are too scanty to accept the risk of this procedure as an ethically legitimate tool to achieve a “definite” nosological diagnosis. Actually, the therapeutically liable histapathological brain conditions in a neuropsychologically demented individual are almost nil. There is the still open question of the “formes mixtes”, namely of patients with probable AD in whom post mortem examination reveals both vascular lesions that had been unrecognised in life and full-fledged histopathological signs of AD. It is said, essentially by pathologists, that these patients may represent over 10% of those with suspected AD. It is, of course, a matter of opinion as to whether the unique or predominant role in progressive cognitive deterioration should be assigned to either one or the other of these common age-linked brain pathologies. More generally, this issue raises doubts surrounding the true role in generating dementia once assigned to multiple vascular lesions (Lopez et al., 1994; Roman et ah, 1993). We are inclined to visualise a progressive weakening of the argument of vascular aetiology in the dementia nosology with a concomitant strengthening of the degenerative counterpart (AD and above all non-AD dementias; see Chapter 34). The neuroradiological contribution to the diagnostic accuracy in AD still remains rather marginal, at least for the routine evaluations by means of CT and MRI. What they do offer is the opportunity to exclude the presence of encumbrant lesions (such as hematomas and tumours), to confirm the clinical suspicion of Normotensive Hydrocephalus and of some subcortical dementias (such as Huntington’s Disease) and to demonstrate the presence of vascular lesions. Whereas CT and MRI provide the morphological picture of brainatrophy at ventricular and cortical level, in some cases demonstrating its initial asymmetry and seldom its circumscribed predominance (on pathological grounds once labelled “lobar”), goal-directed MRI assessments can furnish a volumetric account of the hippocampal structures (possibly the earliest target of AD) or of the whole temporal lobe (an early biological trace of Semantic Dementia). Whenever topographical questions of disproportionate atrophy (particularly if referred to

the temporal or frontal lobes) are at issue, MRI coronal sections should be given preference with respect to scans from other views: this applies to AD as well as to all slowly progressive, neuropsychologically focal degenerative cases (see Chapter 33). In general, studies of the correlations between neuroradiological indexes of atrophy and neuropsychological deficits (the latter are commonly collapsed in overall cognitive scores) have failed to achieve an important reciprocal predictivity. PET, SPECT, and functional MRI data in AD provide a means, albeit to a variable degree, to distinguish typical temporo-parietal AD patients from fronto-temporo (or exclusively frontal; Neary & Snowden, 1996) degenerative cortical dementias, possibly falling into the realm of non-AD dementias. A significant improvement in the interrater consistency of the neuroimaging conclusions and diagnostic accuracy of cognitively very mildly deteriorated AD patients seems to have been achieved by means of a technique of threedimensional displaying of PET data (Burdette et al., 1996). However, these assessments, if methodologically reliable (with a sound ageadjusted comparison with normal brains), are not routinely available, and their use remains restricted to selected single cases for research purposes. Whereas it is obvious that the diagnosis of a fullfledged dementia is easy to reach, as is the nosological diagnosis of AD when clear retrospective longitudinal data are available, this is not always the case for very old people, such as those over 80 years. In particular, the risk of falsepositive diagnoses is rather high for old poorly educated people, as is that of false-negative statements for old well educated subjects. The availability of reliable age-adjusted neuropsychological norms is of paramount importance in these cases (Brazzelli et al., 1994; Spinnler & Tognoni, 1987). The inter-rater reliability studies reported in the literature are almost entirely limited to tools of general assessment, such as DSM III, and behavioural check-lists, such as NINCDS-ADRDA criteria, and so on. The inter-rater reliability found by Kukull et al. (1990) never exceeded kappa values of .64, even though the raters were experienced neurologists. This is one further argument against

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the routine (bureaucratic) practice of diagnosing dementia and its nosological syndromes on the sole basis of general tools or check-lists. At best, they give a measure of deterioration, its presence and nosology being instead, respectively, suspected and ascertained by the convergence of the heterogeneous information as set out under the heading of definitional issues. Restricting the use of tools with a clear-cut neuropsychological background (such as MMSE, or MODA, Brazzelli et al., 1994) is likely to improve the inter-rater and test-retest reliabilities. Nevertheless, in our opinion the challenge of making an early diagnosis of dementia and AD still relies on neurological and neuropsychological skill, mainly that of excluding other nosological conditions possibly giving rise to cognitive deterioration. Survival rate AD has to be conceived of as a “malignant” disease, namely a disease that can be neither definitively cured nor halted. Until fairly recently, it was believed that AD significantly shortened the lifespan of patients in comparison to the expectancy of healthy subjects comparable by age, education, sex, census, and other variables. It was said that 5 years after onset only 50% of the patients were alive, that after 10 years the ratio was of 25%, and thereafter the slope of the curve dropped sharply. Martin et al.’s (1987) data are much less catastrophic, perhaps also as a consequence of the improved internistic and geropsychiatric care of AD patients in their late stages of illness (e.g. over 7-9 years from behavioural onset of deterioration). In some comparisons, such as that of Sayetta (1986), the difference in survival between AD patients and healthy people falls short of significance. One might speculate that the good functioning of the associative areas plays a small role in ensuring the survival of an individual, provided that others take care of the more elementary needs (such as washing, moving, eating, drinking, and also overcoming the inability to indicate needs). As this is the case, the length of survival depends more or less entirely on the quality of care, that is the money available to the patient, and the goverment’s allocation of health-care funds.

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There is an on-going series of studies that aim to ascertain the rates of progression in AD (Morris et al., 1993, with reference to CERAD) and whether there are predictors of this rate. Psychotic and extrapyramidal signs are consistently held to predict a rapid progression (Mortimer et al. 1992; Stem et al., 1994) but there is the risk of having mismatched AD with diffuse Lewy bodies dementia. The comparison of the rate of cognitive worsening between patients with an onset of AD in the young versus old age yielded conflicting results (Bracco etal., 1994; Capitanietal.,1990; Lucca etal., 1993); early and severe language impairment (and also apraxia, Yesavage et al., 1993) is rather consistently associated with a rapid worsening of AD (Becker et al., 1988a; Bracco etal. 1994; Mortimer etal., 1992; but see findings of Capitani et al., 1990). Recent multivariated regression analyses by Rasmussen et al. (1996) yielded rather bewildering findings, leading, however, to an enlightening discussion on the several variables that might render the overall picture sometimes obscure or misleading. In a recent follow-up study conducted by Capitani, Manzoni, and Spinnler (1997) in 53 AD patients periodically assessed with MODA (Brazzelli et al., 1994) the confirmed average 12-point drop per year (1.15 per month, SD = .99) did not appear to be influenced by sex, education, length of illness, MODA severity at the first assessment, or length of the inter-test period; only the patient’s age at first assessment significantly predicted the average rate of progression, which was faster in the elderly. It is very likely that there is a great individual variability that can also be extended for a minority of cases to the nosological uncertainity of the underlying degenerative process. Moreover, one source of heterogeneity across AD patients—besides the topographical and chronological spreading style of the AD degenerative process— is likely to reside also in the premorbid cognitive coping style of each of the subjects who later on in their life become experimental patients in an AD study. It is worth emphasising that another way of discovering whether or not a new dmg acts on the evolution of AD is to take into consideration already well-established slopes of deterioration in untreated AD patients on neuropsychologically characterised tests of overall cognitive functioning (e.g. MODA)

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or, with a much sounder goal-directed approach, on selected psychometric targets. At least in exploratory studies, this would eliminate the burden and uncertainties inherent in the placebo-treated sample.

Neuropsychology of AD Under the following headings the neuropsychological deficits hallmarking the progressive cognitive incompetence of the AD patient will be analytically teased apart in its ecological and psychometric aspects. Within the framework set forth earlier, memory disorders (section 1 in Table 31.1), deficits of the “instrumental functions” (section 2), and disorders of the “control functions” (section 3), inclusive of psychiatric symptoms, will be described. The cortical degenerative pathology is credited for its propensity to generate isolated psychological deficits in accordance with its site of predominant (or even temporarily exclusive) density of degenerated neurones. Over time, the degenerative process is capable of producing new phenotypical exemplars of the same genotype or demographical individual. After decades of neuropsychological research, almost entirely limited to focal braindamaged patients (e.g. stroke patients), patients with degenerative brain diseases were found to be a valuable source of “cognitive dissociations” (Shallice, 1988b), that is, presenting the hallmark relevant to verifying cognitive models of normal psychological functioning of the brain. The approach, characterised by selecting single cases of heuristically relevant dissociations, overcomes the pitfalls of considering double dissociations of average performances in group experiments, in which there might not even be a patient who is really dissociating in the directions apparent in the statistical working-out of the means. We adopted this multiple single case approach in many studies on AD patients: for instance, Baddeley et al. (1986, 1991a, b), Spinnler et al. (1988), Dall’Ora et al. (1989) and Della Sala et al. (1992) for memory disorders, Della Sala et al. (1993) for language disorders, Della Sala et al. (1995) for face processing disorders, Capitani et al. (1988) and Della Sala et al. (1992) for visual selective attention disorders.

A brief comment on the theoretical framework into which neuropsychological studies of AD are backed, is warranted. Classical examples of the effort to reproduce upon an entirely transparent scheme both the correlation between anatomically defined “centres” and inherent links, and the sequential functioning of the living brain, are Lichtheim’s (1885), Lissauer’s (1889), Wernicke’s (1903), and Liepmann’s (1908) sets of box-andarrow models designed to make sense of the variability (hence, the syndromes) of the aphasic and agnosic phenomena. In our view, AD offers an opportunity to do the same, namely to add to the construction of the “functional architecture” of the working brain. Fodor’s (1983) “neophrenological” views—entirely in line with the “breslauer psychologische Anatomie" of Wernicke’s school— bolster most of the cognitive experiments carried out in AD patients. “Modules”, akin to Luria’s (1966) cortical processors, are meant to process information as separate (“encapsulated”) entities and pass on the processing result to other modules or peripheral executors of decisions. Presently, AD studies of cognitive neuropsychology continue to follow this modern reformulation of classical modularity. It is thought that this approach allows the development of models of functioning, which encompass the correlative links with the neuronal networks taking advantage from the gradual microdissection of them brought about by the spreading of the AD degenerative process. As pointed out by Morris (1996), there is much valuable evidence of “information encapsulations” provided by AD, such as the evidence of “unimpaired modules in the presence of widespread cognitive decline”. This is the precise counterpart (already mentioned earlier; see for the translation there) of what Pick (1908, p.29) already pointed out with reference to “senile dementia” and its erratic and focal spreading through the cortex: “Es wäre dadurch... umfunktionell umschriebene Ausschaltungen ... g e k o m m e n At the opposite end of modularity is the theoretical view of “parallel distributed processing” by which a strongly interactive (“connectionistic”) processing of information is proposed (Farah & McClelland, 1991; Silveri et al., 1996). The view of modularity is more in line than that of connectivity with the

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progression of the cognitive deterioration of AD patients. In fact, AD provides scanty evidence of functional plasticity and even transient amelioration of cognitive deficits. One could surmise that there are radically different working styles between the retro-rolandic associative areas and the frontal ones, with a strong prevalence only in the former of anatomo-functional “focal” syndromes. So it might well be that cognitive studies in neuropsychology take greater heuristic advantage from the “vertical modularity” approach when investigating the instrumental functions of the retro-rolandic cortex and, on the other hand, from the connectionistic approach when the prefrontal “managerial” areas are at issue (Goldman-Rakic, 1987, 1988). It is important to make clear that we approached the neuropsychology of AD from two different viewpoints. First, that of studies contributing to the diagnostic framing of the multifaceted clinical picture of AD. Second, that of taking every advantage of the natural experiment provided by AD, namely that of progressively stripping one’s cortex of its associative areas in a chronologically and topographically relatively ordered sequence. The latter viewpoint predominates in this chapter. The neuropsychological description follows the three longitudinal sections of Table 31.1.

MEMORY DISORDERS Describing memory defects in AD draws upon a generally agreed taxonomy of the facets making up the several processings of memory (see Chapter 15). Theoretical views on memory have not changed dramatically in the last decade, while neuropsychologically reported phenomena of deficits have greatly enriched some aspects of memory processings, particularly those linked to remote and implicit memory, that is, to the use of overt and unconscious knowledge. In this sense, AD contributes much to our understanding of normally functioning memory. It is almost universally agreed that disorders of the memory processing of information are the most consistent and earliest traits of the neuropsychological picture of AD (McKhann et al., 1984)

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with an episodic supraspan learning defect presenting before (Miller, 1971, 1973) semantic memory impairment (Hodges et al., 1992). Memory deficits, however, are not specific to AD. It is possible that in future the analytical dissection of the memory disorders in AD will reveal more specific profiles. With the exception of the Huntingtonian (and possibly also Parkinsonian) anterograde procedural memory deficits (Butters et al., 1988; Tranel et al., 1994), the amnesic syndrome in AD shares most of the features of other dementias (see Chapter 30). The memory deficits in AD are the same as those described in other neuropsychological conditions, such as diencephalic or ammonic or frontal amnesia (see Chapter 15), and in other brain conditions, such as strokes, tumours, and encephalitic and traumatic damage. There are few studies of metamemory in AD patients, briefly reviewed in a recent paper by Lipinkaet al. (1996). In this group-study on factual information tested by recall and recognition on 48 general knowledge questions, early- and mid-stage AD patients, when requested by means of a graded guess of “feeling-to-know” (Hart, 1966), produced metamemory scores that were nearly equivalent to those of healthy controls and radically dissociated from those reporting factual information. Supervision of the stored information seems to withstand AD despite dramatically deficient specific access to it. The neuropsychological heterogeneity of AD patients, especially within their early stage of disease, is apparent both across patients (Becker et al., 1988b) as well as in the same patient across aspects of memory functioning (e.g. verbal versus visual dissociations, Baddeley et al., 1991b; recency versus primacy, Capitani et al., 1992). This modularity in memory impairment (Desgranges et al., 1996) is likely to reflect the inter-patient variability of site, severity and style of spreading of the Alzheimerian degeneration of neurones. The encroachment of the AD degeneration on the limbic, especially the hippocampal (or ammonic), neuronal networks (as demonstrated by MRI evident temporo-mesial early occurring bilateral atrophy) is the universally agreed correlation of the anterograde amnesia of AD patients. Moreover, it has now been convincingly

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ascertained, at variance with previous claims (Squire & Cohen, 1982), that frontal lobe damage impairs both episodic and semantic memory. It appears likely that the frontal involvement in declarative memory tasks is not only of an attentional nature as was presumed up to now, but should be traced back to a direct memory role of the frontal cortex itself.

The amnesic syndrome in everyday life The presence of clear-cut amnesic traits can be observed in the early and mid stage of AD. Later on, amnesic traits become less distinct in the steady dysexecutive and confusional state of the patient, a condition in which attentional disruption strips amnesia of its genuine memory defect. In the early stages, memory disorders outweigh all other cognitive deficits, whose ecological presence in these stages may be doubtful in many patients. Almost all AD patients are sent to our consultation because of memory deficits that seriously and progressively interfere with their everyday lives. Actually, in most patients in their first or second year of disease, memory complaints are, at least at a superficial enquiry, their only predicaments. Thus, so-called “memory clinics” are efficient nets to catch early AD patients for research purposes. The presence of memory disorders is a conditiosine-qua-non for the clinico-behavioural suspicion of impending AD. AD patients’ chief complaint is their worsening ecological forgetfulness, that is, an ecological disorder of anterograde memory. It consists of an extremely rapid (within a matter of minutes) or slightly slower (within days or weeks) dissipation of ongoing information. The content of information liable to be forgotten changes in the longitudinal period of the early stage, from proper names of people, geographical sites, currencies, drugs etc., to the location of objects, verbal messages, and finally complex social events (movies, parties, conferences, etc.). Items of “ongoing amnesia” that make themselves irrecoverable to consciousness at a given moment, might become recoverable either unexpectedly or as a consequence of successful recollection through connected items at different moments of the same day. This points to a retrieval (or access) disorder and not to the dearth of stored information. As time

passes (often just a few months), this fluctuating defect of retrieval changes: less and less ongoing information leaves a trace in the brain until it finally fails to be recollectable at all. An intrinsic aspect of “ongoing amnesia” is “prospective amnesia”, the forgetting of future events (such as appointments, etc.). Such a picture is highly reminiscent of what happens with a milder severity to many and at a certain point to almost all healthy elderly. Thus, the first diagnostic distinction to make is that between an onset of AD and a deficit of a brain in the process of normal ageing. The diagnostic alternatives when faced with short-lasting ecological forgetfulness are: an anxious-depressive neurosis; true global amnesia of recent onset, perhaps because of a focal lesion strategically located in the structures devoted to memory; progressive lesional output such as in Korsakov’s amneso-confabulatory syndrome or in some locations of tumours or radionecrosis; Benign Senile Forgetfulness (BSF; Krai, 1978) presently gathered within the realm of “slowly progressive circumscribed” degenerative disorders (see Chapter 33); finally, “malignant” forgetfulness that is the first symptom of a dementia, which is very often AD. In addition to a psychometric assessment, the diagnosis of neurosis requires psychiatric evaluation; the second and third are neurologicalneuropsychological questions, whereas the last two conditions (BSF and AD) require a longitudinal (and analytical) neuropsychological assessment, including a psychometric enquiry aimed at assessing, respectively, the limitation to anterograde memory of the defect or its extension over time to extramemory domains of cognition. In the months following the ecological onset of anterograde amnesia (i.e., ongoing forgetfulness) in AD patients, retrograde amnesia also becomes apparent: the patient fails to correctly date and recollect past memories such as those belonging to the archives of his or her autobiography, to that of media-mediated information (public events, names, etc.) and, later on, semantic, lexical, and encyclopedic knowledge (education-mediated contents). Retrograde amnesia usually dates back to a lacuna beginning in the early stages of AD. It is often denied by the patient themselves and their relatives, but becomes apparent on testing, for instance, for

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the most sensitive autobiographical and mediamediated contents. Progression of retrograde amnesia to lexico-semantic and even encyclopedic amnesia is a much slower process compared with the rapid worsening of anterograde amnesia, and some evidence of the content-specificity outlined earlier is apparent. In the normal elderly, retrograde amnesia is much less apparent than its anterograde counterparts: the healthy elderly are occasionally unable to date and recollect the content of only some autobiographical or media-mediated information, very seldom of tokens of encyclopedic knowledge. The concurrence of anterograde (episodic) and retrograde impairment of declarative memory gives rise to the syndrome of global amnesia, a feature normally occurring in all AD patients. Interestingly, some AD patients generally in the late stages of the disease, present highly unusual disorders of the memory and reality check, the most common of which is passing their time as if they were living and experiencing the multifarious context belonging to their existence of many decades before (e.g. when they were children, had living parents, lived elsewhere, and so on); this is sometimes called “diachronic transposition of dwelling” (Spinnler, 1985). In some ways, this phenomenon suggests the fine-grained, albeit misdated, availability of very remote information. This evidence in late-stage AD patients, coupled with the irrecoverability of less remote information about their past experience, points to the existence of a “temporal gradient” in remote memory amnesia of AD (Sagar et al., 1988) akin to that established in Korsakov patients.

The amnesic syndrome in the laboratory Psychometric studies are more closely linked to the theoretical distinctions drawn upon memory processing of information (see Chapter 15). Reference will be made to the two most popular memory models. Squire and Zola-Morgan (1985) proposed a parallel model essentially grounded on the declarative (explicit)/nondeclarative (implicit) dichotomy in rendering apparent the role of memory. Tulving (1987, 1995) proposed an “enriched” hierarchical model from episodic to semantic to procedural memory systems, recently also implementing therein short-term memory and

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the perceptual representational system. Here again one tries to follow the longitudinal sequence of the onset of the different memory deficits. Given that the diverse “modules” of memory processing differ with regard to their sensitivity to the degenerative process, it seems appropriate that these aspects should be regarded—in a modular view—as a set of different functional processing devices, possibly with different links with the nervous structure. This explains why AD patients present different kinds of functional intra-memory dissociations (e.g. Dall’Ora et al., 1989, between impaired autobiographical and spared semantic memory; or Capitani et al., 1992, between primacy and recency components of the serial position curve).

Short term amnesia The representation of verbal and visuo-spatial features of the environment as well as the prompt access to it are essential to adapt to a wealth of ecological demands, from verbal interactive competence to self-moving, and object handling and recognising even in a predictive (i.e. imaginative) way. Such representations both in the learning and in the retrieving dimension are intrinsic to the working memory system. Their coordinated use becomes more and more laborious in AD patients right from the early stages of their disease. One of the most popular conceptualisations of “primary memory” is the “working memory” model envisaged by Baddeley and Hitch in 1974 (see Chapter 15). At first glance short- and long-term memory dissociate in AD patients as they do in patients with global amnesia secondary to an ammonic or diencephalic focal lesion. However, closer examination of AD patients’ primary memory, making use of the working memory model, reveals clear-cut differences. In fact, from the very early stages of the hippocampal neuronal degeneration, the “central executive” component of Baddeley and Hitch’s (1974) model appears to become progressively impaired in AD (Baddeley et al., 1986,1991a, b; Morris & Baddeley, 1988). This is a finding, at least early in the course of AD, of dissociation within the components of short-term memory (review in Della Sala & Logie, 1993). Central executive functioning falls short with respect to the peripheral components (the

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“articulatory loop” and the “visuo-spatial scratch pad”), which appear to function almost normally (Della Sala et al., 1992). This was first evident in the recency (spared)/primacy (impaired) dissociation found in serial position experiments (Spinnler et al., 1988). However, when the experiment was replicated with closer statistical scrutiny (Capitani et al., 1992) the striking heterogeneity of AD patients became apparent and the classical dissociation just mentioned was merely the one that occurred most frequently, all other dissociations (including the non-dissociation condition) having been found. Experimental findings reported by Trojano et al. (1994) on the visuo-spatial component in AD patients were conflicting too. More generally, it appears that at a very early stage, AD hampers the attentional nature (Bayles et al., 1987) of the “central executive”, whereas in slightly subsequent stages the peripheral components of working memory also become involved. From Brown-Peterson experiments (see Chapter 15), it appears that in AD patients short-term traces last but seconds, thus supporting the view of an accelerated rate of forgetting. This finding might be traced back to insufficient support of the “central executive” in one of its activities, namely the peripheral encoding linked with the articulatory loop. A word of comment is called for here as it might throw some light on the slightly conflicting shortterm memory findings just listed. Whereas the neuropathological-neuropsychological heterogeneity of AD patients makes them a good source of single (possibly, multiple single) cognitively outstanding cases, they yield a rather mixed bag of data when lumped together as a unitary sample of experimental subjects. In the latter condition, the only consistent findings are strong effects, such as the hardly earthshattering finding that AD patients are worse in nearly all memory performances when compared with the healthy elderly.

Long term amnesia Here, reference is made to episodic memory, that is, to the explicit (declarative) aspect of anterograde memory and not to retrograde memory aspects, which will be considered later on. There is a universal consensus that the first defects to become

apparent in the everyday coping of AD patients— and therefore in terms of severity out of proportion to the other cognitive defects experienced over the entire career of an AD patient—belong to the realm of learning new information (Miller, 1971, 1973). Episodic amnesia is likely to be traceable back to two sequenced mechanisms. A first one, possibly transient over less than 12 months, is of a predominantly neurotransmitterial nature, namely hippocampal neurones are insufficiently supplied by acetylcholine, a condition akin to a scopolamine experiment. This stage can be expected to be ameliorated by anti-cholinesterasic drugs until the second mechanism comes into play. This is linked with the drop below hypothetical functional threshold of the available synaptic pool in the hippocampus and related structures, a condition that cannot be improved by supplying drugs to interact with the cholinergic availability. Of course, the two stages have a period of partial overlap. It should be taken into consideration that recent consistent findings in PET-studies assign an important role to intentional (conscious) episodic retrieval to the dorso-lateral aspects of the frontal lobes, with a surprisingly more important role of the right than the left side irrespective of the features of the memorandum. In psychometric terms, AD patients fall short whenever they have to consolidate their learning of a supraspan string of items. This is apparent in the verbal domain with paired-associate learning, as well as with Buschke-Fuld selective reminding technique and Prose Memory (also called “logic” memory, stressing the use of information embedded in canonical stories acting as memoranda), or, likewise, in the spatial domain with Corsi’s Block Tapping or Philips’ testing technique. Of course, there are many other formal and informal means of identifying and assessing the deficit, a recent one with excellent sensitivity and specificity values in early-stage AD patients is the Grober-Buschke recognition version of the original verbal recall Buschke-Fuld test. Such means yield near-perfect discriminating scores between the healthy elderly and early-stage AD patients (Masur et al., 1989). In our experience, the most efficient discriminator appears to be Prose Memory (Barigazzi et al., 1987; Capitani et al.,1994; Spinnler & Della Sala, 1988)

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irrespective of whether one resorts to the hierarchical or the nonhierarchical score (the former taxes mid- and late-stage AD patients more than the latter, possibly because of its organisational, i.e. “frontal”, demands). Prose memory performances are often worse than those on supraspan learning tasks. AD patients’ accounts are often hallmarked by numerous intrusion errors, that is, of spurious information belonging to previous tests (so-called “intoxication” errors) or of entirely extraneous information (false memory information, or confabulations). The excellent diagnostic value of reporting stories by memory is likely to be ascribed to the spurious quality of the Prose Memory tests: besides the declared target of long-term verbal memory, it includes planning, attentional, and lexico-syntactic components, all of which are progressively hampered in AD patients. For instance, Spilich (1983) showed how AD patients had severe difficulties in organising their account around the thematic structure of a canonical story, a defect close to a planning and semantic defect and formally independent of anterograde memory. Even the right hemisphere contributes to the narrative account involved in prose memory (Davis et al., 1997). The case of prose memory is a typical example of the divergent trend inherent in a psychometric tool: optimal diagnostic efficiency on the one side, and concealed heuristic indications on the other. It appears that AD patients are characterised by a faster rate of long-term forgetting (Salomon et al., 1989): this appears to be related to a deficit in the encoding activity. The long-term deficit of AD patients could result from a basically attentional impairment (see “attentional strain” under later heading on attentional deficits) that interferes with encoding and trace storage or, perhaps alternatively, degradation of the semantic network that offers a no longer efficient anchor to consolidate the new incoming (episodic) information. In favour of the latter view, Bay les et al. (1987) pointed out the lack of proactive interference (see Chapter 15) and the inability of AD patients in a learning setting to take advantage of taxonomic (lexico-semantic) cues offered by the examiner. On the side of a basically attentional defect, considering the effort AD patients put into the supraspan learning activity, it

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is apparent how small such a capacity for effort is (Corkin, 1982; but see Martin etal.’s, 1985, findings of normality). The “superficial” feature, meant in Craikand Lockhart’s (1972) sense (see Chapter 15) of AD patients’ elaboration of the to-be-learned stimuli, is really impressive. These observations point towards an attentional and even motivational cause of the supraspan learning defect of AD patients, possibly within Baddeley and Hitch’s (1974) or Norman and Shallice’s (1980, 1987) general frameworks of, respectively, the Central Executive in the working memory model or the Supervisory Attentional System. In a continuous series by Baddeley et al. (1991b) the few amnesic AD patients who were found to dissociate in both senses (i.e. the attentional or the mnestic direction) lend support to Becker et al.’s (1988 b) hypothesis of a double functional component in episodic learning. One ought, however, to consider the proposed dichotomisation as an oversimplification of the functional trade-offs underlying anterograde amnesia in AD. With regard to episodic amnesia in AD, still unaswered is the question of the cognitive locus of the functional impairment in the traditional cascade of the learning: encoding, storage, retrieval. As reviewed by Nebes (1992) the most advocated and already mentioned explanation is of an encoding deficit in AD patients with an underlying attentional cause. This is in line with Baddeley et al.’s (1989, 1991b) findings on the primarily central executive impairment. Studies focusing on the possibility of defective storage have tended to conclude with the hypothesis of an accelerated forgetting rate (Hart et al., 1987, without interference; Corkin, 1982, with interference). Dannebaum et al.’s (1988) very accurate and recently confirmed study of forgetting, starting from a preliminary psychometrically controlled equalisation of the level of encoding, confirmed the role of accelerated rate of forgetting in the poor anterograde memory of AD patients. However, this evidence does not tie in with “normal” forgetting on picture recognition. The differential sensitivity of different neuronal networks (possibly related to different hemispheres and to a different timing in their degenerative involvement) might underly the contrasting forgetting rates for words and pictures. Finally,

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retrieval studies with cued and uncued recall, compared with recognition (see Chapter 15), have failed to demonstrate that in AD patients poor anterograde learning is a consequence of a retrieval deficit (review in Granholm & Butters, 1988). There are, however, a variety of reports of retrieval deficits. Different explanations accounted for particular aspects of such impairments. For instance, impaired inhibitory efficiency on an hypothetical lexical output device following a reduced availability of attentional resources enhance intrusion errors in all recall tests performed by AD patients when compared with the healthy elderly. This simple finding emphasises both the role of interlaced effects between memory and attention, which still remain widely underspecified, and the need for a detailed qualitative analysis of the error made on attempting to recall verbatim supraspan lists of words. In other terms, analysis of wrong answers may be more enlightening than the mere statistical working-out of hit answers. Unfortunately, group studies are biased by a static idea of AD, that is an assumption of a more or less uniform deterioration both in its global dimension (e.g. assessed by means of MMSE or MOD A) and in its analytical components (see the scattering of deficits set forth in Table 31.1). As mentioned before, uniformity is extremely hard to achieve even within a continuous series of AD patients with an approximated same length of behavioural illness, unless one is prepared to collect huge samples. More recent surveys have followed a cognitively more proficient and less burdensome strategy, namely that of singling out from the AD sample at study those patients who, within the sound framework of well-achieved age- and educationadjusted norms, show dissociated performances, which, on statistical grounds, possibly deserve to be referred to as warranted “double dissociations” (Shallice, 1988a). Such a strategy was followed in Della Sala et al.’s (1995) study of face processing in AD patients. Longitudinal studies would greatly improve our basic understanding of the deterioration of memory systems in AD.

Semantic amnesia Here reference is made to one of the retrograde aspects of long-term memory. Two dimensions

ought to be considered in describing semantic memory. One is the way by which its informative contents are brought into consciousness (recollection), and the way its semantic (meaningful) nature is defined. Recollection from remote memory is the ability to retrieve past information (i.e. remote memory traces) into a conscious experience. It might run an automatic course (e.g. the statement that Paris is the capital of France) or, alternatively, be the output of an hypothesis-guided, tentatively reconstructed idiosyncratic effort (e.g. the attempts at remembering something unusual that happened during our first years at school). It appears likely that there is also an implicit (i.e. unconscious) use of semantic information, which is probably mildly impaired in early-stage AD patients (e.g. Russo & Spinnler, 1994). Semantic memory is defined as the remote memory structure devoted to assigning meanings to words, objects, situations, and perhaps to fanciful thinking. It is a crucial device for interpreting the environment and guiding behaviour by recruiting past knowledge. Its link with the left (dominant) hemisphere is of great relevance. However, it is likely that the right hemisphere also contributes to semantic perceptual contents. There is converging evidence that neural substrates of semantic memory are located bilaterally in the infero-lateral temporal neocortex with a probably greater role of the left side (Damasio et al., 1990; Hodges et al., 1995). There is, however, good reason to believe that the mechanism used (the “retrieval cycle”) to unearth remote information, such as semantic information, calls for executive functions for which the frontal lobes are universally credited to play a major role (see short review in Lucchelli, Muggia, & Spinnler, 1998). It is well-acknowledged that the concept of semantic memory is presently in rapid evolution, and that blurring of its meaning could risk it being transformed into a passepartout issue. Therefore a more detailed definitional lay-out is needed. The blurring of the concept of “semantic memory” is particularly apparent for what concerns its distinction with respect to procedural memory, if one stresses the frequent automaticity of the semantic retrieval (Stanovich & West, 1983), and to the knowledge systems and intelligence (Sternberg, 1994) if one

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stresses the reconstructive and problematic rein statement into consciousness of most remote memory traces. In broad terms, semantic deterioration is such an important hallmark of AD that it might help our general understanding of the whole neuropsychological deterioration occurring in AD. This will be discussed separately under an ad hoc heading. As stated elsewhere (Chapter 15) the label “semantic memory” (invented by Quillian, 1968) indicates our estate of knowledge, that is, the organised framework of long-term memory traces, which become increasingly crystallised (i.e. less and less modified over time) and reciprocally related to one another (thereby becoming knowledge systems). The construction of these progressively more fine-grained and richer archives starts from the very first years of life. The characterisation of knowledge and of its progressive re-elaboration in abstract systems gives the semantic memory its relative universality, in other words a common background shared by all other individuals of a given society, census, historical period, geographical site, and so on. What is recalled is a piece of knowledge derived from a common data-base. Semantic memory marks the transition from remembering and describing to knowing, and, perhaps, in its impairment the transition from amnesia to dementia, or at least to a very important aspect of it. According to Tulving (1987) it represents, perhaps also philogenetically, an intermediate level between episodic and procedural memory. Unlike procedural memory, episodic and semantic memory share the declarative (explicit) and conscious nature (Squire & Zola-Morgan, 1985): in the artificial intelligence terms (Cohen & Squire, 1980; Squire & Cohen, 1982) “knowing what” (episodic and semantic memory) as opposed to “knowing how” (procedural memory). A current distinction is made between a lexical semantic memory and a perceptual one, intended, respectively, as the knowledge of the meaning of the verbal items and that of the visual forms (at least in their canonical perspectives). Therefore, “knowledge” is intended herein as the specificity of the link between meanings and their lexical or visuo-structural representations. Abstract procedures (such as mathematical and logical rules), which are perfectly automatised high-level routines (Reason, 1984),

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would be better taxonomised within the great procedural memory system, together with, for instance, grammatical-syntactic and prosodic rules of language. Whereas episodic memory has much to do with “fluid intelligence” and its predominance in the young ages, semantic memory (particularly lexical knowledge) has more links with “crystallised intelligence” (Horn, 1982), and its predominance in older ages. In everyday coping activities the use of semantic knowledge (or “general knowledge of the world”) is continuous, particularly in actions and perceptions involving plausibility (an inner decision of likelihood in a coherent frame of assumptions) and prediction (likelihood that, given some knowledge data, the occurrence of some specific thing is predictable). Let us first briefly describe some very different ecological disorders of AD patients which are currently traced back to semantic impairment. An ecologically mid-stage disorder of AD patients is the progressively greater “emptiness” of their speech. In fact, they use fewer and fewer content words in their spontaneous discourse (one anomic aspect): this lack is progressively more poorly circumlocuted with an increasing use of passepartout words. Eventually, some of them are barely, if at all, able to convey comprehensible propositions. Lexical comprehension is also impaired in AD patients: this has long been known for nouns (e.g. Grossman & Mickanin, 1994; Hodges et al., 1992) and has recently been extended to verbs (Grossman et al., 1996), the latter possibly being a crucial defect in the appreciation of a concept (see Chapter 34). Although in the AD impoverishment of the informative value of discourse there is a strict aphasic component, AD patients are good examples of the condition of poor communication due also to a great semantic deterioration (loss of meanings). Another prominent ecological trait of the AD patient is his or her pervasive hesitancy in all cognitive everyday performances (Spinnler, 1985). In our practice, we have often observed AD patients becoming highly embarrassed and doubful even in the simplest situations (such as being asked to guess the approximate price of a pound of potatoes). They approach the task as if it were an entirely new and complicated problem, making large errors and

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continuously referring to their companion anxiously seeking her/his confirmation. Such common behaviour can probably be traced back to the impairment of the prompt availability of the interconnected strands of semantic information which allow a plausibility decision. It should not be confused with a defect of intelligence. In fact, it often occurs in early stage AD patients, when their performance on, for instance, Raven’s Progressive Matrices (whose loading with Spearman’s factor “g” is held to be very high) is still within the normal range. The semantic impairment of early and midstage AD patients makes a great difference with respect to global amnesics following a focal and strategically located lesion: the latter, as a rule, do not present with semantic amnesia. Nowadays, semantic memory testing with formal batteries, avoiding the interference of aphasic or agnosic defects, is a flourishing topic of research. The assessment of semantic contents of remote memory, including autobiographical memory, is beset by the psychometric problem of not being able to establish the patient’s premorbid estate of knowledge. Henceforth, reference must be made to an agreed data-base of norms collected in healthy people, at least disaggregated by age and education. Such an enterprise often yields surprising findings and involves testing large samples of healthy people for many categories of knowledge that encompass besides semantic memory for the lexicon and the forms, autobiographical, media-mediated, encyclopedic (education-mediated) and even procedural contents. Given the present scarcity of such tools, one is forced to resort to informal batteries, often including a small case-control matched sample of healthy controls in the experiment. Category modelled batteries (Capitani et al., 1993; Laiacona et al., 1993b), standardised in healthy normals, are soon to be employed in demented patients too (e.g. Barbarotto et al., 1995, in case MF of possible Semantic Dementia) in order to assess whether AD patients’ semantic impairment follows categoryspecific patterns akin to those found in herpetic patients. Actually, there are few contradictory findings as to whether the category-specific impairment in semantics of many post-herpetic patients is also present in AD patients. In Montanes

et al.’s (1995) study a category defect for living things was found in AD patients with a possibly important role displayed by the features (chromatic or not) of the sensory information. These findings are at variance with previous ones on the same topic (e.g. Hodges et al., 1992). As mentioned earlier, one of the earliest and most readily documented defects of a demented patient is anomia (Williams et al., 1989), which is apparent on tasks of confrontation or definition as well as in spontaneous discourse or writing (see Chapter 34). Naming defects often lead to semantic paraphasias (Martin & Fedio, 1983) or semantic errors when the patient has to match a content word with ad hoc arranged alternative pictures (Diesfeld, 1989). Gainotti et al. (1989) pointed out that AD patients achieve particularly poor performances in the appreciation of semantic relationships (e.g. between an object and its attributes). It is thought that a severe disorder of a lexico-semantic nature hampers the process eventually subserving the naming output of AD patients (e.g. see recent findings by Grossman et al., 1996; Hodges et al. 1991, 1992, 1996). The semantic interpretation of an early naming defect in AD is linked to the neocortical left perisylvian (posterior transcortical regions; Henderson, 1995) spreading of the AD process in its early stages. The deterioration of the semantic traces is conceived either as a loss of the stored information ( Chertkow et al., 1989; Gainotti et al., 1996) or as a breakdown of the intrinsic semantic network (Abeysinghe et al., 1990) or both (Hodges et al., 1996). This view is challenged by Nebes and Brady’s (1990) data which confirm previous conclusions pointing to a hampered conscious access to still-stored information. The access view is akin to that proposed for the naming disorders of the healthy elderly (Nicholas et al., 1985). In their analysis of the naming errors of AD patients, Nicholas et al. (1996) failed to find significant differences between mild-moderately deteriorated AD patients and healthy controls on a semantic relatedness measure. The meaning of a word partly depends on the context in which it appears: this evidence has also been found in AD patients (Nebes & Halligan, 1996), thereby suggesting some retention of the semantic knowledge belonging to attributes. These findings

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parallel, at least in part, the data of La Berge et al. (1992), Astell and Harley (1996), and Bayles et al. (1996), suggesting that the nature of AD patients’ naming defect is more of lexical (i.e. aphasic) or even perceptual (Goldstein et al., 1992) than of purely semantic origin. It is likely that the discordant findings mentioned here are a reflection of the different composition of the AD samples entering the studies, at least as far as the advancement of the single patient’s dementing process is concerned. In spite of the inherent burden and drop-out risk, longitudinal single patient studies appear a promising approach to address questions such as that of a keener distinction of the verbal and strictly semantic contribution in the naming disorder of AD patients. In a similar vein, single case studies might be helpful to tease apart the perceptual contribution to naming impairment from that possibly consequent to a defect in the semantic knowledge of the visual forms. Questions like these are interlaced with those raised by the access/store alternative interpretation of the semantic memory impairment of AD patients. In Gainotti’s (1993) review of semantic memory topic in AD patients, semantic amnesia could not be traced back to a single mechanism. It appears more likely that different mechanisms, each with its own idiosyncratically different rate of progression, contributes to the semantic amnesia in AD, above all in the way it can be discerned in experimental settings. So it is surmised that the course of AD is characterised by aphasic deficits (Gainotti et al., 1986), followed by attentive insufficiency (see hints in this sense in Margolin et al., 1996) and finally a definite loss of semantic information owing to the destruction of the relevant archives. There is a growing tendency to kaleidoscopically tease apart different modules (or/and uses) of knowledge systems. Given the early occurring agraphic errors of AD patients, a good example of this strict cognitive strategy to achieve also an understanding of a normal activity (orthographic writing) is to isolate the patient’s knowledge of spelling. Rapcsak et al. (1989) provided evidence in AD patients of a defective lexical spelling system that can be traced back to the degeneration of dedicated neurones in the left temporo-parietal areas. There is an increasing non-

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availability of the spelling representations of words, i.e. a circumscribed knowledge disorder and, accordingly, emergence of orthographic errors in oral spelling and writing. In line with this very Fodorian view are Patel et al.’s (1993) longitudinal data on spelling deterioration during the lexical, then phonological, and finally articulatory stages of AD. Lambert et al. ’s (1996) data on agraphia in AD agree with Rapcsak et al.’s (1989) cognitive microdissection of the components of the lexical representations of words, providing evidence of an independent deterioration of the orthographic knowledge component. In attempting to sum up a growing body of data, which are in part conflicting, it appears that in an early stage of the disease the semantic amnesia in AD is the consequence of an access deficit to semantic “nodes” and that, in a hierarchical framework, such a defect develops in a bottom-totop fashion, that is, from the attributes of objects to their supraordinates. The nature of the deficit is likely to be an increasing distortion of the structure of the normal semantic network with an increasing modification of the number and strength of the connections (Chan et al., 1997). However, a word of caution is in order. A drawback of this kind of study is the tendency to generalise group findings to all AD patients. Actually, it might be that semantic impairment both in its lexical and visuoperceptual aspects, is the hallmark of the, admittedly frequent, AD patients with severe temporal atrophy, a condition that in the early stages of the disease might not be the same in all AD patients. The latter case is, instead, likely to occur in mid-late stages of AD. It might be wise to take a more flexible view of the access/storage dichotomy employed to interpret failures to make explicit memory traces. Forthcoming longitudinal surveys on AD patients might provide data to support a continuous evolution towards a storage defect of the trade-off between the two incomplete defective conditions, and even suggesting a radically different conceptualisation of retrieval in the frame of parallel distributed models (Silveri et al., 1996).

Autobiographical amnesia Autobiographical memory refers to one particular aspect of the remote memory archives and stands

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somehow apart from episodic and semantic longterm memory, poorly fitting into this dichotomy. In our view it is better to construe autobiographical memory as a knowledge system, that is, a very particular file in the remote memory archives with a proper organized structure (the “autobiographical knowledge” system; Conway, 1991,1996; Conway & Rubin, 1993). Autobiographical memory refers to the ability to reinstate events vividly into consciousness, reconstructing by means of “generative retrieval” sets of the personal past history that is peculiar to each one. It represents a crucial variable in characterizing and preserving one’s own personal identity, above all when one has to cope flexibly with other members of one’s society (Fitzgerald, 1992). It remains to be seen (review in Linton, 1986; Rubin, 1986) whether autobiographical memory should be considered part of the episodic or the semantic memory. There is still dispute as to whether autobiographical memory is part of both memory categories according to the different autobiographical contents (Kopelman et al., 1989). An event enters this particular knowledge system as an assemblage of actively selected factual data and contextual items. Thereby, autobiographical memory is also conceptually in between the episodic and the semantic systems. The long-term inclusion of personal events into one’s autobiographical knowledge owes much to a priori determinants such as early imprinting, beliefs, attitudes, and life-style as well as other items of the “general knowledge of the world”. Undoubtedly, strong cultural imprinting plays a major role in the construction and reconstruction of autobiographical knowledge. This is also suggested by the “reminiscence bump” (i.e. the easier recall of autobiographical and media-mediated traces belonging to age 15-25 of the rememberers), which, surprisingly, changes from Western to Japanese people (i.e. shifting to 20-30 years of age). The reminiscence bump is a robust effect as can still be observed in AD patients (Fromholt et al., 1992). Testing the efficiency of autobiographical recall is a difficult enterprise both on the side of the test standardisation in normals scattered by age, education, sex, and cultural background and on that of the test construction. Besides strategic retrieval (i.e. recollection), visual imagery and language play

a crucial role in bringing about an explicit report of an autobiographical episode or event. An autobiographical report is constructed by piecing together fragments of information dispersed in different areas of the cortex according to different taxonomies, such as sensory modal-specificity, spatial, verbal, emotional, as well as associative aspects. This pattern of interlaced variables makes sense of the multi-systemic correlative data and speculations raised by autobiographical retrieval: besides limbic and diencephalic structures, temporal, frontal as well as occipital lobes are thought to be involved in bringing to consciousness an item of autobiographical knowledge (Moscowitch, 1989; Ogden, 1993). There are now many standardised tools able to provide measures of the efficiency reporting autobiographical information. There are the word-prompted enquiries derived from the Galton test modified by Crovitz and Shiffman (1974) and the questionprompted enquiries providing, or not, the life- or external time-period to which the question refers, and distinguishing, or not, the retrieval of facts or events. In this group are the Borrini et al. (1989) Autobiographical Enquiry and the Autobiographical Memory Interview of Kopelman et al. (1989). Both have been standardised on healthy subjects and employed in studies of AD patients. Autobiographical amnesia (i.e. inaccessible personal knowledge) is almost tantamount to the inaccessability to consciousness of the items of the individual identity. This is documented in pure retrograde amnesia patients (De Renzi et al., 1995, 1997; Lucchelli, Muggia, & Spinnler, 1998). In Dall’Ora et al.’s (1989) study on autobiographical memory by means of a standardised semi-structured enquiry (Borrini et al., 1989), about 80% of AD patients presented a very early and severe impairment of their ability to retrieve tokens of their autobiographical past. AD patients’ poor performances were not correlated with their semantic or episodic memory scores. Sagar et al. (1988) and Kopelman (1989), at variance with Dall’Ora et al. (1989), found some temporal gradient in AD patients, even if it was not as distinct as that shown by Korsakovians. The difference between these findings seems to be entirely traceable back to the different features of the

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autobiographical testing tools employed. In Dali’Ora’s (1989) experiment, AD patients’ poor autobiographical recall lacked any of the confabulatory traits that other patients such as some single frontal patients (Baddeley & Wilson, 1986) and many Korsakovians or anterior comunicating artery-patients (De Luca & Diamond, 1995) present. In line with the findings of Della Sala et al. (1992, 1993) in frontal patients and focal amnesic patients, the defect underlying the poor autobiographical recall of AD patients was traced back to their inertia (similar to that of most frontals) when they are called on to set in motion the self-directed strategy that characterises the active searching process of recollection of past traces. Greene et al. ’s ( 1995) findings agree with Della Sala et al. ’s ( 1992, 1993) speculations. It is likely that the uncertainty about crucial personal details contributes to the continuous irresoluteness and anxiety that hallmarks AD patients. The nature of the recollective defect in AD patients is not specific to autobiographical information, but rather involves every kind of active search in the Remote Memory archives, including those dedicated to semantic memory. The traces closest to the autobiographical for sensitivity to AD are those belonging to mediamediated information. The autobiographical deficit of AD patients appears to share both memory storage defects and planning impairments, in other words a combined impairment of memory and control functions. In our opinion, autobiographical amnesia in AD needs to be integrated within the broader framework of the studies on the archives of remote memory (Lucchelli, Muggia, & Spinnler, 1998). Indeed there is every likelihood that studies of remote memory in AD patients together with findings from herpetic encephalitics, Korsakovians, and patients suffering from pure retrograde amnesia (Della Renzi et al., 1995,1997; Della Sala et al., 1996; Lucchelli et al., 1995) will be helpful to model the architecture of knowledge systems.

Procedural amnesia Procedural memory is one aspect of long-term memory. It deals with motor and perceptual information and with motor skills. It is defined in operative terms as follows: the fact of having had

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the possibly repeated and contextually sterotyped experience of a procedure (i.e. a fixed sequence of actions) gives rise to a facilitation in reproducing the same procedure whenever contextual conditions akin to those of the original experience occur. In procedural settings this phenomenon takes place without any conscious registration of it, and its attentional cost is minimal. The most intriguing aspect of procedural memory resides in its definition. Using the term very extensively, procedural memory encompasses the implicit memory performances of the laboratory setting (e.g. stem completion with words or motor skills with the pursuit-rotor device) as well as everyday repetitions of syntactic and prosodic rules, logic procedures and ecological goal-directed complex actions (e.g. Shank’s, MOPs, or “Memory Organised Packets”, 1982). Moreover, it covers both the factual retrieval from an already consolidated stock of skills and the learning of new ones, which means that there is an anterograde as well as a retrograde procedural memory (and thereby amnesia). Procedural learning in its motor aspects seems to be linked to the primary projective areas (e.g. to areas 4 and 6 for motor skill learning; to area 17 for visuo-perceptual learning), to the neostriatal structures, and perhaps even to the cerebellum. Taking the term of procedural memory in a more restricted sense it refers only to overtrained motor skills and rules. In ecological settings, it appears that AD patients retain most of their premorbid motor habits, and the same holds true for everyday MOPs. It is not always easy to disentangle procedural from apraxic (see ideational apraxia in Chapter 18) or agnosic defects (see Chapter 16) in everyday coping, particularly if one has to decide on the sole basis of abilities reported by relatives. Implicit memory is much more a laboratorydriven concept. It refers to the facilitation that the prior study of a stimulus reveals in subsequent processing of the same or a related stimulus despite reduced or absent awareness of the learning episode: this is the typical experiment of long-term priming. Implicit memory dissociates from explicit memory performances in normals and between normals and amnesics (for a theoretical account, see Roedinger, 1990, and Schacter, 1990). Implicit

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performances are considered to be an extra-limbic memory function related to the activation of neocortical input areas which differ according to the perceptual or lexical nature of the stimuli at issue. In AD patients implicit memory is by far better functioning than explicit memory. Moreover, in these patients there is a trend towards an intraimplicit dissociation between a nearly intact perceptual and an impaired lexico-semantic priming as well as between data- and conceptdriven processes (Russo and Spinnler, 1994). There are findings by Butters et al. (1988) suggesting that in a pursuit-rotor experiment AD patients are capable (as are global amnesiacs from focal lesions) of post-onset procedural learning at variance with Huntington’s patients, at least in the motor domain. This evidence lends some preliminary support to the role of basal ganglia (in particular, of the neostriatum) in subserving such kinds of procedural abilities. Procedural memory in the sense of the preserved ability to retrieve well consolidated skills (which might also be of a strictly cognitive nature) is a frequently replicated finding in AD patients. Data on the learning of new cognitive skills by AD patients has yielded conflicting results. As a concluding remark, it is noteworthy that in AD patients a memory dissociation is at work between declarative memory performances (episodic and semantic), which are severely and early impaired, and procedural performances which are unimpaired or at best only marginally affected. The result is that AD patients can be managed within the strictly stereotyped ecology of their familiar setting long into their disease, and this holds true also for those patients (the vast majority) whose declarative amnesia is paramount. Admittedly, there are everyday defects such as those involving cookery and the use of electric appliances mainly occurring in the late stages of AD, which cannot be accounted for by a relatively pure agnosic or apraxic deficit: by exclusion, they are suspected to stem from a procedural amnesic disorder. Particularly frequent coping disorders in late-stage AD patients occur with toilet facilities and connected procedures. It might well be that such defects are examples of a disorder of complex, habit-mediated procedures, akin to those described

by Shank (1982) as MOPs. Given their complexity, and chunking needs into subgoals to be correctly carried out, it might well be that in AD patients there is a slowly evolving and late occurring deterioration of even well practised procedures. Procedural amnesia involves complex procedures (such as the strategically ordered MOPs) before easier habits, such as chronologically paced and topographically primed habits of everyday life.

DEFICITS OF THE “INSTRUMENTAL” FUNCTIONS Despite decades of strong anti-localisationistic criticism, we agree that there are functions whose topographical correlation with cortical sites is still worth upholding. In this regard, neuropsychological functions are qualified as “instrumental” (e.g. Spinnler, 1985,1991) whenever there is consistent evidence in focal brain-damaged patients that their efficiency is linked to retro-rolandic cortical areas of either the left or the right hemisphere or both of them. For AD, reference is chiefly made to temporal and parietal associative cortices, given that the encroachment of the occipital aspects (peri-striate areas) is generally much less consistent, particularly under histopathological scrutiny. Going back to section 2 (defects of “instrumental” functions) of Table 31.1, we will now outline the neuropsychological defects arising from the left (dominant) retro-rolandic encroachment of the AD process, and thereafter those resulting from right homologous encroachment. In line with the longitudinal history of AD, instrumental defects occur in the early and mid stages of the disease. Of course, they persist and worsen in the late stage, but to single them out in ecological and psychometric settings once the derangement of control functions is severe, is all but impossible. Not all possible instrumental deficits will be described herein, and attention will be focused on those we have encountered most frequently. Moreover, one must bear in mind that the following are intended as neuropsychological descriptions, meaning that emphasis will be placed on that majority of disorders (ecological or

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psychometrical) we believe can be understood in neuropsychological terms within an acceptable range of arbitrariness.

Defects arising from left hemisphere retrorolandic damage Reference is made essentially to oral and written (see review of reading disorders in AD in Mathias, 1996) language disorders, and to apraxic defects. Some other defects, such as acalculia (ecological evidence of which is both frequent and early), are not considered, as their psychometrical study in AD patients, given its multifactorial nature (see Chapter 26), has yet to start (e.g. Kessler & Kalbe, 1996). Language disorders The study of language disorders in AD was constructed around the crude observation of poor test performances on tasks designed for the assessment of aphasia in left focal hemispheredamaged patients. In more recent times, a more cognitively modelled approach has been adopted. The ongoing studies of language disorders concentrate on subtypes of AD patients hallmarked by early and subtle verbal disorders or on different subtypes of primary progressive aphasia. In fact, many recent studies have been designed around the lexico-semantic view of anomia, in a less verbal (and aphasiological) and more conceptual (semantic) oriented framework of the impairment of verbal comunication in AD (see earlier heading on semantic amnesia). As already mentioned, word finding in spontaneous discourse and confrontation naming are among the first defects to be reported by relatives; they also emphasise the great variability of the disorder and perhaps its dependence on occasional exacerbating variables (such as fatigue, fever, anxiety, and so on). This last point merits further investigation in order to ascertain the extent to which mild language defects can be overcome by extra-attentional effort. Language disorders are characteristic of the early stages of AD (Capitani et al., 1986,1990; Gavazzi et al., 1986; Martin et al., 1987). They usually develop within 12 months or so of the ecologically apparent anterograde memory disorders, and their onset may even coincide with the first anterograde amnesic traits. Provisionally, language disorders may be dichotomised into true

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aphasic deficits in oral and written language and defects of discourse planning, given that these sets of disorder are possibly of different (i.e. prefrontal) correlative origins. A radical change in the verbal output of some AD patients becomes apparent in the late stage of the disease, when patients appear to be in a permanent state of mild confusion (see later). Their spontaneous speech becomes more and more laconic until reaching a pseudo-mute state; however, when asked to answer the closed-loop traditional language tests, the same patients provide short and surprisingly accurate answers, sometimes with satisfactory circumlocutions to overcome their recurrent anomias. On the other hand, if the same AD patients are asked to provide an articulated account (e.g. how the working day went) they utter only few, poorly organised, words almost devoid of information. This outstandingly poor performance by collateral evidence cannot be entirely traced back to amnesic or aphasic deficits. The dissociation between a rather mild impairment in closed-loop test answering and a severe inability to self-generate and organise a narration was pointed out by Luria (1970) in nondegenerative patients with frontal lobe damage. Thus one can try to distinguish two different types of verbal communication impairment in AD patients. The first is apparent in the early stages of the disease and dominated by anomic, circumlocuted, and fluent speech aphasia due to the left temporal atrophy, and the second is apparent in the late stages and dominated by a laconic verbal output and a severely disorganised narrative ability due to the frontal encroachment of AD. It is worth emphasising that the AD involvement of the dominant (left) hemisphere often becomes manifest before that of the right hemisphere. This is not solely the consequence of the greater attention and weight given to communication deficits than to visuo-spatial disorders in modern societies. Actually, evidence of an asymmetrical encroachment upon the retro-rolandic aspects of the hemispheres is sometimes apparent in CT and MRI atrophy data as well as in PET findings (Duara et al., 1986; review in Capitani et al., 1990). Neuropsychological data on asymmetrical instrumental involvement tie in with neuroimaging evidence (Foster et al., 1984). In some series of early

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stage AD patients (Martin et al., 1986) subtypes of AD were suggested according to the onset picture. InCapitaniet al.’s (1986) series, 10% of the patients were classified neuropsychologically as “probable AD patients with a pseudofocal aphasic onset”. Besides being grossly aphasic, these patients were also mildly amnesic. Within three years (usually in less than two) pseudofocal aphasic patients evolve to a picture of full-fledged AD. Pseudofocal aphasics must not be confused with patients showing “slowly progressive circumscribed deficits” (see Chapters 32 and 33), in this case of the aphasic type (i.e. one of the subtypes of primary progressive aphasia), for which an exclusively language deficit hallmarks their neuropsychological syndrome, for more than a conventional period of three years. In any case, even the latter patients develop a global demential syndrome, which often proves to be of the AD nosology. The issue of language disorders in AD is so important and intricate that it will be dealt with in a separate chapter (Chapter 34). Apraxias Reference is made to the classic functionalistic taxonomy of ideational, ideo-motor and melokinetic (or innervatory) apraxia (see Chapter 18). The first two are disorders of sequences of acquired and goal-directed movements following a lesion in the parietal and also the frontal (e.g. buccofacial apraxia) aspects of the left hemisphere. The latter (also known as “gliedkinetische Apraxie”, Liepmann, 1900, or “innervatorische Apraxie”, Kleist, 1907) follows pre-motor frontal lesions of the contralateral hemisphere, with no hemispheric dominance, in some cases coupled with callosal anterior and/or supplementary motor area damage. Apraxic disorders of every kind are not accounted for by elementary sensory or motor deficits. Schematically speaking, ideational apraxia is a disorder of intentional movements due to the disruption of the conceptual, goal-directed motor plan; ideo-motor apraxia follows an error of the exact implementation of movements in order to perform a successful gesture; melokinetic apraxia follows impaired control of the isolated motor actions making up a gesture, which is a defect akin

to ataxia, but consequent to a cortical lesion in the motor associative areas. At variance with ideational and ideo-motor apraxia, innervatory apraxia might be circumscribed to parts of the motor apparatus (even eyelids, even unilaterally). Definitions of the exact meaning of these terms (Freund & Hummelsheim, 1985) are still lacking consensus, and its bridging from the classical approach of Heilbronner (1910), Liepmann (1902, 1920) and Kleist (1934) to modern cognitive views implemented in ad hoc experiments (e.g. Ochipa et al., 1992) remains a matter of fiery debate. To gain further insight into the phenomenology of AD patients in intentional motor sequences it may be useful to refer to Roy and Squares’ (1985) conceptualisation of the motor system. It is surmised that a knowledge structure of the motor act (its meaning with respect to goal and context) and a production system are both devoted to controlling the motor act. Whereas the damage to the former system could entail Liepmann’s ideative apraxia, that to the latter could give rise to ideomotor apraxia, both predominantly linked with left parietal damage. The extent to which the neuronal network of the latter system can be extended to encompass the bilateral somatotopically arranged frontal depositoire of Liepmann’s “Bewegungsformeln ”, whose damage is believed to provoke contralateral melokinetic apraxia (see later), is still a matter of speculation In AD patients, movement disorders of neuropsychological origin are observed both in everyday settings and in the few experiments devoted to this issue. Features of the disorders fit all possible types along the polarisation from “conceptual” (Ochipa et al., 1992) to the melokinetic apraxia. The disorders themselves are often more severe than those observed in focal left hemisphere damaged patients. Ideational apraxia (thoughtful review in Poeck, 1983a) is most frequently reported in patients suffering from cortical dementias (chiefly AD; Ochipa et al., 1989,1992). A good way of testing it uses standardized batteries of “utilization apraxia” with objects associated with a definite everyday use (see Chapter 18). Pure utilisation disorders are rarely reported in the early stages of AD; on the

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contrary, in the mid-late stages of AD this is a frequent impairment observed ecologically (for instance, with items such as a spoon or a knife). Given the long spared procedural memory abilities (unconscious retrieval of habit-mediated complex motor sequences), defective use of common household objects can be confidently traced back to ideational apraxia. There are, however, instances of visual object agnosias that of course involve an inappropriate handling of the unrecognised object. Supramodal spreading of the lack of recognition as well as a naming defect, suggest a semantic defect similar to that hallmarking “semantic dementia” (see Chapter 33) for which ideational apraxia is merely one of the consequences. Ideo-motor apraxia in AD patients is easily tested by means of imitation procedures. One should consider that ideo-motor apraxic defects (at variance with ideational and melokinetic) are hallmarked by the Jacksonian automatic/voluntary dissociation and therefore by an unimpaired handling of common objects in their ecological context. Ideo-motor apraxia is less frequently observable in AD patients than was claimed in the past (e.g. 70% of AD patients according to Sjogren et al., 1952): Della Sala et al. (1987) documented it psychometrically in a third of their early-mid stage AD patients. Such contradictory findings are rather surprising given that left parietal involvement in nearly every case of AD is a long and well acknowledged notion. A recent (still unpublished) study of ours, in which De Renzi et al.’s (1980, 1983) ideo-motor apraxia test was employed in 56 AD patients (nearly all with less than three years of length of illness), showed an apraxia rate of 19%. The apraxia scores correlated in our research with a global score of cognitive deterioration (i.e. MOD A-score) to only .40 for the right hand and .54 for the left hand. In AD patients, as in left hemisphere focal damaged patients, ideo-motor apraxia is frequently associated with aphasic defects of language. Melokinetic (or “innervatory”) apraxia (Kleist, 1907, 1934) is still awaiting a general agreement about its existence as a separate conceptual form of complex motor disorders.

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Freund and Hummelsheim (1985), reporting on 11 focal frontal-damaged patients, upheld the existence of melokinetic apraxia and their revisitation closely replicated that of the classic German reports. Melokinetic apraxia is hallmarked by clumsy and coarse movements, sometimes awkward to the extent that their purpose is thwarted. It is capable of also rendering awkward everyday skilled quasiautomatic motor procedures, as it escapes the Jacksonian automatic/voluntary dissociation that is apparent in ideo-motor apraxia. However, the general form of the roughly executed movement is always recognisable by the examiner as if it were a bad copy of the model movement that the patient has to imitate (Kleist, 1934; Lange, 1936; Heilman’s, 1975, 1985, “kinetic apraxia”, Freund et al., 1985). Patients often appear to perform movements as if they were in the course of learning them for the first time. The reasonable suspicion might be raised that an unpredictable number of failures in ideo-motor apraxia testing in AD patients could be construed more appropriately as melokinetic failures, casting doubts once more on the mere scoring of hit answers without fully analysing in detail the wrong answers. We have the growing general impression that the analysis of the many types of wrong answers provides more finegrained information than that from hit anwers. The most confusing neurological condition when testing for melokinetic apraxia is ataxia (both cerebellar or sensitive), or even very mild paresis. If, in the lines of Kleist (1934), one accepts this form of apraxia (as we do), one has to consider that it is likely to involve every topographical district of the body according to the distribution of the cortical damage. Among the most likely candidates to present innervatory apraxia are cortical dementia patients, as their pathological process entails neither paresis nor ataxia (a forecast that is easily verified by a routine neurological examination). Neuronal thinning out in AD is both widespread and bihemispheric, two features likely to enhance the probability of bilateral “innervatory” movement disorders and their clinically apparent severity. AD often entails bilateral melokinetic defects,

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whose somatic distribution is variable, ranging from the eyelids to the whole axial musculature. In the classical, mainly German, literature such apraxic patients are mentioned in the bilateral frontal glioblastomas and in few instances of cortical degenerative dementias (e.g. Kleist’s, 1934, cases Zorn and Hliettinger, and Lange’s, 1936, case, all with probable Pick’s disease; Marcuse’s, 1904, case with possible AD). One can predict that in AD patients, particularly those at advanced stages of the disease, innervatory apraxia should not be an infrequent finding and that, as already said, it should be bilateral. The classical neurologists maintained that one peculiarity of innervatory apraxia is that, at variance with ideo-motor apraxia, it also impairs the axial movements from the hairline (facial apraxia) to the torso and rizomelic movements of arms and legs. Apraxia of upright standing and walking (“Stand- und Gangapraxie”, Kleist, 1934, or “Torsoapraxie”, Sittig, 1931) has been reported and traced back to bilateral innervatory apraxia of bi-frontal (and/or callosal) origin. According to the findings of a very recent (still unpublished) study of ours in which a new ItaloScottish transnational^ standardised test of gesture imitation was used, 38.6% out of 57 AD patients had a Stand-Gangapraxie, whose severity was correlated .66 and .70 with, respectively, the right and left ideo-motor hand score, and .68 with global cognitive deterioration (i.e. MODA-score). If one explores how well an AD patient in the mid-late stages of the disease copes with standing, sitting, lying down, standing up, and even walking, it is not uncommon to find a progressive worsening, which in our opinion can be traced back to the presence of melokinetic (i.e. innervatory) apraxia. Of course, such an impairment adds to the profound akinesia of late-end stage AD patients. In Chapter 33 slowly progressive apraxia (with/without aphemia) is considered. At the end stages of AD, apraxic behaviours, which are unusual in focal brain-damaged patients and of difficult neuropsychological understanding, sometimes come to the fore, such as those linked with the inability to coordinate the motor sequences needed to chew, copulate, swallow, or even

defecate. Ingestion of false teeth can occur. All these losses of motor skills are likely to be apraxic, more precisely of the innervatory type. Visual object agnosia Reference is made to Chapter 16 for the general outline of the agnosic defects. The complex processing culminating in object identification and recognition draws back to different cognitive layouts, such as, for instance, that of WernickeLissauer (Lissauer, 1890), of Liepmann (1908), and most recently of Coslett and Saffran (1996). It relies, in part on the posterior left-sided neuronal network; on the whole, it can be held as a bi-hemispheric function (in the occipito-temporal cortical aspects). If asked directly, relatives of mid- and late-stage AD patients give ecological accounts of sporadic instances of misrecognition of common objects. Skilled or trained care-givers take notice of such defects too. There are some agnosic defects that reach an ecological evidence rather consistently, such as prosopagnosic and alexic defects (for written language disorders, see Chapter 34). The detailed psychometric study of visual object agnosia in AD patients is a difficult enterprise (Saffran et al., 1990), first of all because of the blurring effect that aphasic, apraxic, and supramodal semantic disorders (likely to be at work together in the same patient) have on the genuine agnosic deficit. A second difficulty is to overcome the often poor understanding of tests and lack of compliance of mid-late stage AD patients; actually, one has to consider how laborious and detailed the neuropsychological formal assessment for visual objects agnosia is (see, for instance, in a focal braindamaged patient, De Renzi & Lucchelli, 1994). Disorders of visual recognition in AD patients can arise from pre-semantic stages of visual processing (Fletcher & Sharpe, 1988; Hutton et al., 1987) as well as from the Lissauerian “associative” stage or from the concurrence of the two. Visuoperceptual errors in AD patients are often reported in studies on AD patients’ anomia. Actually, visuoperceptual deficits are thought to play a part in their word finding difficulties on confrontation naming (e.g. Cormier et al., 1991; Goldstein et al., 1992; Henderson et al., 1993; Silvieri & Leggio, 1996). Montanes et al. (1995) suspected that perceptual

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defects could be one important variable even in bringing to the fore semantic category effects on naming found in AD patients. Finally, there is the suspicion that AD patients’ poor object recognition is often of the supra-modal semantic type. In fact, when Liepmann (1908) laid the foundations of “disjunctive agnosia”, his descriptions stemmed from the multi-modal recognition and naming defects sometimes observed in “senile” demented patients (see the heading on “semantic dementia” in Chapter 33). It might well be that at different stages of the disease, the same AD patient presents recognition defects stemming from “peripheral” isolated and from progressively more complex cognitive deficits (true visual agnosias) as well as from an overwhelming semantic disorder (semantic access agnosias). As far as we know, an AD study modelled on a cognitive flowchart of healthy processing from the pre-semantic to the different visual agnosic steps, to disjunctive agnosia and to the visual imagery of objects is still outstanding. A multiple single patient approach is likely to allow the teasing apart of several different patterns of impairments, as has already been done in face processing studies in AD (e.g. Della Sala et al., 1995). In our experience, visual imagery is severely impaired in many AD patients at the early-mid stage of disease. This adds to their cognitive hesitancy in everyday coping.

Defects arising from retro-rolandic right hemisphere damage The asymmetrical encroachment of the retrorolandic areas of the right hemisphere is a long recognised pattern of early stage AD (Becker et al., 1988a; Crystal et al., 1982; Martin et al., 1987). It is, however, a rarer phenomenon than early predominant left hemisphere involvement. “Pseudofocal right hemisphere onset” patterns were found in 3% of Capitani et al.’s (1986) AD patients. In the subsequent early-mid stages of AD neuropsychological evidence of right hemisphere involvement is almost always present both in the ecological and the psychometric setting. Sometimes the right hemisphere appears to be more severely involved than the left; this might also be apparent in terms of asymmetrical degree of atrophy assessed by neuroimaging techniques. In Capitani et al.’s

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(1990) series, 17% of the AD patients, irrespective of their onset pattern, appeared to be psychometrically more impaired in performances subserved by right hemisphere functions, against 55% with the opposite trend and 28% without a significant left-right difference. That a right hemisphere retro-rolandic encroachment of the AD process can be predominant is also attested by the not at all unusual cases of almost pure spatial impairment in slowly progressive visuo-spatial (Della Sala et al., 1996) and visuo-perceptual deficits (Gentileschi, Sperber, & Spinnler, submitted); see also Chapter 33. Predominantly spatial defects A typically mid-stage disorder in the ecological setting is dressing apraxia, in consequence of which the patient becomes entirely dependent on the help of a care-giver for all his or her daily dressing needs. Its frequence is such that it is seldom missing from the ecological array of an AD patient’s disorders. Two separate defects underlie dressing apraxia: the spatially compelling need to orient clothes and parts of one’s own body in the correct reciprocal way permits normal dressing and the sequential stratification of the different clothing items. Whereas the first (i.e. personal and extra-personal interactive spatial cognition) is the predominant defect and is classically traced back to the right parietal lobe, the second might be predominantly subserved by left hemisphere functions. Often only the first component is apparent. The disorder is not to be confused with the seemingly endless and inconclusive performances of many AD patients when they have to choose what clothes to wear, and to adapt the choice to the season, weather, social occasions, and so on. Another spatial disorder is the inability to cope with the landmarks whose sequential use make up a journey. Navigational abilities of AD patients go awry early in the course of their disease (Henderson et al., 1989) and pose a considerable burden on caregivers. In fact, nearly all AD patients in their early-mid stages experience getting lost. Transient topographical disorientation without defects in recognition of surrounding buildings is a rather frequent “demential episode” (Spinnler, 1985); it occurs in the very onset months of AD. This

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disorder is currently known as topographical disorientation (for the terminological and the heuristic questions, reference is made to the excellent review recently provided by Farrell, 1996); it has nothing to do with general disorientation or confusion (see later, under the heading about “control” functions). There is a series of external conditions in which topographical disorientation occurs more frequently, and may also occur in isolation (Scotti & Spinnler, 1969). This is particularly apparent in AD patients. As a rule, they get lost first on the less practised outdoor routes, then also on the familiar ones, and lastly on the indoor routes (e.g. from the bedroom to the toilet). Learning new routes (e.g. finding one’s way around a hospital; finding a parked car) is perhaps one of the most difficult tasks for a very early stage AD patient, but this is likely to belong to the realm of the very early-arising anterograde amnesia. Encoding and manipulation of allocentric landmarks allows efficient navigation in a novel environment; also the egocentrically organised space is involved in navigation. Recollection of route maps (a retrograde memory task) allows to move in a familiar environment, and to monitor ongoing errors. Topographical disorientation has at least two components (but see the analysis provided by Gruesser & Landis, 1991): the first belongs to the spatial egocentric orientation ability, the ability to perceiving and exploring extra-personal space (see Chapter 22); the second entails composing the spatial qualities of the items from an already available internal map (De Renzi, 1982). Whereas the former refers to the information needed to find one’s way around, the latter is essentially a spatial deficit of retrograde memory, and as such an early aspect of AD. One aspect of the latter is geographical disorientation, which is expected to be a frequent defect of AD patients in accordance with what is informally witnessed: formal testing on mute maps (Spinnler & Tognoni, 1987) upholds the early geographical disorientation of AD patients (Spinnler, unpublished data). Visual imagery, enquiring about spatial cues (i.e. asking the patient to list the furniture or fittings to the right, in front, and to the left of her/his bedroom door) has proved to be a very effective way of elucidating spatial disorders in early AD patients

(Dall’Ora & Spinnler, unpublished data). This can be regarded as an aspect of deficient visuospatial imagery. At formal testing, early AD patients do badly on spatial perception tests (such as the judgement of line orientation in Benton’s test) and, more consistently, on constructional apraxia tasks (Ajuriaguerra et al., 1960) (see Chapter 20). The features of their grossly impaired performances are comparable to those shown by right hemisphere focal patients, that is, a pervasive disorganisation of the spatial elements hallmarking the model to be copied, as if the right parietal contribution to patient’s performance on the task were the predominant one. However, a detailed analysis of the line drawing errors of AD patients of Moor and Wyke (1984) does not entirely support the predominant impairment of the right hemisphere in the frequent constructional apraxia in AD. Indeed, the “closing-in phenomenon” is a very frequent behavioural trait of AD patients; moreover, they sometimes attempt to disentangle the components of the model and copy them separately. After a few years of disease, AD patients fail to make any attempt to copy, all too aware that such a task is beyond them. Impairment in early-stage AD patients offreehand drawing of everyday objects in canonical view is frequently reported by relatives and care-givers. A recent reappraisal of this issue by Grossman et al. (1996) suggests that this early disorder is of a multifactorial origin involving impairment in both lexico-semantic and visuostructural knowledge as well as in spatial shifting of visual attentional resources. These defects seem to be overwhelming in freehand drawing rather than just a problem of constructional apraxia. In some rare patients with apparently only memory impairments, one of the first everyday instrumental defects is their inability to reproduce geometrical arrangements (e.g. a patient who was a tailor was no longer able to cut out patterns). Possibly close to constructional apraxia, a common complaint of mid-stage AD patients is that they are no longer able to lay the table (i.e. the correct positioning of the cutlery and crockery). The same patients have increasing difficulty in folding laundry, in organising clothes in a wardrobe or

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drawer, in reversing the car into a parking space, and so on. Although it has been suggested that AD patients have early defects in space exploration (Fletcher & Sharpe, 1988; Hutton et al., 1987) sometimes with the inconsistent appearance of the “locked gaze” phenomenon, it is only at the late stages that clearcut instances of Balint-Holmes syndrome and simultanagnosia (see Chapter 21) can be observed. Spatial discrimination of the source of a stimulus is, even in normals, an attention-demanding task. Source monitoring appears to be impaired at an early stage in AD patients, as if their searching strategy (systematic and goal-directed attentional displacement) and even the attentional angle of perception were narrowed, a trait akin to similar phenomena (e.g. locked gaze) occurring in BalintHolmes syndrome following bi-parietal damage. The in-depth study of most spatial disorders in AD still has a long way to go, and here again a Fodorian cognitive approach predicting some specific inter-test dissociation in single patients is likely to prove the most fruitful research strategy. Predominantly visuo-perceptual defects Reference is here essentially made to disorders in the visual modality; in fact, there are very few studies on recognition performances of AD patients in the auditory and other modality realms. Difficulty in recognising faces (as well as other perceptual items that share a common structure and differ in small details) is one of the most common early stage examples of defective visuo-perceptual functioning in AD (Becker et al., 1988a; Mendez et al., 1990). It is an ecologically common complaint, occasionally experienced by many healthy elderly people; namely, that a patient can no longer identify by name or even semantic attributes once familiar acquaintances, even if his or her familiarity guess remains correct. Later stages involve the difficulty in distinguishing familiar from unfamiliar faces (formally known as clinical prosopagnosia; see Chapter 16). There is a hierarchical link with the further identification stage, so that missing the familiarity guess also entails the lack of any knowledge (including the name) of that person (Gentileschi, Sperber, & Spinnler, submitted). In AD patients there is a clear-cut time-lag between the

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moment they fail the familiarity judgement of faces and the naming of familiar ones, the latter ability becoming impaired earlier than the former, a condition that gives rise to a dissociation of face performances. From time to time there are hints, although only in late stage AD patients, that even nonhierarchical face processings, such as recognition of sex, race, age, and emotion-loaded physiognomic expressions becomes impaired. In a recent study of ours (Della Sala et al., 1995) it emerged that one third of a continuous series of early stage AD patients had some kind of psychometric deficits with face recognition in a visuo-perceptual set of tests: this figure is keeping with that of Mendez et al. (1990). In a Lissauerian dichotomy, patients with associative (or semantic or amnesic) defects are by far more common than those with “appreciative” defects, and the search for dissociated cases fits in neatly with the processing subsets predicted by Bruce and Young’s (1986) model of familiar face processing. Correlative data with optico-visual efficency (contrast sensitivity), with overall cognitive deterioration (MODA) and the ability to make a face/nonface decision (Della Sala et al., 1996) were all too small to warrant any suggestion of a causal link with each of the four face tests involved in the experiment. When AD patients fail the familiarity judgement of a familiar face, there is often evidence that they are no longer capable of also utilising extra-facial cues to achieve recognition (Gentileschi, Sperber, & Spinnlere, submitted). This is at variance with classical prosopagnosia from focal right or bilateral hemisphere damage. The suspicion is then raised in AD patients of an overwhelming semantic defect similar to the lexico-semantic impairment. Following this line, Evans et al. (1995) surmised a right hemisphere equivalent of semantic dementia in their case of progressive prosopagnosia with a predominant right temporal atrophy (presumably due to Pick’s disease). Like right retro-rolandic hemisphere-damaged patients, AD patients appear to be impaired in figure-ground discrimination, an inability that is sometimes also evident in ecological settings (e.g. finding a tool jumbled up among others in a drawer). This was suggested on the basis of findings of Capitani et al.’s (1986) study with Gottschaldt’s

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Hidden Figures, and directly confirmed in Della Sala et al.’s (1996a) study with PoppelreuterGhent’s Overlapping Figures. It is striking how easy and common it is to uncover deficits in early-stage AD patients that are highly comparable to those found in studies on focal brain-damaged patients (De Renzi, 1982; see also Butter et al., 1996, in an ophthalmological perspective). Nowadays, however, the neuropsychological studies of AD patients should no longer focus on such replication surveys or group studies, but rather take fresh impetus from the frequency with which dissociated cases, which confirm (or not) processings set out by cognitive models, can be singled out even in small series of AD patients (see, for instance, Della Sala et al.’s, 1995, study on face processing modelling). Given the microdissection carried out by the AD process on the single neurones of a functional network, cases with transiently dissociated performances are more likely to occur in an AD series than in focal brain-damaged patients following massive lesions such as strokes, traumas, or tumours. In conclusion, let us quickly go through the contributions of AD patients to Coslett and Saffran’s (1996) model of visual processing. There are AD patients who present with disproportionately severe visual impairments across the three main general components of the model at issue. In fact, (i) since Pick’s times (1908) several degenerative patients have been reported (Coslett & Saffran’s, 1996, review; Della Sala et al., 1996; Rogelet et al., 1996), some with histopathologically proved AD, who became progressively more and more deficient in using the “spotlight” of their visual selective attention. It appears as if their spotlight became too narrow to allow them to collect the wealth of details making up by means of progressive integration the visual appearance of an object. Thus, they fail to achieve in a transient working memory buffer the exhaustive representation of the object at issue, consequently failing to carry out the subsequent spatial (“where”) and/or recognition (“what”) work-out. It appears that areas 18 and 19, and contiguous posterior cortices play a crucial role in this preliminary representational assumption of the outer visual world, (ii) Starting from the demented patient reported by Taylor and

Warrington (1971), there have been AD patients whom the features of their failure in object recognition suggested a loss of (or insufficient access to) the structural description of common objects. This condition is equivalent to that envisaged by Lissauer (1890) as a defect in “primary identification”, or “apperceptive visualobject agnosia”, (iii) Finally, other AD patients have been described who lost the ability to extract from the transient analogical representation of the visual information the spatial map “that provides an egocentric modality-independent spatial representation” (Coslett & Saffran, 1996). It is likely that the great majority of AD patients present visual processing disorders due to the disproportionate impairment of all three components of the model at the same time. Complex patterns of impairment will then arise, such as simultanagnosia or BalintHolmes syndrome (see Chapter 33), that is, a “where” and “what” combined impairment (Della Sala et al., 1996). In our opinion, the “where” and “what” systems are not functionally equivalent in the two hemispheres. In particular, the spatial system pertains more to the function of the right than of the left occipito-parietal areas. This ties in with the evidence in longitudinally studied AD patients that spatial disorders differ in their chronological onset from anomic deficits in confrontation tasks. Indeed, they are revealed as a frequent post-anomic disorder. This lends support to the view of different nervous substrates involved by the spreading of the degenerative process alternatively linked to the left (anomias) and to the right hemisphere (spatial deficits). The “what” system (and its occipito-temporal correlates) is likely to owe its ability to the functional collaboration of both hemispheres. This is in line with the temporal role in the knowledge of both the structural description and the meaning of objects.

DEFICITS OF THE “CONTROL” FUNCTIONS Conventional reference is made here to attention (see Chapters 23,24, and 25) and intelligence, and, in a less traditional line, also to motivation (Norman & Shallice, 1980, 1987). For these rather roughly

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demarcated functions, the critical role of the associative areas of the frontal lobes are traditionally envisaged (e.g. Mesulam, 1986; Shallice, 1982; Stuss & Benson,1986; review in Brazzelli et ah, 1994; Della Sala et al., 1993; Perecuman, 1987). Even if this correlation has been debated for as long as a century and a half (Ferrier, 1887; Harlow, 1848), this current claim is still by no means a clearly documented and specified item of neuropsychological knowledge (review in Spinnler, 1991). In a strict correlational view, AD patients develop both the dorso-lateral and, possibly later on, the orbito-mesial prefrontal syndromes. Lack of temporal organisation of behaviour and of planning of everyday actions, attentional defects, environmental dependency syndrome, and dynamic aphasia fit in with what has been learned from focal patients with dorso-lateral lesions. Lack of inhibitions with socially and personally inappropriate behaviours and motivational disorders (up to inertia) are traced back to orbito-mesial involvement of the prefrontal associative cortex. At face value such neuropsychological defects and behavioural disorders are a feature of mid-late stages of AD, clinically hallmarked by constant confusion and inertia. The psychotic aspects of AD will be considered in this section too.

Defects of attention The all-embracing notion of attention and the related understanding of consciousness are held as psychological constructs likely to provide the wideranging control that is believed to be essential in the adaptation of complex living organisations. The presence of reduced speed of information processing (Nebes, 1992) and of increasing attentional defects in AD patients is a commonsense observation, but its assessment by means of formal experiments (see, for instance, the selective visual attention studies of Alberoni et al., 1988, Cossa et al., 1989, Della Sala et al.,1992; Nebes & Brady, 1989) has occurred rather late in the history of AD studies. Before going into the description of the attentional impairment in AD, it is perhaps worthwhile to outline the reference assumptions from which our description is drawn. Researchers

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now sustain that attention has a pivotal role in the governing of all cognitive activity. There are attentional aspects (informally labelled “concentration”) believed to exert the protective role against internal and external interference whenever the subject is engaged perceptually and mnestically in selecting and processing information, or attempts to prepare a new strategy to solve an unexpected problem (i.e. a problem for which a ready-made procedural routine is not available; Luria, 1966; Sternberg, 1994). Moreover, planning of action, irrespective of its contents, is traced back to a primarily attentional attribute (Norman & Shallice, 1987): for instance defining in advance the point at which to radically change the way of generating an answer (e.g. the decision about the ratios of the speed/accuracy trade-off or even of giving up answering). Such a broad extension of the operative qualifications of attention entered the traditional realm of “intelligence” (Sternberg, 1980), particularly in the trade-off between new and old-practised routines to solve unexpected problems (Reason, 1984; Spinnler, 1991). Hence, the psychological understanding of attention draws progressively away from the neurophysiological view of arousal. Operationally, attention is viewed as the allocator of resources to all actions (included thoughts), thereby becoming the central steering device (“supervisory”, Shallice, 1982; “managerial”, Grafman 1989) of any complex system such as that made up by the instruments producing the psychological activity. Panic-stricken normal people use uncoordinated and unplanned instrumental abilities: nevertheless, by no means can they be considered to have a defective instrumental machinery or to be demented, it is simply that their instruments are under bad steering control. In the wake of Kahneman’s (1973) conclusions, resources are held to be drawn from a general pool of limited capacity which fluctuates around a given value according to physiological (e.g. degree of arousal), psychological (e.g. fatigue), emotional, vegetative, endocrine, and pathological (e.g. frontal damage; drunkeness, and so on) variables. Conscious attentional effort improves the level of performance, but at the same time gives rise to the sensation of “mental” fatigue (Pillsbury, 1908). The repetition of a performance reduces the

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corresponding degree of fluctuation around the optimal value achieved; in the meanwhile repetition renders the performance less and less demanding in terms of resources to be allocated, progressively transforming it into an automatic (Le. costless and near-perfect) action (Hasher & Zacks, 1979). In normal subjects, automaticity of performances entails a tendency to emphasise speed rather than accuracy. Particularly resource-consuming are performances that imply the inhibition of an automatic routine, for instance well exercised MOPs (Shank, 1982). This becomes apparent while performing random generation tasks of numbers, digits, and scrawls. Informal defects in sustaining concentration in the healthy elderly (up to conference sleeping) and even onset AD patients are part of commonsense knowledge. In AD patients, such defects are linked with the apparent amount of attentional load required by the situations in which they find themselves. AD patients’ attentional weakness is particularly apparent whenever they have to resist being distracted while performing an unusual task (hence, “difficult”: one component of “task difficulty” is exactly its attentional demand; Spinnler, 1991) or find themselves in a noisy environment, or when they have to withdraw from a routine mode of action. Motor impersistence and the “façade phenomenon” in AD patients with its Jacksonian automatic/intentional dissociation (Spinnler, 1985), are examples of reduced attentional efficency; that is, still sufficient degree of attention to be able to cope with quasi-automatic tasks, but not with unusual ones. On the other hand, the long resistance of strictly contextualised professional and intellectual MOPs or scripts (Shank, 1982) provides evidence that attentionally undemanding activities, albeit of high intellectual qualification, are highly resilient to AD. On reviewing the small body of literature documenting the performance of AD patients on tests of attention, one faces the difficulty of comparing the findings of different studies, as the average degree of deterioration and that of the interindividual dispersion of deterioration are often irretrievable. In general, however, only early stage AD patients can cope with the demands of attention studies. Nebes and Brady (1989) and Freed et

al.(1989) suggest that visual selective attention of the focal type is spared during the early stages of AD. This finding is at variance with the consistent conclusions on visual selective attention of the divided type pointing to an early loss of efficiency (Baddeley etal., 1989;Capitanietal., 1988a; Cossa et al., 1989; Foldi et al., 1987; Grady et al., 1989; Mohr et al., 1990; Morris, 1996; Nebes & Brady, 1989). A recent study by Brazzelli et al. (1994 ) in which the Mackworth clock was used in a task of over 45 minutes showed an impressive waning of tonic alertness (vigilance) in AD patients at a very early stage of disease and, hence, with extremely mild cognitive deterioration. After all, these are the sole patients in whom such a task can be carried out. In laboratory settings test performances can be aligned along a continuum, from those making the greatest attentional demand to automatic ones. For instance, language tests require different amounts of attentional control: the repetition of words is less taxing than the word searching within the inner lexicon; morphological routines are less demanding than discourse planning; oral spelling is more taxing than written spelling (Croisele et al., 1996). In memory processings, episodic supraspan learning and recollection from remote memory are far more exacting than generating well rehearsed procedural skills. We can list the discrepancies of impairment in a large sample of traditional tests (Spinnler & Della Sala, 1988) according to what their face value attentional demand appears to be, irrespective of their cognitive domain. But, unfortunately, we do not have a psychometrically credited measure of what the attentional cost of each test is. These observations fuel the debate surrounding attention in AD, or more specifically, whether the progression of cognitive deterioration in AD merely reflects the gradual reduction in attentional resources (Jorm, 1986). The model of attention that presently appears to best accommodate the neuropsychological findings accumulated to date, is Norman and Shallice’s (1980, 1987) Supervisory Attentional System, a hierarchical model drawn from Luria’s (e.g.1966) assumptions on the functions of the frontal lobes: a supraordinate device is capable of interfering with the functioning of routine devoted and contextdependent control systems of action. Baddeley and

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Hitch’s (1974) “central executive” in the working memory model can be viewed as a particular instance of the supraordinate level of Norman and Shallice’s (1987) model. The increasingly used term “executive functions” refers to a set of cognitive skills necessary to lead and coordinate psychological activities; this is a continuous requirement of any ecological coping and surviving enterprise. A way of weaving the attentional involvement into the longitudinal history of the cognitive deterioration in AD essentially envisages a sequence of events characterised by two steps (Spinnler, 1991). In the first step, the deteriorating memory and instrumental functions call for greater attentional resources, which are supplied by the still unhampered frontal network. The second step starts when the frontal network is also affected by the degenerative process: a steady waning of attentional efficiency takes place. In slightly different words, before becoming globally impaired, attention and executive functions show selective defects, even early in the course of AD (Morris, 1996). The two steps of the growing over-request of attentional resources and that of the worsening attentional insufficience will now be separately outlined. 1. Attentional strain caused by deteriorating instrumental functions. As the interneuronal interview of the retro-rolandic associative areas gets poorer and poorer (Collerton, 1986; Scheibel, 1983), their functional output becomes increasingly hallmarked by nonsy stematic errors and lengthening latencies: the machinery works but ever more noisily. Consequently, attention is called on to increase its control. This extra-effort of resource allocation for an unpredictable time may succeed in overcoming the reduced efficiency. Cognitive processing brings the early stage AD patient to the point of very frequent mental fatigue. Closer scrutiny reveals that the once fully automatic actions now call for attentional control as if their automatic trait could be retained only as long as the subserving neuronal networks were under normal conditions. In fact, there is a regression from the fast and flawless automatic processings to a controlled, attentionally exacting generation of performances. The net result may be of

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acceptable quality but at the cost of great attentional strain. The attentional strain is evidenced by the ease with which general tiredness, pharmacological and metabolic variables, and most of all psychological interference produce transient attentional insufficiencies and bungled performances. It is likely that brief spells of “tip of the tongue phenomena” point to some transient excessive attentional demand. Possibly most of the “demential episodes”, such as confusional states, short and transient periods of aphasia and amnesia, and so on (Spinnler, 1985), hallmarking the early stages of AD, have an attentional origin. There seem to be strong indications (Jorm, 1986) that performances which under normal conditions are already the most controlled will be the first to show a loss of accuracy. One valuable experimental design able to elucidate hidden attentional strain is the growing assortment of dual task tests (i.e. divided attention experiments). Whereas single tasks are fulfilled at a normal level, when they have to be carried out at the same time, the performance of one or both declines. Such experiments have pointed to “central executive” involvement very early in AD (Baddeley et al.,1986) with a rather selective longitudinal decline (Baddeley et al., 1991a; Della Sala et al., 1995; Green et al., 1995). A modified and standardized paper-and-pencil version (Baddeley etal., 1997; Della Sala etal., 1995)of the dual task provided confirming data in AD (Baddeley et al., 1997) and a subgroup of frontal patients (Baddeley et al., in press). 2. Attentional insufficiency when prefrontal areas are involved. When the neuronal networks of the prefrontal associative areas are involved by the AD process, resources devoted to what remains of the retro-rolandic instrumental functions are only sufficient to cope with some of the once automatic, now controlled, functions, that is, with actions of still relatively little attentional demand. In the late stages of AD, the patient’s activity is more or less entirely driven by environmental stimuli with a steady “environmental dependency syndrome” (Lhermitte, 1986; Lhermitte et al., 1986; see Chapters 24 and

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25) often including imitation and utilisation behaviour (Della Sala et aL, 1994; De Renzi et al., 1996): a good example is the echolalia of late-stage AD patients. The progressive loss of any coping flexibility and the permanent confusional state hallmark this eventual stage of attentional insufficiency. It seems very likely that measures of the first stage of attentional strain collected with testing procedures that succeed in minimising the instrumental requirements will soon be developed. Actually, procedures such as go/no go, Stroop, random generation, tonic alertness, and dual task tests produce flexible scores for assessing AD patients’ attentional conditions. Recently, Robertson et al. (1996) developed three parallel forms of a standardised test of everyday attention (TEA) for ecologically plausible activities (such as looking through telephone directories, and so on). It entails nonlateralised sets of selective and sustained attention. These kinds of cognitively based measures of attention should become crucial variables in pharmacological trials of new anti-AD drugs replacing the traditional all-embracing scores (e.g. MMSE, MODA, ADAS) or the staging enterprises. A good policy would be to compare slopes of attentional decline of treated AD patients with norms on the same tests achieved by nontreated patients.

Defects of intelligence In the days when the favoured approach to furthering psychological knowledge was to adopt psychometric strategies, “dementia” was conceived as the opposite of “intelligence”: the amount of intelligence lost was regarded as the best descriptor of the degree of “mental” deterioration. Psychometric evidence of dementia was provided by gradual worsening of the nonverbal performances on the Wechsler-Bellevue or Wechsler Adult Intelligence Scale (WAIS), provided it was out of all proportion to the age-dependent decline or, better, to the age-dependent discrepancy with respect to the decline in the verbal performances. This latter was a sound criterion, namely to employ the norms of an age-dependent variable in order to check the presence of an abnormal decline (i.e.

psychological impairment). The criticism levelled against such an approach is surely not for the psychometric methodology that was later to be universally adopted, but rather for the general multifaceted modern conception of dementia (see Chapter 30) and the paramount importance given to the inability to cope with the needs of everyday life (e.g. see the operational definition of “dementia” provided by the Committee of Geriatrics of the British Royal College of Physicians, 1982, reported in Chapter 30). In the present view, the exclusive use of intelligence scales to reach a diagnosis of dementia (sometimes mismatched tout court with AD) ought to be regarded as a pernicious habit, which still survives in some forensic and geriatric approaches. The most relevant criticisms of the intelligence scale approach to the diagnosis of dementia are based on the complexity and theoretically unjustified heterogeneity of the items making up the testing batteries: in fact, these aspects are bewildering whenever one—free from the faith in the dogma of a unitary intelligence function— wants to understand what exactly has been measured by an “intelligence scale”. In fact, these scores defy interpretation, at least in the unitary sense of a function labelled “intelligence” (Nebes, 1982). Most “intelligence” tests imply as a beneficial strategy making operational divisions into subgoals while performing the test. This essentially calls for a great working memory load, which renders the final “intelligence” score more of an attentional score. Moreover, in a critical survey (Logson et al., 1989), it was pointed out that the WAIS-R Profile has a poor utility when it is employed to distinguish AD patients from healthy comparable subjects. Paradoxically, one can revisit the outmoded concept of dementia as the opposite of intelligence provided that one has adopted a multicomponential view of intelligence (thus losing almost every specificity of that concept; e.g. Sternberg, 1980). Progressive loss of functional components makes “intelligence” and dementia two sides of the same coin, namely the subject’s overall cognitive competence. It is beyond the scope of this chapter to venture into the age-old dispute about what is encompassed by the term “intelligence”, and, consequently, the extent to which the historically proposed tools are

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able to measure it. Like every other item of the taxonomy of the psychological functions, intelligence has undergone a kaleidoscopic fractionation of inter-related operations. It is now considered to be an assortment of abstract procedural frameworks devised to process information in order to formulate and solve different problems (Sternberg, 1980, 1994): for instance, to overcome the gap between the state of a welter of information and that of a desired goal, or to extract from a vast array of data by means of conscious selection and combination only the information that is needed to solve a specific problem. Uncovering a piece of information is probably the requisite for activating possibly extremely complex processing routines. Reference is made to the archives of routines that are more or less enriched during a lifetime of cultural activity. Here there is an obvious reference to Cattel’s (1963) and Horn’s (1982) “crystallised intelligence”. The general present understanding of “intelligence”— a set of skilled procedures capable of identifying the relevant traits of ongoing phenomena and processing them in a goal-directed way—has been shaken by the progressive widening of the realms of semantic and procedural memories as well as by the all-capturing executive role of attention. The reference to attention is particularly directed towards abstract procedures (Reason, 1984) ranging from the very general (the logical mechanisms of induction, deduction, abduction) to more domain-related (e.g. mathematical, linguistic, even ethical and aesthetical, and so on) up to those linked with professions or games (e.g. cooking, playing chess, bridge, and so on). Relevant to AD, are the outstanding features of these procedures, namely, the promptness of recall, the flexibility with respect to the unexpectedness and, in Goldsteinian terms (Goldstein & Scheerer, 1941), their abstractness and relative universality within a definite cultural setting. To reject the outmoded view of the demented as individuals who have simply lost their unitary qualification of being “intelligent”, is not to deny that intelligence tests, together with divided attention, supraspan learning, lexical and semantic tests, are among those performed worst by mid-late stage AD patients. The inter-test reliability in the

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same patient is not very high, thus suggesting that the AD patient has a variably impaired access to single abstract procedures possibly featuring in an intelligence performance, and that, in time, a rising number of these routines gets definitively disrupted. Given the long survival of well rehearsed procedures (e.g. those related to a profession, or to a favourite game), there is scarce ecological evidence of an impairment of abstract routines unless a particular patient consistently falls short in some outstandingly creative intellectual activity (e.g., that of a novel writer, a negotiator, a “professional” thief, and so on). Intelligence testing in AD, both verbal and nonverbal, ranges from the classical Kleistian judgements on differences (e.g. a bush and a tree), proverbs, absurdities (e.g. the pope had two churches built; one where the skull of St. Paul as a young man was found, and the other where his skull as an old man was found), semantic grouping (e.g. does a spoon go with a plate or an axe?), to more formal standardised tests, such as Raven’s Progressive Matrices (see Nebes’s, 1992, critical remarks), Weigl’s Sorting Test, and Elithorn’s Visual Maze (age-, education-, sex-adjusted norms for the three tests in Spinnler & Tognoni, 1987) or the Milan version of the Hanoi Towers Tests (Allamano et al., 1987). We suspect that given the heterogeneity of the supposed structure of intelligence tests, it is very likely that inter-test dissociations among AD patients could emerge. In some studies, judging about intelligence decline from the guessed pre-morbid levels is one of the questions raised. NART (National Adult Reading Test; Nelson, & O’Connell, 1978) -based tests of pre-morbid intelligence estimation also appear to work well in severely deteriorated AD patients (MattMaddrey etal., 1996).

Psychiatric aspects The bulk of the characterisation of AD is neuropsychological, coupled with an essentially negative neurological examination; there are, nevertheless, some behavioural and even psychiatric traits. Since the formal separation of neurology and psychiatry, which occurred in Italy some 20 years ago, AD has been considered within the realm of the former, given the clear-cut

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encroachment on the nervous structure of the underlying degenerative process, and, more cogently, given the much closer link of clinical neuropsychology with neurology than with psychiatry. The awareness that something is going wrong with the mind, which is close to the feeling of being well on the road to dementia, is an almost invariable feature of the onset stages of the disease, which very often persists up to the mid stages. Moreover, many patients show some glimmer of awareness from time to time up to the end stages of the disease. It is important not to lose sight of the possibility that even in the case of pervasive amnesia, uncontrolled comments on the patient’s deterioration could exacerbate her/his vague awareness of having an incurable disease and thereby deepen depression. Depression deserves some comment. By and large, AD seems to be stalked by depression, even if the slowly increasing inertia (see later) exaggerates this impression. It is said that between one fifth and one third of all AD patients are deeply depressed, and that this aspect can be improved in an unpredicted number of them with nonanticholinergic anti-depressant drugs. Of psychiatric relevance are neurotic anxious and depressive traits in the initial stages of AD, often easily traceable back to the patient’s full awareness of mishandling everyday events signalling his or her declining cognitive functioning. In most cases, depression coincides with the onset of memory defects and word finding difficulties. In retrospect, depression sometimes appears to be part of the onset pattern, that is, to have arisen in a severe and not clearly reactive form months before the cognitive onset of AD. Moreover, among the suggested risk factors, depression is mentioned, as a relapsing psychiatric trait preceding the neuropsychological emergence of AD by years (Alexopolous et al., 1993; Cummings & Benson, 1992; Lishman, 1987). All in all, it appears to be good policy to assess senile patients with depression thoroughly from a neuropsychological perspective in order to rule out the suspicion of impending AD. This is particularly worth being recommended since depression per se can give rise to pseudodemential behaviours with a predominantly executive trait (Van Gorp et al., 1996): both depression and cognitive deficit are

pharmacologically reversible in patients who are not in the throes of a neurological dementia. Possibly connected with depression are ruminative thoughts. These occur frequently in AD patients from the mid stages on, and progressively inhibit other thoughts. Ruminative thoughts occur in absence of environmental demands, are repetitive, and most often of a hypochondriac nature. Many so-called verbal disorders are more appropriately traced back to frontal defects. Reference is made to verbal perseverations, deprived of any communicative aim, which are a frequent end-stage phenomenon. Moreover, AD patients often confabulate (i.e. produce false stories based on false memories). This occurs early in the course of AD as a consequence of lacunar retrieval of recently learned information in a “provoked” setting of assessment. Instead, “spontaneous” confabulations, sometimes involving wide-ranging contents, are a late stage and rather seldom occurrence, possibly linked to a prefrontal impairment of the “stop rules”. Some very strange prima facie perceptual disorders occur in the late stages of AD. Two examples are worth reporting, even if neither of them has been put to a cognitively modelled testing assessment. The former refers to some severely deteriorated AD patients’ inability to recognise themselves even in a full-length mirror (mirror imperception). They speak to the reflected image as if it were a person standing in front of them, sometimes bumping into the mirror itself, but in no case beginning to suspect that they are speaking to a reflection that is their own. The latter, namely Capgras syndrome, has already been described in focal hemisphere damaged patients and psychotics and also in a few AD patients. A late stage AD patient of ours (Lucchelli, Spinnler, & Zerbi, unpublished data) once summoned his wife (and succeeded in his wish) to accompany him to the police to report her disappearance: actually, the patient felt that the person with him was not his real wife, but another extremely similar person (same face, same voice, same clothes, same name, only a bit younger), who had been surreptitiously put in her place. The number of his bogus wives grew over the months, and the patient plainly stated that he, a cultured and upright old gentleman, was somewhat

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embarrassed by this increasing number of young women living in his house. In both of these superficially perceptual disorders, a severe disturbance in distinguishing the inner from the outer life is apparent. In both the mirror imperception patients and the serious gentleman with Capgras syndrome, patients were constantly confused and their instrumental defects were blurred by a severe dysexecutive syndrome, that is, an impairment of several aspects of the “control functions”. The appearance of steady confusion (i.e. chronic confusional state) may be taken as the conventional turning-point between mid- and late-stage AD deterioration. There are often long periods of transient confusional states (episodes of acute confusion, or delirium; see Chapter 25; Spinnler, 1985) usually triggered by completely unexpected external conditions, tiredness, acute, mostly febrile, diseases (such as urinary infections), metabolic imbalances, and so on. Confusion is the clinical syndrome of poor attentional functioning (Geschwind, 1982) and it points (Lipovski, 1985) to an organic brain disease or a psychiatric disorder (e.g. maniacal syndromes). In the first case it can tie in with a stuporous state, possibly ending in coma. Clouding of consciousness is part of the clinical syndrome, albeit it may be very mild and, most of all, in the acute syndrome (Chapter 25) fluctuating. Chronic confusion refers to a steady state of attentional insufficiency induced by permanent and irreversible cerebral damage such as that caused by the AD process. We agree with the speculation that given the attentional derangement hallmarking every kind of confusion, the essentials of the neuronal dysfunction underlying confusion are linked with the frontal lobes or the reciprocal frontoparietal roles (Mesulam et al., 1976; Mori & Yamadori, 1987). To underscore the involvement of the frontal lobes in AD, there is the frequent evidence in advanced stages of tonic grasping, groping, and imitation behaviour (Della Sala et al., 1994; De Renzi et al., 1996). The chronic confusional state of late-stage AD patients is characterised by relatively pure neuropsychological (even psychometric; Chedru & Geschwind, 1972) traits, all stemming from poor attentional functioning. Chronically confused AD patients (i)

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are almost systematically impaired on all tasks that require them to make explicit notions, calling for a continuous, largely automatic updating process (Cossa et al., 1995), such as their age, the time elapsed from a given point onwards (e.g. since entering the ward, since being under medical evaluation, since having left home, etc.), the date, day of the week, month, year, and so on. This means that AD patients have problems with most tasks tapping knowledge that has some autobiographical trait (time, space, family, personal identity cues, etc.) and particularly with those calling for continuous updating; (ii) moreover, they are impaired in every selective attention demanding task of even short-spanning vigilance and divided attention (Spinnler, 1991): in fact, they appear to be easily distracted (often with context-dependent features), and often lose the thread of their discourses and those of other people. Psychomotor excitement or apathetic acynesia, neurovegetative disorders, hallucinations and misperceptions, reduced arousal, great variability over minutes, hours, or days, are all traits of the acute syndrome but do not figure in the confusion of late-stage AD, or at least represent transient spells during the chronic syndrome. Frequent behavioural traits of confused AD patients can be traced back to a lack of any planning in their activities or thoughts. All in all, these features seem almost paradigmatic of the lack of functioning of Norman and Shallice’s (1980, 1987) upper level of the Supervisory Attentional System; (iii) there are many features of the confused AD patient which can be traced back to ongoing amnesia or poor lexical availability. Presently, it is a matter of opinion whether these specific deficits should be traced back to pure instrumental impairments or to attentional insufficiency emerging at the level of widespread derangement of cognitive functioning. Once arisen, steady confusion becomes a permanent worsening trait of that patient. Whereas progressive loss of empathy and flattening of affect (also labelled “emotional inertia”) is a common hallmark of late-stage AD patients, inappropriateness of affect, unconcerned and socially disturbing behaviour due to disinhibition, ritualistic traits, and eating and sex disorders (such as bulimia and high intake of sweet

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foods with progressive weight gain) are rather rare in AD patients. The same could not be said of patients with non-AD dementia of the frontal type (Galante, Muggia, Spinnler, & Zuffi, in press). An almost universal behavioural feature of motivational downregulation occurring in the late stages of AD patients is inertia, or as Luria (1966, 1970) more descriptively called it in frontal patients, “akinetic-abulic-apathetic” or “adynamic” syndrome, tracing it back, in the lines of Kleist’s (1934) “Antriebsmangel ”, to a widespread damage to the frontal lobes. It is nearly always accompanied by chronic confusion and increasingly laconic speech, identical to Kleist’s (1934) “Spontanstummeit”, or to Luria and Tsvetkova’s (1968) “dynamic aphasia”, traced back to the involvement of the supplementary motor area and/or the anterior cingular cortex (Damasio & van Hoesen,1980; Gelmers, 1983). Full-fledged mutism is a rather frequent end-stage characteristic of AD patients. Increasing social withdrawal and later on poor collaboration with the care-givers go on for years before the adynamic syndrome permanently rules the patient’s behaviour. Within the neuropsychological framework of AD, inertia is regarded as the most reliable indication of a functional deficit due to frontal degeneration. It covers aspects that per se would lead to the nosological suspicion of dementia of the frontal type if the neuropsychological longitudinal features were not recognised. Inertia is clinically hallmarked by its steady and slow progression from loss of social awareness and personal neglect up to the mute and immobile end-stage behaviour of almost all AD patients. Many inert AD patients present intermittently short spells of “utilisation behaviour” (for comparison see the herpetic frontal patient reported in detail by Brazzelli et al., 1994; Brazzelli & Spinnler, 1998). Stereotyped behaviour, that is, behavioural perseverations, is seldom observed in AD patients. Short-lasting aggressive outbursts are relatively frequent in end-stage AD patients; however, very rarely do they reach a steady belligerent state (akin to that sometimes occurring in psychotic patients). Even if inertia strongly contributes to the dull appearance of the patient and the suffering it induces in the relatives, it is after all

a paradoxically beneficial trait for the strict purpose of managing a severely deteriorated patient because of his or her total passivity. Pseudo-maniacal (uninhibited), also labelled “moriatic”, traits appear as short-lasting spells, with the AD patient usually spontaneously returning to his steady inertia. There is a wealth of very inconsistent behavioural traits of mid-end stage AD patients, whose features tie in with neither a definite psychiatric syndrome nor a reliable neuropsychological explanation. The most outstanding aspects are diachronic transposition o f dwelling (with surprisingly congruent misrecognitions of persons, places, and so on), misidentifications with TV, collectionism with edible and inedible things (often from litter), bulimia and hyperorality (with subcontinuous smoking and chewing activities) up to a complete bi-amigdaloid Kliiver and Bucy syndrome, Pick’s para-amnesic reduplications and Capgras ’ syndrome, dromomania (all-day impulse to walk out of doors), acatisia (more often, however, of pharmacological rather than AD origin), and handling o f stools. Hypochondriac predicaments are frequently reported in the mid-late stages of AD, and they often give rise to endless medical examinations supported as they are by the relatives’ hope that the complaints are the true origin of the patient’s disease, and may be cured. Not to be overlooked here are the psychotic symptoms that arise in about one third of mid-late stage AD patients and may be linked with the frontal encroachment of AD. A recent study of ours (Della Sala, Francescani, Muggia, & Spinnler, 1995) in a continuous series of 180 AD patients, revealed that 64 of them also had psychotic symptomatology: old age and overall severity of deterioration (assessed by MOD A) significantly increased the occurrence of psychotic traits (hallucinations, false beliefs, and misperceptions, in order of frequency), but their interaction was not significant. Other variables considered, such as education, length of illness, sex, and familial occurrence of AD, failed to reach significance. Psychotic symptomatology was not linked with premorbid psychiatric traits (usually absent in AD patients). Neuropsychological signs of a frontal involvement of the AD process were more frequently associated with “psychotic” AD patients. Most of these findings are in line with those

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of the literature (e.g., Friedland, 1993; Lopez, 1991). Finally, worth considering here is the diagnostic issue raised by psychotic symptoms in the elderly without a previous history of schizophrenia. Kraepelin (1909-1913) was the first to call attention to the sudden psychotic (essentially visual hallucinations) outbursts in the previously nonpsychotic elderly. Roth (1987) revisited the issue of “late paraphrenias”, or more precisely, of those symptomatologies that cannot be traced back to metabolic, traumatic, neoplastic, vascular, or infectious accidents of the brain, and that arise in apparently normal and nondemented elderly subjects. Whereas one could argue that an essentially florid “frontal” picture hallmarked by well organised hallucinations, often with some confusion and confabulation, and an overactive behaviour might be a questionable onset of non-AD frontal dementia, such a hypothesis fails to account for the rapid disappearance of the entire paraphrenic picture with low dosages of neuroleptic drugs. In our experience, in the months or years that followed, none of the few patients with this picture presented any signs or symptoms to suspect the insidious onset of cognitive deterioration either of the AD or the non-AD type.

TENTATIVE GENERAL UNDERSTANDING OF AD Going beyond the correlative efforts undertaken in this chapter, one has to acknowledge that AD still lacks an agreed model by which the multifarious aspects of the progressive cognitive decline can be understood. One of the many backlashes of this state of affairs is the want of a comprehensive organisation of cognitive research on AD and, as a consequence, the predominant piecemeal production of papers. The first to try to shed light on dementia was Alois Alzheimer when he surmised that in all stages of the evolving disease, the degree of neuronal degeneration paralleled the degree to which the patient proves behaviourally to be demented. The question of interest to present-day researchers is

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whether there is a neurobiological determinant of a proportional coping impairment. There is widespread agreement that the cognitive insufficiency in AD is attributable to the upshot of a reduced interview among neurones of the ammonic and associative areas of both hemispheres (Collerton, 1986; Morris, 1996; Morrison et al., 1986). However, this quasi-metaphoric tenet has yet to be demonstrated. There are rather unimpressive empirical findings, and accordingly poor agreement, on what more accurately on the neurobiological side portrays the critical determinant(s) and what on the neuropsychological side is (are) the basic disorder(s). In order to gain insight into the first issue, tangles, plaques, the numerical drop in the neurones of the external layers of the associative cortices, the overall degree of supratentorial atrophy, cholinergic (and extracholinergic) neurotransmitter reductions have all been taken into account with disappointing or even inconsistent correlative results, that is, with scanty reciprocal predictive power. At present it appears that the reduction in the number of synapses predicts the degree of cognitive incompetence of the living patient better than other variables (Arrigada et al., 1992). Indeed, the correlation value between loss of synapses and MMSE reaches .73 (Terry et al., 1991). After all, this seems a reasonable finding in light of the interview tenet. On the psychological side, the once-believed best descriptors of cognitive incompetence are thought to be general (i.e. composite) scores of everyday coping abilities or of neuropsychological performances or, more often, of a mixture of the two (e.g. MMSE, MODA, ADAS, etc). In a screening and rate-of-change perspective on groups of AD patients, general tools are likely to provide useful information. In our experience, however, these general scores lack the sensitivity to predict the degree of impairment in single abilities (e.g. face processing, Della Sala et al., 1995, or apraxia, unpublished findings) and, most of all, in single patients. Such negative empirical evidence clearly cautions against regarding “global” cognitive (or coping) measures as good descriptors of the degree of overall deterioration of a given patient, and hence able to match a comparably satisfactory descriptor on the neurobiological side. The even greater than

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expected heterogeneity in the mixture of cognitive spared/impaired abilities across AD patients may help to clarify the poor predictive power of global scores with respect to isolated test performances. Taking this evidence in its utmost sense means that, outside the socially and geriatrically relevant behavioural evaluations, the neuropsychological concept of “overall deterioration” is a conceptual misnomer. It would be more realistic to go back to Pick’s general views, that is, of dementia as an assemblage of isolated neuropsychological defects which changes across patients because of the presently unpredictable, different topographical courses taken by the spreading of the degenerative process. In our view, the latter conclusion is the most realistic. The issue of heterogeneity across patients both in the cognitive profile and in the speed and quality of its longitudinal modification goes back a long way. Alzheimer (1907) conceived the “eigenartige Erkrankung der Hirnrinde” (“the very special disease of the cerebral cortex”), which Kraepelin (1909-1913) later named “Alzheimer’s Disease”, as a diffuse involvement of all neurones (at least, of all those not devoted to elementary neurological functions). At the same time, he conceived the behavioural output of the brain as a matter of the holistic interplay of almost all neurones. Thereafter, a proportional relationship between degenerated neurones and cognitive coping ability became a rational prediction. Pick (1906), who was more deeply rooted in detailed clinical observation than Alzheimer, forwarded, as already mentioned, another view: he interpreted dementia as an advanced stage of a progression that assembled “focal” defects, such as amnesia, aphasia, apraxia, agnosia and so forth. Each defect was the consequence of nondiffuse, topographically targeted hotbeds of degeneration (“cortical processors” in Luria’s, 1966, or “modules” in Fodor’s, 1983, terms) gradually drifting over time from one already degenerated cortical site to the attack of another. The general interpretation of AD we presently favour is surely Pick’s which also offers a plausible account of non-AD dementias. It accounts for the rather unsuccessful correlative enterprises because, on the neurobiological side, they failed to consider the relevant topographical

distribution over the associative areas of, for instance, the synaptic impoverishment. On the neuropsychological side, by resorting to poorly transparent general scores of deterioration, the correlative efforts have failed to take stock of the single patient’s cognitive peculiarities, the corresponding measures being possibly the only ones to match the synaptic impoverishment of a specific associative locus in the cortex. In the near future, it is possible that functional imaging of the brain (particularly functional MRI studies) will substantially add to the topographically constrained neurobiological correlates of single neuropsychological performances. There is, however, a subtle uncertainty behind all activation studies (SPECT, PET, and functional MRI): to what extent does a function need the measured biological resources (blood flow, glucose or oxygen metabolism, or even transmitter-availability) to produce a given performance? The neurobiological significance of double dissociations, which are one of the deadlocks of neuropsychological speculation (Shallice,1988), might be blurred by the disproportionate demands made on resources to fulfil different tasks. Such a state of affairs would greatly confound the interpretation of neuropsychological dissociations even in the light of topographical measures of employed resources during test activity. The contrast between the Alzheimer and Pick views were again highlighted by modern approaches. Close to Alzheimer’s views, the socalled “stage model” of AD predicts a homogeneous decay across all cognitive domains (e.g. Cummings & Benson, 1992). The interpatient psychometric (and also behavioural) discrepancies are claimed to be related to discrepancies in the stage of evolution of the patients making up the considered sample, the evolution perse progressing according to a rather fixed timetable (Reisberg et al., 1982) with, at least, a slight unpredictable interpatient variability of the tempo of progression. Such a view underlies the many staging and progression rating enterprises undertaken in order to group AD patients into classes of progression believed to be fairly homogeneous from a psychometric and ecological perspective of impairment. They are still credited by methodology leaders, such as the Food

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and Drug Administration of the US, with reference to pharmacological trials of new anti-AD drugs. There is, however, a growing dissatisfaction with the “stage model(s)” of AD in as much as they poorly accommodate findings on psychometric profiles in AD patients, particularly when less “typical” AD patients are also taken into consideration. There are risks of including as well as of excluding such, unfortunately frequent, possible/probable AD patients in experimental settings aiming at providing conclusions inferential from the studied sample to the population of AD patients. In line with Martin et al.’s (1986), Capitani et al.’s (1986), and Capitani et al.’s (1990) findings, extraneuropsychological support to the subgroupmodel is lent by CT and MRI morphological and by PET and SPECT functional data. A three-subgroup clustering pattern resulted, with the majority of patients falling within a globally deteriorated subgroup, the remaining patients forming a predominantly semantically and a predominantly visuo-spatially involved cluster. Content-specific (i.e. hemisphere-specific) anterograde memory defects failed to differentiate the latter two subgroups. The “subgroup model” appears to lend strong support to general conceptualisations of AD’s progression. All in all, there is now converging evidence that the spreading routes taken by the degenerative process after the initially limbic, bilateral encroachment vary across AD patients along the left/right dicotomy of the retro-rolandic associative cortices. Such discrepancies of the instrumental functioning, more frequently on default of the left hemisphere (Capitani et al., 1990), give rise to the anomic, apraxic or, alternatively, the visuo-perceptual, spatial subgroups, amnesic defects being present in both. The later involvement of the prefrontal and cingulo-anterior cortices progressively reduces the evidence of a left/right clustering of patients, as it entails a reduced availability of control resources (see heading on “attention”). However, the variables that determine the topographical features taken by the spreading course of the degenerative process in the single patient remain totally obscure. It seems likely that the stage and the subgroup models can be reciprocally integrated within the correlative frame purported in this chapter (Table 31.1): this, in fact,

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ought to be viewed as a compromise between the two models of AD evolution. Other tentative models developed within a predominantly cognitive framework and with a poor correlative counterpart, can be used to gain a basic understanding of cognitive incompetence in AD. Two general views can be envisaged. One assumes that theprimum movens of the progressive degradation of cognitive competence in AD lies in the attentional strain. This all-encompassing view does not conflict with postero-anterior spreading of the AD process. It simply states that ecological and psychometrical evidence of memory and instrumental defects (and later on, confusion) is essentially the inability of attention to compensate for the ever more awkward working of the retrorolandic machinery. The attentional interpretation of AD’s neuropsychology is close to a similar view of the changes in cognitive competence induced by normal ageing. There is another general psychological view, which, at first glance, is radically different from the attentional one. This view hinges on the speculation that the primum movens in the cognitive incompetence in AD patients is tantamount to semantic amnesia or, more generally, of the patient’s impaired capacity to retrieve information from remote memory. Specifically, the AD patient gradually loses more and more elements of the lexicon, knowledge of words, encyclopedic knowledge, and sophisticated abstract procedures, as well as the ability to learn them again. In King Lear’s sense of progressive impoverishment, this condition leads to total lack of knowledge. Essentially, the demented state is held to result from the radical progression of amnesia. If we dwell on more semantic aspects of general knowledge, everyday cognitive incompetence appears to result from the patient’s inability whenever he or she has to grasp the meanings and associations of words, scenes, and situations. An important point here is that one of the attentionally most demanding activities is the recollection of specific pieces of knowledge from remote memory in order to adapt immediately to the environment. This view is more closely linked with a clear-cut abnormal condition of the working brain that does not have a milder counterpart in healthy elderly subjects. It is possible to recognise a vague

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link between the attentional and mnestic model in the intricate reciprocal connection between attentional and knowledge systems (Margolin et al., 1996).

DIAGNOSIS, CONTACT WITH RELATIVES, AND ETHICAL ISSUES Although the issues touched on under this heading have little to do with neuropsychology, they are of utmost professional interest for the clinical neuropsychologist.

Diagnosis The diagnosis of AD on the basis of consistent formal and informal evidence must remain a clinical matter pertaining to the neurologist. As mentioned in Chapter 30, the diagnosis ought to be formally expressed under two separate headings, one regarding the presence of progressive cognitive deterioration and the other identifying the disease likely to be responsible for it (in the present case, AD). Every diagnostic uncertainty should be clearly expressed. A frequent matter of uncertainty concerns the extension of the neuropsychological assessments: provided that the patient is compliant enough to consent to carry out psychometric tests exploring the many items set out in Table 31.1, does a reliable diagnostic statement of cognitive normality or progressive deterioration need to be bolstered by an extensive analytical evaluation of performances? Over the years, we have gradually cut down on the number of psychometric evaluations, but at the same time enhancing the space and role of a meticulous collection of facts attesting to the multifaceted (Table 31.1) ecological coping difficulties (i.e. a retrospective, neuropsychologically oriented, longitudinal study). In most typical early stage AD patients, the diagnostic workups of the last four years of activity have included only one formal overall score (e.g. finding out where the age-, and education-adjusted score falls with respect to the healthy norms on MOD A). The rather infrequent divergence between MODA and history of everyday cognitive coping strongly calls

for undertaking careful, detailed biological and psychometric assessments, as a diagnostic statement is, in these cases, far from being easily ascertained. The nosological diagnosis of AD is formally expressed by the exclusion of other diseases that could have given rise to cognitive deterioration. Nontypical cases of deterioration (perhaps suggesting a cortical non-AD degenerative dementia; see Chapter 32) or cases with suspected slowly progressive circumscribed cognitive deterioration (see Chapter 33) call for an extensive (that is, analytical and longitudinal) psychometrical evaluation. Similarly, patients inducing the suspicion of impending dementia, who are elderly and poorly educated, or young and highly educated, need a particularly careful neuropsychological evaluation with tests reliably standardised for age and education (e.g. Spinnler & Tognoni, 1987) in order to avoid, respectively, the risk of “false positive” or “false negative” diagnoses. Conclusive diagnoses in the earliest stages of suspected AD call for the repetition of the whole assessment after 6-12 months. In our opinion, a 6 - 12-month follow-up assessment of a behavioural and psychometric worsening that yields congruent findings with the predictions set out in Table 31.1, supports the early diagnosis of probable AD most reliably.

Relatives An intrinsic part of the duties of the neurologist who signs the positive diagnostic statements of dementia and AD is to explain to the relatives in comprehensible and unambiguous words that the patient and his or her family are about to begin a period of many years (presumably at least 10, from onset), which will be hallmarked by the patient’s cognitive and behavioural decline. It has to be made clear that at the present time there is no way to reverse or halt this course, and that trials with new, rationally oriented, drugs are in progress, whose predicted virtue, however, is, at best, to slow down the rate of progression of the disease, not to cure it. Moreover, there are drugs whose efficacy is supported by evidence from conditions other than AD (e.g. psychoses, epilepsy), which play a role in the treatment of the AD patient, that is, in making him or her more manageable in the family setting. In the latter case, it should, however, be made clear

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that these drugs are not meant to slow down the AD progression. Sometimes they appear to worsen the cognitive competence of the late-stage AD patient. More generally, one has to take the policy of curtailing any hope of miracles, and to encourage the relatives to face the day-by-day care of their patient as rationally as possible (e.g. by joining ADAssociations). The neurologist has to open the patient’s and relatives’ eyes to the complete inefficacy of the still numerous drugs sold with the all-embracing claim to “help people with an outstandingly severe brain ageing” (review in Nordberg & Winblad, 1990). Relatives must be told that there are useful measures to take: for instance, as long as the patient is able to go out for a walk alone he or she needs to be equipped with personal documents and phone numbers of friends and relatives, so making it easier for the police to bring the patient back if necessary. It is also important to explain to the relatives that any changes in surroundings (even in the house or in the patient’s bedroom) are potential causes of long-lasting confusion, and so on. Tasks of instruction such as those just exemplified, are best fulfilled by the Associations for AD. The general suggestion is to organise the patient’s day according to standard sets of fixed habits so as to take full advantage of the relatively long-spared retrograde procedural memory. The recommendation that the patient be cared for in the family setting should be made in accordance with the limits posed by the interaction between the family’s characteristics and the increasing amounts of assistance required by the patient. However, a time comes when the neurologist has to reverse his or her initial policy and suggest the definite institutionalisation in a nursing home. In principle, this decision is legitimate when the patient is constantly and severely confused (sometimes with varying degrees of psychotic agitation), with permanent loss of personal identity, without any apparent verbal or nonverbal congruent interaction with care-givers, family members, or the surrounding world. More pragmatically, institutionalisation in a nursing home is decided when the burden (even if only emotional) of caring for a severely confused AD patient is too great for the family. There are of course other ways

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of institutionalising AD patients far before the end-stages: for instance, in private clinics (with or without public financial assistance) where possibly well trained staff take care of the patient, relieving the family of the burden. Such clinics often provide what without any understatement they currently call “AD rehabilitation” programmes, which are entirely symptom-driven. Our inexperience in this field does not allow us to support our almost total scepticism about such enterprises. Of course, this is not to deny that some entertainment to break the monotony of days spent in a nursing home is better than merely leaving the empty hours to tick by.

Ethical issues There are a number of ethical issues, which to a great extent are common to all nosologies of dementia. Two of them will be considered in brief. (i) If the diagnosis of AD is made when the patient is in the early stages of the disease, should he or she be told? In our opinion there are good reasons for doing so. From the clinical onset (at least in typical cases of AD) there is a respite of years (at least two or three, but possibly more for less difficult decisions) during which knowing that there remain a few years of fairly efficient coping and freedom might have some bearing on strictly personal decisions, some of great importance (e.g. making a will, organising social and private life, including entering a clinic, and so on) up to the decision to leave advance directives (the so-called “living will”), or to update them, or to put a, perhaps assisted, end to one’s own life. Moreover, entering a rational clinical trial (of course with the 50% risk of being assigned to the placebo arm of the experiment) in search of a therapeutic aid as well as a better general and future understanding of AD is a decision far better taken by the patient than by his or her relatives. (ii) If the patient is in the throes of AD in its very late stages with neither verbal nor nonverbal contact with the care-givers, and has entirely lost his or her self-identity, irrespective of whether he or she is institutionalised in a nursing home or in the family setting, what is the policy of the general practitioner (or the neurologist) if confronted by a contingent, immediately life-threatening condition (e.g. surgical relief of tumoral complications or of an

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aneurysm, myocardial infarct, broncopneumonia, and so on)? Is this a case for suggesting euthanasia, akin to that more or less explicitly and aggressively expressed by the laws of some countries (e.g. the Netherlands; Nowak, 1992; Van der Maas et al., 1991). In Italy, there is still great uncertainty about this issue and, accordingly, a noticeable absence of official guidelines. There is even a blatant avoidance of public debate. Setting aside the neuropsychological description, as a concluding remark to the neuropsychologists involved in the diagnosis of AD and to the medical and nonmedical care-givers dealing with AD patients, it seems appropriate to quote Lucianus of Samosata. In about 175 b c , he surmised that “the human existence is prone to two utmost powerful feelings, hope and fear, both of them capable of quickly enriching everyone who is sly enough to catch the right moment to contemplate them. Both for the hopeful and the fearful man, the forecast of the future outcome is a vital request.” Religious faith is often given credit for providing a bridge between wretchedness of the present (e.g. of AD) and a better future. The predominant Catholic feelings in Italy seem to generate great faith in the miraculous. Unfortunately, AD is one of the incurable (malignant) diseases, that is, the biological conditions that allow fairly precise and individualised predictions and datings of the forthcoming worsening quality of survival, and even death. The only realistic miracle is that the

diagnosis is wrong. AD is radically different from healthy conditions, which allow only statistically warranted predictions of survival, and say very little about its quality. In our opinion, the rational approach of the physician or the psychologist dealing with patients suffering from incurable diseases with long rates of survival such as AD, is to make every effort to ensure that patients and relatives dismiss any hope and, as far as possible, fear, and face the AD phenomenology, making purely pragmatic day-to-day efforts to reach the most bearable compromise.

ACKNOWLEDGEMENTS I am indebted to Margherita Alberoni, Sergio Bressi, Andrea Francescani, Valentina Gentileschi, Alessandro Lunghi, Laura Manzoni, Silvia Muggia, Carla Stangalino, Sarah Sperber, and Marta Zuffi who in different years were the research fellows who tackled the neuropsychological features of AD patients. It is on this body of information that the essentials of this chapter are based. The critical suggestions of Ugo Lucca and Federica Lucchelli on this entirely new edition of the corresponding chapter of the Manuale di Neuropsicologia (1996), Bologna: Zanichelli, are acknowledged. I am also greatly indebted to Gillian Jarvis for her careful revision of the English text.

32 Non-Alzheimer Dementias François Boiler and Silvia Muggia

only one-third of the total cases of dementia are due to non-AD pathology (Cummings & Benson, 1992). This chapter deals with the main etiological categories of non-AD pathologies, specifically degenerative dementias, dementias associated with extrapyramidal conditions, vascular dementias, and dementias due to transmissible agents. We will also discuss briefly pathologies often associated with cognitive changes such as normal pressure hydrocephalus, multiple sclerosis, metabolic and nutritional deficiencies, as well as some psychiatric conditions and other causes of acute or chronic cerebral involvement. With the exception of focal pathologies, most non-AD dementias are characterised by what has become to be known as subcortical dementia or dysexecutive syndrome (see the chapter by Spinnler & Della Sala in this volume). The essential features of fronto-subcortical syndromes are psychomotor slowing, memory deficits, disorders of affect and behaviour, together with a relative preservation of “instrumental” functions such as language and praxic abilities. In many cases, clinical examination of cognitive functions is not sufficient for a clear distinction between these syndromes and AD because they are not sufficiently specific (Whitehouse 1986). They must therefore be completed by clinical and neurological data. This is

INTRODUCTION In recent years, Alzheimer’s disease has become a “household” word and in many people’s minds has become synonymous with dementia. In reality of course, even though AD is the most frequent dementia syndrome, it is by no means the only one. The symptoms of dementia or pseudodementia may be related to a large number of processes including degenerative, vascular, infectious, and metabolic pathologies. In addition, Alzheimer pathology in the elderly often coexists with other pathologies, especially cerebrovascular disease. These pathologies can sometimes be prevented, or are potentially treatable and reversible. This explains in part why non-Alzheimer dementias have fostered a considerable amount of interest in the last decade, leading to considerable advances in understanding their pathology and in improving their classification, diagnosis, and therapy. The prevalence and the incidence of nonAlzheimer dementias vary according to the type of populations that are selected. For instance, in hospital-based series, (Tatemichi et al., 1994) AD represents a little over one half of the diagnoses of dementia. Other population studies suggest that 747

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the reason why the present chapter will include more clinical data than could be expected in a Textbook of Neuropsychology.

DEGENERATIVE DEMENTIAS The Manchester group (Neary et al., 1986) was one of the first in “modern” times to repropose the notion that localised cerebral atrophy associated with cognitive disorders may be distinguished from the classical picture of AD. Since these first descriptions, much has been written on this topic. It is now clear that degenerative processes involving limited portions of the nervous system may give rise to a series of heterogeneous clinical pictures of dementia. Non-Alzheimer Degenerative Dementias (NADDs) represent a sizeable proportion of the dementing diseases. Even though the diagnosis of each form of NADD is made rather uncommonly, they probably represent altogether about one-fourth of all non-vascular dementias (Knopman, 1993). It is now clear that NADDs differ from AD not only in terms of their clinical expression and neuropathology, but also in terms of genetics and perhaps even of therapeutic responses (Dalla Barba & Boiler, 1994). All NADDs, just like AD, tend to have an insidious onset and a chronic and progressive course. Unlike AD, however, neurological examination may show objective signs even in the early phases of the disease. This is particularly true when the pathology involves subcortical areas such as the striatal system (with resulting extrapyramidal signs) or structures located in the brainstem. Neuropsychological manifestations of NADD patients vary according to the different clinical syndromes, but many NADDs show, soon after onset, a pre-frontal type behavioural syndrome (Mayeux et al., 1983), often associated to bradyphrenia, personality change, vague memory impairments (Dubois et al., 1991; Rafal et al., 1984; Rogers, 1986). This is because in most cases, at least initially, the degenerative process does not affect the associative retro-rolandic areas, but rather the subcortical structures such as the basal ganglia and brainstem, sometimes in association with the

pre-frontal areas. As the disease progresses toward a more “global” decline of cognitive functions, the distinctions between AD and the NADDs may become blurred and finally disappear. In some cases, however, the behavioural disturbances represent the dominant feature from the onset of the disease to the death of the patient. Despite the connectivity between cortical and subcortical structures, the patterns of cognitive and behavioural impairment in the NADD can be distinguished from those typical of AD, and the distinction between cortical and subcortical features remains the main guide to the work-up and differential diagnosis in terms of clinical neuropsychology (Darvesh & Freedman, 1996; Muggia & Spinnler, 1993). We will now discuss in more detail some of the clinical NADD entities.

Frontotemporal dementia (FTD) Frontotemporal dementia is a clinical definition, recently adopted (see Neary & Snowden, 1996; Pasquier et al., 1996 for a review) to indicate the behavioural and cognitive progressive disorders associated to the degeneration of the frontal and anterior temporal lobes. In the majority of cases FTD affects the presenium, and seems to constitute the second cause of primary dementia, in a 1 to 6 ratio with AD (Amouyel & Richard, 1996). The differential diagnosis is still not an easy one, as the features distinctive of FTD have been agreed upon only in the last few years. Prominent personality changes, alterations in affect, cognition, and social conduct hallmark the syndrome of FTD and may help the clinician to differentiate it from AD. Neuropsychological testing, accurate history taking, and clinical assessment usually reveal the features of frontal or temporal lobe dysfunction. A consensus conference (The Lund and Manchester Groups, 1994) has proposed a series of criteria for the clinical and neuropathological diagnosis of FTD. The clinical criteria are summarized in Table 32.1. Two major histological pathologies underlie the syndrome: Pick’s disease, which is rare, and Frontal Lobe Degeneration of non-Alzheimer type (FLD), which is the most common etiology of FTD. In some cases spinal motor neurone degeneration may

32.

be associated to FTD and give rise to the symptoms of the amyotrophic form of motor neurone disease in addition to the dementia syndrome. Neuroimaging studies of FTD patients show atrophy affecting predominantly the anterior temporal and frontal lobes (more evident on MRI). SPECT studies show a diminished blood flow ratio in the anterior cerebral hemispheres (see Scheltens & Van Swieten, 1996 for a review). As is the case in all neurodegenerative disorders, the clinical picture reflects the location of the anatomical damage more than its specific histological features—this implies that a precise nosological attribution of FTD to one or the other pathologies in vivo is arduous, if not impossible, to reach. The relationship between Pick’s disease, FLD, and other lobar atrophies that may give rise to FTDlike complexes remains a matter of debate because of the overlap of their clinical and pathological features: an “inventory” of these includes, in

NON-ALZHEIMER DEMENTIAS

addition to Pick’s disease and FLD, progressive aphasia, semantic dementia, and more (see Chapter 33 on progressive focal degenerations, by Della Sala & Spinnler, this volume). Moreover, a few conditions bear a clinical resemblance to FTD, such as PSP, Huntington’s disease, some of the MIDs with strategic infarcts or white matter destruction, particularly in the frontal lobes area, and even some psychiatric disorders involving affect and personality. Of course these all differ from a neuropathological point of view (Gustafson et al., 1992), but often much less in terms of behavioural and neuropsychological features. We address here the main features of the frontotemporal dementias through the description of the two major illnesses involved in the diagnosis. Pick's disease In 1892, Arnold Pick described the case of a 71year-old man with a severe language disorder and a selective atrophy of the left temporal lobe (Pick,

TABLE 32.1 Clinical criteria for frontotemporal dementia (From The Lund & Manchester Groups, 1994). B e h a v io u r a l d i s o r d e r

• • • • • • • • • •

insidious onset and slow progression early loss of personal awareness (neglect of personal hygiene and grooming) early loss of social awareness (lack of social tact and misdemeanours) early signs of disinhibition (unrestrained sexuality, violent behaviour, inappropriate jocularity) mental rigidity and inflexibility hyperorality (overeating, excessive smoking and drinking, oral exploration of objects) stereotyped and perseverative behaviour (wandering, mannerisms, ritualistic preoccupation) utilisation behaviour distractibility, impulsivity and impersistence early loss of insight

A f f e c tiv e s y m p to m s

• depression, anxiety, excessive sentimentality, suicidal ideation, delusion • hypochondriasis • emotional unconcern, indifference, remoteness, lack of empathy, apathy • amimia S p e e c h d is o r d e r s

• • • •

progressive reduction of speech (aspontaneity and economy of utterance) stereotypy of speech echolalia and perseveration late mutism

Spatial orientation and praxis preserved

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1892). It was, however, Alzheimer who later (1911) described the characteristic histological features such as the neuronal swelling (now known as Pick cells), the intracytoplasmatic argyrophilic inclusions (Pick bodies), and the astrocytosis. Until a few years ago, it used to be taught that Pick’s disease was the most common NADD and that it represented the main differential diagnosis of AD. Actually, Pick’s disease is quite rare. Its prevalence is estimated at between 30 to 60 cases per 100,000 in the general population (Constantinidis, et al., 1985). This must be compared to an incidence between 1 and 5 per thousand in AD (Spinnler, 1990). In his review of NADD, Knopman (1993) summarises some series where the prevalence of Pick’s disease is estimated to range from 0 to 5%. Most clinical studies, however, are based on small series of cases (Mendez et al., 1993), or on single cases (Graff-Radford et al., 1990; Holland et al., 1985). Familiar cases are known to occur, including a Dutch family with 25 diagnosed cases over six generations (initially reported by Sanders, 1939). The etiology of sporadic cases remains unknown. The age of onset, averaging about 60, is younger than in AD; the prevalence is slightly greater among males than females. The diagnosis rests on a triad consisting of focal neuropsychological deficits presenting in a context of dementia, focal cerebral atrophy affecting the temporal and/or frontal lobes, and the typical argyrophilic inclusions. Normally, only histology can confirm the diagnosis suspected clinically, with the characteristic intraneuronal Pick bodies, the large and swollen Pick cells, in addition to neuronal loss and astrocytosis (Lantos, 1992). Obviously, the pathological element of the triad is not available to the clinician. The neurological examination may show extrapyramidal signs in the early stages. In addition, later on, pyramidal signs become apparent, particularly when there is involvement of the frontal lobes (Tissot et al., 1985). The neuroradiological data are often unclear at the onset and become evident only in more advanced stages. Hence the difficulty of a clinical diagnosis which represents a considerable obstacle to prospective experimental studies. The main clinical entity that raises problems in terms of differential diagnosis with Pick’s disease

is the syndrome known as Frontal Lobe Dementia (for the neuropathologist “frontal lobe degeneration of non-Alzheimer type”, or FLD) discussed later. The main discriminating factor, although still quite debated, remains, post mortem, the presence or absence of an adequate number of Pick bodies and Pick cells. FLD cases show more frequently familial history of dementia (Gustafson, 1992; Neary et al., 1988). In clinical practice, the differential diagnosis between Pick’s disease and FLD is quite difficult and this diagnostic uncertainty has contributed to the frequent confluence of these two entities in clinical case series. Behavioural and neuropsychological data. The clinical picture of Pick’s disease varies according to the main localisation of the lesion; frontal, temporal or both. Even taking into account this rough distinction, the disease tends to remain very heterogeneous and typical characteristics are difficult to identify. This also applies to the neuropsychological profile which has been defined “evanescent” (Knopman et al., 1989). Mendez et al. (1993) have proposed a summary of the main differences between Pick’s disease and AD, based on the comparison between 21 cases of autopsyconfirmed cases of Pick compared to 42 matched AD cases from the University of Minnesota. All the Pick patients, but none of the AD, showed at least three of the following clinical features: • Presenile onset (< 65 years) • Early behavioural changes (bizarre behaviour, apathy, irritability, loss of trustworthiness etc.) • Hyperorality with mouth exploration and hyperphagia • Disinhibition (impulsivity, inappropriate social behaviour etc.) • Roaming behaviour or wandering. All of these (except for the first one, of course), bring to mind the typical clinical pictures of patients with frontal lobe lesions. In addition eight of the Pick patients (38%) had a clear-cut language disorder versus six (4%) of the AD patients. This difference was not statistically significant, but a qualitative analysis suggested that patients with Pick’s disease tended to show a decrease of verbal

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initiative and even mutism, linguistic reiterative phenomena (such as echolalia or stereotyped utterances) etc. On the other hand, Pick patients did not show major disorders of auditory comprehension or fluent verbal jargon, as often observed in AD. Review of the neuroradiological data showed that out of 16 patients who had had a CT scan, 7 showed lobar atrophy mainly affecting the frontal and temporal areas. None of the AD patients showed such finding. Detailed neuropsychological analysis of a patient followed longitudinally has been provided by Hodges and Gurd (1994): the patient showed a marked disorder of retrieval. The authors hypothesised an interruption of fronto-striatal circuits. As in other brain-damaged frontal patients, memory defects may be ascribed to poor recollection strategies and output monitoring, due to the impaired frontal executive abilities. Other reports suggest a fair degree of preservation of visuo-spatial abilities and calculation, again at odds with the usual findings in AD (Folstein et al., 1975). Early observations by Sjogren et al. (1952) indicated a relatively low incidence of agraphia, alexia, and apraxia, compared to AD patients. Left temporal lobe involvement is reported in patients showing anomic disturbances in fluent speech, rapidly followed by supramodal impairment of semantic knowledge, Such patients have been described as cases of semantic dementia in a few reports (Barbarotto et al., 1995; Hodges & Patterson, 1996; Snowden etal., 1989; Warrington, 1975). Pick’s disease may well be responsible for some cases of semantic dementia or fluent progressive aphasia (see also Della Sala & Spinnler’s chapter on focal degenerative disorders, this volume). It is likely that the rare occurrence of progressive fluent aphasia and semantic dementia, coupled with their more specific neuropsychological features and the frequent appearance of frontal symptoms at follow-up, have been keeping the temporal syndrome from being described and considered as much as is frontal dementia in the clinical literature addressing Pick’s disease. The nosology of NADD has changed considerably in recent years because of the description of some clinico-pathological entities

NON-ALZHEIMER DEMENTIAS

751

characterised by focal atrophy, with or without the presence of other diagnostic features suggestive of Pick’s disease. This applies particularly to primary progressive aphasia, discussed by Della Sala and Spinnler in another chapter of this volume, to semantic dementia, to corticobasal degeneration, and to frontal lobe degeneration. In summary, considering Pick’s disease’s unknown etiology and the great variability of its clinical expression, it appears more reasonable for the clinician to describe it as a “lobar atrophy syndrome” while waiting for more specific nosographic criteria. Frontal Lobe Degeneration o f non-Alzheimer type (FLD) This entity, which is often considered the second most frequent primary degenerative dementia after AD (Gustafson et al., 1992) was described for the first time in southern Sweden in 1987, in a study that included clinical as well as cerebral blood flow data (Brun, 1987). In agreement with the Swedish data, Neary et al. (1988) have described under the name “Frontal Lobe Type Dementia” a syndrome characterised by early and rapidly progressive changes of personality, inappropriate or disinhibited behaviour, loss of self-evaluation, and progressive language deterioration. Family history of dementia was frequent and blood flow studies showed frontal hypometabolism. Many of the cases described by Knopman et al. (1990) under the name of “dementia lacking distinctive histology” (DLDH) showed behavioural and language changes similar to those described in FLD. It is not easy to estimate the real prevalence of FLD among degenerative dementias. Neary (1990) suggests that they account for about 20% of these conditions. The onset of FLD is typically presenile and affects more males than females. In almost half the cases, familial history is positive for similar dementia syndromes. What is the neuropathology of FLD? One finds in all cases cerebral atrophy, cortical and, to some extent, subcortical gliosis, especially at the frontal and anterior temporal level, with matching neuroradiological and blood flow data. One notices the typical absence, except in some older subjects, of involvement of the insula, anterior cingulate, and of the anterior part of the temporal lobes. Senile

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plaques, neurofibrillary tangles, Pick cells and inclusion bodies are also typically absent (Brun, 1987). Despite a strong suggestion of a genetic component, the etiology of FLD remains unknown (Gustafson et al., 1992). Later in the course of the disease neurological signs such as primitive reflexes and extrapyramidal signs such as akinesia, rigidity, and tremor may emerge. One can also find urinary incontinence, and unstable blood pressure. Laboratory tests often show a normal EEG. In contrast, in “typical” AD, after the appearance of clear-cut dementia, the EEG is often abnormal. Behavioural and neuropsychological data. Here again, the clinical features of FLD patients reflect the location of the lesions. In most cases, there are marked personality and behavioural changes and a progressive language disorder resembling Luria’s dynamic aphasia (see Chapter 7 by Gainotti, this volume), while memory and spatial functions tend to be relatively spared. Because of the importance of behavioural changes among the earliest symptoms, the patients or, more often, their families, seek medical advice because of improper conduct, car accidents, or alcohol abuse. One almost always finds nonspecific emotional changes which are often difficult to interpret. There may be emotional incontinence, tendency to inappropriate joking (Witzelsucht), and emotional flattening. Not uncommonly one observes marked inertia and apathy, or belligerent or aggressive behaviour which may be extravagant and difficult to control. Because of this clinical picture, these patients are often referred to psychiatrists. Not uncommonly the initial diagnosis is that of mood disturbances, schizophrenic reaction and so on. Neuropsychological tests are useful in the early stages of FLD, also because they provide the opportunity of observing patients in a more constrained setting. Obviously the behavioural changes represent a challenge for the examiner. FLD patients are usually quite well oriented in space, though their wandering drive and bizarre “trips” may be interpreted as spatial disorientation. Less well preserved time orientation is reported. Linguistic functions are often difficult to evaluate

in view of the logorrhea, echolalia, verbal stereotypes or, more often, the reduction of spontaneous speech. Comprehension remains in general well preserved, at least for words and simple sentences. Although free from typical aphasie errors, speech becomes impoverished early and invariably progresses to mutism. Examination will almost always reveal disorders of executive functions, with defective sustained and divided attention performances, poor set shifting, pathological distractibility, perseveration, and difficulties in output monitoring and control. If memory failures emerge, they are variable and inconsistent and they are usually ascribed to the frontal impairment: attentional, monitoring, and retrieval strategy disturbances, more than primary retention deficits, are responsible for the bad performances. A clear benefit from cueing procedures and multiple choice alternatives in recall tasks contrasts with Alzheimer’s patients’ performance (Neary & Snowden, 1996). Calculation disorders may be present even in the early stages. A comparison of FLD with AD patients shows in the former greater deficits in the language tests while visuo-spatial and praxic functions are relatively spared (Elfgren et al., 1991). A tendency to mouth inedible objects may be observed, and it is not always clear whether recognition and semantic knowledge defects participate in the inappropriate choice and use of objects.

Diffuse Lewy Body Disease (DLBD) Of all the NADDs, this is the most similar to AD, to the extent that the two conditions are often clinically indistinguishable from one another. DLBD still represents a somehow controversial nosological entity. According to some authors, DLBD is a frequent cause of organic dementia. One autopsybased study by Hansen et al. (1990) indicates that among 36 patients with “dementia of Alzheimer type” (which exclude Parkinson-like features), 13 (36%) had neuropathological features consistent with DLBD. Another paper based on 150 unselected cases of dementia (Joachim et al., 1988) and another retrospective study of Lennox (1992) have presented similar data, suggesting that about 20% of patients with diagnosis of dementia could in fact have DLBD.

32.

A genetic component for Lewy body diseases seems likely and familial forms have been described (Golbe et al., 1990), but to this day, the etiology remains unknown. Recently Katzman et al. (1995) described the Lewy Body Variant (LBV) of Alzheimer’s Disease (in which Lewy bodies are observed at autopsy together with AD changes) as a specific form of dementia in which the cognitive deficits clearly precede extrapyramidal symptoms. The authors found that the apolipoprotein E4 allele is a significant genetic risk factor, as it is for AD. As no comparable risks have been demonstrated for DLBD or PD, this paper supports the hypothesis that LBV may be distinguished from DLBD and represent a phenotypic variant of AD. Because of the overlap of clinical and pathological features, some have suggested that PD and DLBD may represent the extremes of the same spectrum, which gives rise to PD if the pathology is confined to the brainstem and to dementia if it is diffuse; indeed, transitional expressions are possible (Kosaka et al., 1980, 1984; Yoshimura, 1983). On the other hand, there are also common characteristics between AD and PD (Alvord, 1971; Boiler, 1980): DLBD could therefore be part of that continuum as a new entity. Some data indicate that the disease is more frequent among males, just as happens for PD. The mean duration, around six years, is shorter than that usually encountered in both AD and PD, but comparable to that of PD patients with dementia (Boiler, 1980). The clinical features of DLBD include progressive dementia, often accompanied by major psychotic symptoms, depression, and fluctuating confusional states; moreover, extrapyramidal signs emerge in the course of the disease. The neuropathological findings which to this day define the disease (Kosaka, 1993) include the typical cytoplasmatic inclusions in the cortical neurones and in some subcortical and brainstem structures, with a specific distribution that belies the label of “diffuse Lewy body disease”. At the level of the locus coeruleus and substantia nigra where the Lewy bodies are always present, one also finds neuronal losses and gliosis. Altogether, the neuropathology of DLBD corresponds to that of Parkinson’s disease, but with a larger number of cortical Lewy bodies.

NON-ALZHEIMER DEMENTIAS

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In summary, clinical and neuropathological data have suggested in the past few years that the presence of Lewy bodies in the brain cortical layers may give rise to a dementia syndrome, as well as brainstem Lewy bodies are assumed to imply PD. Many cases with widespread Lewy bodies also have concomitant AD changes, but the increasing number of reported DLBD cases without significant AD changes warrants the hypothesis that they can be considered apart. Although the classification of Lewy bodies-correlated diseases is still controversial, it is worthwhile to describe the cases of dementia associated with Lewy bodies as they seem to constitute a significant proportion of dementia cases in the elderly (Filley, 1995). Behavioural and neuropsychological data The main clinical feature of DLBD is the progressive deterioration of cognitive functions. Presenting symptoms include difficulties with memory, disorders of attention, and difficulty maintaining thoughts in a logical order; impressive psychotic symptoms with structured hallucinations and complex paranoid delusions are often associated from onset. These are followed by deficits of the “instrumental” functions such as aphasia, apraxia, agnosia, acalculia, and visuospatial disorientation. Hence, the clinical picture of DLBD very much resembles that of AD, as pointed up previously, but with marked variability and presence of fluctuations with acute exacerbations, episodes of delirium, and partial remissions (Byrne et al., 1989; Perry et al., 1990). Some neuropsychological studies suggest a greater involvement of temporoparietal areas with worse performance at tests of visuoconstructive and visuospatial abilities as well as greater psychomotor and attentional disorder than in AD (Salmon et al., 1996). Tests commonly thought to be affected by impairment of prefrontal structures are also impaired (Hansen et al., 1990). Psychotic symptoms, which are found in about half the cases (Perry et al., 1990), sometimes mark the presenting picture, preceding other symptoms by many months ( Galasko et al., 1996; Hely et al., 1996; Kosaka & Mehraein, 1979). Progression of the disease is marked by a decrease of the fluctuations and episodes of delirium, while cognitive deficits

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become dominant, bringing total incompetence and need for total external assistance. Among the neurological signs, Parkinsonism (with marked preponderance of hypertonia) may precede or follow the dementia by several months or even years. This reflects the extension of the cerebral lesions in various regions of the cortex over time. Axial rigidity, limb tremor gait disorders, and postural anomalies are also described. Dysarthria and autonomic disorders can also occur. The extrapyramidal symptoms of DLBD are initially responsive to therapy, but dopaminergic and anticholinergic drugs have a reduced therapeutic margin in DLBD, because of marked vulnerability to side-effects such as hallucinations, delirium, and amnesia which force the clinician to abandon or use very parsimoniously these therapies. Neuroleptics, often prescribed to control psychotic symptoms, can cause severe worsening of motor signs. The extrapyramidal signs also raise the question of differential diagnosis between DLBD and other forms of dementias accompanied by similar signs (PSP, dementia pugilistica, Huntington and Wilson’s disease, etc.). This emphasises the need for a thorough clinical history and general physical examination. In terms of differential diagnosis with AD, Crystal et al. (1990) have described EEG changes which, albeit nonspecific, are present more frequently and more prominently than in AD. Table 32.2 summarises the most currently accepted clinical features of DLBD.

Corticobasal degeneration (CBD) This condition has been described in the past 20 years under various names such as dementia with swollen chromatolytic neurones and progressive apraxia. It represents a rare condition, characterised mainly by motor symptoms. Its pathology corresponds to frontal and parietal atrophy, associated with degeneration of the basal ganglia and other subcortical nuclei. Cortical and subcortical atrophy tend to be focal with localised swollen and achromatic neurones. These features bring to mind Pick’s disease, but in CBD, the typical argyrophilic inclusions (Pick bodies) are usually absent. In addition, the atrophy tends to be frontoparietal rather than frontotemporal. One cannot exclude, however, that Pick’s disease and CBD may represent two different expressions of the same pathological process (Jendroska et al., 1995; Lang et al., 1994; Rinne et al., 1994). Even though the clinical picture of rigidity, akinesia, involuntary movements, and apraxia with asymmetrical onset are relatively characteristic, the diagnosis of CBD remains difficult. Its etiology is unknown and there is no evidence of genetic factors (Thompson & Marsden, 1992). Both sexes are equally affected with a mean age of onset between 60 and 80 years; the average duration of the disease is 7 to 10 years. Neuroimaging techniques may demonstrate focal atrophy and frontoparietal asymmetries. Positron Emission Tomography (PET) has shown

TABLE 32.2 Clinical features of Diffuse Lewy Body Disease (adapted from Lennox, 1992). F e a tu re

Dementia Fluctuation Psychosis Depression Parkinsonism Myoclonus Other abnormal movements Pyramidal signs Other brainstem signs Autonomic failure

F req u en c y

100 >10 33 15 90 10 10 25 10 10

N otes

present by definition noted in 80% of cases in a recent report mainly visual hallucination and paranoid ideation includes rigidity (80), tremor (50), bradykinesia (40), gait disorder (50), and flexed posture (30) include dystonia, chorea and drug-induced dyskinesias usually occur late include dysphagia and supranuclear gaze palsy includes orthostatic hypotension

32. NON-ALZHEIMER DEMENTIAS

a pattern of asymmetrical hypometabolism involving frontal-medial and striatal areas (Riley et al., 1990; Sawle et al., 1991). These findings reflect the distribution of neuropathological lesions. Clinical and behavioural data These include, according to most descriptions (Rinne et al., 1994) motor disorders of frontal and extrapyramidal type, usually asymmetrical with clumsiness, apraxia, rigidity, involuntary movements, dystonia, dysarthria, and supranuclear disorders of ocular motion. The rigidity and akinesia of the limbs are progressive and fail to respond to dopaminergic therapy. Symptom onset is insidious and typically asymmetrical, with motor slowing and loss of dexterity involving the hand, the arm, or more rarely one lower limb, often complicated by involuntary movements. These signs lead to gestural apraxia, difficulty in initiating movements, and apraxia of gait with frequent falls. It is not uncommon to find a trunk apraxia with ensuing difficult and slow postural changes. Muscle tone is altered, with plastic hypertonus and opposition to passive movements (Gegenhalten). The affected limb may also present tremor and myoclonus, the tremor being irregular unlike that of Parkinson’s disease; the myoclonus is sensitive to cutaneous stimuli and to muscle stretching. Both contribute significantly to the difficulty experienced by the patient in the use of the affected limb. The disorder tends to extend to the contralateral limb usually within three to four years. Other signs include grasping, sucking, and an alien hand syndrome. This phenomenon, recently relabelled “anarchic hand” (Della Sala, Marchetti, & Spinnler 1994), was originally described in association with callosal tumors (Brion & Jedanyk, 1972) and consists of severe difficulty in hand control. Even though the limb is not paralysed, the hand fails to respond in the way expected by the patients and “acts on its own”, to the point of often interfering with the normal activity of the other hand. The progression of motor disorders and the worsening rigidity and postural and limb dystonia force the patient to bed within three to five years from onset.

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CBD may also be accompanied by supranuclear gaze paralysis with possible confusion with Progressive Supranuclear Palsy (PSP). As in PSP, the disorder is progressive, consisting essentially of difficulty in the voluntary initiation of saccades and pursuit movements, even though they are preserved as a reflex response. One also encounters gaze impersistence, slowing and incoordination of pursuit movements, and fixation spasms, leading to loss of voluntary eye movements. Later on, the patients exhibit progressive dysarthria and dysphagia, while linguistic abilities are generally preserved. There may also be a progressive loss of sensory functions affecting discriminatory sensations, pain and temperature, and later on, pain, suggesting thalamic involvement. In the early phases of the disease, cognitive functions are not clearly altered. Later on, however, there may be signs of hemispheric involvement which may be either asymmetrical (visuospatial disorders) or more generalised. Dementia in all cases appears to be milder than in AD. Cases of disorders of memory and language have also been reported (Lippaetal., 1990,1991)aswell as apraxia of the dominant hand. Recently Pillon et al. (1995) underlined the dysexecutive features characterising cognitive deficits showed by CBD patients (learning, control, and inhibition deficits) coupled with the more commonly described gesture disorders. Such features, resembling the subcorticofrontal syndrome, would help the clinician in distinguishing CBD from AD and other neurodegenerative disorders. The main differences between CBD and AD emerge in memory, significantly better and more sensitive to cued recall, and motor performance, significantly worse in CBD than in AD patients (Massman et al., 1996). As clumsiness, rigidity, and loss of dexterity are not sufficient to explain CBD patients’ disturbances in voluntary movement, praxic disturbances in CBD have been interpreted in terms of ideomotor apraxia, as the concepts of “what to do” remain much better preserved than the “how to do it” schemata. Moreover, limb gesture impairment appears to be more severe when initial symptoms are in the right arm or leg, in agreement with the dominant left location of the praxic functions (Massman et al., 1996; Pillon etal., 1995).

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In summary, there are areas of overlap between CBD and PD, PSP, pseudo-focal varieties of AD, and Pick’s disease. The general picture is dominated by neurological signs while the neuropsychological component (with the noticeable exception of apraxia) is only marginal.

DEMENTIAS ASSOCIATED WITH “EXTRAPYRAMIDAL” PATHOLOGY The most frequent pathologies of the extrapyramidal systems, all degenerative, often present an association with specific cognitive disorders or with full-blown dementia. There is marked clinical variability among these different pathologies, and even within them. The relationship between cognitive symptoms and degeneration of the nigro-striatal and mesolimbic subcortical systems and with possible additional cortical damage remains to be determined. We will discuss here the clinical picture of the most frequent syndromes, namely Parkinson’s disease, progressive supranuclear palsy, and Huntington’s disease.

Parkinson’s disease (PD) Idiopathic PD is characterised by tremor, bradykinesia, rigidity, and loss of normal postural reflexes. The neuropathology of PD is characterised by neuronal loss in the substantia nigra and other pigmented subcortical nuclei such as the locus coeruleus. Many surviving cells show characteristic inclusion known as Lewy bodies. The cellular loss is accompanied by reduced availability of dopamine in the substantia nigra, striate nuclei, and other structures. In the initial part of his original description of 1817, Parkinson emphatically stated that “the senses and intellect (are) uninjured”. Careful reading of the monograph shows, however that he was aware that some of the patients he described showed speech disturbances, depression, or a confusional state. We owe to Trousseau and Charcot the merit of having first noticed the presence of actual cognitive deterioration. Ball, psychiatrist at Sainte Anne, was probably the first to point out the

frequent psychiatric manifestations that accompany the disease (Ball, 1882). In the early 1960s, Pollock and Hornabrook initiated an epidemiological study of the frequency of dementia in PD (Pollock & Hornabrook, 1966). The literature suggests that the frequency and importance of cognitive disorders accompanying PD have increased markedly since the beginning of the 1970’s (Boiler, 1980), a period that coincides with the introduction and large scale use of L-Dopa and other dopaminergic drugs. The possible association of PD and AD was initially pointed out in 1979-1980 (Boiler et al., 1980; Hakim & Mathieson, 1979). DLBD, described earlier, may represent an intermediary condition between the two diseases and probably affects prevalence data concerning dementia in PD. It needs to be emphasised that many patients with PD, probably a majority, seem to remain cognitively unimpaired throughout the course of the disease, and that dementia is not a necessary consequence of Parkinson’s disease. Careful neuropsychological tests show, however, that even subjects without clinical evidence of deterioration show some deficits. It is therefore important to separate mental status changes of PD into several categories and clearly separate bradyphrenia and other specific cognitive changes from genuine “dementia”. Dementia Data concerning the incidence and prevalence of dementia in PD vary tremendously from one series to another. As stated earlier, there has been a distinct increase in reported percentages after 1970 (see Della Sala, 1990 for an extensive review of the literature). It is still unclear to what extent this increase is due to L-Dopa per se, or rather to better diagnostic methods, more awareness of the possibility of dementia, longer survival of the PD population, or some other unknown factor. The instruments more commonly used to diagnose dementia such as DSM-III or DSM-IV, or quantify it such as the MMS (Folstein et al., 1975) are not always easily applicable to PD patients. Leaving aside methodological problems, the majority of authors conclude that the risk of dementia in PD is significantly greater than would be expected in control subjects of comparable age. The patients at

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greater risk for developing dementia are those with more severe extrapyramidal symptoms and with depression, those of male gender, and those with later onset of the disease (beyond 70 years of age). A recent prospective cohort study estimated the risk for development of dementia in patients with PD as twice that of the controls (Marder et al., 1995). At risk patients, in addition, are those with reduced tolerance to pharmacological therapy because of the appearance of hallucinations, delusions, and confusional syndromes (Tatemichi et al., 1994). It has been clearly established that dementia in PD significantly decreases life expectancy. From a therapeutic standpoint, it is important to keep in mind the differential diagnosis of dementia related to anti-Parkinson drugs and to depression (see later). The clinical picture of dementia in PD is quite heterogeneous. It is usually labelled as a subcortical dementia (Della Sala, 1990), a diagnostic category that includes pathologies such as Huntington’s disease (Brandt, 1991), dementia associated to HIV (Stem & Marder, 1991), and many others. Although fronto-subcortical type of disturbances, as, for instance, poor fluency performance (Jacobs et al., 1995), may support such classification, there is no universal agreement about the rationale of this diagnostic category. The pattern of hypocortical functioning demonstrated by metabolic neuroimaging techniques is quite similar to the one observed in AD (Tatemichi et al., 1994). We agree with Brown and Marsden (1988a) who argue convincingly that, when the dementia is sufficiently advanced, it becomes indistinguishable from that of AD. The neuropathology of dementia in PD varies from case to case. There are at times cortical (Boiler et al., 1980) and subcortical (Whitehouse et al., 1983) changes indistinguishable from those of AD. In other cases, the cortex shows numerous Lewy bodies (Gibb et al., 1989). In yet other cases, the cortex appears entirely normal. Agid and his collaborators have convincingly shown that PD patients show a cholinergic deficit (see Dubois et al., 1991 for a review). Preliminary data suggest, however that, contrary to what happens in AD, dementia in PD is not associated with the apolipoprotein E4 (Marder et al., 1994).

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Selective cognitive disorders The term “bradyphrenia” introduced by the French neurologist Naville in 1922, includes impairment in several areas, cognitive and psychological; as a result, PD patients exhibit loss of concentration, inability to create logical connections, tendency to perseverate, and generalised slowing of the thinking process. Experimental studies have confirmed that PD patients tend to have increased reaction times and a disorder of attention particularly affecting sustained attention (see Spinnler, 1991 for a detailed review). It must be pointed out that not all authors agree on the presence of generalised slowing in PD (Spicer et al., 1994). Bradyphrenia may be present in the absence of full-blown dementia, and PD patients’ cognitive slowing often appears disproportionate to their general level of cognitive performance (Pate & Margolin, 1994). What is the pathophysiological basis of bradyphrenia? The results of an evoked potentials study have been used as an argument in favour of a frontal disorder of attentional processes regulation (Stam et al., 1993). Many authors have found impaired performance at tests traditionally thought to reflect frontal functions such as the Wisconsin Sorting Card test (Caltagirone et al., 1989), the Stroop test (Brown & Marsden, 1988b), and the Trail-making test (Taylor et al., 1986). Cognitive shifting impairment have also been proved to be associated with the severity of motor symptoms, as opposed to fluency, which seems independent; it has been surmised that PD is not associated with a general decrease in executive functions (Van Spaendonck et al., 1996). Leaving aside the controversial question of anatomical localisation, there is no question that a lot of data show a deficit in mechanisms of control, maintenance, and shifting attention (Downes et al., 1993; Owen et al., 1993). Once again, it must be pointed out that a few studies have failed to confirm these deficits (Alberoni et al., 1988). Further discussion of these points can be found in Dubois et al. (1991). Some experimental research seem to show that the linguistic abilities of PD patients are intact. Others, however, have found disorders involving naming with the appearance to a marked degree of the “tip of the tongue” phenomenon (Matison et al., 1982), and of grammatical comprehension. In

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nondemented PD patients, these phenomena do not affect global verbal abilities. A high percentage of patients show a disorder of phonation, particularly frequent and pronounced in advanced stages of the disease (Uziel et al., 1975). This disorder is not strictly related to cognitive functions, but it often has negative consequences on communication. The dysarthria is related to multiple factors such as difficulty in controlling breathing and rigidity of bucco-facial, pharyngeal, and laryngeal muscles (Luchsinger & Arnold, 1965; Mulct, 1987). More recent studies have shown a decrease of articulation speed and a disorder of “language planning” (Connor et al., 1989). The nature of these disorders is similar to the one that interferes with movement of other parts of the body. There are, however, occasional discrepancies between disorders of phonation and other motor symptoms of the disease. Pharmacological therapy often improves phonation to a marked degree, but at times, dysarthria persists or improves only slightly even when other symptoms improve markedly (Critchley, 1981). It must also be kept in mind that bucco-facial dyskinesias (so-called “peak-dose dyskinesias”), one of the side effects of L-Dopa and other dopaminergic therapies, may in turn severely affect speech (Marsden & Parkes, 1976). As far as nonpharmacological therapies are concerned, it has been stated that traditional speech therapy does not help PD patients (Sarno, 1968). Researchers from the University of Colorado have proposed a therapy that addresses the problem directly (voice treatment instead of speech therapy), claiming a good rate of success (Ramig & Scherer, 1992; Ramig et al., 1994). Short-term memory is usually well preserved, but interfering tasks may produce a deficit. For instance a nonverbal task based on techniques challenging working memory shows impaired performance of PD patients (Panisset et al., 1994). Long-term memory tends to be impaired, especially episodic (El-Awar et al., 1987) and procedural memory (Saint-Cyr et al., 1988). Visuospatial abilities defects are among those most frequently reported (Boiler et al., 1984; Lees & Smith, 1983). Here again, however, not all authors agree and there is lack of consensus on the specificity and significance of experimental data.

This is probably due not only to methodological differences, but also to the different demands made on motor speed, strength and dexterity, presence or absence of pharmacological treatment etc. It has been suggested that loss of visuospatial abilities in nondemented PD may be due to a “generic” increase in reaction times or other aspects of attentional disorders (Della Sala, 1990; Della Sala et al., 1986). Psychiatric disorders PD patients are often depressed, with frequencies that go well beyond those found in other chronic disorders. The degree of depression is rarely very severe, but it may complicate the diagnosis (particularly the neuropsychological diagnosis) and the therapy. Several authors (Santamaria et al., 1986; Starkstein et al., 1992) have suggested that depressed PD patients may represent a subgroup with a greater decline of cognitive abilities and ADL. In general the depression fails to respond or responds very little to pharmacological treatment. When it is light to moderate, it does not seem to interfere with cognitive abilities (Boiler & Marcie 1994).

Progressive Supranuclear Palsy (PSP) PSP, also called Steele-Richardson-Olszewski’s disease (Steele et al., 1964), is a disease that affects structures located in the rostral portion of the brainstem. It is a relatively rare disorder, with an estimated prevalence ranging from 1 to 2/100,000. From the neuropsychological point of view slow information processing, difficulties in orienting and shifting attention, forgetfulness, and emotional changes are the most striking features of the disease. The frontosubcortical pattern of cognitive disorders characterising PSP persuaded some authors to label it as “Subcortical Dementia “ (Albert et al., 1974). PSP patients exhibit an extrapyramidal syndrome associated with other fairly typical neurological signs, including axial rigidity, postural instability, and oculomotor disturbances with a supranuclear gaze palsy that particularly affects vertical motion. Depressed mood, obsessive behaviours, irritability, and sleep disorders are often associated and may precede the other symptoms; in 20-60% of cases a clear-cut dementia emerges. As

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stated earlier, the symptom complex of PSP has been proposed as a model of subcortical dementia (Albert et al., 1974; Pillon et al., 1991). Symptoms vary markedly, especially in the early phases of the disease when the differential diagnosis with other extrapyramidal disorders, especially PD, may be difficult. It may therefore be hazardous to discuss cases of PSP without pathological confirmation (Capitani et al., 1993). Lees (1987) has proposed some diagnostic criteria that include presence of supranuclear opthalmoplegia with paresis of downward gaze, and at least two of the following criteria: (a) dystonia and axial rigidity, (b) pseudobulbar syndrome, (c) bradykinesia and rigidity, (d) frontal signs, (e) postural instability with tendency to fall backward. The progressive course of the disease, its scant response to levodopa treatment, and exclusion of other lesions possibly explaining the clinical picture usually help the clinician in confirming the suspected diagnosis. The main neuropathological feature of PSP is neuronal loss and neurofibrillary tangles (NFT) (Gray, 1988). NFT vary from those observed in AD by their subcortical localisation and also by their morphology. Cortical NFT, not numerous but constant, have been described (Hauw et al., 1990). Significant prefrontal lobe hypometabolism may be evident in functional neuroimaging studies of PSP patients (Blin et al., 1992). Clinical data The axial rigidity that leads to postural instability, together with the disorder of eye movements, is the most frequent symptom of PSP. Patients show a progressive increase in muscle tone that affects typically proximal segments. The dystonia affects mainly the neck, but also the limbs and the eyelids (palpebral retraction, blepharospasm) as well as the entire face (rigidity, amimia, deep folds around the nose and mouth (Rafal & Friedman, 1987). Pseudobulbar signs (dysphonia, dysarthria, dysphagia) may also occur (Ruberg, 1991). An early

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sign in many patients is a gait disorder with frequent falls (Lees, 1987), but in other patients, the neurological signs are accompanied or even preceded by behavioural or speech disorders. Opthalmoplegia may be a late sign and there have been cases of PSP without disorders of eye movements (Dubas et al., 1983). Behavioural and neuropsychological data The very existence of a dementia syndrome in PSP has been disputed, even in the late stages of the disease (Steele, 1972). Clinical measures of disease severity and duration do not correlate closely with psychometric performance or depression (Esmonde et al., 1996). However, most studies have shown a series of cognitive deficits. Some authors have proposed that neuropsychological disorders affect mainly nonverbal, visuoperceptive tasks (Kimura et al., 1981). This hypothesis was confirmed by a study that has shown a significant decline in performance IQ (affecting mainly symbol-digit substitution) with relative preservation of verbal IQ (Fisk et al., 1982). It must be pointed out, however, that a similar trend occurs in most dementias and even in normal ageing (Boiler, Dalla Barba et al. 1996; Boiler, Marcie et al. 1996). Extensive batteries assessing specifically language, memory, visuoperceptive, and executive functions have shown significant impairment in almost all cognitive areas in PSP. These studies demonstrated generalised slowing of mental processes, accelerated forgetting with normal short-term memory performances, constructional apraxia, and especially a profound impairment of sustained and divided attention. Other studies have found perseveration, utilisation and imitation behaviour, as well as deficits in verbal domains such as synonyms and proverbs interpretation, impairment of logical reasoning, verbal fluency; impoverished speech and verbal adynamia have also been found. Finally, the presence of personality and behavioural changes with apathy, depression, and emotional incontinence have been pointed out (Cambier et al., 1985; Esmonde et al., 1996a, b; Grafman et al., 1995; Maher et al., 1985; Pillon et al., 1986). This general picture corresponds to that described in patients with lesions of the frontal lobes and may account for the

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label of “frontal syndrome of PSP” (Cambier et al., 1985). A comparative study of PSP, PD, and AD patients focused mainly on verbal, visuospatial, and memory tasks (Pillon et al., 1986) showed that the three groups scored significantly below control subjects. AD patients showed the most severe impairment of memory, while PSP patients had worse performance at frontal tasks. Another study from the same group (Dubois et al., 1988) comparing PD and PSP patients has shown that both groups had significant impairment of memory, verbal IQ, speed of cognitive processes, and frontal tests. In these last two sets of tasks, the PSP patients performed clearly worse than PD patients. Data suggesting a prefrontal dominance of deficit in PSP as opposed to other dementias, have been extensively confirmed (Grafman et al., 1995; Pillon etal., 1991; Pillon and Dubois, 1992;Robbins etal., 1994) . At variance with PD, in which motor problems, bradyphrenia, and cognitive defects often prove to be differentially involved in performance deficits, PSP patients demonstrate a clear-cut and consistent slowing of information processing in addition to their altered motor response times (Grafman et al., 1995). Executive dysfunction, the major behavioural abnormality of PSP, is held to derive from deafferentation of the prefrontal cortex secondary to interruption of frontostriatal feedback loops (Esmonde et al., 1996b; Grafman et al., 1995); indeed, post-mortem studies confirm that cortical lesions are minimal, and subcortical structures strategic for frontal function are the most damaged in PSP. Moreover, supranuclear gaze palsy demonstrated to correlate with higher rates of dementia and attentional deficits has been found to correlate with the severity of eye movement disorders, supporting the hypothesis that the integrity of midbrain regions may be critical for these processes (Esmonde et al., 1996a). The severity of executive ability disturbances must be considered in separating PSP from cortical neurodegenerative disorders.

Huntington’s Disease (HD) Huntington’s disease is also called chorea (from the Greek word for “dance”) major or heredo-

degenerative chorea, in opposition to chorea minor (or Sydenham’s chorea). The latter, which has practically disappeared in the Western world, is a late consequence of rheumatism and is not accompanied by cognitive deficits. HD is uncommon, with a prevalence between 30 and 100 per million, while its incidence is estimated between 3 and 5 per million (Conneally, 1984; Kurtzke, 1979). The lower frequency observed in Japan (Imaizumi, 1989) and in China (Leung et al., 1992) seems to corroborate the European origin of the mutation responsible for the disease. Despite its relative rarity, HD is of considerable interest for at least two reasons. First it is the best known example of “genetic dementia”. In addition, it is accompanied by a fairly characteristic series of neuropsychological changes and the clinical description of dementia in HD has provided one of the first occasions for the development of the concept of subcortical dementia (McHugh, 1973; McHugh & Folstein, 1975). The genetic transmission of HD is autosomal dominant with generally very high penetrance. The region of genetic alteration has been identified on chromosome 4, but its precise pathogenesis is still unclear. Biological tests for the pre-clinical diagnosis of at-risk subjects are now available (Meissen et al., 1988). The ethical problems raised by the use of such tests have been studied extensively. Neuropsychological tests of at-risk subjects tend to show decreased performances of the group as a whole (Brandt, 1991) and within the group some individuals have an inferior performance (Wexler, 1979). In addition to the obvious problems raised by these early diagnoses, one should consider the conceptual issue that subjects with inferior cognitive performances may already be affected and not in a “pre-clinical” stage. A recent genetic linkage case control study on persons at risk for HD showed some lower IQ measures in the predisposed subjects, but no indication emerged that genetic predisposition to develop HD produces greater impairment than that seen in nonpredisposed persons. The discontinuity hypothesis of HD surmises that neuropsychological symptoms may appear close to the time of disease onset (Giordani et al., 1995).

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The mean age of onset of HD is between 35 and 40 years of age and the mean duration is around 14 years. The atrophy of the caudate nuclei and, to a lesser extent, of the frontal cortex can be demonstrated by neuroimaging techniques and is correlated to the severity of the clinical picture. Antidopaminergic drugs may reduce the choreic movements, but pharmacological agents cannot delay or correct the cognitive changes. Clinical and behavioural data The involuntary choreic movements characteristic of HD consist of facial grimacing, tremor of the head, and alternating flexion and extensions of the limbs and trunk. In terms of mental status, the early stages are characterised by personality changes, depression, mania, at times hallucinations similar to those of schizophrenia; this psychopathology may precede or, less commonly, follow even by several years the involuntary movements. Memory changes tend to be precocious and progressive. They affect mainly anterograde memory, but may also produce retrograde amnesia with no gradient, suggesting a retrieval problem, (Albert et al., 1981) in opposition to patients with Korsakov syndrome (patients with AD also have an uncertain gradient according to Beatty et al., 1988). HD patients also show deficits of procedural memory, and of motor and visuospatial planning. The “frontal” trait in planning and organisation is associated with bradyphrenia and attentional deficits (Della Sala, 1990). A more detailed description of these changes can be found in Folstein et al. (1990) and in Brandt (1991).

VASCULAR DEMENTIA The risk of dementia in association with cerebrovascular pathology is greater than any other known risk factor, including head injuries (Tatemichi et al., 1994). According to O’Brien (1988) at least one third of demented patients have a significant vascular component. Other authors disagree and suggest instead that the diagnosis of vascular dementia is made much too often (Brust 1988) because a causal relationship between

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vascular lesions and dementia is hard to prove. The precise meaning of vascular dementia is still debated. The generic term “vascular” lacks the necessary nosological or etiological precision. Similarly the term dementia seems to make the diagnosis more difficult, with the risk of not making it early enough to take care of its symptoms. On this basis the concept of vascular dementia is simply considered obsolete by some authorities (Hachinski, 1994). The diagnosis of vascular dementia is generally based on the presence of dementia, of cerebrovascular lesions, and on the determination of a causal link between the two. It is of course this last aspect that raises most problems. The latest neuroimaging techniques have allowed much progress in the areas of understanding and classifying this class of diseases. Recent attempts to redefine vascular dementia have been made to allow a diagnostic process that takes into account the following parameters: early identification of patients at risk; accurate description of the cognitive changes; precise correlation with the specific causes of the vascular lesions in order to provide a rational basis for appropriate prevention. The concept of vascular dementia most currently includes all dementias following cerebrovascular accidents (CVA) whether ischaemic or haemorrhagic in nature (Erkinjuntti, 1994). It therefore includes single or multiple infarcts and large vessel pathology as well as necrotic-ischaemic pathology such as following small vessel lesions, with their characteristic multiple lacunas located throughout, but particularly at the diencephalic level and in the subcortical white matter. It also includes a series of haemorrhagic and ischaemic pathologies that affect some vulnerable portions of the brain following hypoperfusion of cardiovascular origin (Roman etal., 1993). On the other hand, the concept of “arteriosclerotic dementia” is no longer considered acceptable. Actually most current studies are based on ischaemic pathology with resulting multiple small infarcts, hence the prevailing name Multi-Infarct Dementia (MID). Generally speaking, MID includes three features: presence of cerebrovascular pathology, stepwise progression or at least fluctuating course of the associated cognitive

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changes, and focal neurological signs (American Psychiatric Association, 1987). One of these elements is missing, however, in about 15% of cases (Erkinjuntti, 1987), hence a series of diagnostic difficulties. It must be kept in mind that the clinical sequels of a focal or multifocal cerebral lesion vary considerably from one individual to another, in relation to age, pre-existing diseases etc. One frequently observes the co-existence of cerebral lesions of different nature such as senile plaques and NFT (Boiler et al., 1989; Mirra et al., 1991; Todorov et al., 1975). The use of scales and indices such as those proposed several years ago by Hachinski et al. (1975) is of some use in the differential diagnosis between vascular dementia and AD but is practically useless in the presence of mixed dementia and cannot help in the identification of subtypes of vascular dementias. Incidentally, Hachinski’s index was proposed before CT scan was largely available and some authors prefer therefore more recent scales such as that of Loeb and Gandolfo (1983). Two international consensus conferences have contributed to greater reliability of the diagnosis of vascular dementia, therefore facilitating communication and collaboration among different groups. They have produced respectively the ADDTC (Chui et al., 1992) and the NINDS-AIREN (Erkinjuntti, 1994; Roman et al., 1993) criteria. Chui et al. (1992) consider that the clinical judgement of dementia and of loss of competency and autonomy is more important than the systematic, detailed analysis of cognitive functions. Physical examination and neuroimaging techniques allow the clinician to ascertain and define the presence of vascular damage. Documentation of a chronological relation between a CVA and the onset of dementia represents a necessary and sufficient condition to establish a causal relationship between the two. The NINDS-AIREN criteria (Roman et al., 1993) insist on the necessity of a memory deficit associated to at least two focal deficits (apraxia, aphasia, agnosia, and executive deficits), producing functional impairment in everyday life and executive disorders in order to consider the diagnosis of dementia. The essential role of neuroimaging is maintained for determining the

presence of vascular lesions. If these are not found, the diagnosis of vascular dementia cannot be made. The causal relationship between cerebrovascular pathology and dementia rests here again on their temporal association (with a limit of no more than three months in between) and on the fluctuation and stepwise progression of cognitive decline. The correlation with the clinical data is considered essential. Despite these advances, many questions remain open as there is not sufficient compatibility between the diagnostic criteria of AD and MID. The area of mixed dementias remains a “no man’s land”. The role of “silent”, very small, or single infarcts on the onset and evolution of the dementia is not defined. Finally, the inclusion of patients with hemiparesis, aphasia, and other focal signs leads to a series of methodological difficulties in the evaluation of cognitive deficits (Drachman, 1993). Impairment of everyday life because of severe aphasia and/or visuo-spatial difficulties cannot be equated to dementia, even if they certainly do not prevent its later occurrence In terms of neuropathology, one can find cerebral infarcts of widely different size and localisation, according to the diameter and distribution of the vessels involved. In addition to large infarcts, small lacunar lesions are considered particularly important for the appearance of dementia, especially when they are located in subcortical areas (Marshall, 1993). The frontal white matter seems most vulnerable to small infarcts because of its peculiar vascular anatomy. In recent years, much discussion has centred on alterations of the deep cerebral white matter known as “leucoaraiosis” (from the Greek words for rarefaction of the white matter) as demonstrated by CT scan or MRI. These “lesions” are quite aspecific, but some studies suggest a relationship between leucoaraiosis, cognitive slowing, and attentional deficits in normal ageing and in dementia (Kertesz et al., 1990). Other authors consider leucoaraiosis as potential biological markers of depression and cognitive deterioration in old age (Nussbaum, 1994). Lesions are more often located anteriorly. When the lesions are mainly subcortical, the neurological signs may correspond to a pseudobulbar picture, with gait disorder, postural

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changes, urinary incontinence, or extrapyramidal signs. For vascular dementia to occur, the presence of vascular risk factors such as high blood pressure, diabetes, age, dislipidemias, smoking, atrial fibrillation, cardiovascular pathologies, etc. is also considered crucial. The identification of these factors is particularly important for prevention and therapy of vascular dementia. Some studies have identified age and recurrence of CVAs as best predictors of the incidence of dementia following cerebral infarcts (Tatemichi et al., 1994). Males seem to be more frequently affected. In terms of physiopathology, the factors most often responsible are tromboembolisation and lipojalinosis of the parietal walls, as a consequence of arterial hypertension. The lesions are often multiple and bilateral while the volume of loss of cerebral parenchyma varies. A great deal has been written concerning the “critical mass” of cerebral destruction necessary to produce dementia. It has been stated that dementia appears only after a threshold of 50ml of parenchymal loss (Tomlinson & Henderson, 1976) and that beyond 100ml dementia becomes highly probable. These concepts, inspired by Lashley’s (1929, 1938) principle of “mass action”, belie the fact that what counts is the location as much as the size of cerebral loss. In summary, the mechanisms likely to produce vascular dementia are related to both the mass of parenchymal loss and to the cognitive specificity of the affected regions. Clinical and behavioural data The dementia is usually of fairly sudden onset, in contrast to the insidious appearance of symptoms in AD. It is also possible for the dementia to long remain “masked” by the neurological signs associated with infarcts. The course is one of progressive worsening, with fluctuations related to the succession of small or large CVAs. Altogether, even though life expectancy of MID patients is reduced, the picture of vascular dementia tends to be less severe than in AD. It may be justified to separate “cortical” deficits from those more specifically subcortical. As mentioned earlier, single or multiple cortical lesions

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may produce a severe focal deficit or the association of two or more deficits which may severely interfere with the patient’s autonomy. Whether such state of diffuse cognitive impairment can be characterised as a dementia remains a matter of debate. The disease in the majority of cases affects small vessels with subcortical-like deficits, to the extent that vascular dementia often fits the model of subcortical dementia. In comparison with AD, MID is usually associated with better preservation of personality, more emotional lability, and more frequent depression. Neurological signs that may help differentiate MID from AD include gait disorders and urinary incontinence, both of which occur early in MID, but late in AD. It remains that the most important difference rests on the occurrence of strokes, the presence of focal neurological signs, and of urinary and emotional incontinence, as well as the clinical course (Tatemichi et al., 1994). Dysarthria, articulatory slowing, changes of pitch and vocal production are characteristics of MID, with a picture close to that of pseudobulbar syndrome. Semantic-lexical disorders are more often found in AD than in MID. Memory disorders are often among the early manifestations of MID and are not much different from those of AD, except for a greater impairment of episodic memory in AD (Gainotti et al., 1989; Mendez & Ashla-Mendez, 1991), and relative sparing of remote memory in MID. The “closing-in” phenomenon in copying pictures and a tendency to produce “primitive” responses at the test of Raven Progressive Matrices seem to characterise AD more than MID patients (Gainotti et al., 1992). Some authors have also reported greater deficits in executive functions in MID patients (Mendez & Ashla-Mendez, 1991; Villardita, 1993). Binswanger ( 1894) first described the cognitive deterioration known today as “chronic progressive subcortical encephalopathy”. The clinical picture is essentially indistinguishable from subcortical MID known as “lacunar state” with atrophy and ventricular dilatation. The dementia is gradually progressive and is associated to motor signs in patients with chronic arterial hypertension (Caplan, 1985; Caplan & Shoene, 1978). The gait disorders,

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often apraxic in nature, are in contrast with the more or less normal strength of the lower limbs. There may be urinary incontinence, pyramidal and extrapyramidal, and a pseudobulbar syndrome. Personality changes (apathy or abulia) are also described, together with changes of behaviour and of affect, psychomotor slowing, and memory deficits. Neuropsychological examination reveals a picture of subcortical dementia with disorders of retrieval, attentional deficits, and cognitive slowing (Kertesz et al., 1990). Aphasia, apraxia, and agnosia are usually absent, corresponding to relative sparing of cortical structures. Functional autonomy is usually preserved in the first years of disease. Speech is characterised by disorders of prosody, perseverations, hypophonia, and, more rarely, anomia and paraphasias. Dysexecutive symptoms (difficulty in logical memory and problem solution) as well as bradyphrenia may be explained by the frequent destruction of subcortical associative fibres in the frontal white matter (Ishii et al., 1986). In summary, the main features of vascular dementia are a predominantly fronto-subcortical type of cognitive decline, with relative sparing of lateralised hemispheric functions, a frequent association with motor disorders and other neurological signs, the irregular progression of the disease, together with neuroimaging evidence of cerebrovascular lesions. However, the frequent coexistence of different types of pathologies makes unrealistic any hope of unequivocally separating neuropsychological features of vascular dementia from that of degenerative and other pathologies. It is in any case important, both in research and in clinical practice, to clearly identify mixed forms in order to separate them from AD.

DEMENTIAS AND COGNITIVE DISORDERS ASSOCIATED WITH INFECTIOUS PATHOLOGY Some infectious pathologies of the CNS count among the causes of confusional state and dementia. We will briefly deal with the main ones, then, because of its growing importance discuss more in detail the pathology related to HIV (AIDS). The

greater vulnerability to infectious agents of immunodepressed subjects has brought back on the scene pathologies that were thought to be have become quite uncommon, such as neurosyphilis and progressive multifocal leukoencephalopathy. Herpes simplex encephalitis often produces an acute necrosis of the cortical and subcortical cerebral tissue of the temporal and orbito-frontal regions (basal fronto-temporal necrotic haemorrhagic encephalitis). Patients who survive the acute phase (mortality is around 30%) may present severe and often irreversible cognitive deficits. These include impairment of language, calculation, and memory, in addition to severe personality and behavioural changes. The “slow” infections of the nervous system may induce chronic, progressively evolving clinical syndromes with characteristic neurological signs such as cerebellar ataxia, convulsions, and myoclonus. These are invariably accompanied by cognitive deterioration and personality changes. Two main groups of slow infections can be distinguished: those due to viruses with known properties (“conventional”) and those secondary to much less known, i.e. non-conventional, transmissible agents. These include the so-called prions, protein particles—which have recently become the subject of a passionate debate, not only in the scientific community. Progressive multifocal encephalopathy (PML) belongs to the first group. This condition is characterised by rapid evolution going within a few weeks from a picture of multiple functional impairment to dementia, delirium, seizures, coma, and death. It is typically seen in patients with impaired immunological competence following for instance severe granulomatous pathology, tumours, or leukaemia; it can also be associated with AIDS. Prion diseases are neurodegenerative conditions related to non-conventional transmissible agents, the prion proteins. The transmissible agent is a modified isoform of a glycoprotein, the prion protein PrP, which is normally produced by the host cells and encoded by a host gene. Unlike the other disease agents, the modified form of this protein appears to be able to induce the disease although lacking informational nucleic acids. It is characterised by its resistance to proteolysis, it

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aggregates in the host’s brain interacting with cellular PrP and possibly causing its conversion to the modified form, thus producing the typical spongiform changes in brain tissue. CreutzfeldtJakob disease (CJD) is the most common type of the prion-linked spongiform encephalopathies; it presents between 55 and 70 years with rapidly progressive dementia following depression or behavioural changes. The dementia is associated with early cerebellar ataxia, visual disturbances, and myoclonus. Most patients have a typical electroencephalogram showing pseudoperiodic sharp waves. The disease is known to occur in sporadic (most of the cases), familial (around 15%), and iatrogenic form (treatment with human pituitary-derived growth hormone, dura mater, or corneal grafts) and is usually fatal within a few months from onset. No therapy is available. The families identified have mutations in the PrP gene, located on chromosome 20. Both iatrogenic and sporadic cases occur predominantly in genetically susceptible individuals. Heterozygote individuals seem to be at lower risk of developing prion disease. Recently a hot debate has grown around the presence of a new variant of prion disease in young people in the UK and a few other countries, its possible relationship with bovine spongiform encephalopathy (BSE), and the safety of beef and bovine offal. The features characterising this new variant include a younger age of onset, absence of typical CJD electroencephalographic features, and a more prolonged course. Strains of transmissible spongiform encephalopathies have been distinguished, and the new variant strain seems to resemble those of BSE, suggesting that BSE may well be the source of the new disease. BSE has been transmitted to mice, domestic cats, and macaques. Transmission to transgenic mice expressing human prion protein is still under trial (Collingeetal., 1996; Will et al., 1996). Subacute sclerosing panencephalitis, extensively studied by Van Bogaert, is a rare pathology of the CNS, associated with increase of antibody titles for measles. It produces, in children and adolescents, a rapidly progressive dementia with disorders of language and personality changes. EEG abnormalities associate to seizures and myoclonus. This disease is usually lethal.

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Neurosyphilis, which had become quite uncommon since the introduction of antibiotics, used to be one of the leading causes of institutionalisation for dementia up to a few decades ago. Its psychiatric and neurological symptoms and the dementia characterised by cognitive slowing, amnesia, confabulations and delirium are known under the name “general paresis of the insane” (GPI). GPI occurs as a tertiary manifestation which follows, by 5 to 30 years, the original infection, after a meningo-encephalitis. These symptoms are responsive to treatment (Farina et al., 1994). The present pandemic of AIDS has made syphilis (and its neurological complications) a more frequent occurrence. Tuberculous meningoencephalitis, another pathology that has decreased considerably in the last decades in the industrialised world, is a more frequent occurrence in developing nations and among the least protected individuals in all countries. Its symptoms include subtle personality changes with confusion and amnesia evolving later into clear-cut disorientation, alterations of consciousness which may lead to coma and, if no adequate treatment is provided, death (Williams & Smith, 1954). The cognitive and behavioural symptoms, usually related to cerebral vasculitis, occur within a context of increased intracerebral pressure, normal pressure hydrocephalus (NPH), subacute or chronic meningitis, involvement of cranial nerves, and occasionally focal signs due to haemorrhagic infarcts or to tuberculomas. Even in cases of improvement, now practically guaranteed by appropriate and timely therapeutic intervention, cognitive sequelae, particularly amnesia, are frequent.

Dementia associated to human immunodeficiency virus (HIV) AIDS is an infectious disease transmitted by contact with biological fluids (such as blood, sperm, vaginal secretions, maternal milk), characterised by severe impairment of cell-mediated immunity. It is accompanied by a dramatic vulnerability to various opportunistic infections (viral, bactérie, mycotic, as well as protozoa and helmints) and by some types of tumours such as lymphomas, Kaposi sarcoma etc. Virtually all tissues and organs may be affected including the central and peripheral nervous system

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and the muscles. In addition to the opportunistic infections, the CNS is also exposed to direct action by the HIV virus which is considered responsible for several of the neurological and neuropsychological sequel of AIDS (Price et al., 1988). Some experimental data have suggested that seropositive subjects may develop cognitive symptoms in the early stages of the infection, possibly even before other symptoms appear (Grant et al., 1987). The suggested subtle beginning of progressive and selective cerebral damage in the pre-clinical stage (i.e. preceding the symptoms of immunological impairment) has led to a series of social and political problems, particularly in the United States where the possible continuing role of seropositive individuals with specific professional responsibility has been questioned. It is too early to be certain that the decline in cognitive performances is due to an infectious action of the HIV virus and no reliable conclusion can be drawn in terms of prognosis (Burgess et al., 1994; McArthur et al., 1989). Recent studies do not seem to fully confirm these early data and have shown that neuropsychological test results of seropositive subjects before developing AIDS do not significantly differ from those of control subjects (Seines et al., 1995). Some longitudinal studies have shown that the course and progression of the cognitive impairment is erratic in its timing and in its evolution (Seines et al., 1990). Neuropsychiatric findings in HIV infected patients need further clarification. Many studies may have presented a selection bias because for the most part they include white Western homosexual men. This does not guarantee that the data obtained in such samples can be generalised to other populations. For that reason, the World Health Organisation has sponsored an international multicentric study in order to define the prevalence and natural history of the psychiatric, neuropsychological, and neurological manifestations of HIV virus which produced its first results in 1994 (Maj et al., 1994). It is important to point out that the immunological status of the patients bears no significant relationship with the cognitive impairment. Moreover, there seems to be no relationship between performance at neuropsychological tests of seropositive patients

and their performance in everyday life (Maj et al., 1994). A recent review of 57 studies addressing the debate on the presence or absence of neuropsychological impairment in asymptomatic HIV-1 seropositive individuals concludes that there is an indication of deficit on the median rates, with a modest increase in the risk of impairment. This paper, however, warns about possible effects of gender, racial, and ethnic composition of subject groups which have not yet been sufficiently explored. More care in study design is needed, in particular mode of infection, neuropsychological test battery size and type, and data analysis methods must be specifically addressed in future studies (White etal., 1995). The diagnosis of early cognitive impairment is particularly important in the light of an early and rational therapeutic plan. Some experimental studies suggest that therapy with zidovudine (AZT) has a positive effect on cognitive symptoms (Riccio et al., 1990). Retrospective studies have shown a dramatic reduction of the incidence of HIV-related dementia, in apparent relation with AZT treatment (Portegies et al., 1989). It is possible of course that these positive results are short-lived. In addition, the causal relationship with pharmacotherapy is not entirely established (Schmitt et al., 1988; McArthur et al., 1990 cited in Burgess & Riccio, 1992). CNS manifestations of HIV virus infection include neurological, neuropsychological, and psychiatric aspects. The nomenclature and the diagnostic criteria used are in continuing evolution. The same symptoms have been labelled “encephalopathy”, or “HIV encephalitis”, and later as “AIDS Dementia Complex” (Navia et al., 1986; Price et al., 1988). More recently, a group of neurologists, neuropsychologists, psychiatrists, and sociologists under the sponsorship of the American Academy of Neurology AIDS Task Force (1991) has proposed a new terminology parallel to that of ICD-10 and DSM-IV (Diagnostic and Statistical Manual) of the American Psychiatric Association (1994). In this new classification, HIV-1-associated cognitive/motor complex (which corresponds to the previous “AIDS Dementia Complex”) may be considered as a single entity with a large spectrum of clinical pictures and varying severity. The complex has been divided in two categories. The

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first is more severe, (HIV-1-associated dementia complex) while the second, (HIV-1-associated minor cognitive/motor disorder) is less malignant. The latter represents an “alarm” for the clinician. For the definition of “probable” or “possible” forms of these presentations, a series of criteria (cognitive, motor, and behavioural) are proposed. Of course symptoms occurring in the most severe forms of AIDS are sufficient for the diagnosis, but this is not always the case for minor forms. It is not yet clear whether these represent two levels of the same entity, or whether patients with minor forms always

evolve toward the more severe form. Prospective studies actually in progress will help define the natural history of the disease and to specify the response to therapy of its manifestations. Table 32.3 summarises the criteria currently considered necessary for the diagnosis of probable cognitive-motor complex associated with HIV, respectively in its major (A) and minor form (B). If the clinician is in doubt about the diagnosis and another potential etiology or if the clinical evaluation is incomplete, only a possible diagnosis

TABLE 32.3 Criteria for clinical diagnosis of HIV-1-associated cognitive/motor complex. (Adapted from American Academy of Neurology AIDS Task Force, 1991). (A) HIV-1 associated dementia complex (sufficient for the diagnosis of AIDS) probable (must have each of the following): 1. Acquired abnormality in at least two of the following cognitive abilities (present for at least 1 month): attention/concentration, speed of processing of information, abstraction/ reasoning, visuospatial skills, memory/learning, and speech/language. The decline should be verified by reliable history and mental status examination. Cognitive dysfunction causing mild, moderate or severe impairment of work activities of daily living. This impairment should not be attributable solely to severe systemic illness. 2. At least one of the following: (a) acquired abnormality in motor function or performance verified by clinical examination, neuropsychological tests of manual dexterity or both (HIV-1-ADC motor) (b) decline in motivation or emotional control or change in social behaviour. (HIV-1-ADC behaviour) 3. Absence of clouding of consciousness during a period long enough to establish the presence of # 1.

4. Evidence of another etiology, including active CNS opportunistic infections or malignancy, psychiatric disorders, active alcohol or substance use or acute withdrawal must be sought out of history and must not be the cause of the above cognitive, motor, or behavioural symptoms and signs.

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(B) HIV-1-associated minor cognitive/motor disorder (not sufficient for diagnosis of AIDS)

probable (must have each of the following): 1. Cognitive/motor/behavioural abnormalities (must have each of the following): (a) at least two of the following acquired cognitive, motor or behavioural symptoms (present for at least 1 month) verified by reliable history: impaired attention or concentration mental slowing impaired memory slowed movements incoordination personality change or irritability or emotional lability (b) Acquired cognitive/motor abnormality verified by clinical neurological examination or neuropsychological testing (e.g. fine motor speed, manual dexterity, perceptual motor skills, attention/concentration, speed of processing of information, abstraction/reasoning, visuospatial skills, memory/learning, or speech/language). 2. Disturbance from cognitive/motor/behavioural abnormalities causes mild impairment of work activities of daily living. 3. Does not meet criteria for HIV-1-associated dementia complex. 4. No evidence of another etiology, determined by appropriate history, physical examination and laboratory and radiological investigation.

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is made. (American Academy of Neurology AIDS Task Force, 1991). In practice, the essential characteristic of HIV1 -associated dementia complex is a severe cognitive deterioration generally accompanied by motor and behavioural disturbances. The main difference between HIV-1-associated dementia complex and HIV-1-associated minor cognitive/motor disorder is the degree of impairment in activities of daily living, in social and professional life. This is always severely impaired in the former case (and therefore closer to the definition of dementia as incompetence in everyday life), while it appears only in the more demanding tasks in the latter. Patients with HIV-1-associated dementia complex, contrary to those with the minor form, show neuroradiological (CT and MRI) evidence of diffuse cerebral atrophy (Navia et al., 1986). So far, however, at the level of neuroimaging, neurophysiology, or CSF examination, there are no pathognomonic signs of neurological impairment associated with HIV-1 (Working Group of the American Academy of Neurology AIDS Task Force, 1991). Behavioural data Patients with HIV-1-associated cognitive deterioration represent probably the best illustration of the concepts defined, many years before HIV appeared on the scene, under the label of subcortical dementia. They exhibit psychomotor speed decline, difficulties in concentrating and in sustaining attention. They are impaired in problem solving and unable to correctly carry to conclusion complex tasks. They are impaired in reading; show anterograde amnesia; difficulty with motor control; increased motor and verbal response times. There may be confusion and spatio-temporal disorientation. Psychomotor slowing with slow speech and hypophonia may lead in the terminal phases to a sort of akinetic mutism (Burgess & Riccio, 1992; Heaton et al., 1995; Miller et al., 1990; Navia et al., 1986; Price et al., 1988; Seines et al., 1995). Other, more strictly linguistic disorders of language are uncommon and generally reflect added focal lesions. Cortical symptoms such as aphasia, apraxia etc. are uncommon and late findings; if

they occur early and progress rapidly, they may reflect focal lesions, as just stated, due to superimposed pathology such as, for instance, PML or a mass compressing or destroying the cerebral tissue. Therefore these symptoms require prompt and in-depth diagnostic work-up, mainly neuroradiological. The clinical picture is further complicated by motor disorders such as ataxia, hyper-reflexia, asthenia, tremor, hypertonus, disorders of coordination and gait. There may also be apathy and even lethargy, changes in social behaviour, decreased motivation or emotional control, together with anxiety and depression. It has been stated that the emotional disorders of HIV patients are related to the time elapsed since the beginning of seropositivity and, later, of chronic disease, and that there are four phases, not very different from what is observed with the realisation of other potentially lethal conditions (Gala & Pergami, 1994): an initial crisis with reactions of rage, fear, denial, and shock following the realisation of seropositivity; this is followed by a transitional phase which generally leads to an acceptance phase and to adaptation, specific for every patient, to the new condition. Worsening of symptoms may transiently bring the patients to a previous phase. In a minority of patients, about one third, the emotional changes may become organised and permanent or evolve toward psychiatric disorders such as disorder of adaptation with depression and anxiety (Gala & Pergami, 1994). This underscores the importance for the clinicians to pay careful attention to the psychological and psychiatric conditions of their HIV patients. Depression, for instance, falls within the symptoms included in the diagnostic criteria (see Table 32.3); when found, depression is therefore a symptom of organic lesions and may play a crucial role in the choice of antiviral, as well as psychotherapeutic and psychopharmacological treatment. In addition, as the majority of HIV patients are not clinically depressed, the clinician who considers depression as a justifiable reaction in HIV patient, and does not treat it, runs the risk of colluding with their psychiatric pathology (Markowitz et al., 1994). In the phases of definite AIDS, it may become very difficult to distinguish symptoms of depression

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from those of HIV dementia, and careful assessments both of cognitive (particularly frontal functions) and mood disorders should be performed.

DEMENTIA OF NORMAL PRESSURE HYDROCEPHALUS(NPH) The term “normal pressure hydrocephalus” was first proposed by Hakim, a Colombian neurosurgeon to describe a condition characterised by gait disorders, cognitive deterioration, and urinary incontinence in adult subjects with hydrodynamic hydrocephalus. These patients tend to improve, sometimes dramatically, following removal of CSF even though, paradoxically, CSF pressure as measured at a lumbar puncture may be normal (Adams et al., 1965; Hakim & Adams, 1965). Normal pressure hydrocephalus which may represent up to 6 % of cases of dementia occurs mainly between 50 and 70 years of age (Vanneste, 1994). The pathogenesis of NPH in its idiopathic form (about 50% of cases) is far from clear and is difficult to treat, as only 30% respond to shunting. It differs from hydrocephalus secondary to other neural pathologies, such as bleeding or infections, for which shunting is generally successful. For either form, the characteristic neuroradiological finding is a considerable enlargement of the cerebral ventricles in the absence of cerebral atrophy (no widening of the sulci). Diagnostic procedures include, in addition to standard neuroradiological data, the following tests: neuropsychological evaluation, test-removal of 50ml of CSF (tap test), not always reliable, and monitoring of CSF pressure. Despite its popularity in previous years, dynamic cisternography with marked isotopes is currently considered unreliable (Vanneste, 1994). The clinical symptoms are at least in part related to decreased periventricular blood supply with consequent axonal and myelinic damage which becomes less reversible with the prolongation of ischaemia. The disorder of gait sometimes referred to as apraxia of gait is characterised by difficulty in starting to walk (magnetic phenomenon or “frozen foot”),

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postural instability and small steps with sometimes evidence of spasticity. These changes are the most easily reversible after shunt. Behavioural data The cognitive deficits in NPH vary in severity and do not always fit the model of true hydrocephalic “dementia”. In cases where dementia clearly dominates the clinical picture, one should suspect (and rule out) other forms of dementia. Attentional disorders, difficulty in remembering, behavioural inertia, and difficulty in planning are all found in NPH. This represents another instance of subcortical or, better, fronto-subcortical dementia. The evolution tends to be slow with progressive worsening, affecting first vigilance and finally producing complete motor and verbal inertia. In the earlier stages, there may be diagnostic confusion with AD, but the absence of cortical deficits and the characteristic “frontal” features of the memory deficit facilitate discrimination between the two conditions. The early detection of the cognitive symptoms is of course of crucial importance as far as clinical recovery is concerned. To this end, the usual screening tests such as the Mini Mental State Examination (Folstein et al., 1975) are inadequate, and more extensive test batteries, including tests of executive functions are necessary. Urinary incontinence is a relatively late symptom but urinary urgency is present from the early stages. There is hyper-reflexia of the bladder detrusor muscles and decrease of contraction inhibition, without evidence of incontinence of the vescical sphincter. If the frontal dysfunction is severe, there may be “indifference” to inappropriate micturition which, in association with the bladder hyper-reflexia worsens the symptom. It must be emphasised that the ataxia-dementiaincontinence triad may produce diagnostic difficulty in case of vascular encephalopathy (particularly in the presence of a pseudobulbar syndrome). A diagnostic error may be costly in NPH in view of the prognostic and therapeutic implications. In view of the considerable diagnostic difficulty, this potentially reversible condition underscores the need for complete diagnostic tests in all cases of dementia, the only way so far of reducing errors.

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COGNITIVE DISORDERS ASSOCIATED WITH MULTIPLE SCLEROSIS (MS) Multiple sclerosis is the most common demyelinating disorder. It tends to affect young adults and has a chronic progressive course. Its clinical manifestations are highly heterogeneous. Their origin is related to the foci of demyelination which may be located in just about any portion of the CNS. Generally motor and visual symptoms dominate the picture with added ataxia, sensory impairment, and urinary disorders. There may also be symptoms affecting cognition and affect. MS takes different forms, according to the anatomical and functional systems affected, but also to the clinical course which may be intermittent with remissions and periods of worsening. Alternatively, there may be steady deterioration. The etiology of MS, considered one of many autoimmune disorders, is still quite obscure. Numerous epidemiological data suggest a relation with the environment which takes the form of a geographic gradient, tendency for familial aggregation, relation with immune variables, and greater incidence in females. The prevalence of cognitive anomalies in MS, which are almost always less debilitating than the motor symptoms is quite variable, oscillating between 0 to 90% of cases (Rao, 1986). The varying presence of motor and visuo-perceptive deficits is likely to contribute to this variability. Dementia in MS must be clearly separated from selective deficits, and cognitive symptoms must be correlated with specific anatomo-functional or clinical data. To this day, no variable predictive of the cognitive deterioration has been isolated (Jennekens-Schinkel et al., 1990). There is, however, a correlation with neuroradiological data, such as the degree of atrophy of the corpus callosum and the cognitive deficit (Barnard & Triggs, 1974; Franklin et al., 1988; Georgy et al., 1993; Huber et al., 1987). Behavioural data Clear-cut dementia, mainly fronto-subcortical in nature, is relatively rare. It is mainly found in rapidly deteriorating MS or in the chronic phase of the

disease (Della Sala, 1990; McKhann, 1982). The cognitive symptoms most frequently reported concern memory, with relative preservation of short-term memory and a defect of retrieval in longterm memory (Della Sala, 1990), attentional deficits and cognitive slowing, with increased reaction times (Elsass & Zeeberg, 1983; Heaton etal., 1985; Jennekens-Schinkel et al., 1990). These data perse do not corroborate a diagnosis of subcortical dementia. It is not clear to what extent the slower information processing noted in MS is cognitive in nature or is essentially related to the motor disorder. Follow-up of patients with cognitive disorders has shown a correlation between increased reaction times and impaired motor programming and cognitive deficit (Kujala et al., 1994). The psychomotor slowing may therefore be related to other neuropsychological deficits (disorders of visuoperceptual behaviour, and impaired attentional and planning abilities), and independent from motor deficit. Affective disorders with depression or, less commonly, euphoria or generic difficulties in emotional control have been described (Baretz & Stephenson, 1981). In conclusion the feature that most recurs in the literature is the extreme variability of the cognitive status of MS patients. It would therefore be inappropriate to describe a “characteristic” picture without a better definition of patient subgroups. More in general, it must be emphasised that no specific neuropsychological pattern has been identified in MS.

DEMENTIA ASSOCIATED WITH METABOLIC AND DEFICIENCY STATES It is important to recognise this class of diseases because of the frequent reversibility of symptoms following appropriate therapy. Metabolic encephalopathies tend to produce a deficit of selective attention, vigilance, and confusional state and, if not treated, may lead to metabolic coma. Of course the alteration of the level of consciousness is hardly compatible with the diagnosis of dementia. In any case, the most frequent feature of dysmetabolic

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“dementias” is an attentional disorder. There are also frequent disorders of memory, psychomotor slowing, and personality changes. Specific deficits of focal cortical functions are much less common (Feldman & Cummings, 1981). Table 32.4 summarises the main categories of metabolic disorders associated with dementia. Hyperthyroidism may be accompanied by agitation, but also by dementia with psychomotor slowing and apathy, especially in elderly subjects. Hypothyroidism may present with a psychotic-like picture (delusions, hallucinations), mania, delirium of persecution, or more specific cognitive disorders such as disorders of memory, abstracting abilities, and attention (Feldman & Plum, 1993). Thyroid screening continues therefore to be performed routinely in dementia work-ups. Disorders of cortico-adrenal functions such as Cushing’s and Addison’s disease may also be accompanied by dementia, as may pancreatic insufficiency and the consequent recurring hypoglycemia. Chronic anaemia and cerebral hypoperfusion following pulmonary and cardiac insufficiencies may produce lethargy, somnolence with ensuing cognitive deficits even after the resolution of the anoxic state. Chronic renal insufficiency and the use of dialysis may be associated with encephalopathies and motor symptoms associated to the electrolytic imbalance (Brancaccio et al., 1981, Serdaru, 1991). Hepatic insufficiency may also be accompanied by episodes of cognitive disturbance, behavioural alteration, mental confusion, movement disorders, and altered consciousness.

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Vitamin deficiencies represent another category of disease that may be associated to cognitive disorders. This applies particularly to vitamin B l, vitamin B 1 2 , folic acid, and niacin deficiency. These are particularly deficient in malnutrition syndromes (alcoholism, malabsorbtion syndromes etc.). These hypovitaminoses are accompanied by complex syndromes where memory impairment represent the most frequent cognitive symptom (Lindenbaumetal., 1988; Lipschitz, 1992; Serdaru et al., 1988).

DEMENTIA AND PSYCHIATRY As anxiety and depression may interfere with cognitive performances, elderly subjects may challenge the clinician who has to attempt a differential diagnosis between these syndromes and cognitive deterioration. In most cases, the diagnostic procedure is not helped by presence or absence of these psychiatric symptoms which may coexist with dementia It is particularly important to recognise those conditions where depression presents as a dementia because of the potential reversibility of the cognitive symptoms following appropriate psychiatric treatment. Chronic anxiety, on the other hand is accompanied by a characteristic inverted U profile of performance which tends to improve up to a point and then to deteriorate when anxiety prevails (Yerkes & Dodson, 1908 cited by Spinnler,

TABLE 32.4 Metabolic disorders associated with dementia. (a) 1. 2. 3. 4.

. Organ insufficiency conditions Endocrine disturbances (thyroid, parathyroids, adrenal cortex) Cardiopulmonary insufficiency Renal failure (electrolyte disturbances, uremic encephalopathy, dialysis encephalopathy) Liver diseases (portocaval encephalopathy)

(b) 1. 2. 3. 4.

. Vitamin deficiency secondary to malnutrition Thiamin (vit. Bl) Cyanocobalamine (vit. B12) Folic acid Nicotinic acid (niacine)

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1991); both hypoactivation (as seen in frontosubcortical dementia) and anxious hyperactivation (as often seen in early staged of AD) are associated with cognitive deterioration. It is important to take into account this anxiety component in the evaluation of suspected dementia, keeping into account these “quantitative” data. Retrospective observation of some groups of patients with diagnosis of dementia has demonstrated that some of them did not show any cognitive decline or had better scores than previously recorded (Marsden & Harrison, 1972; Ron et al., 1979). This reversible cognitive impairment associated with depression is traditionally called pseudodementia, (a misnomer because when observed, the cognitive impairment is real) and is one of the most frequent inappropriate dementia diagnoses. The cognitive impairment that accompanies depression in elderly subjects may be considerable and may include complaints concerning memory and concentration. Attentional tests, timed tests, tests involving planning and abstraction may demonstrate these deficits. The cognitive deficits associated with major depression may leave partial sequelae, even after resolution of the episode. The degree of difficulty of the tasks employed usually helps (Lachner & Engel, 1994) in differentiating pseudodementia from AD type dementia; moreover, a good indication can be drawn from memory tests involving recognition. Analysis of the response criterion to these tests has shown that depressed patients tend to make more omission errors, while AD patients make more commission (false alarm) errors (Gainotti & Marra, 1994). In addition, the better performance of depressed patients at recognition tasks (as opposed to straight learning tasks), and the normal ability to organise the material to be remembered clearly differ from what is observed in dementia (La Rue, 1992). In general, the cognitive disorders of patients with depressive pseudodementia are not structured according to a precise picture; their follow-up does not show focal deficits; severe dementia syndromes are relatively uncommon. The depressed patients often have a greater subjective feeling of impairment than what is found objectively when they are tested. Clinical history may

show previous episodes of depression and the onset may be relatively sudden or precipitated by an emotional stress. The cognitive impairment is generally proportional to the severity of the depression and usually improves when depression improves. Additional clinical cues may be provided by the fact that demented patients may present anxious depression in reaction to the awareness of their disorder. The cognitive disorders of patients with pseudodementia, on the other hand, are a corollary, rather than a cause, of the depression. Patients with schizophrenia often show a series of changes on performance at various neuropsychological tests (Frith, 1992). In addition, several authors have described that schizophrenic patients are more vulnerable than controls to cognitive deterioration. A subgroup of patients shows evidence of intellectual deterioration together with CT scan evidence of changes such as widening of the lateral ventricles (Johnstone et al., 1978): according to those researchers, these are patients with “negative” symptoms, such as poverty of language, affective changes, social isolation, and inertia (corresponding to the dementia praecox described by Kraepelin, 1919). This subgroup of schizophrenic patients is said to suffer from a frank decline of cognitive functions; on the other hand, patients with “positive” symptoms, such as hallucinations, delusions, and thought disorders are thought to be less vulnerable to cognitive decline. Although the distinction between the two types of clinical pictures seems indeed significant in terms of cognitive prognosis, the timing of decline is far from clear. It is considered that within the first five years of disease, patients reach their “minimal” level, often synonymous with genuine dementia (Frith, 1992). In addition to the cognitive decline, some schizophrenic patients are reported to exhibit isolated deficits such as perceptive or memory disorders. Focal deficits may also be encountered either as prominent manifestations of otherwise global deterioration, or in isolation. Memory disorders resemble the amnestic-confabulatory syndrome of Korsakov rather than the global deficit found in AD (McKenna et al., 1990). The frontal character of the dementia (inertia, perseverations, behavioural stereotypes, and

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disorder of self-generated action resembles a deficit of executive functions, attention, and motivation (Frith, 1992). A characteristic feature observed particularly in the language domain is “nonrelevance” (some sort of “frontal indifference”), failure to follow logical rules of association, and organisation of thoughts and spatio-temporal parameters, in a context of preserved knowledge of the semantic-lexical rules of language. Impairment within many cognitive domains seems to confirm the hypothesis that the deficit involves diffuse, nonspecific processes, particularly the “frontal” functions.

MISCELLANEOUS Many pharmacological agents, particularly those with psychotropic actions such as neuroleptics and benzodiazepines), but also others (diuretics, antihistaminic, steroids, anticholinergic, antiepileptic, etc.), may produce cognitive deficits, confusional state, attention disorders, and psychomotor slowing. These side effects, particularly frequent in elderly patients, represent an important differential diagnosis of dementia in view of their potential reversibility. Other neurotoxic agents that may be accompanied by cognitive symptoms include alcohol which, in addition to its acute effects may produce chronic sequelae. Experimental studies have shown an association between alcohol abuse, cerebral damage (functional and structural), and cognitive-behavioural disorders. Following abstinence, chronic alcoholics may show sequelae ranging from severe mental organic syndromes such as Korsakov syndrome and alcoholic dementia. There may also be subacute sequelae with cognitive symptoms revealed only by more in-depth neuropsychological testing (Parsons & Nixon, 1993). Various hypotheses, often in contrast to one another, concern the etiology of the cerebral damage. These hypotheses include acceleration of physiological ageing, or deterioration related to greater vulnerability of some cerebral structures. It is not yet certain whether there is a direct effect of alcohol or a toxicity mediated by intermediate

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metabolites, hepatotoxicity, nutritional and vitamin deficiencies. Numerous studies have attempted to clarify the relationship between alcoholism, sociopathy, and personal behavioural traits (OscarBerman, 1990). The relationship between alcohol abuse and cognitive disorders is not entirely clear. Some data, however, appear frequently in the literature. They include in most cases a global IQ within normal limits or slightly below, but decreased memory and learning, abstractions, problem-solving, perceptive, and visuo-spatial abilities (Brandt et al, 1983; Freilich & Byrne, 1992). Several studies report data suggesting that cognitive deficits in disintoxicated chronic alcoholic may be reversible. Within a month of abstinence, improvement of attention, verbal learning, and visuo-spatial abilities has been claimed (Fein et al., 1990; Parsons & Leber, 1981). Korsakov’s syndrome (see also the chapter by Vallar, this volume) is characterised by a severe deficit of learning affecting storage and retrieval (generally with a temporal gradient), frontal symptoms such as distractibility, perseverations and, especially in the initial phase, tendency to confabulate; there is relative preservation of semantic aspects of memory and of logical intelligence. There is pathological evidence of damage of cholinergic structures in the basal forebrain, thalamic structures, and cortical regions (Arendt et al., 1983). The association of cholinergic deficits to the diencephalic lesions may be peculiar to Korsakov and may explain the severity of the syndrome, compared to other amnestic syndromes found in chronic alcoholism (Butters & Granholm, 1987). The term “alcoholic dementia” refers to patients with severe amnesia, abstraction and problem solving difficulties, who because of their cognitive impairment no longer fit the diagnosis of Korsakov’s syndrome. The label “dementia” often appears inappropriate (Lishman, 1981; Wilkinson, 1987). Wilson’s disease, or hepatolenticular degeneration, is a congenital error of metabolism of copper, with autosomal dominant inheritance. It is characterised by a hepatic cirrhosis and degenerative lesions affecting the basal ganglia, the cortical grey matter and the white matter. The disease is rare with

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a prevalence estimated around 30 cases per million, but an early diagnosis is important because, with appropriate therapy, it is reversible. It represents one of the most important among the hereditary metabolic pathologies causing dementia in adult subj ects (Tatemichi et al., 1994). About one third of the patients, even in the early stages, show an extrapyramidal syndrome with rigidity, tremor, dystonia, and dysarthria. Another third start with psychiatric symptoms or behavioural changes (apathy and abulia). The clinical picture of the remaining third is dominated by the progressive hepatic pathology. Cognitive symptoms such as deficits of memory and attention, associated with psychomotor slowing and behavioural alterations are witnessed in about 6 % of patients (Lang et al., 1990; Marsden, 1987; Rosselli et al., 1987). Patients with vasculitis, (whether due to immunological, infectious, or toxic factors) may show involvement of the CNS with subsequent cognitive symptoms. In systemic lupus erithematosus, for example, cognitive deterioration is the most frequent neurological symptom (Kirk et al., 1991). Other neurological symptoms include psychosis, chorea, neuropathies, strokes, and seizures. Bradyphrenia, memory and attentional deficits associated with confusional episodes, and impairment of vigilance are characteristic among cognitive symptoms, which tend to fluctuate in time. In general, the clinical diagnosis can be reached keeping in mind the age of the patients (younger than those commonly found to have degenerative disorders), the clinical history, and the accompanying clinical and neuroradiological signs. Following head trauma, there may be residual, more or less focal, cognitive deficits. Isolated

cognitive deficits are associated with neurological signs. Patients with frontal signs, and impairment of attention and memory are less likely to show localising focal neurological signs (Della Sala, 1990). Dementia pugilistica represents the prototype of cognitive deterioration consequent to closed, repeated head injuries, usually connected with the practice of certain sports (Jordan, 1987; Martland, 1928; McLatchie et al., 1987). The clinical picture, usually of late onset, includes psychomotor slowing (which may be associated with Parkinsonian symptoms), amnesia, dysarthria, and personality changes (Della Sala, 1990). Cerebral tumours are frequently associated with neuropsychological deficits, either selective or generalised. The explanation of this “tumoral dementia” used to be that impairment was related to tissue destruction, a theory based on the principle of mass-action, proposed by Lashley (1938). Actually, in view of earlier diagnosis and therapy, it is now considered that the quality and location of the lesion is more important than its quantity. This is exemplified by frontal mass lesions. In treated patients, radiotherapy and chemotherapy may be responsible for cognitive deficits and for outright dementia. The retrospective evaluation of a series of patients who had survived cerebral tumours has demonstrated the possible presence of residual cognitive deficits. The greater risk is represented by reactivation of the tumoral pathology, but a slight impairment of attention and memory has been observed even in asymptomatic patients. This may explain the difficulty of functional improvement observed in patients with long survival (Giovagnoli & Boiardi, 1994)

33 Slowly Progressive Isolateci Cognitive Déficits Sergio Della Sala and Hans Spinnler

Theophile Alajouanine) because he was suffering from insidiously progressive language problems. Ravel’s language deficits were apparent in some of the letters that he sent to relatives and friends: they were scattered with spelling errors and several words were omitted. Moreover, they were slovenly and untidy, not really befitting his usual meticulous behaviour. His writing gradually became cumbersome and hesitant, and he complained that he took days to write a single page or a brief musical review. He also complained that increasingly he had to look up words in the dictionary to understand their meaning (Petit, 1970). The neurological examination was normal as were the results of the analyses then available. Therefore, a cerebral tumour was excluded. His dysgraphia deteriorated to the point that he could no longer sign his autograph for his fans. However, he did not show any sign of global deterioration or dementia for at least four years post-onset (Dalessio, 1984; Christy, 1985; Wainapel, 1985). An unfortunate neurosurgery performed by Clovis Vincent at the clinic in Rue Boileau, in an attempt to treat a non-existent hydrocephalus, ended the musician’s life when he was 62.

OVERVIEW In this chapter we discuss the slowly progressive cognitive impairments that occur in the absence of an overt derangement of other cognitive faculties observed in some cases of degenerative diseases of the central nervous system. Given the relative rarity of these cases and the dearth of accepted taxonomies, we have opted for an anthologic approach subdivided into subheadings that mirror the classification derived from the classical neuropsychological literature based on focal brainlesioned patients. The crucial features of these cognitive impairments are that they mimic selective focal lesions (e.g. strokes) and that they worsen with time (as tumours). These combined features provide a unique natural experiment which might add to our understanding of the cognitive architecture of the brain.

INTRODUCTION In October 1932, after a period of apathy, Maurice Ravel consulted a neurologist (Prof. 775

776 DELLA SALA AND SPINNLER

Several diagnoses have been postulated which could account for Ravel’s disease (e.g. Baeck, 1996). Alajuanine himself (1948) proposed Pick’s disease as the most likely pathology. However, given the slowly progressive course of Ravel’s language deficits, which remained isolated for some years, another diagnostic label can be put forward: slowly progressive aphasia without generalised dementia (Mesulam, 1982) (see also Chapter 34).

DEFINITION Most of the issues discussed in this chapter might be found in scattered single-case reports which date back almost a century. However, surprisingly, it is unusual for a neuropsychology handbook to include chapters on isolated slowly progressive cognitive disorders. Therefore before discussing the individual syndromes, we will provide a general frame of reference.

Slowly progressive isolated cognitive deficits (SPICD) The slowly progressive aphasia (see the review by Poeck & Luzzatti, 1988) that vexed Ravel, was observed by German neurologists at the turn of the nineteenth century (Pick, 1892; Rosenfeld, 1909) and recently reappraised by Mesulam ( 1982). It is a typical example of a slowly progressive cortical degeneration, which remains confined to one cognitive domain, language in this case. In the last decade SPICD affecting other cognitive domains have been reported in the literature. In this chapter we will discuss them in some detail. Several papers can now be gleaned from the literature describing these astonishing syndromes. These papers might be seen as good examples of the fruitful interaction between clinical observation and research. The growing interest in SPICD is twofold: clinical and theoretical. From the clinical perspective SPICD represent a challenging diagnostic puzzle. Their insidious onset and their slow progression, once the presence of a brain tumour has been excluded, point towards a degenerative disease. However, SPICD are characterised by the derangement of only, or

predominantly, one cognitive system. This peculiarity calls for a discussion about their relation with the dementias (see also Chapters 30 and 31, this volume). The neuropathology characteristics of these forms are rather aspecific, adding little to their nosographical taxonomy, although often the histological picture is not discernible from that of a typical Alzheimer dementia. From the researchers’ point of view, SPICDs represent a powerful natural model to investigate the multifarious processes subsuming different cognitive domains and their interactions. In fact, the selectivity of the slowly progressive derangements allows the experimenter to verify, locus after locus (Caramazza, 1989), the hierarchy of different steps within cognitive models, as well as detect possible fine-grained dissociations. These dissociations, if thoroughly defined (Shallice, 1988), are one of the most fruitful paradigms to infer the cognitive architecture of normal subjects from patterns of neuropsychological deficits. In this chapter we report the different SPICD, adopting the descriptive strategy crystallised by 150 years of neuropsychology on focal brain-lesioned patients. Therefore, in the absence of a more conceptual frame of reference, we will describe the clinical picture of slowly progressive degenerations in the domains of language, spatial cognition, memory, praxis, and so on employing an anthological approach. This is, of course, an oversimplification which does not account for the manifold pictures clinically observed and for their progression. The clinical profiles at onset, in fact, range from deficit of a single cognitive domain (e.g. prosopagnosia) to “superordinate” domains (e.g. semantic dementias). Moreover, SPICD deteriorate from well defined symptoms to syndromes encompassing deficits in multiple cognitive domains, mirroring the spreading of the neurostructural degeneration.

Clinico-behavioural definition Dementia is often conceived as the global deterioration of cognitive abilities (see also Chapter 31). However, this is the clinical picture that characterises the more advanced stages of the disease. At onset, deficits of only one or a few cognitive domains are not uncommon (Capitani, Della Sala,

33.

& Spinnler, 1986; Della Sala, Nichelli & Spinnler, 1986a; Martin et al., 1986). As an example Table 33.1 shows the data of a sample of 39 patients with Alzheimer’s disease (AD) in the early stage, tested with a large psychometric battery (Della Sala et al., 1986a). The performance of these patients was classified as “global deficit” or “pseudo-focal deficit” according to whether they were showing impairment in all or only in some of the cognitive domains assessed, i.e. memory, language and visuo-perceptual abilities. The table shows that pseudo-focal onset is not rare (23%) in AD. From what we have discussed so far, it appears that should we assess any AD patient very early on in the course of his/her disease (i.e. immediately after the threshold for functional redundancy in the neuronal network has been exceeded), we would observe a particularly selective pattern of deterioration, which later will spread to encompass other neuropsychological functions. For the sake of argument let us assume that we never diverted our observation from the patient, whom we assessed online. We would detect two phenomena: the worsening of the onset symptom (e.g. episodic anterograde amnesia) and the appearance of a second cognitive deficit, heterogeneous to the first (e.g. fluent aphasia). Later on a third neuro-

SLOWLY PROGRESSIVE COGNITIVE DEFICITS

psychological symptom would be detected, while the first two become more and more severe. It is obvious that if, as is often the case in clinical practice, we first assessed the patient only after the third deficit cropped up, we would observe the polymorphous neuropsychological picture typical of AD. Sometimes the serried progression of the disease could be reconstructed by a careful history taking. Now, suppose that the very first symptom remained isolated for months or even for years. In this latter case we would observe its slow deterioration, perhaps coupled with its spreading to anatomically (and perhaps functionally) close deficits (in the current example adding retrograde to anterograde amnesia). This would be the clinical picture of SPICD. Accepting the assumption (not universally subscribed to) that any neurological degenerative process as such is indefinitely progressive, it derives that the only variable which, at this stage of knowledge, allows a working definition of SPICD should be time-based. It is common experience that once a second neuropsychological deficit, heterogeneous to the first, comes forth, the typical pattern of a full-blown dementia emerges rapidly. The proposed critical interval between the first and the second cognitive deficit to allow the diagnosis

TABLE 33.1 Selective, partly selective or global cognitive deficit in 39 patients with early stage Alzheimer’s disease. Each cognitive domain (language, memory and spatial-perceptual skills) has been assessed with a 4-test battery (modified from Della Sala et al., 1986a). Cognitive domain L only SP only M only L+SP M+L M+SP L+PS+M

AD patients Selective deficit (23%) 4 1

4

Mean duration of the disease in years 1.7 5.0 1.5

Partly selective deficit (21%) 0

7 1

Global deficit (56%) 22

L = language M = memory SP = spatial-perceptive skills

777

1.5 4.0 2 .2

778 DELLA SALA AND SPINNLER

of SPICD has varied between two (Weintraub & Mesulam, 1993) and five years (De Renzi, 1992). We suggest three years, not only as a sound compromise, but also on the basis of syndromic trajectories of AD patients, which established 35 months as the limit of pseudo-focal onset of typical AD (Haxby, Raffaele, Gillette, Schapiro, & Rapoport, 1992). Of course this is not a dogma, and new meta-analyses might well show its limitation, or even demonstrate the need to adjust this time-based working definition to fit differential clinical progression of the diverse SPICD. The role of individual variability, pre-morbid cognitive and synaptic architecture, and different underlying pathologies, is still obscure; even the role of age at onset of the degenerative process on the pace of progression of the disease is far from understood (Capitani, Della Sala, & Spinnler, 1990; Bracco, Gallato, Grigoletto, Lippi, Lepore, Bino, et al., 1994). It may be linked to neuronal reserve of the relevant functional system. Therefore, degenerations of the central nervous system that lead to cognitive disability might be classified as follows: (i) classic chronic progressive cognitive deterioration (see Chapter 30): between the first (also from the clinical history) and the second cognitive deficit, less than 36 months; (ii) SPICD: between the first and the second deficit, more than 36 months. The use of this scheme might ease the nominalist uniformity of the diagnosis. A methodological caution is worthwhile. Before labelling patients as SPICD it is important to check their cognitive status many times and longitudinally, using both a very accurate history-taking technique and a large psychometric battery (possible using tests with norms) to demonstrate that the clinical picture is really monosymptomatic. The follow-up should be prolonged for many years, to detect the incipience of a full-blown dementia, which we deem ineluctable.

SLOWLY PROGRESSIVE APHASIA Slowly progressive deficits of language were the first SPICD to be reported (Franceschi, 1908; Pick, 1892; Rosenfeld, 1909; Serieux, 1893) (see also

Chapter 32). At the beginning of the twentieth century several cases could already be gleaned from the literature (Mingazzini, 1914, see review by Poeck & Luzzatti, 1988); slowly progressive aphasias were also the first SPICD to be reappraised in recent times (Mesulam, 1982). The conundrum of language deficits in the frame of cortical degenerative diseases is still (Della Sala, Luzzatti, & Spinnler, 1986) a matter of debate which sprang up at the turn of the century between Arnold Pick, active in Prague (Kertesz & Kalvach, 1996) and Alois Alzheimer (1911), then working in Heidelberg. The controversy revolved around the concept of dementia itself (see also Chapter 30). Pick conceived dementia as the accretion in time of isolated neuropsychological symptoms, i.e. the summation of various dementias en miniature. Conversely, Alzheimer, following Wernicke (1906), considered dementia a progressive homogeneous deterioration of all cognitive functions, therefore denying the possibility of isolated deficits, such as the slowly progressive aphasias. The contention could not be solved by histopathological studies, and Alzheimer himself very cautiously postulated the hypothesis of two diseases, anatomically distinct—one, which took his name (Kraepelin, 1910), being characterised by deposits of amorphous material scattered through the brain and detected by silverstained methods (the so-called senile plaques), by the presence within the brain cells of neurofibrillary tangles, and by granuovacualar degeneration of hippocampal neurones; the other (later named after Pick) histopathologically hallmarked by ballooned neurones with inclusions (so-called Pick’s cells). The four cases originally described by Pick (1892, 1904, 1906) are summarized in Table 33.2. They were all characterised by symptoms due to left hemisphere lesion, and indeed the atrophy of the left hemisphere (in particular of the temporal lobe) was prevalent. Therefore, the idea of a slowly progressive aphasia associated with left temporal degeneration was put forward. To illustrate the difference between aphasia in Alzheimer’s disease and slowly progressive isolated aphasia we report the case of two patients who came under our observation with similar complaints but with rather different clinical histories.

33.

SLOWLY PROGRESSIVE COGNITIVE DEFICITS

779

TABLE 33.2 The four cases originally reported by Pick of dementia hallmarked by slowly progressive aphasia and prevalent atrophy of the left hemisphere, in particular of the temporal lobe. M a c r o s c o p ic a n a to m y ( h e m is p h e r e ) Y ear

C lin ic a l d a ta

1892

A .H ., M, 71 yrs (24 m onths since onset), sensory transcortical aphasia

1904

V.J., F, 58 yrs (24 m onths since onset),

T ransversal diam eter in the left tem poral

am nesic aphasia

in the left tem poral lobe 1cm shorter than the right

1906

F = female

L e ft

R ig h t

470 gr

500 gr

A .J., F, 75 yrs (36 m onths since onset), am nesic aphasia, alexia, agraphia and cortical deafness

377 gr

430 gr

J.V., M , 60 yrs (24 m onths since onset), am nesic aphasia, ideom otor and ideational apraxia

385 gr

460 gr

M = male

One of these two patients (ST) showed a clinical course very similar to the patients reported by Mesulam (1982); the other (EV) presented with a comparable language deficit, which quickly evolved into a full-blown generalised dementia of the Alzheimer type. The comparison of these two cases demonstrates that the distinction between the two forms of slowly progressive cognitive derangement could only be based on the time of its epicrisis.

Case ST ST, a 67-year-old chemist, came to our unit complaining o f slowly progressive language deficits, insidiously begun some three years before. These deficits became so severe as to convince the patient that he must leave his work. His spontaneous language was very poor and verbal communication was severely limited by several anomias, phonetic paraphasias, and frequent utterances and interruptions o f the fluency o f the speech. Most o f S T ’s attempts to communicate ended up in stock-phrases, emptied o f content. In the formal language examination (AAT; Gavazzi, Luzzatti, & Spinnler 1986) ST showed deficits in repetition, naming, and comprehension, but no dysarthria. Written language was relatively preserved, both in

spontaneous writing tasks and under dictation, as was his reading ability. Other tests based on the use o f language, such as verbal fluency, word association, short and long verbal memory were severely impaired (see Table 33.3). ST did not show overt deficits in any other cognitive domain, neither in everyday tasks nor in formal assessment (see Table 33.3). The neurological examination was normal. The patient did not show impairment in tests o f ideo-motor and oro-facial apraxia. Four years from onset, ST was still carrying on most o f his daily routine, including the administration o f family affairs. His language skills, though, decreased even further. Communication o f verbal content was virtually impossible; his speech, still exempt from articulatory problems, was fluent but curtailed to stereotyped sentences florid in neologisms. Now ST was also showing a severe impairment o f auditory comprehension, and in the attempt to grasp the meaning o f a question he repeated it silently to himself over and over. He could no longer write although he did not show overt decrement in tasks o f repetition, reading, and dictation. ST did not show any deterioration in extra-verbal cognitive domains (see Table 33.3).

780 DELLA SALA AND SPINNLER

from the oligo-symptomatic language-centred SPICD to a global dementia, indistinguishablefrom a typical Alzheimer’s Disease.

Five and a half years after the onset o f the disease, ST had a disorientation episode: he cycled to the nearest motorway and could notfind his way home. His relatives reported similar episodes o f spatial disorientation in the following months, and some instances o f confusion. He began to show more widespread symptoms akin to those o f typical dementia: his clinical picture rapidly transmuted

Case EV A 64-year-old engineer, EV had complained o f anomias, writing difficulties, and some memory problems fo r some months. The neurological

TABLE 33.3 Neuropsychological assessment of patients ST and EV. The scores are adjusted for age and education. T est (b e s t p o s s ib le s c o r e )

E.V. ( 6 4 y e a r s )

S.T. ( 6 7 y e a r s ) 1st a ssessm en t

(a f e w

m o n th s

2 n d a ssessm en t

(o n e y e a r

I

1 st a sse ssm e n t 2nd. a sse ssm e n t

(th re e y e a r s

(s ix m o n th s

p o s t o n s e t)

a f te r th e f i r s t)

p o s t onsets )

p o s t o n s e t)

19* 0 * 0 * 8 * 125(67) 83(93) 72(43) 2.25* 0 * 0 * -

16.5* 0 * 0 * 2 * 117(56) 82(93) 50(41) 0 * 0 * 0 * -

5 15.61 36.25 12.75 25 32.5 7.25 12.25 30

5 7.39 46.25 12.75 24 33.5 6.25 11.25

Amnesic aphasia

Transcortical sensory aphasia

Amnesic aphasia

No changes

Left atrophy more pronounced

(i) Verbal tasks

Token test (36) # Semantic fluency # Word association + Object naming (32) Repetition t Written language $ Comprehension (auditory/written) t Verbal span (forward bisyllabic words) # Supra-span learning (Buschke-Fuld) (180) # Prose memory (151)° Verbal judgements (60) #

29 4.5* 2.25* 15* 117(56) 64(54) 76(46) 3.25* -

34.75

* * 0.25* 7 * 109(49) 42(49) 72(43) 2.25* 33* 0 * 2 1 0

(ii) Non-verbal tasks

Spatial span (9) # Supra-span learning (Corsi) (29.16) # Digit cancellation (60) A Constructive apraxia (14) # Segment length discrimination (36) # Raven Progressive Matrices (48) # Weighs Sorting Test (15) # Elithorn’s Perceptual Maze (16) # Gottschaldt’s Hidden Figures (34) t

-

-

43.25 12.75 -

19.5 7.25 10.75 25

* * 7.25* 10.75 2

0

21

* 8.25 5.25*

0

-

(iii) Aphasic syndrome

Severe Wernicke aphasia with semantic aphasia

|

(iv) CT scan

Minimal symmetrical atrophy 1

Even larger L-R difference in atrophy

* scores below cut-off; # Spinnler and Tognoni, 1987; + Bandera et al., 1991; - Novelli et al., 1986; t Gavazzi et a., 1986 (percentile scores in brackets); 0 Capitani et al., 1994; '' Della Sala et al., 1992; t Capitani et al., 1988.

|

33.

examination was normal. A formal language assessment revealed the presence o f frequent anomias and several paraphasias, some agraphia but no overt deficits in reading aloud. An extensive neuropsychological assessment showed a mild acalculia, but neither ideo-motor nor oro-facial apraxia were detected. EVdid not show agnosia or spatio-temporal disorientation and he performed all tests tapping executive functions and attention within the normality range (Table 33.3). The patient was testedfrequently in thefollowing months. His neurological picture did not change. However, his language deficit worsened and his performance on several extra-verbal neuropsychological tests declined. Six months after the first assessment his speech was belated and burdensome, although still without articulatory problems. His verbal communication attempts were scattered by frequent anomias and ineffective circumlocutions sometimes intermingled with par agrammatisms and blendings. Repetition and writing under dictation were relatively more impaired than reading aloud. Notwithstanding a few relatively spared cognitive domains, his overall neuropsychological deficits spread well beyond language (Table 33.3). In the following months, E V ’s cognitive picture worsenedfurther, to the point of impeding any social life. He stopped reading the newspaper and lost interest in family affairs. His language deficit became so severe that he could no longer express even the simplest o f concepts and was reduced to passe-par-tout words and stock-phrases; paraphasias, mainly semantic, were numerous and his speech output little more than pure jargon. Neuropsychological assessment demonstrated a further spreading o f his symptoms which now encompassed ideo-motor and constructive apraxia as well as a severe acalculia. In the following year E V ’s clinical picture developed into a severe global deterioration; he became inert, lost the ability to look after himself, and needed supervision to have a wash and eat. His language consisted only o f some logoclonic stereotyped utterances: formal testing was impossible. Summing up, EV showed a slowly progressive language deficit which remained isolatedfor almost

SLOWLY PROGRESSIVE COGNITIVE DEFICITS

781

a year, then evolved into a homogeneous deterioration o f many cognitive domains. Alzheimer’s disease was considered the most probable diagnostic label.

SEMANTIC DEMENTIA The clinical picture that we are going to describe has been recently postulated, and not universally agreed, as a possible variant of the slowly progressive aphasia discussed in the previous section. It has been proposed to distinguish two clinical pictures between the progressive aphasies. This distinction is not dissimilar from the classic dichotomy stemming from the studies of focally lesioned patients: fluent and non-fluent progressive aphasies (see Chapters 8 and 9 this volume). Schematically, the picture of progressive fluent aphasies is characterised by slowly progressive anomia coupled with semantic paraphasias, whereas phonology and articulation are preserved. Non-fluent progressive aphasies present with a troublesome articulation of verbal sounds, even at the level of single words, and phonetic paraphasias. Within the fluent progressive aphasies, it has recently been proposed to disentangle those with a clinical picture similar to that presented by patients with a focal left retro-rolandic lesion, i.e. patients with a clinical picture essentially centred on anomias and semantic paraphasias (Hodges, Patterson, Oxbury, & Funnell, 1992; Patterson & Hodges, 1992; Saffran & Schwartz, 1994) from those with agnosie, (for instance prosopoagnosic) traits (Barbarotto, Capitani, Spinnler, & Trivelli, 1995). Their atrophy extends to the right hemisphere (Barbarotto et al., 1995; Breedin, Saffran, & Coslett, 1994). The neuropsychological profile of these latter patients seems to indicate a supra-ordinate deficit, semantic in nature, sometimes characterised by categorical specificity (Barbarotto et al., 1996). The clinical picture of these patients is the focus of the present passage. Currently these patients are classified under the term of “semantic dementia” first proposed by Snowden et al. (1989) and then adopted by Hodges et al. (1992, 1994) and others. The slowly

782 DELLA SALA AND SPINNLER

progressive semantic deficit might remain isolated for a long time (Barbarotto et al., 1996; Basso, Capitani, & Laiacona, 1988; Breedin et al., 1994; Funnell, 1995; Hodges et al., 1992,1994; Patterson & Hodges, 1992; Snowden, Griffiths, & Neary, 1994; Taylor & Warrington, 1971; Tyrrel, Warrington, Frackowiak, & Rossor, 1990; Warrington, 1975). The multifarious neuropsychological derangement of Alzheimer patients often includes semantic deficits. As for the majority of the clinical forms discussed in this chapter, only appropriate longitudinal studies will probably clarify whether the isolated semantic deficits and their anatomical correlate hallmarked by a selective atrophy of the dominant temporal lobe (Hodges et al., 1992) should be conceived as unusual onsets of a more generalised dementia, or if they deserve a place on their own within the taxonomy of cortical degenerations. While this riddle is tapped by ad hoc studies we deem it convenient to use the term “slowly progressive semantic dementia” to identify these patients, even though literally this term is inappropriate, as these patients are not demented. In the Japanese literature they are, perhaps more appropriately, labelled Gogi aphasia, i.e. aphasia for the meaning (see e.g. Tanabe, Ikeda, Nakagawa et al., 1992,1994). The lack of conceptual (abstract) representation of objects has been frequently observed in brainlesioned patients affected by nondegenerative pathologies, typically herpetic encephalitis (e.g. De Renzi, Liotti, & Nichelli, 1987; Laiacona, Barbarotto, & Capitani, 1993; Warrington & Shallice, 1984). The investigation of such cases was prompted by the patients reported by Taylor and Warrington (1971) and by Warrington (1975). These patients showed normal perception and were able to construct normal 2[àD and 3D (Marr, 1982) representation of the objects. However, they failed to recognise and to name the objects, whether the stimuli were visually or acoustically presented. They were also very anomic and failed to understand the names of the same objects both acoustically and in written form. However, these patients performed normally on intelligence tests (for instance the patient AB, reported by Warrington, 1975, had an IQ of 122). Warrington

therefore put forward an hypothesis similar to that postulated by Liepmann (1908): the recognition deficit might be interpreted in terms of deficiencies in the semantic network; these deficiencies were thought to muddle the semantic representations of the non-recognised non-named objects. Liepmann (1908) devoted an insightful dissertation to the agnosic deficits sometimes arising in “senile dementias”. In these demented patients the object recognition failure did not arise from a deficit in matching the perception of the outer world to the crystallised engrams (dissolutorische Agnosien, to use Wernicke & Lissauer’s terminology). Rather, the recognition failure was due to the acquired deficit in accessing the concept (engram) of the object, causing the breakdown of verbal (e.g. categorisation) and non-verbal (e.g. handling) performance. Liepmann labelled these agnosias, recently reappraised as semantic dementias (Snowden et al., 1989), “disjunktive” (or ideatorische). The careful assessment of the patients with semantic impairment demonstrated that the deficit was very rarely uniform across all possible fields of knowledge. Some of these patients (e.g., Warrington and Shallice, 1984) presented with peculiar dissociations in performance, for instance between the ad hoc created categories of living (e.g. animals, vegetables) and non-living items (e.g. man-made tools). Although this particular dissociation has been criticised on the basis that animate objects have high structural similarity (Riddoch & Humphreys, 1987a), several other peculiarly sectorial semantic deficits have been reported, pointing to the notion that semantic deterioration is not a homogeneous process (Sheridan & Humphreys, 1993). Rather, it is believed to be characterised by the lack of access to some specific categories of knowledge, which may be different in different patients. To support the notion of such selectivity, it is worth emphasising that most of the reported patients with semantic dementia, unlike Alzheimer patients (Dall’Ora, Della Sala, & Spinnler, 1989) and retrograde amnesics (Della Sala, Freschi, Lucchelli, Muggia, & Spinnler, 1996), performed normally on autobiographical enquiries. From our discussion, it should be clear the interest these cases raise in trying to understand the

33. SLOWLY PROGRESSIVE COGNITIVE DEFICITS

783

organisation of the “general knowledge of the world” in the human brain. An old hypothesis (Collins & Quillian, 1969), in analogy with Linnaean taxonomies, held to an hierarchical organisation in which information was ordered in supraand sub-ordinate patterns: the latter were thought to be more vulnerable to brain pathology (Patterson & Hodges, 1994; Shallice, 1988). More recently, other authors (e.g. Rapp & Caramazza, 1989), taking as a model the neuronal network of the Parallel Distributed Processing systems, proposed the view that the richer the associative cerebral/cognitive network of given information, the more resistant it would be to the assault of the disease. The testing paradigm used in different studies might well be a very important variable in guiding the speculations on the data gathered (Funnel, 1995; Hodges, Graham, & Patterson 1995). The neuropsychological picture of the slowly progressive semantic dementias has still to stabilise due to the unrelenting publication of new cases. To date, its most salient characteristics can be summarised as follows:

disease, whose lexical/semantic deficit, similar to the case reported by Breedin et al. (1994), was category-specific (more pronounced for living objects). Magnetic resonance revealed a bilateral temporal atrophy. The right temporal atrophy detected in the slowly progressive prosopagnosic patient (see later) reported by Evans et al. (1995) tallied with the observation of a severe prosopagnosia noticed by Barbarotto et al. in their case. Henceforth, there might be two forms of “semantic dementia”: one more linked to left temporal damage (lexico-semantic type) and another due to right temporal lobe derangement (agnosic-prosopagnosic type). The notion is upheld of a strict link between these forms and the frontotemporal dementias with temporal prevailing deficit (Neary & Snowden, 1996). As an example of the clinical history and neuropsychological profile of a typical patient with semantic dementia we now describe a case (case 3) taken from the sample reported by Hodges et al. (1992).

. Patients are nondemented either in everyday behaviour or on psychometric screening tests. 2 . Patients seek medical advice because of slowly progressive insidious language deficits, which consist of frequent anomias in an otherwise fluent speech. When formally tested they show non-modality-dependent naming deficits for common objects; often even to provide a name of a verbally defined object proves an insurmountable task. Verbal comprehension is also impaired and often the patients show a reduced verbal fluency, sometimes limited to a few semantic categories. Syntax and grammar are relatively spared. 3. The pre-semantic perception is normal. However, the patients do not recognise an increasing (with the progress of the disease) number of common objects (or pictures of them) in any sensory modality, not even with the help of verbal definition. The objects they fail to recognise are the same as those they fail to name.

MC, a 42-year-old teacher was referred to Hodges et al. (1992) after a history o f 2-3 years o f anomias and comprehension deficits. The patient became aware o f her difficulties trying to help her sons with their homework. Soon thereafter her comprehension deficit, in particular fo r proper names, was noted by her relatives, who also pointed out her semantic errors in everyday spontaneous conversation. On the other hand, MC did not show any memory problem. She was perfectly able to plan her own time and activities, and she was still supervising the organisation o f her largefamily; no behavioural change was noticed and the patient was absolutely aware o f her deficit. On formal tests, MC demonstrated normal fluency and prosody, no syntactic errors but a few semantic paraphasias. Her performance o f naming tasks was pathological. Moreover, she had clear difficulty in reading irreglar words and in spelling. She did not show acalculia, was well oriented, and did not show any deficit in perception or spatial knowledge. A CT scan and a bloodflow investigation (SPECT) did not reveal abnormalities.

Case MC 1

Barbarotto et al. (1995) recently reported the case of a patient likely to be affected by Pick’s

784

DELLA SALA AND SPINNLER

After a year her memory and visuo-spatial abilities were still intact. However, her semantic breakdown worsened considerably. Furthermore, some behavioural modification emerged, among which were the traits o f the KlUver-Bucy syndrome. The neuroradiological investigations demonstrated a bilateral temporal atrophy, more evident in the polar aspects o f the lobes and more pronounced in the left hemisphere.

SLOWLY PROGRESSIVE APHEMIA To the best of our knowledge, isolated progressive “loss of speech output” (aphemia in our terms) has been formally reported only once (Tyrrel et al., 1991). Aphemia (Déjerine, 1914) defines the “deficit of the articulatory motor sequences” (Heilbronner, 1910); that is, a deficit of the program of the motor engrams specific for language (Broca, 1888). This deficit has been recognised since the dawn of aphasiology as a possible sequela of a focal lesion in the anterior areas of the dominant hemisphere. We will use the term “slowly progressive aphemia” to identify the few cases one can glean from the literature of patients showing a progressive loss of speech output characterised by deficits in producing articulated language ( “les sons articulés du langage”; Broca, 1888). The slowly progressive aphemia could be isolated or, often, coupled with overt oro-facial apraxia. From a taxonomic point of view it can be debated whether or not one should consider progressive aphemia as a variant of the “anterior” slowly progressive aphasia. Heilbronner (1910) maintained the need to differentiate between articulatory deficits due to neurological (e.g. paralysis, ataxia, amyotrophy, spasms or tremors of the phonatory muscles) and ear-nose-throat (e.g. tumours of the pharynx) aetiologies, which he labelled with the umbrella term “dysarthrias” or “anarthrias”, from those that could be attributed to a neuropsychological cause. However, as Bonhoeffer ( 1895) had already pointed out, this distinction proved to be a far from easy task. One classical example of this difficulty comes from the analysis of some of the symptoms characterising

the anterior bi-opercular syndrome (known as FoixMarie-Chavany) which could be described either as a “central paralysis” or as an “oro-facial apraxia” (Mariani et al., 1980). The distinction between neurological and neuropsychological forms could mirror the lesion (in the case under discussion degenerative in nature) site. If the lesion encroaches mainly upon a projective area (in the case at issue, for instance, the primary motor area in the inferior half of the pre-central homunculus) the clinical picture will be classified as neurological. On the other hand if the lesion damages an associative area (for instance the cortex of the frontal operculum) then the symptoms fall into the domain of neuropsychology. It is worth emphasising that the two types of areas can be contiguous and therefore, in theory, a lesion could damage them both. This is even more apparent in the case of a degenerative disease which can slowly spread to encompass nearby areas. Liepmann ( 1900, 1913) traced back the neuropsychological aphemias to a deficit eminently apraxic in nature ( “Sprachglidkinetische Apraxie ” and “Apraxie des Sprachapparates ”) pointing to the fact that often the deficit did not involve other functions that use the same neuro-muscular apparatus, such as the act of swallowing. This view was later shared by Pick ( 1913) and by Kleist (1934) who identified the “Lautstummheit” (dumbness of articulated sounds). In some of his cases Kleist reported a clear dissociation within language output, the articulation being devastated in the presence of normal writing skills. Most of the slowly progressive language deficits (reviewed by Poeck & Luzzatti, 1988) can also be found in patients affected by dementia of the Alzheimer type. This is not the case for dysarthrias that are seldom associated with the clinical picture of cortical dementias. Dysarthria is not listed among the symptoms that characterise frontal dementia (see Chapter 32, Boiler & Muggia, this volume), a feature confirmed by our own series of 1 1 cases of fronto-temporal dementia. This is probably the reason why Tyrrel et al. (1991), describing three cases of slowly progressive aphemia, opted for the descriptive label of “progressive loss of speech output and oro-facial dyspraxia”. The cases reported by Tyrrel et al. (1991) can undoubtedly be

33. SLOWLY PROGRESSIVE COGNITIVE DEFICITS

classified as another example of SPICD. All the three cases observed by Tyrrel et al. showed dysarthria from the very onset. Dysarthria deteriorated to a complete mutism and eventually was coupled with severe oro-facial apraxia. All other cognitive functions, including verbal comprehension and writing skills, remained unhampered. This picture closely resembled that reported by Nathan (1947) in patients with left fronto-parietal lesion due to missile injuries and named by him “cortical dysarthria”. In agreement with Nathan’s neurotraumatological observations, PET investigations performed on the patients reported by Tyrrel et al. (1991) showed bilateral hypometabolism in the frontal lobes, particularly overt in their inferior portions. This anatomical correlate is also congruent with the anatomopathological observations of Kleist (1934) in patients showing the clinical picture he named “Gliedkinetische Apraxie ” (a form of apraxia which was also known as “melokinetic” when referred to limbs). However, contrary to the cases with focal lesion observed during the war period, Tyrrel et al.’s patients, after an interval that varied from six months to four years, showed a marked deterioration and their deficits spread to encompass other language skills and then other cognitive domains. Eventually the picture became indistinguishable from that of a typical full-blown global dementia. The picture of the cognitive symptoms was similar in all the three cases reported by Tyrrel et al. However, the accompanying neurological symptoms were markedly different. Cases 1 and 2 showed a normal neurological picture with the partial exception of a few release signs (e.g. snout reflex). On the other hand, case 3 complained of swallowing difficulties, particularly for liquids without nasal regurgitation. Moreover, on the general neurological examination he showed muscle waste, scattered fasciculation, and bilateral extensor plantar response. Electromyography (EMG) showed “fasciculation with fibrillation, and sharp waves in upper and lower limbs, consistent with anterior horn cell disease” (Tyrret et al., 1991, p.353). The neurological features presented by case 3 of Tyrrel et al.’s series call for a differential diagnosis

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with other neurological degenerative diseases. This need is sustained by the notion that, although nontypical (Capitani, Della Sala, & Marchetti, 1994), cases can be gleaned from the literature of motoneurone disease associated with dementia of the frontal type (Mitsuyima & Takamiya, 1979). Moreover, rare instances of pure supranuclear motor degeneration have been reported (Beal & Richardson, 1981; Russo, 1982). This rare supranuclear variant runs a slower course than the typical amyotrophic lateral sclerosis and can mimic a pseudobulbar palsy (Gastaut et al., 1988). Cases of this particular variant of motor system degeneration have been reported which are phenomenologically reminiscent of the anterior opercular syndrome (Foix, Chavany, & Marie, 1926). The frontal operculum (see Fig. 33.1) is a poorly defined anatomical area (De Smet, 1994). It is contiguous with the foot of the frontal motor cortex and lies just behind the portions of areas 44 and 45 (Broca’s areas in the left hemisphere) which are dipped inside the Sylvian scissure (Brodal, 1992; Bruyn & Gathier,1969; Foerster,1936; Testut, 1915). This area has been identified in the macaca mulatta as the cortical locus responsible for the homolateral (rostral part) and contralateral (posterior part) movements of the lower muzzle muscles and of the larynx (Crosby et al., 1962). The data from comparative anatomy might assist in accounting for the bipolarity of the deficit due to a unilateral frontal opercular lesion, provided one takes for granted the undemonstrated lack of redundancy in the functions of the undamaged operculum. A bilateral lesion of the frontal operculi produces a paralysis of some of the movements of the face muscles and of the larynx and pharynx (Alajouanine & Thurel,1933). Therefore, the affected patients are unable to perform a facial movement on command. Moreover, as they cannot command their tongue, lips, and cheeks appropriately, they soon become dysarthric. The aetiology of the bi-opercular syndrome is for the most part vascular (Mariani et al., 1980), although observations of slowly progressive degeneration of the supranuclear motor system have been recently reported (Bruyin et al., 1995; Pentore et al., 1995; Weller etal., 1990).

786 DELLA SALA AND SPINNLER

FIGURE 33.1 The frontal operculum in a left lateral view of the human brain.

The problem of interpreting these symptoms as a lack of supranuclear innervation (paralysis) or as a lack of praxic control of the motor sequences becomes obvious. For instance the case reported by Venneri et al., OB, for three years showed only dysarthria and oro-facial apraxia. However, eventually the patient developed a spastic tetraparesis without general cognitive derangement, therefore a “neurological” and not “neuropsychological” picture, accordingly to Heilbronner’s dichotomy. On the other hand, other cases, such as cases 1 and 2 in Tyrrel et al.’s series, or the case RW (Carey, Coleman, & Della Sala; unpublished observation, case still under study) did not present any neurological or neurophysiological abnormality after, respectively, three, six, and five years from the onset of dysarthria. We observed cases of slowly progressive aphemia. Given their rarity we report two of them in detail.

Case EN We first saw EN, a multilingual international telephone operator, a year after she started to complain o f progressive language deficits. The neurological examination revealed only the presence o f a clear “motor impersistence,y and a slight amimia. No cranial nerve deficit was detected, no problem in swallowing nor rinolalia.

Several EMGs excluded the presence o f denervation signs and repeated magnetic resonance revealed some generalised aspecific cerebral atrophy unusual fo r the age o f the patient. A formal language assessment (Italian version oftheAachenerAphasieTest;Luzzatti, Willmes, & De Bleser, 1991) revealed that EN showed a severe deficit in her spontaneous speech. Conversation aboutfamiliar topics proved troublesome even with the help o f the examiner and often EN failed to convey the message she wanted to communicate. Articulation was normal fo r three-four syllable words, but was very cumbersome with longer words, and sometimes E N ’s attempts to communicate resulted in a logoclone. The structure o f the sentence was simplified, though true agrammatism was notan issue. Phonemic paraphasias were very rare and she performed normally on tests o f language comprehension: all in all aphasic deficits were at the most uncertain. The articulation problem was paramount. The neuropsychological assessment demonstrated a grave oro-facial apraxia which also encompassed eye and eyelid movements. EN could not close her eyes on command and failed to move her eyes in either direction without at the same time turning her head (note the analogy with the classic case o f Lewandowsky, 1907). The clinical picture was that o f an innervatory apraxia o f the face, the

33. SLOWLY PROGRESSIVE COGNITIVE DEFICITS

tongue, and the larynx like that reported by Kleist (1934) in patients with lesions at the foot o f the frontal lobe, immediately in front o f the cortical motor face area. Moreover, EN showed ideomotor apraxia, more severe fo r thefine finger movements, and a mild dysgraphia, characterised by a few repetitions and omission o f syllables. Her performance on non-verbal memory and selective attention tests was at the lower end o f the normality distribution. On a second assessment, some months later, E N ’s articulation was worse and her speech was unintelligible. On a formal language test, her performance on verbal comprehension showed a clear deterioration. Contrarily, her scores on tests o f spatial abilities and visual perception were still within the normality range. The neurological examination was unchanged. E N ’s initial neuropsychological deficits, initially limited to a severe aphemia, spread to encompass other language skills and apraxia. We could not follow-up the patient with formal tests; however, her relatives updated us by phone on her condition: her behavioural and cognitive modifications pointed to a complete dementia, although the case rests on assumptions.

Case LMM The deficits shown by LMM consisted in gradually worsening language problems, which started slowly about a year before our first observation. The patient was then 62 years old. We followed her up fo r three years. The neurological examination revealed signs of right hemiparkinsonis, which could not accountfo r the bulk o f LM M ’s neuropsychological picture. CT scans were normal. Ourfirst assessment confirmed the presence o f language deficits, namely frequent anomias, incessant articulatory pseudo-stuttering problems and some instance o f agrammatism. Writing skills were unimpaired. The patient was living a very active social life and successfully supervised her nephew’s homework. Accordingly, her extra-language neuropsychological profile was entirely normal. After a year her language was clearly worse: the number o f anomias increased consistently and the use o f circumlocutions was not as successful as it

787

had been, mainly because new anomias found their way into every attempt she made to circumvent her word finding problem. Her verbal initiative appeared drastically reduced, her verbal output was little more than a series o f “telegraphic” utterances. Given her paramount articulation problems, it was not clear whether the anomias were true or could be accounted fo r by the constant struggle to complete a word, and failing to do so, trying with synonyms or circumlocutions that also were bound to misfire (Wortstummheit, dumbness fo r words). Therefore, her anomias might be different from those o f a typical aphasic patien t. LMM was now showing some writing deficits: she misplaced single or groups o f graphemes in a word. Moreover, she showed migrographia (she was affected by Parkinson’s disease). Conversely, her comprehension and reading skills were still unhampered, she was not showing overt cognitive problems in her everyday life and her performance on extra-verbal tasks was comparable to the previous assessment: in particular she was not apraxic. In the ensuing two years no neuropsychological or behavioural change was detected by her relatives. LMM, by now virtually mute (with the exception o f highly automatised sequencies, such as prayers), was still autonomous in her daily life, which she carried on on her own with considerable endurance. Her graphia became incoherent and the few words that were intelligible were flawed with orthographic errors; she could not read even to herself. She was well aware o f her increasing language deficit and deeply concerned by it. However, the formal neuropsychological assessment carried outfour years after the onset of the symptoms, demonstrated an initial spreading of the disease beyond language. LMM scored less well than in previous examinations on tests o f ideomotor apraxia, spatial memory and non-verbal intelligence (as measured by the Raven Progressive Matrices). Unfortunately, oro-facial apraxia was not tested. These cases of slowly progressive aphemia demonstrate the existence of a progressive deficit of word articulation, with insidious onset, which remain isolated and limited to the sequences of

788 DELLA SALA AND SPINNLER

phonemes and word stressing, often coupled with apraxia— oro-facial and ideomotor (Tyrrel et al., 1991)— and agraphia. In the course of our observation of the patients EN and LMM we could document only a mild spreading of the cognitive deficits beyond the language domain. The clinical picture is dominated by the wearisome articulation of the words, which prevents verbal communication. However, communication through gestures or miming is still possible. The language problem is particularly acute in spontaneous speech, but it might be noticeable even in automatic sequences (e.g. months of the year) and during repetition tasks. In many patients, perhaps all of them if longitudinally assessed, the deficit also spreads to written language, with frequent errors in graphemic sequencing. Comprehension is relatively spared, at least in the first years of the disease. The presence of true anomias is doubtful, given the laconicity of the language output. Agrammatism has not been thoroughly investigated, and nothing is known about the reproduction of non-verbal sounds, such as melodies or naturalistic noises.

SLOWLY PROGRESSIVE GERSTMANN SYNDROME Strub and Geschwind (1974) reported the case of a patient with slowly progressive Gerstmann syndrome. This case allowed them to support the notion of the syndrome itself and to dispute the hypothesis that the tetrade of symptoms of Gerstmann syndrome was entirely accounted for by the concomitant aphasia these patients often display (Poeck & Orgass, 1966).

Strub and Geschwind’s case A 52-year-old secretary from New Orleans was referred to the neurological ward because o f some worsening writing problems she was experiencing over one semester. Two months after the onset o f her writing difficulties, her arithmetic skills began to deteriorate. Because o f these problems she lost her job. The neurological and neuropsychological examinations were normal. Her speech was fluent with normal prosody, no reading, repetition,

naming, understanding, or spelling errors were detected in the formal language examination. On the contrary, writing was grossly impaired in all testing modalities, spontaneous production, under dictation, and copy. She was densely acalculic, both with oral and written presentation. She performed poorly on tasks o f left-right orientation (for instance she failed to indicate with her left hand the left hand o f the examiner) and had some problem with map reading. She also found it extremely difficult to set a non-digital clock. She showedfinger agnosia, although she could easily recite the names o f all fingers. Neuroradiology showed a mild aspecific atrophy and the authors made the diagnosis o f Pick’s disease, primarily involving the parietal lobe or, alternatively an atypical presentation of Alzheimer’s disease without memory deficits. Slowly progressive cases could give new fuel to the debate (for a review see Gardner, 1975) that is still hot (Benton, 1992; Della Sala, & Spinnler, 1994), revolving around the specificity of Gerstmann syndrome, perhaps offering some hints for a new, more cognitively oriented interpretation.

SLOWLY PROGRESSIVE APRAXIA Apraxia is not a common complaint in the early stages of Alzheimer’s disease (Della Sala, Lucchelli, & Spinnler, 1987). Moreover, contrary to the overstated (Cubelli & Della Sala, 1996) dogma of automatic/voluntary dissociation (see De Renzi, 1985, 1989 and Chapter 19 this volume) slowly progressive apraxia becomes severe enough to hamper the patients’ everyday activities (see e.g. De Renzi, 1986, case 3). Therefore, the few patients who present with isolated slowly progressive apraxia should stimulate the interest of neuropsychologists. We will give an account of some of the slowly progressive apraxic patients we have observed.

Case ML ML, a 69-year-old right-handed lady was referred to our unit because o f a gradual loss o f her manual skills, the insidious onset of which dated back about

33. SLOWLY PROGRESSIVE COGNITIVE DEFICITS

three years. She was aware o f her deficits and actively participated to reconstruct her clinical history with the help o f her husband. She first noticed that she had difficulty in writing. Her problems soon spread to other daily tasks, such as dressing, having a wash, and using kitchen tools. Her dexterity deteriorated to hinder virtually any finalistic use o f her hands, in particular her right hand. The severity ofM L’s apraxia was overt since our first assessment. Requested to put on her glasses (see Fig. 33.2), which she promptly recognised among other objects, she made several clumsy attempts, trying toforce the lenses o f her specs onto her forehead, hitting her nose with the bar, then putting them on with the frame upside down (laughing heartily at her own awkwardness). After various ineffectual endeavours the patient, to her dismay, gave up.

789

ML met analogous failures in any attempt to use the objects that the examiner passed over to her (see her fruitless effort to properly handle a bail-point pen in Fig. 33.3) Her speech was rather laconic, but exemptfrom articulatory deficits. Her answers were precise and straight to the point although scattered with hindrances, sparse anomias, and a tendency to verbal perseveration. A formal language examination elicited as many as 50% naming errors when items were verbally defined and a few paraphasias in object naming tasks. ML did not have any overt comprehension deficit and her repetition was errorless both fo r single words and fo r short sentences. Due to the severe apraxia she could not write even single letters. Her reaching was also impaired both in foveal and peripheral vision, her movements were always coarse and mainly performed with the upper parts o f the arms,

FIGURE 33.2

A sequence from a videotape showing various attempts by ML to put on her glasses. She first grabs them with her left hand (a), then she presses them to her right hand, but with the lenses toward her face and the bars down toward the table (b). She then tries to put them on with the frame upside-down (c,d) realises her errors and laughs at them (e), puts the spectacles back on the table (f) and tries again clutching them with both hands (g), and, after several failures, gives in, laying them on the table with the lenses upside-down (h).

790 DELLA SALA AND SPINNLER

FIGURE 33.3

A sequence from a videotape showing MLs attempts to write with a ball-pen. First she reaches for the ball-pen with her left hand, with her fingers inappropriately wide-open (a), she manages to grasp the pen, but points upwards (b), she then transfers the pen to her right hand (c) failing to hold it appropriately and dropping the grip (d).

while she used her hands as little more than unrefined appendices. Her motor sequences were often inappropriate, no matter how hard she tried to overcome her difficulties. The patient performed atfloor in allformal tests o f apraxia, in all modality of presentation, imitation, verbal command, use of objects, and oro-facial stimuli. It was possible to recognise the aim (the idea) o f each gesture she attempted, and her description o f what she intended to do was accurate. However, her gestures, invariably abortive, were performed in a manikinlike manner. Therefore, ML was not showing an ideative deficit o f intentional gestures, nor did she show deficits in the sequence o f the different components o f the intended gestures; rather her deficit might be subsumed as “innervatory”. Innervatory apraxia (“gliedkinetische Apraxie” in Liepmann \s terminology, 1920) also encompassed the so-called “Stand-Gangapraxie” (upright stance and gait apraxia) and trunk apraxia (“Torso-Apraxie”, Sittig, 1931). Kleist attributed this kind of apraxia to a bilateralfrontal lesion, with or without callosal involvement (Kleist, 1934). The neurological examination o f ML showed paratonia (Gegenhalten), a few release signs and some balance difficulties, more overt while walking. No paresis or ataxia was detected. MUs trunk movements were also clumsy and cumbersome in semi-automatic movement sequences such as sitting or lying down. She

performed these everyday actions wearily, literally letting herself drop onto the chair or on the bed “as a statue ” (her description). However, even for the clumsiest trunk movement the overall Gestalt was still recognisable, a feature reported in the classic innervatory apraxia cases. This picture is reminiscent o f that observed by Gerstmann and Schilder (1926) in patients with bilateral anterior focal brain lesion. Moreover, ML moved her forearms and hands in a single block, as if she had no wrists; her movements were puppet-like, akin to those o f a robot. Fine finger movements were impossible, and she used her right hand only as a rigid extension o f her arm (jokingly she described her hand as a small shovel). She could still use her left hand to perform goal-directed movements, although bulky, such as grasping her handkerchief to wipe her tears. Peripheral nerve conduction o f the peroneal nerves and bilateral somatosensory and auditory evoked responses were normal. A series ofCTscans showed generalised atrophy, slightly more pronounced in the peri-silvian region o f the left hemisphere (see Fig. 33.4). When we last saw her, four years after the onset o f her disease, MUs clinical picture was very severe, although the neurological examination did not change overtly, with the exception o f the deterioration o f her equilibrium, to the point that she could no longer walk without help. She could no longer look after herself (she could not wash or

33. SLOWLY PROGRESSIVE COGNITIVE DEFICITS

dress unsupervised). Moreover, she was incontinent and her language was unintelligible, but her comprehension remained unmodified, even when formally assessed. The patient was well aware o f the worsening o f her symptoms and extremely concerned about her failures. We labelled M Ls picture as slowly progressive apraxia, and diagnosed her apraxia “innervatory” (ormelokinetic). In the ensuing months she became progressively aphemic, supporting the view which interprets aphemia as an apraxic-innervatory deficit (see earlier). A few cases with a slowly progressive apraxia, similar to ML’s, have been reported in the literature. They are summarised in Table 33.4. Apraxia is extremely severe in all these cases, much more so than that usually observed following a left hemisphere focal lesion, and it hampers many everyday activities, including tasks that are generally assumed to be “automatic” (e.g. De Renzi, 1986; Rapcsaketal., 1995). In some of these cases agraphia is reported (Carey, Coleman, & Della Sala, 1996; De Renzi, 1986; Dick, Snowden, Northen, Goulding, & Neary, 1989; Habib et al., 1995; Moreaud, Naegele, & Pellat, 1996), in others it is explicitly excluded (Legeretal., 1991, case 1; Azouvietal., 1993, cases 2 and 3). Some show oro-facial apraxia (Azouvi et al., 1993, case 2; De Renzi, 1986, case 3; Della Sala &Spinnler, 1996), some do not (Azouvietal., 1993, case 1; Carey etal., 1997). Many cases present with

791

visuo-spatial deficits and gait or balance disorders; some show myoclonus and rigidity; eye movement deficits are also reported (see Table 33.4). Some cortical parietal atrophy is invariably present, often it is bilateral, and when it is unilateral, it is contralateral to the side of apraxia. Within the classic apraxia taxonomy, the ideational form (De Renzi, 1989) is the less frequently reported in the slowly progressive apraxic patients. Our patient ML, even in the late stages of her disease, showed good comprehension of the sequences of gestures she would have needed to perform the desired action. However, she was unable to perform it. Similar behaviour is reported in other cases (e.g. Dick et al., 1989; Leger et al., 1991). Apraxia is often bilateral (Azouvi et al., 1993, case 5; Carey et al., 1996; Caselli, Jack, Petersen, Wahner, & Yanagihara, 1992; De Renzi, 1986, case 3; Dick et al., 1989; Leger et al., 1991, case 2; Okuda, Tachibana, Kawabata, Takeda, & Sugita, 1992, case 1) and coupled with visuo-spatial deficits; therefore, it has been postulated that the most likely label for these patients’ movement planning deficit is ideomotor apraxia (De Renzi, 1992; Leiguarda et al., 1994). We maintain that the most appropriate diagnosis is innervatory apraxia (gliedkinetische, innervatorische, melokinetic, or kinetic limb apraxia; Blasi, Di Salle, Iavarone, Soricelli, & Carlomagno, 1994; Kleist, 1934; Liepmann, 1920; Luria, 1966; Moreaud et al., 1996). Melokinetic apraxia is characterised by the absence of the usual left hemisphere dominance for

FIGURE 33.4

MLs CT scan at onset (a) and after four years (b). Note the progressive asymmetry of the atrophy of MLs brain, which is more evident around the left lateral cerebral fissure.

r\D

£

1992

1993

Azouvi et al.

1991

Leger et al.

Caselli et al.

1989

Dick et al.

1992

1986

De Renzi

Okuda et al.

Y ear

A u th o r s

2

1

7

6

4 5

2

1

4

3

2

1

-

3

C ase

S id e o f

M F

77 51

R R

F F

53 59 L

L+R

L L+R

L+R

F F

F

64

L+R

64 57

M

72

6 8

L

L

M M

3

L+R

F

85 58

3

L

M

69

4

6

P atrophy L>R P atropy R>L

P atrophy L P atrophy L

4 2

P atrophy L>R

P atrophy R>L

-

-

2

1

1

1

-

-

atrophy L>R -

—

4

1

4

3

P atrophy R>L

T-P atrophy R>L

P atrophy R>L

P-0 atrophy R>L

P atrophy R>L

5

2

3

1

0.5

10

2

L+R

M

55

-

atrophy

no yes?

no no

no

no

yes

no

yes (7 yrs) no

yes (13 yrs) no

no

no

D e m e n tia

2

F o llo w - u p (y e a rs)

(y e a rs) L e s io n

D u r a tio n

L+R

s y m p to m s

M

G ender

61

A ge

Cases of slowly progressive apraxia reported in the literature.

TABLE 33.4 O th e r s ig n s o r

left proprioceptive deficits agraphia, visuo-constructive deficits, gait apraxia

anomia

left spasticity, astereognosis proprioceptive deficits, astereognosis quadrantanopsia -

gait apraxia, eye-movement problems rigidity, gaze palsy

myoclonus, visuoconstructivedeficits

visuo-constructive deficits

myoclonus, visuo-constructive deficits myoclonus, visuo-constructive deficits

reflex asymmetry, gaze palsy, trunk apraxia, agraphia, visuoconstructive deficits

paratonia ( g e g e n h a lte n ) visuoconstructive deficits, dysarthria

s y m p to m s

£ co

Ms D

MF

104284

75

70

6 6

6 8

S id e o f

L+R

L+R

F

3

3

1.5

R

P hypoperfusion L>R

Bilateral P atrophy

P atrophy L>R

P atrophy R>L

4

R L+R

P atrophy R

2

3

—

-

1

3

O th e r s ig n s o r

agraphia, visuo-spatial deficits, eye movement problems, left rigidity, dysequilibrium and unexpected falls, gait apraxia, extra-foveal magnetic ataxia

agraphia, visuo-spatial deficit, dysequilibrium, left rigidity, attitudinal tremor, gait apraxia

no

no

right rigidity, anomia, agraphia, myoclonus

visuo-constructive deficits, alien hand?, gait apraxia

right dystonia, vertical gaze palsy, dysequilibrium, gait apraxia, dysgraphia, alien hand?

left rigidity, visuo-constructive deficits

left dystonia, language deficits, anosognosia

visual extinction, reaching deficits, spatial disorientation, problems with saccades, left choreo-athetosic movements, foveal magnetic ataxia

s y m p to m s

no

yes

no

no

yes?

P atrophy R>L

D e m e n tia

F o llo w - u p

no

5

(yea rs)

P atrophy R>L

L e s io n

P hypoperfusion L

2

1

4-5

(y e a rs)

D u r a tio n

4

L

L+R

L+R

s y m p to m s

F

M

M

F

89828 71 102750

F

87632 63

F

G ender

M

61

A ge

86586 63

GW

C ase

M = man; F = woman; R = right; L = left; P = parietal; T = temporal; 0 = occipital.

1997

Carey et al.

1995

Habib et al.

1996

1995

Rapcsak et al.

Moreaud et al.

Y ear

A u th o r s

Cases of slowly progressive apraxia reported in the literature.

TABLE 33.4 continued

794 DELLA SALA AND SPINNLER

praxis (Freund & Hummelsheim, 1985; Kleist, 1934) and has been a matter of debate. Some authors considered it only the effect of a pyramidal lesion (Ajuriaguerra & Tissot, 1969). The supposed localisation of melokinetic apraxia contrasts with the generalised assumption that neuropsychological deficits observed in neurodegenerative diseases (in particular Alzheimer’s disease), are due to dysfunctions of the associative areas in the cortex. The classic authors (e.g. Kleist, 1934; Lange, 1936) maintained that melokinetic apraxia was often coupled with apraxia of stance and gait (Stand und Gangapraxie). Indeed, problems with balance and gait are frequently observed in patients with slowly progressive apraxia (see Table 33.4) as well as in late stages of Alzheimer patients. We turn now to the problem of the diagnosis of the slowly progressive apraxias. In the last few years progressive apraxia has been reported in the context of a symptom complex known as corticobasal degeneration (CBD) (Gibb, Luthert, & Marsden, 1989; Rebeiz, Kolodny, & Richardson, 1968). CBD is characterised by an asymmetric akinetic-rigid syndrome, often coupled with myoclonus, balance problems, eye movement deficits, and visuo-spatial impairments (Black, 1996). Apraxia, which is considered a key symptom of CBD (Gibb et al., 1989; Sawle, Brooks, Marsden, & Frackowiak, 1991), is present in about 70-80% at onset (Leiguarda, Lees, Merello, Starkstein, & Marsden, 1994) and in all patients in the later stages of the disease (Rinne, Lee, Thompson, & Marsden, 1994). Generalised dementia is seldom present, and usually in the later stage of the disease. Table 33.5 summarises the main clinical features of CBD. Analysing the data reported in Tables 33.4 and 33.5, it appears that the picture of slowly progressive apraxia overlaps considerably with CBD, and that apraxia is rarely isolated. Often it is coupled with other cognitive deficits, in particular, visuo-constructive difficulties, as well as neurological signs and symptoms, which are not incompatible with a diagnosis of CBD. Indeed, in some reports of cases of slowly progressive apraxia, CBD has been put forward as the most probable diagnosis (Carey etal., 1996; Moreaudetal., 1996; Okuda et al., 1992); however, other authors

TABLE 33.5 Clinical features of CBD in percentage, at onset and after 5 years of follow up. Symptom M o v e m e n t d is o rd e r

At A fter 5 onset* years**

Some rigidity Balance and gait difficulty Tremor Myoclonus Dystonia

100 73 48 67 67

100 97 ? 57 83

E ye m ovem ent p ro b le m s

59

90

31 ? 53 16 84

30 63 70 ? 100

C o g n itive deficits

Dementia Visuo-spatial deficits Dysarthria Aphasia Apraxia

Total number of cases = 64, based on summaries provided in Riley et al., 1990; Rinne et al., 1994 and Black, 1996 **Total number of cases = 30, from Rinne et al., 1994.

explicitly deny it (Leger, Levasseur, Baron, Cohen, Signoret, & Brunet, 1993). Caselli et al. (1993) emphasised that the histopathological pictures of the syndrome they labelled “asymmetrical cortical degenerative” (Caselli & Jack, 1992) are rather heterogeneous, and might vary from patient to patient. They maintain that the same may be true for CBD. Despite some attempts to disentangle slowly progressive apraxia from CBD (see Caselli et al., 1993 and Leger etal., 1993, for opposite views), we deem it difficult, given the dearth of new evidence, to conjecture reliable differential criteria.

SLOWLY PROGRESSIVE AMUSIA The patient described by Confavreaux et al. (1992) is unusual. She was a 63-year-old choral singer, who complained that she had been unable to sing for the previous two years. She also complained that she could not convey the desired intonation and emotion

33. SLOWLY PROGRESSIVE COGNITIVE DEFICITS

when reading fairy tales to her grandchildren, as she used to. Confavreux et al. (1992) indeed observed that her prosody was monotone and unemotional, and that she could not sing. In contrast, the content of her language was normal and appropriate and her comprehension flawless. She also performed normally on tests of naming, repetition, reading, writing, and arithmetic. Her memory was also normal and no neurological signs could be elicited by the medical examination. Moreover, she was not dysphagic. Neuroradiological investigations demonstrated a distinct atrophy of the peri-silvian region of the right hemisphere. The patient was assessed again three and five years later. The follow-up studies documented a clear worsening of her symptoms: her speech became gradually more difficult and slow, with many pauses, lack of melody, accent, and intonation; she was not aware of her own mistakes. She declaimed poems (Ross, 1981) with an aprosodic voice and was unable to show emotional facial expressions and gestures, although she could understand them in other people. However, she failed to recognise prosodic tones and regional accents. She was not demented, continued to care for herself, and played Scrabble with some success. Her performance on tests of intelligence and memory was well within the normality range. She did not have any problems with semantic and syntactic tasks; oral and written comprehension was unimpaired, as well as writing and mathematical abilities; only sporadic phonemic paraphasias were noticed. Furthermore, she did not show prosopagnosia or constructive apraxia. Somewhat surprisingly, given the prevalent side of lesion, she presented with orofacial, oculomotor, and eyelid apraxia in the absence of ideomotor apraxia. She had been an enthusiastic music-lover throughout her life, and a pianist herself. She now showed a severe amusia, which was assessed formally by Confavreux et al. (1992) following the criteria proposed by Henson (1985). She could still detect the pitch of a note and recognise them on the score. However, she lost the capacity to sing, even single notes, or well known melodies (she reproduced the words of popular songs with a

795

monotone, unmodulated voice without any rhythm). Two years later (i.e. nine years after the onset of the symptoms), the patient demonstrated some deficit in several everyday activities, and her speech production was by now severely impaired and very hesitant. A new MRI showed the extension of the previously observed cerebral atrophy, which now infringed on the left hemisphere as well, although it was still predominant on the right. To sum up, the patient reported by Confavreux et al. (1992) presented with a slowly progressive amusia coupled with a severe dysprosody. Her deficits have been traced back to the selective degeneration of the parietal lobe of the right hemisphere. The clinical picture worsened to encompass the typical symptoms of dementia. Orofacial apraxia (which encompassed eyelid apraxia; Lewandowsky, 1907), could be interpreted as an aspect of an innervatory apraxia encroaching upon the complex motor systems deputed to phonation which are necessary to produce melody and prosody.

SLOWLY PROGRESSIVE PROSOPAGNOSIA Prosopagnosia is the term introduced by Bodamer (1947) to indicate the difficulty some patients with bilateral or right hemisphere lesion show in recognising familiar faces. Prosopagnosia has been reported in patients with Alzheimer’s disease (e.g. Della Sala, Muggia, Spinnler, & Zuffi, 1995a), but has been seldom observed in progressive degeneration of the cortex, in the absence of overt dementia. Spinnler et al. (in preparation) observed a case, whose onset three years prior to assessment was characterised by isolated prosopagnosia. One year later, the patient also presented with object agnosia. Magnetic resonance demonstrated a cerebral atrophy predominant in the retro-rolandic regions, more pronounced in the right temporal lobe. While her prosopagnosia and her agnosia progressively deteriorated, only in the last months did she develop ongoing memory deficits, and performed just below the cut-off on global screening test for dementia.

796 DELLA SALA AND SPINNLER

Tyrrel et al. (1990) reported the case of a 79year-old man with a 1 2 -year history of progressive prosopagnosia. A PET showed a cerebral hypometabolism more apparent in the right temporal lobe. A thorough neuropsychological investigation also revealed that the patient was severely impaired on verbal tasks and had naming difficulties, pointing to a widespread cognitive deficit. Additionally, two cases reported by De Renzi (1986) presented with impairment in face recognition. In both cases CT scans demonstrated atrophy more evident in the posterior region of the right hemisphere. However, the picture presented by these two patients was not that of an isolated prosopagnosia. Both patients’ deficits encompassed several visuo-perceptual abilities. Probably the epitome of the reported cases of slowly progressive prosopagnosia is that reported by Evans et al. (1995). They described the case of VH, a 6 8 -year-old retired clerk, who complained she could not recognise her close friends and even members of her family without relying on their voices. The patient reported that her difficulty had worsened gradually over the previous 1 2 years, but her symptom had become obvious to her friends and relatives only some two years prior to her formal assessment. VH was examined on two occasions separated by nine months. She performed normally and showed no decrement (although the follow-up only lasted nine months) in tests of perceptual abilities, intelligence, executive functions, language, and memory. She also performed within the normal range on tests taxing face perception skills, such as matching of unfamiliar faces, and age, gender, and expression perception. She also scored well above the median of controls in tests assessing her recognition of exemplars from other categories, such as flowers and famous buildings. In contrast, she scored very poorly in tests of familiar face recognition, including familiarity judgement and famous face identification. In the second assessment her performance deteriorated on these latter tasks. Taken together these results support Bruce and Young’s (1986) model of face processing. The model postulates a series of parallel and independent stages in the recognition of familiar (impaired in VH) and unfamiliar faces (spared in

VH). These findings also confirm the possibility that degenerative processes of the brain might give rise to very selective cognitive deficits, which can add to our understanding of the functions of the normal brain (for a discussion see also Young, Newcombe, de Haan, Small, & Hay, 1993; Della Sala, Muggia, Spinnler, & Zuffi, 1995a). Brain imaging demonstrated a selective atrophy of VH’s right temporal lobe, with the relative sparing of the hippocampus. Evans et al. (1995) hypothesised that their patient VH was affected by a slowly progressive degeneration of the right hemisphere which mirrored that observed in the cases of “semantic dementia” (see earlier) and traced back to degenerative lesions of the left temporal lobe. However, it is worth remembering that the case of semantic dementia reported by Barbarotto et al. (1995) presented with an overt right temporal atrophy and also showed a severe prosopagnosia. It bears emphasising that the prosopagnosic pattern of deficits in degenerative patients is different from the typical neuropsychological profile observed in patients with a right (or bilateral) posterior focal lesion. Indeed, most of the degenerative prosopagnosics do not show any feeling of familiarity with the people they do not recognise. This feature points to a supra-modal disorder, in which semantic, attentional, and sensory-integrative aspects add up in giving rise to this complex failure.

SLOWLY PROGRESSIVE UNILATERAL VISUOSPATIAL NEGLECT In spite of the widespread use of visuospatial tasks in test batteries assessing the neuropsychological profile of patients with Alzheimer’s disease, with a few exceptions (Freedman & Dexter, 1991; Huff, Boiler, Lucchelli, Querriera, Beyer, & Belle, 1987; Ishiai, Okiyama, Koyama, & Seki, 1996), unilateral visuospatial neglect has been disdained by researchers and clinicians interested in the neuropsychology of degenerative diseases. This is testified by the fact that even studies focusing on the visuospatial or attentional deficits of demented

33. SLOWLY PROGRESSIVE COGNITIVE DEFICITS

patients disregard neglect (e.g. Mendez, Mendez, Martin, Smyth, & Whitehouse, 1990; Della Sala, Laiacona, Spinnler, & Ubezio, 1992) nor it is mentioned in comprehensive reviews of visuospatial deficits of Alzheimer’s disease (e.g. Nebes, 1992). In their recent review of SPICD, Weintraub and Mesulam (1993) mentioned neglect among the possible symptoms that could be observed in forms with prevailing visuo-perceptual deficits. However, the case that they reported as representative of this category of SPICD (case 4) did not show neglect. We maintain that the study of slowly progressive neglect both isolated as a SPICD or within the general picture of Alzheimer’s disease should not be overlooked anymore, because, due to the peculiarity of bilateral and progressive damage (see for a discussion of neglect in bilateral lesion, e.g. Vuilleumier, Hester, Assal & Regli, 1996; Weintraub, Daffner, Ahern, Price, & Mesulam, 1996) it could add to our understanding of the phenomenon itself. Neglect in degenerative disease might be more frequent than generally assumed. Freeman and Dexter (1991) examined 14 patients with Alzheimer’s disease with a battery of tests assessing neglect and maintained that as many as 1 1 of them showed some signs of neglect, and in five it was rather severe. Moreover, half of these patients showed the symptom on the right side of the peripersonal space. Longitudinal neuropsychological and neuroimaging studies of such patients could throw some light on the cognitive and anatomical architecture of visuospatial attention (Ishiai et al., 1996) and on associated deficits, such as extinction (Crystal, Horoupian, Katzman, & Jotkowitz, 1982). Rarely (e.g. case 12 of Cogan, 1979; case 1 of Shuttleworth, 1984; case 4 of Cutler et al., 1985; cases GC and MP of Venneri, Pentore, & Della Sala, submitted) has neglect been reported as the first or paramount symptom in cases of cortical degenerations. Only in the cases reported by Cogan (case 1 and case 3,1985) and by Ishiai et al. (1996) has neglect remained relatively isolated for a period of time, although within a more general derangement of visuospatial functions, labelled “visuospatial dysgnosia” (Cogan, 1985), or mild Alzheimer (Ishiai et al., 1996). Cogan followed up

797

his two patients respectively for seven years and five months: both showed a clear gradual deterioration of their left neglect, to the point that it heavily interfered with a number of everyday tasks. The first patient, for instance, ignored the food on the left of her plate, and the second patient needed constant supervision in walking because she was unable to avoid obstacles on her left. Both cases eventually showed signs of widespread cognitive deterioration akin to a full-fledged dementia.

SLOWLY PROGRESSIVE SIMULTANAGNOSIA Cases of SPICD have also been observed within the domain of spatial knowledge and processing. As with other SPICD, they were reported first by German authors at the turn of the century (Gruenthal, 1926; Pick, 1892; Rosenfeld, 1909). The deficits that these patients present with encompass all those shown by patients with focal brain lesions (for a review see De Renzi, 1982 and Chapter 20 by Nichelli, this volume): perceptual deficits; deficit of space exploration; “reaching” and visuo-motor coordination problems; topographical amnesia and environmental agnosia; visuoconstructive apraxia. Recently the existence of cases of slowly progressive isolated visuospatial disorders have been reappraised. They have been labelled in various ways, and a list of the terms used to indicate visuospatial SPICD is summarised in Table 33.6. The cases reported in the literature, from those described by Pick (1908) and Rosenfeld (1909) until the recent cases observed by Levine et al. (1993), Attigetal. (1993), and Costlett et al. (1995) number about 50 (see review in Della Sala et al., 1996). However, it is certainly possible that instances of visuospatial SPICD are more frequent than these figures suggest. We observed some of these cases (Della Sala et al., 1996); one of them is detailed next.

Case LM LM, a 67-year-old right-handed housewife complained o f gradually worsening troubles with visual and spatial abilities fo r the previous five

798 DELLA SALA AND SPINNLER

TABLE 33.6 Terms gathered from the recent literature proposed to describe slowly progressive Isolated visuo-spatial deficits. Label

A u th o r(s )

R e p o rte d cases

Benson et al., 1988 Croisile et al, 1991

5

Slowly progressive agnosia

De Renzi, 1986, 1992

2

Posterior cortical dementia

Freedman et ah, 1991 Freedman and Costa, 1992

1 1

Caselli and Jack, 1992 Caselli et al., 1992

9 4

Simultanagnosia as the initial sign of dementia

Graff-Radford et al., 1993

10

Progressive visuo-spatial dysfunction

Weintraub and Mesulam, 1993

2

Victoroff et al., 1994

3

(two cases also reported by Benson et al, 1988) Davous et al., 1995

3

Della Sala et al., 1996

3

Posterior cortical atrophy

Progressive perceptuomotor dysfunction

Progressive posterior cerebral dysfunction

Progressive Balint-Homes syndrome Slowly progressive impairment of spatial exploration and visual perception

years. Because o f her difficulties she consulted an ophthalmologist (who is the first consultant from whom these patients usually seek help, see GraffRadford, Bollings, Earnest, Shuster, Caselli, and Brazis, 1993). Her problems were characterised by a marked inability to establish the spatial relationship between herself and objects in the environment. She told us that she had increasing troubles establishing directions; fo r example, she had to follow other people to exit from shops and she was unsure o f the direction o f the stream o f the water in a river; she needed help in going through a gate, as she could not locate its frame in relation to her body. Her symptoms deteriorated and she noticed reaching problems, fo r example, an expert gardener, she was no longer able to orient the secateurs towards the correct part o f the twig when attempting to prune roses and could not place the clothes-pegs correctly in hanging up the washing. She also manifested problems in everyday tasks requiring fine-grained perceptual skills. For instance, she failed to read nondigital watches and kept losing track o f the line in reading or writing.

Her attempts to practice these tasks to prevent their aggravation were invariably frustrated. When formally assessed L M ’s performance in recognising and reproducing single letters was flawless. She showed overt difficulties in recognition o f everyday stimuli, such as coins or faces. She relied on the voice or on other details (e.g. dressing style) o f the familiar person she was asked to recognise, maintaining that ‘faces look very similar to one another ”. She enjoyed listening to the radio but had problems in identifying the different characters in a TV show, in particular when they swapped places (see Alberoni et al., 1992), and she had apparent problems in analysing a complex visual scene. On the other hand, she was not demented and was still living alone. No sign o f episodic, procedural, or semantic deficit was detected; her oral communication and comprehension were perfect and she showed ready wit and sharp humour. She reorganised her daily life using a number o f intelligent strategies to cope with her difficulties. For example she divided her coins by shape and size

33. SLOWLY PROGRESSIVE COGNITIVE DEFICITS

and put them in different pockets o f her wallets to avoid confusion when going out shopping, and she learned to assess the time by the bell-chimes or by the passing o f trains. Repeated neurological examinations revealed only a severe ataxia and some release signs. A series o f CT scans showed a mild cortical atrophy which became progressively more pronounced in the posterior part o f the parietal lobes, a picture reiterated by metabolic studies with PET. LM did not show neglect. However, a formal neuropsychological assessment elicited a number o f deficits in tasks requiring the process o f visuospatial information: she performed poorly on tests o f constructive apraxia, cancellation, supraspan visuospatial learning, and length discrimination. Observing the patientperfoming the tasks, it was obvious that she was analysing only parts o f the stimuli to be processed, trying to make sense o f them as whole by verbal reasoning and plausible guesses. Typically in trying to identify the stimuli o f Street's Completion Test (1931), she attempted to deduce the figure she was supposed to name from scant details o f it. She was unable to integrate the different parts o f any given picture. Her ability to draw from memory and to copy drawings and objects was severely impaired. However, she performed faultlessly in colour-figure matching tasks (Della Sala et al., 1997) with the pictures she could recognise. She could also provide all the semantic information linked to stimuli she could not recognise visually. We assessed LM at intervals o f six months in the following two years. Although her performance on the verbal tasks did not change, she showed a steadily progressive derangement o f her residual visuospatial skills (see Della Sala, Spinnler, & Trivelli, 1996fo r the detailed neuropsychological follow-up study). She used to comment that her “eyes did not measure properly ” or that they “were going too slowly ”. After afurther three years (more than nine years after the onset o f her symptoms) we enquired by telephone about LM ’s condition. By now, due to the worsening o f her visuospatial abilities, even in her own home she could no longer live alone. She was aware o f her deficits and depressed by them, she had lost her sense o f humour and spent most o f the day

799

just sitting in a chair. Other cognitive deficits had added to the picture. Her speech had become blurred and unintelligible, indicating the diffusion o f the degeneration to other areas o f the left hemisphere. She depended on her relatives fo r her personal hygiene, and although she failed to recognise them by sight, she retained a sense o f familiarity with their voice and behaviour. In conclusion, LM suffered from severe slowly progressive visuospatial deficits, characterised by her impairment in the exploration o f extrapersonal space, reaching, and object recognition including familiar faces, which spanned over a period of more than nine years. The interpretation o f LM ’s deficits is fa r from clear. She showed elements of the Balint-Holmes syndrome. Her visual recognition impairment is not dissimilarfrom that reported in visual apperceptive agnosics. However, she could correctly identify small particulars o f a stimulus, afeature that characterises patients labelled as “integrative agnosics” (Riddoch & Humphreys, 1987b) although LM ’s copying abilities were very poor. Her impairment in making sense o f complex scenes reminds us ofWolpert’s (1924) simultanagnosia. Perhaps the labelling o f L M ’s clinical picture is only a matter o f terminology and opinion. Larah (1990) maintained that some picture of apperceptive agnosia should be relabelled “dorsal simultanagnosia”, while Thaiss and De Blaser (1992) argued that all apperceptive agnosics should be described as pure simultanagnosics. Whatever the diagnostic label o f LM ’s initial visuoperceptual failures, her symptoms eventually spread to encompass deficits o f other cognitive domains and her clinical picture resembled that o f a dementia as is the case o f most patients affected by visuospatial SPICD (see Lig. 33.5). The histopathological nature o f this dementia is often interpreted as Alzheimer’s Disease (Graff-Radford et al, 1993)

SLOWLY PROGRESSIVE ISOLATED ANTEROGRADE AMNESIA Memory deficits are the nucleus of the diagnosis of Alzheimer’s disease (APA, 1994; McKhann, Drachman, Folstein, Katzman, Price, & Stadlan,

800 DELLA SALA AND SPINNLER

FIGURE 33.5

Slowly progressive visuo-perceptual deficits gathered from the literature. Note the scarcity of longitudinal observations. Note also that most of the patients eventually present with a generalised cognitive impairment, which is indistinguishable from that shown by patients affected by typical Alzheimer’s disease. Redrawn from Della Sala et al. (1996), Neurocase, 2, Fig. 2, p.319.

33. SLOWLY PROGRESSIVE COGNITIVE DEFICITS

1984; Nebes, 1992; Spinnler & Della Sala, 1988) (see Chapter 31). Table 33.1 shows that 4 out of 39 patients with Alzheimer’s disease presented isolated amnesia as the onset symptom and that their amnesia remained isolated for about 18 months. An even greater proportion of isolated amnesia onset in Alzheimer’s disease was reported by Haxby et al (1992) in an elegant study charting the decline of Alzheimer’s disease (for a discussion, see also Gray & Della Sala, 1996). Haxby et al., (1992) observed that 5 of their 16 Alzheimer’s patients presented with amnesia at onset and that their amnesia remained isolated for up to 35 months. The frequency of such occurrences was reiterated in a recent study by Bowen et al. (1997) who followed-up for four years, 2 1 patients with severe isolated memory loss out of 811 patients with cognitive complaints. During the follow-up period nearly half of the patients (N = 10) with isolated amnesia developed dementia, and nine of them had a clinical diagnosis of Alzheimer’s disease. Costantinidis (1978) coined the term “simple senile dementia” to identify these cases, which he considered variants of Alzheimer’s disease. Other descriptive labels can be gathered from the literature: “benign senile forgetfulness” (Krai, 1972), “progressive amnesic dementia” (Weintraub & Mesulam, 1993), “permanent global amnesia with unknown etiology” (Kritchevsky & Squire, 1993), “pure slowly progressive amnesia” (De Renzi, 1992), “slowly progressive amnesia without dementia” (Tanabe, et al., 1994), “primary amnesia of insidious onset with subsequent stabilisation” (Lucchelli, De Renzi, Perani, & Fazio, 1994), “isolated degenerative amnesia without dementia” (Caffarra & Venneri, 1996), “isolated amnesia with slow onset and stable course, without ensuing dementia” (Miceli, Colosimo, Daniele, Marra, Perani, & Fazio, 1996). With the only exception being that of Kritchevsky and Squire (1993), who postulated a vascular aetiology selectively hampering the functioning of the hippocampal formations and the medial temporal lobe bilaterally, all other authors opted to diagnose their patients as affected by a circumscribed cortical degeneration. Neuroimaging often revealed atrophy hypometabolism of the

801

medial temporal regions of the brain (Lucchelli et al., 1994; Miceli et al., 1996; Tanabe et al., 1994). In some of these cases the memory disorder eventually evolved into a full-fledged dementia (e.g. case WI reported by Kritchevsky & Squire, 1993; case HY reported by Tanabe et al., 1994; and case AV, reported by De Renzi, 1992), in others the deficits remained confined to the memory domain for several years (e.g. cases JL and WH reported by Kritchevsky & Squire, 1993; cases TK, SS, andMK reported by Tanabe et al., 1994; case BN reported by Lucchelli et al., 1994, case TT reported by Caffarra & Venneri, 1996; and case EDS reported by Miceli et al., 1996). We recently reported the case of a patient, MZ, who showed slowly progressive isolated anterograde memory deficits, which only after 15 years suddenly and rapidly evolved into dementia (Della Sala, Lucchelli, Lunghi, & Spinnler, 1995). The main features of this case are summarised next.

Case MZ MZ, was first referred fo r neuropsychological evaluation at the age o f 49. Both he and his wife were preoccupied by a steadily progressive amnesia which had insidiously begun nine years before (when the patient was about 40). Thefirst symptom o f this previously normal subject consisted in forgetting errands and appointments with increasing frequency, so that he spontaneously began to use reminders. Later he and his relatives became increasingly alarmed by his forgetfulness o f recent events. For instance, a soccerfan, he used to watch games on TV, and to his own and his friends’ dismay he forgot which team had won. In the same period o f time, MZ was working as a welder in a factory and his expertise was highly commended by peers and by the principal, to the point that, despite his low education, he was promoted to foreman. This underlines the integrity o f his procedural skills. In the ensuing years his memory worsened. He had to be reminded o f his tasks at work, forgot what other people had just said, and had to repeat the same question several times over to understand it. Because o f his severe amnesia he lost the ability to work autonomously, not to mention organising someone else’s work, and was downgraded to fellow-worker. However, his

802 DELLA SALA AND SPINNLER

procedural skills remained unimpaired, and provided somebody reminded him o f what he had to do, he was very much in demand fo r his dexterity. No impairment o f remote or autobiographical memory was apparent. His language wasfluent and syntactically correct with no sign o f anomia; no other cognitive deficits were detected in our first formal assessment. The neurological and neuroimaging examinations were normal, and his medical history was uneventful, in particular MZ had no history o f alcohol abuse, childhood episodes interpretable as encephalitis (Damasio, Eslinger, Van Hoesen, &

Cornell, 1985), epilepsy (Victor & Agamanolis, 1990) or developmental learning disabilities (Ostergaard, 1987). During the following four years his memory problems worsened. This decline was mirrored in his performance in formal psychometric tests, which showed a gradual deterioration o f both his short- and long-term anterograde memory first in the verbal domain only and subsequently also in the visuospatial. On the other hand, up to 13 years after the onset o f his disease, his performance on nonmemory tasks was well within the normal range and did not show any apparent decrement. The details

TABLE 33.7 MZ’s performance on memory tests (score range in brackets). M Z s age 49

52

53

54

C ontrols ’ 5th cen tile

C ontrols ’ m edian score

4.50 111

E p is o d ic M e m o ry

Forward Word Span # Supra-span Verbal Learning (Buschke-Fuld) (0-180) # Memory for Prose (0-151) ° Serial Position Curve: ~ - Primacy (0-70) - Recency (0-30) Paired Associated Learning (0-22.5) + Spatial Span (Corsi) (0-9) # Supra-span Spatial Learning (0-29.16) #

2.75* 5* 12* 4.5 9.5

2.75* 0*

2* 1*

2* 0*

2.75 36

0*

0*

0*

24

4.75 7.9

0* 10.5 0.5* 4 5.7

9.5 6.25

8.75 6.25

-

0* 10 3* 2.75* 1.08*

4.5 7.5 6 3.5 5.5

15.5 18.5 12.5 4.75 18.50

6*

4* 2.5* 14 6.25*

7 3.75 10 7.25

17 9.5 16 13.75

-

31.43* 12*

41.53 19

38

-

4

S em antic M e m o ry

Verbal Fluency # Word Association f Colour-Figure Matching (0-16) $ Map of Italy (0-45)#

-

-

-

11

-

-

60

7.5 -

R etro g ra d e M e m o ry

Famous Events (0-80) ~ Autobiographical Memory A Score adjusted for age and education.

• = score below the cut-off (5th inferential centile of the normal position) # 0 ~ + t

= = = = = =

not given From Spinnler and Tognoni, 1987 From Capitani, et al., 1994 From Capitani et al., 1992 From Novelli, et al., 1986a From Bandera et al., 1991 $ = From Della Sala et al., 1997 ^ = From Costa et al., 1989 A = From Borrini et al., 1989.

33. SLOWLY PROGRESSIVE COGNITIVE DEFICITS

o f the various neuropsychological examinations are reported by Della Sala etal. (1995b). Some o f these results are summarised in Tables 33.7 and 33.8. Neuroradiology and neurological examination were unchanged. The deterioration in the subsequent two years (fifteen years post-onset) was dramatic (see Tables 33.7 and 33.8). He had lost his job because he was no longer able to follow his fellow-workers' instructions and his craftmanship had deteriorated. His memory problems spread to encompass remote and autobiographical events. Spatial disorientation had become manifest even infamiliar surroundings

and driving was now impossible also due to his motor awkwardness. In addition he had some language problems, showing difficulties in understanding complex sentences and producing a few anomias. Two years later his decline was even more overt, evolving to a picture o f severe global dementia. Verbal communication was now impossible, his language was reduced to stereotyped utterances, he could not sing (and had to give up his hobby as a singer) because o f his inability to follow the tunes, he showed dressing apraxia, and his motor awkwardness was now apparent in simple everyday tasks, such as eating.

TABLE 33.8 MZ’s performance on memory tests (score range in brackets). M Z ’s age 54

C ontrols ’ 5 th centile

C on tro ls ’ m e d ia n score

49

52

53

21.25 11.25 8.75 41.75

18.25 13.25 -

20 9.25 39.25

8.75* 1* -

14.75 4.25 7.5 32

28.75 10.75 14.25 50

31.5 23 31.15

24.5 21.5 -

13.1* -

8.1* -

23.9 18.25 16.75

40.5 23.25 29.5

32.75 32

34.75 -

24.5* -

18* 27.75*

26.25 28

33 31

65 -

42* -

52 17

69 20

7.75 29 1* 16.25

2 17 20.75 7.75 13.75

7.25 26 31.25 12.5 22

In te llig e n c e

Raven PM 1938 (0-48)# Weigl’s Sorting Test (0-15) # Elithorn’s perceptual maze test (0-16) # Verbal Judgements (0-60) # A tten tio n

Digit Cancellation (0-50) ° Reversal Learning (0-24) # Gottschaldt’s Hidden Figures (0-34) f L a n g u ag e

Token Test (0-36) # Naming (0-32) P ra x is

Ideomotor Apraxia (0-72) t Orofacial Apraxia (0-20) #

71 20

-

Visuospatial a b ilitie s

Street’s Completion Test (0-14) # Segments Length Discrimination (0-32) # Scrawls Discrimination (0-32) # Constructional Apraxia (0-14) # Finger Agnosia (0-24) #

6.25 29 31 10.75 19.25

803

5.25 26 32 10.75 21.25

-

Scores are adjusted for age and education. * = score below the cut-off (5th inferential centile of the normal population) - = not given # = From Spinnler and Tognoni, 1987 0 = From Della Sala et al., 1992 t = From Capitani et al., 1988 1 = From De Renzi et al., 1980.

804

DELLA SALA AND SPINNLER

He required constant supervision and spent most o f his time in purposeless activities, such as moving objects around. CT scans and MRI showed a progressive enlargement o f a nonspecific generalised atrophy (see Fig. 33.6). A PET study demonstrated bilateral parietal and temporal hypometabolism, a pattern considered indicative of Alzheimer’s disease (Friedland, Budinger, Koss, & Ober; 1985; Haxby, Grady, Duara, Schlageter, Berg, & Rapoport, 1986). In conclusion, MZ presented with a clinical history o f isolated anterograde amnesia for about 15 years, 6 o f which were documented by periodic testing with large neuropsychological batteries (Della Sala et al., 1995b). The patient’s clinical picture evolved to a severe dementia, probably o f Alzheimer’s type.

To better illustrate the difference between the picture o f MZ and that o f a typical Alzheimer patient, in Fig. 33.7 we plot the performance ofM Z on a screening test fo r dementia (the MODA, see Chapter 30) together with that o f a typical patient with Alzheimer’s disease. From the figure the difference between the two clinical histories is apparent. The sudden global decline ofM Z started after a 15-year period o f isolated amnesia, a typical Alzheimer patient shows a steady decrement o f two points each year in the MODA (Brazzelli, Capitani, Della Sala, Spinnler, &Zuffi, 1994). The difference in cognitive decline depicted in Fig. 33.7 well typify the key feature ofSPICD. The cognitive history of MZ is similar to other patients reported in the literature and mentioned

FIGURE 33.6

CT (a,b) and MRI (c) scans of MZ, 7,1 4 , and 16 years post-onset, showing from top to bottom the progression of his generalised cerebral atrophy. Reproduced from Della Sala et al. (1995), in Conway and Campbell (Eds.), B roken m em ories, Blackwell Publisher.

33. SLOWLY PROGRESSIVE COGNITIVE DEFICITS

805

FIGURE 33.7 Progression of dementia as measured by a screening test (MODA) in patient MZ and in a typical patient affected by Alzheimer’s disease.

earlier. The common feature is the isolated anterograde memory deficit, which slowly deteriorates for a number of years. The retrograde aspects of memory seem to be more resistant to the degenerative process, although this is not the rule (e.g. Miceli et al., 1996). When dementia appears, its onset is rather abrupt and its course precipitous.

CONCLUSIONS The material discussed in this chapter is unusual in neuropsychology textbooks. It describes a far from complete anthology of cases, the common denominator of which is the neuropsychological syndromic diagnosis of SPICD. Their prevalence among degenerative diseases of the brain is uncertain (see Table 30.2). The main common features of SPICD can be summarised as follows: 1. The average age of onset of SPICD is rather young, around 50-60, and sometimes even before, compared to Alzheimer’s disease age of onset range of 50-90, with an average of around 65-70. It looks as if only the younger age offers

the possibility to the degenerative disease to “choose” between a full-blown dementia and a more selective course. 2 . The effective “purity” of the slowly progressive cognitive cases is an heuristic oversimplification, partly due to the inadequate traditional neuropsychological taxonomies. Perhaps the time is ripe to revisit them, drawing on the fine-grained dissociations reported in several cognitive models, which cut across the performance of many traditional neuropsychological diagnostic instruments. 3. The evolution of SPICD towards a full-fledged dementia is almost the rule, as if the selectivity of their clinical picture is no more than a first manifestation of a dementia-to-come. Skimming through the literature one encounters a few exceptions (in particular, aphemia, apraxia, amnesia) to this rule, perhaps partly due to the limited period of follow-up. One way to account for the selective onset of SPICD that end up in the similar picture of dementia, is to assume a certain inter-individual variability. This in turn could be the result of a diverse redundancy of structural resources (i.e. neurones, synapses) functionally afferent to a given

806 DELLA SALA AND SPINNLER

cognitive module(s). This hypothesis postulates that heterogeneous cognitive derangements remain isolated until the threshold of functional resources is exceeded. As a matter of fact, in all chronic failures of internal organs (liver, kidney, etc.) it is necessary to transcend a given threshold for symptoms to appear. Inter-individual differences in resources availability and allocation might play a role in the emergence of different SPICD which eventually end up in the common picture of a rapid generalised cognitive deterioration. We foresee that the progression of the research concerning the SPICD will be fast and manifold. One of its aspects will focus on neurobiology, and will probably be centred on functional MRI (given its good temporal and spatial resolution and its relative low cost). This field of study will aim at defining the functional topography of fine-grained cognitive deficits, of which SPICD are the best representatives. A second problem to be tackled is the relationship between SPICD and dementia, in particular Alzheimer’s disease. The SPICD raise the issue of the unusual two-phase slope of progression (slow for several years and then abruptly swift) of degenerative processes which could well show histopathological or biochemical traits different from that of the typical Alzheimer’s disease. This slope of progression could be different in different SPICD or indeed, as already mentioned, in different individuals within the same SPICD—a problem that calls for the discussion of the pre-morbid inter-individual variability in the genesis of several neuropsychological clinical pictures. Assuming that SPICD are dementia in fieri, the problem arises as to the mechanism of the spreading of the deficits to other cognitive domains. Two alternatives may be postulated: (i) the degenerative process extends by contiguity to nearby neuronal (synaptic) populations; (ii) the degenerative process strikes simultaneously different anatomo-functional loci. This latter, pluri-focal, hypothesis needs to account for the spacing out of the different symptoms in time. Three variables might play a role: (a) pre-morbid redundancy of “local” resources; (b) different resource needs by different functions (and therefore different performance patterns); (c) variability of attacking power of the

degenerative process according to different neuronal populations. Of course, lacking more information, all possible combinations of these mechanisms might be conceived. The third area of research is more akin to the classic interests of clinical and cognitive neuropsychologists. This consists in the meticulous mapping of deficits on the basis of cognitive models of information processing. This is an onerous task in so far as it requires the ability of a skilled clinician to detect the subtle deficits of a SPICD as well as the knowledge of a cognitive psychologist to arrange for ad hoc testing of the patient, aiming at adding information on the functioning of the normal brain. It is an easy prophecy to foresee an endless series of case reports of SPICD with a production not dissimilar from that of the neuropsychologists, mainly German, of the turn of the century. Cases of SPICD will be distilled from samples of relatively homogeneous Alzheimer patients (Baddeley, Bressi, Della Sala, Logie, & Spinnler, 1991; Becker, 1988), or they will be reported as single cases (e.g. Thaiss & De Bleser, 1992), or using the so-called “multiple single case approach” (Baddeley, Della Sala, & Spinnler, 1991; Della Sala et al., 1993b, 1995b). This search will provide researchers with what Pick (1908) alluded to as “histologische Psychologie”. Pick’s (1904) opinion was that: “... it is possible that [in cortical degenerations] an atypical clinical picture emerges due to the unbalanced distribution of the pathological processes on the cortex . ” 1 His opinion has recently gained some popularity with the demonstration that selective cognitive derangements due to cortical degeneration could add to the assortment of empirical data on which cognitive models are based. Moreover, the longitudinal aspect of the SPICD might offer a new prospective from which to validate the modular architecture postulated by the various models. Patients with peculiar cerebral degeneration akin to SPICD, even if not in their purest form, allowed researchers to observe clear-cut dissociations of performance patterns. For instance the dissociation between impaired anterograde and spared retrograde memory (Della Sala et al., 1995b), and that between the preservation of the knowledge of the function of an object and the inability to execute

33. SLOWLY PROGRESSIVE COGNITIVE DEFICITS

transitive gestures (Rapcsak, Ochipa, Anderson, & Poizner, 1995), which allowed the authors to hypothesise a dichotomy of the praxic system into two components: concept and execution. Other cases of SPICD allowed reconsideration of the accepted model of face recognition (Bruce & Young, 1986) and demonstration of a specificity of face processing in respect to the processing of other complex visual stimuli, such as flowers or famous buildings (Evans et al., 1995), to rediscover, under a new light, old syndromes, such as the semantic dementias (Hodges et al., 1992), to reiterate the strength of some associations of symptoms, e.g. Gerstmann’s syndrome (Strub & Geschwind, 1974), to show associations, e.g. that between dysprosody and oro-facial apraxia (Tyrrell et al., 1991), to report rare instances, such as a surface dyslexia in a “transparent” language like Italian (Chiacchio, Grossi, Stanzione, & Trojano, 1993), and to contend assumptions, such as the inescapable automatic/voluntary dissocation in apraxia (De Renzi, 1986, see Cubelli & Della Sala, 1996, for a discussion). A final point ought to be raised. Often the onset of the so-called non-Alzheimer dementias (see Chapter 32) is characterised by rather isolated behavioural and neuropsychological disorders, which eventually progress towards the typical incompetence of coping with everyday demands. A good example of these is the “fronto-temporal dementia” (Neary & Snowde, 1996), particularly when the frontal aspects prevail. The underlying histopathology of different dementias might vary and nevertheless give rise to identical behavioural phenotypes. In principle, from a clinical point of view, independently of the degenerative process underlying it, the term SPICD might be applied to any slowly progressive cognitive degeneration, whenever the interval between the focal onset and the widespread nature of the disease is outstandingly long. However, given the unsettled definition and poor understanding of the

807

behavioural features of many “non-Alzheimer dementias” (Lewy’s bodies disease, progressive supranuclear palsy, Pick’s disease, frontal lobe degeneration), we deem it premature to include them in this chapter (see Chapter 32, this volume). Finally, some practical considerations to round off the chapter. The diagnosis of SPICD is based on a temporal agreement. The follow-up of the patients is essential to diagnose a slowly progressive cognitive deficit. Therefore, it is necessary to devise ad hoc severity scales for specific cognitive domains. The all-encompassing screening tests, modelled on Alzheimer’s disease (such as the MODA, see Chapter 30) are not suitable instruments to assess patients with SPICD longitudinally. A progressive cognitive deficit, even isolated, can be a very serious handicap. It is therefore necessary that, when it is appropriate, the neuropsychologist argues for these patients to receive the benefit of a disability pension, analogous to that nowadays attributed to better recognised forms of dementia.

ACKNOWLEDGEMENTS The case reports described in this chapter are gathered from the pool of patients observed in the last 1 0 years with various collaborators including M. Brazzelli, D. Carey, A. Lunghi, C. Marchetti, S. Muggia, C. Stangalino, C. Trivelli, A. Venneri, M. Zuffi.

NOTE 1.

. die M o e g lic h k e it eines, infolge u ngleichm aessiger Verteilung des Krankheitsprozesses a u f das in b e trach t kom m ende G ebiet, atypischen S ym pom encom plexes n ic h tau s zu s ch lies sen ” (P ic k, 1904, p .3 7 8 ).

Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

34 Language Disorders in Dementia Claudio Luzzatti

1904). However, in the periods following the first and second world wars neurologists and neuropsychologists dedicated relatively little attention to these types of disorder. In fact, clinical neuropsychology was practised principally in American, English, French, and Soviet Veteran Administration centres with the principal objective being almost exclusively the rehabilitation of neuropsychological damage from war lesions in young adults. The few studies published in these years on cognitive modifications in ageing and in dementia focused their attention on intelligence and memory deficits, whereas studies on language modifications were sporadic (Ajuriaguerra & Tissot, 1975; Critchley, 1964; De Renzi & Vignolo, 1966;Irigaray, 1967,1973). Over the last 20 years, however, neuropsychologists' interest in AD and associated language disorders has been rekindled. On the one hand, lower birth rates, lower mortality rates, and increased life expectancy have resulted in a higher incidence of elderly subjects in the populations of the industrialised northern hemisphere. If it is considered that approximately 15 % of the inhabitants of these countries are over 60 years of

INTRODUCTION In this chapter verbal communication disorders accompanying degenerative diseases in adults and in the elderly will be described, with particular reference to Alzheimer's dementia. Though the term aphasia is also used by many contemporary authors to define language deficits following a degenerative disease, in this chapter it will be used in a more limited sense, i.e. only for language deficits resulting from focal brain injury; the term Alzheimer's dementia (AD), on the other hand, will be used in its more extensive meaning, i.e. no distinction will be made between presenile dementia and the senile form of the disease (senile dementia of Alzheimer's Type = SDAT) and between forms with typical AD histopathology (senile plaques + neurofibrillary tangles) and those forms of dementia in which the diagnosis is only putative (dementia of Alzheimer's type - DAT). Studies carried out on language disorders in cerebral degenerative diseases constitute an important area of research in the history of neuropsychology (Liepmann, 1900; Pick, 1892, 809

810 LUZZATTI

age and that the prevalence of medium to severe dementia reaches approximately 2 0 % in individuals of over 80 years of age (Schoenberg, Anderson, & Haerer, 1985), the impact of this disease on national health services is easy to imagine. The US Health Care Financing Administration estimates that in the United States the cost of nursing AD patients alone amounts to approximately 6000 billion dollars and another 2 0 0 0 billion dollars spent on medical and rehabilitative aid (Bayles & Kaszniak, 1987). In spite of the fact that only a few patients with suspected AD undergo full cognitive evaluation, the impact of this segment of the user population in neurolinguistic and neuropsychological laboratories is very high. On the other hand, the interest in language disorders with degenerative aetiology has a further theoretical foundation. In 1976 Harry Whitaker described a patient whose spontaneous speech was reduced to echolalic production only, and he demonstrated the existence of dissociation between a very severe lexical semantic deficit and the relative preservation of the phonological and syntactic skills. A similar case was studied a few years later by Schwartz, Marin, and Saffran (1979). Their two patients, of whom the individual aspects will be described later, supplied relatively important evidence of an independent organisation of the lexical-semantic component of language from the phonological and syntactic components. In focal brain injuries, an isolated lexical-semantic impairment is relatively unusual, while dissociations with partial lexical-semantic sparing and morpho-syntactic (see agrammatism) or phonological (see conduction aphasia) disruption are more common. The aetiology of both patients was degenerative and their data were clearly in line with the observations made by the French linguist Luce Irigaray (1973) on the language disorders of demented patients. The possibility that selective lexical-semantic impairment can exist in the absence of phonological and syntactic deficits provoked renewed interest in language disorders in AD: the isolated damage to lexical-semantic representations permits a more focused study of mental organisation than aphasic language deficits, where damages to different linguistic components usually overlap. Some

authors (e.g. Bayles & Kaszniak, 1987) have argued that the lexical-semantic damage observed in AD is completely different in nature to that which follows a left focal brain injury. Thus, the language disorder of an aphasic patient would result from impairment to access to almost spared lexical and semantic knowledge (Butterworth, Howard, & McLoughlin, 1984), whereas that of an AD patient from an actual loss of representations. These issues are discussed in greater detail later in the section on lexicalsemantic deficits in AD, and in another chapter of the present book (Semenza, Chapter 11). In the present chapter the major studies on language disorders in AD will be considered and the relevant clinical and psycholinguistic aspects will be analysed. The first section is dedicated to studies on the modifications of language in the elderly and the problems inherent in distinguishing these modifications from possible overlapping AD disorders. In the second section the peculiar aspects as well as the variability of language deficits in AD are discussed, while the third section deals with a review of the psycholinguistic literature of lexicalsemantic deficits, of dissociation from morphosyntactic and phonological deficits, and of the disorders of written language. The fourth and fifth sections summarise the problems inherent in clinical differential diagnosis of language disorder between different dementing aetiologies and between dementia and aphasic deficits from focal brain injuries. In the sixth and final section a degenerative disorder known as “primary progressive aphasia” will be described, and the relation between this form and the standard form of AD will be discussed.

LANGUAGE MODIFICATIONS IN THE ELDERLY The majority of elderly subjects complain of a progressive deterioration of cognitive skills. Memory and concentration deficits are the most common complaints. Studies carried out in an attempt to bring objectivity to these subjective impressions show that cognitive functions are subject to at least partial transformation during the

34.

ageing process. This obviously constitutes a problem for the identification of neuropsychological and language deficits in demented patients, as it means that the degree of modification to be attributed to the ageing process must be quantified as a preliminary step to an unequivocal evaluation of AD disorders. However, the studies that have actually taken these methodological issues into account are rare. Furthermore, the observations are often anecdotal and divergent, to the extent that the state of the cognitive functions reported ranges from rapid and radical breakdown to complete preservation. Acquisition of new information in memory, speed and dexterity of controlled motor responses, and the ability to resolve complex problems requiring the use of dual task activities or the acquisition of new strategies (fluidfunctions) seem to be the most impaired, while those learned and organised in the past (crystallisedfunctions) are said to be relatively stable (Horn & Cattell, 1967). Crystallised functions generally include language, the deterioration of which would thus only be marginal and any modifications simply the consequence of the deterioration of other cognitive functions which are only instrumental to linguistic performance. Some authors, on the other hand, consider language modifications as a more consistent symptom: spontaneous speech would become more fluent, with increasing syntactic complexity, the active lexicon impoverished (Obier, 1980), while the passive one is said to be stable (Lewinsky, 1948; Thorndyke & Gallup, 1944) or even richer (Fox, 1947; Owens, 1953). Furthermore, only a few authors have systematically studied language modifications in the elderly. Ulatowska, Cannito, Hayashi, and Fleming (1985) compared samples of spontaneous speech produced by subjects of different age groups. The samples were taken from different communicative contexts (spontaneous speech, narration of memorable events from the past, story retelling, descriptions of simple and complex procedures). Although there was a decrease in the overall quantity of language produced, the authors found a progressive impoverishment of the information content, and an increase of pronominalised noun phrases and of elements with ambiguous co-

LANGUAGE DISORDERS IN DEMENTIA

811

references. Kynette and Kemper (1986), who analysed samples of spontaneous speech in subjects from 50 to 90 years old, found that subjects of over 70 make more inflectional errors in past tenses and subject-verb agreement as well as in the use of articles and possessive pronouns. This is particularly true in the case of multiembedded sentences (e.g. [the cat [which chased the mouse [which ate the cheese [that was left out of the fridge]]] climbed a tree]) and in left branched clauses (e.g. after having chased the antelope, the lion devoured her). As the processing of these syntactic forms requires more phonological shortterm memory (Fodor, Bever, & Garrett, 1974; Yngve, 1960), Kynette & Kemper (1986) consider that these results indicate a short-term memory deficit rather than primitive damage of syntactic knowledge. Davis and Ball (1989) drew similar conclusions. Little agreement is to be found in the data on lexical-semantic performance in production tasks. The performance of 70- to 90-year-old subjects on the Boston Naming Test (Kaplan, Goodglass, & Weintraub, 1983) was on average better, with lower standard deviation, than that of the younger individuals who made up the control group (LaBarge, Edwards, & Knesewich, 1986). On the other hand, Flicker, Ferris, Crook, and Bartus (1987) did not find any difference between a group of young individuals (18-30) and an elderly group (62-80), whereas VanGorp, Satz, Kiersch, and Henry (1986) found that the performance of the older group was only slightly inferior, with a mild increase in the standard deviation. Finally, the low confrontation naming performance recorded by Borod, Goodglass, and Kaplan (1980) would appear to be due to a higher rate of visual perceptual deficits in the older subjects (Goodglass, 1980). On the contrary, the results obtained through free naming tasks (fluency naming), in which the older subjects gave significantly fewer responses both in category and in phonemic cueing (Butters, Granholm, Salmon, Grant, & Wolf, 1987; Hochanadel & Kaplan, 1984; Novelli, Papagno, Capitani, Laiacona, Vallar, & Cappa, 1986; Spinnler & Tognoni, 1987), are more consistent. Spinnler and Tognoni (1987) obtained similar results from a free association naming task,

812 LUZZATTI

in which the subjects had a limited time span in which to produce as many words as possible, which are semantically related to the stimulus word (e.g. “cat”: whiskers, to miaow, claws, mice, ball of wool, milk, to purr, tiger, etc.). When performances were compared by age level, a significant decrease in the number of responses resulted (Bandera, Luzzatti, Santoro, & Spinnler, 1991), however a qualitative analysis of the words produced did not show any difference, either in frequency, prototypicality rate, or in the type of relation with the stimuli (paradigmatic vs. syntagmatic). This stability of performance was in line with the results obtained by Burke and Peters (1986) on a classic word association task (Palermo & Jenkins, 1964). Verbal input ability would also appear to be subject in ageing to partial impairment only (Beland & Lecours, 1990; Cohen, 1979; Obler et al., 1985). Lexical and syntactic comprehension of a period would appear to be spared. However, a certain difficulty has been observed in integrating levels of information and particularly in operating inference processes, such as those necessary for a link between new information and the relevant one contained in a preceding sentence (Cohen, 1979). On the other hand, a more consistent deterioration on the Token Test (De Renzi & Vignolo, 1962b) is evidenced by a general agreement of the results obtained (Luzzatti, Willmes, De Bleser et al., 1994; Orgass, 1976; Spinnler & Tognoni, 1987). The comprehension measured by the Token Test is for the most part connected to the phonological shortterm memory capacity. In fact, analogously to the previous observations on the production of sentences with complex syntactic structure, a working memory reduction, rather than an actual deficit of syntactic processing, appears to be the cause of deterioration in the performance on comprehension tasks. However, even after the scores were adjusted for the correlation between sentence comprehension and the short-term memory span, the comprehension scores of the older subjects were still significantly lower (Feier & Gerstman, 1980). Therefore, a reduced working memory capacity does not seem to be the only cognitive factor underlying sentence comprehension deficit. On the other hand, if the profile

values of elderly subjects are adjusted for their lexical and verbal short-term memory capacity, half of the subjects obtain scores that are comparable to those of the younger subjects, while the scores of the other half are significantly lower. Written language abilities, on the contrary, do not appear to undergo modifications. Luzzatti et al. (1994) studied the performance of 110 normal subjects ranging in age from 15 to 80, using a writing task which was constructed keeping in mind cognitive models of written language processing (for a full description of these models see Chapter 14, by Denes, Cipolotti & Zorzi). The subjects were asked to write words with regular orthography, words with irregular orthography, high-frequency loan-words and regular non-words. According to contemporary cognitive models, a regular word may be written on both the lexical and the phoneme-to-grapheme conversion route, while words with ambiguous or irregular transcriptions may be written on the lexical routine only, and nonwords may only be transcribed along the phonemeto-grapheme conversion route. All subjects, irrespective of age and level of education, were able to write regular words almost perfectly. The level of education had a significant effect on the transcription of irregular words (both Italian and loan-words), while age affected the writing of loanwords and non-words. The effect of age on lexical writing of loan-words has been explained as a lack of acquisition of orthographic output representation of these words by older subjects, rather than as a specific effect of ageing. Less obvious is the explanation for the effect that age has on the writing of non-words. In elderly patients even mild hypoacusia can compromise the writing of nonwords with peripheral mechanisms due to the lack of lexical feedback. Another explanation for lower performance in the writing of non-words is based on the observation that the processing of this type of material puts a higher load on phonological short-term memory (Bisiacchi, Cipolotti, & Denes, 1989), and it has been shown in the previous paragraph that during the ageing process this function does undergo progressive decay (Orsini, Grossi, Capitani, Laiacona, Papagno, & Vallar, 1987; Spinnler & Tognoni, 1987).

34.

Conclusions On the basis of these observations we can conclude that although language is the neuropsychological function that is least subject to transformation during ageing, modifications, especially of a lexical nature, cannot be excluded. Modifications appear to involve the active lexicon (spontaneous speech output and fluency tasks) without any significant damage to the passive one (confrontation naming, naming on definition, lexical comprehension, etc.). There is no evidence of an impairment of the more “superficial” skills such as repetition, reading aloud, and writing under dictation. When diagnosing and quantifying a potential acquired language disorder in an elderly patient, it is necessary to evaluate the verbal performances net of the specific modifications attributable to the ageing process. This means however that clinicians and cognitive psychologists have to face the following two-fold problem: on one hand, owing to the verbal and neuropsychological modifications that are part of the ageing process, the identification of a dementing disease requires the precise definition of normative data related to the age of a patient; on the other hand, the high incidence of chronic internal and neurological diseases that affect elderly subjects makes the choice of an adequate criterion for the selection of the normative sample difficult.

LANGUAGE DISORDERS IN ALZHEIMER’S DEMENTIA The language deficits shown by patients during the various phases of dementia are traditionally described by neurological and neuropsychological literature as following an almost standard pattern (Critchley, 1964; Murdoch, Chenery, Wilks, & Boyle, 1987; Obler, 1983; Stengel, 1964). However, clinical practice and the results of some group studies suggest that the symptoms may lack homogeneity, both at onset and during the evolution. These two points of view reflect different interpretations of AD symptomatology: a “unitary” clinical description suggests relatively widespread and homogeneous anatomical damage, whereas heterogeneous disruption patterns imply increased

LANGUAGE DISORDERS IN DEMENTIA

813

variability of the disease, with regard both to onset site and evolution modalities. The description of AD language deficits given in the following paragraphs will reflect these two aspects. Thus, data regarding the major variables of language disorders (frequency, interaction with other neuropsychological symptoms, evolution) will be reviewed, and an attempt will be made to identify their most typical elements.

Epidemiology of language deficits in AD The prevalence of language deficits is the first issue on which epidemiological studies tend to differ. According to certain authors, these deficits are present in all subjects from the earliest stages of the degenerative process (Appell, Kertesz, & Fisman, 1982; Cummings, Benson, Hill, & Read, 1985; Hodges & Patterson, 1995; Murdoch et al., 1987). Other authors found language deficits in between 50% and 85% of the subjects studied and consequently considered them as a nonessential element of the dementia syndrome, or as a sign of the later stages of the disease (Chui, Teng, Henderson, & Moy, 1985; Della Sala, Nichelli, & Spinnler, 1986; Neary, Snowden, Bowen, Sims et al., 1986; Neary, Snowden, Mann, Bowen et al., 1986). Table 34.1 summarises the results of the principal clinical and epidemiological studies. The varying prevalence recorded in the various studies may be explained partially by the differences in the procedures used for the selection of the experimental subjects and the study of language disorders. For example, in studies where language was not tested in detail, minor deficits may not have been individuated (Neary et al., 1986a, b); whereas a higher rate of language disorders may be accounted for by diagnostic procedures that did not take the natural ageing modification into account (Appell et al., 1982), or by the study of severe and/or institutionalised AD patients only (Appell et al., 1982; Murdoch et al., 1987). Some authors found more severe language impairment in AD cases that had early onset (Chui et al., 1985; Faber Langendoen, 1988; Filley et al., 1986; Roth, 1986; Seltzer & Sherwin, 1983), while Bayles (1991) found a prevalence of language deficits in older patients. According to Cummings et al. (1985) earlier impairment of language is an index of more

4^

Oo

-

-

Lexicon is reduced; inertia and loss of verbal initiative; perseverations. Pts. selected for the absence of clear aphasic symptoms. Language is fluent, semantics more impaired than phonology and articulation. Language deficits are heterogeneous; lexical impoverishment with spared phonological and morphosyntactic skills; informative content is incoherent and/or impoverished; sentences are incomplete and there are many stereotyped elements.

Stengel, 1964

-

Language deficits in all AD patients. (6 G, 7 W, 4 TS, 1 C, 5 A, 2 TMo).

Appell et al., 1982

25 AD age 76±7

-

Different patterns; semantic structure is severely impaired, the morpho-syntactic abilities are less damaged, but these only appear in automatised utterances; phonemic or articulatory disorders are rare.

Ajuriaguerra & Tissot, 1975

9pts; age 45-59 (diff. etiol.)

Ernst et al., 1970

-

32+20pts (diff. etiol.)

Irigaray, 1967, 1973

Difficulty with logical-grammatical structures; deficits of repetition; anomia in only one subject; no phonemic or articulatory deficits.

32pts (diff. etiol.( mean age 61

De Renzi & Vignolo,

-

F o llo w -u p

-

L a n g u ag e

Anomia; lexicon is reduced to most concrete words and cliché sentences; ideatory inertia.

Subjects

Critchley, 1964

A u th o r

High correlation between length (of institutionalisation) and severity of language deficits.

-

E v o lu tio n

Pts. are very old and dementia is very severe (all pts. are already institutionalised).

C om m ents

Major clinical and epidemiological studies on language disorders in dementia of Alzheimer’s type (A = anomic aphasia; C = conduction aphasia; G = global aphasia; MiT = mixed transcortical aphasia; TMo = transcortical motor aphasia; TS = transcortical sensory aphasia; W = Wernicke’s aphasia; nvy deficits = neuropsychological deficits, LS deficits = lexical semantic deficits; VC deficits = visuo-constructive deficits; COM = comprehension; NAM = confrontation naming; REP = repetition; TT=Token Test; WRI = writing).

TABLE 34.1

01

00

19AD; age: 63±6

41 AD; (2365) 42AD; mean age: 59.3

Gavazzi et al., 1986

Filley et al., 1986

Martin et al., 1986

146AD; age 68±10

Chui et al., 1985

39AD; age: 62±5

30AD; (1565)

Cummings et al., 1985

Della Sala et al., 1986

34AD+31SDAT

Seltzer & Sherwin, 1983

31 AD; mena age: 69

8pts (diff. etiol.)

Kirshner, 1982

Kaszniak & Wilson, 1985

Subjects

A u th o r

TABLE 34.1 continued -

F o llo w -u p

3 years

3 major clusters: 25 (60%) diffuse, 9 (21%) prevalent language, 8 (19%) prevalent visuo-constructive deficits.

Language deficits are more frequent in pts. 65.

-

Mean profile: A/TS; language deficit in 16/19 (84%); type of deficit: 7 A, 2 TS, 2 W, 1 C, 1 B, IMiT, 2 non classifiable forms.

Only language deficits in 4/39 (10%); memory & language deficits in 7 (18%); language, memory & visuospatial deficits in 22 (56%); in 6 subjects (15%) no language deficits.

Mild deficit with prevalent anomia (generative naming by category).

Language deficit in 87/146 (60%), especially in those with early onset.

Deficit in all pts., mostly anomia and/or TS; no difference beween presenile and senile forms.

Language disorder is more severe in presenile forms. Speech is reduced; there is disorder of NAM, COM, WRI. 22% left-handers in presenile forms, and no left-handers in senile forms.

Fluent deficit with preserved syntax; anomia in all pts; preserved reading aloud, but with no comprehension.

Language

Only males.

~

C om m ents

-

Deficit has frequently a focal onset, but it generalises during evolution.

-

-

5/19 have severe visuoperceptual deficits.

Homogeneous progressive Pts. described only as a damage in all tasks. group.

Presence and severity are in relation to length.

Also repetition is Pts. described only as a impaired; low correlat. group. of language deficit with disease length; high correlat. with n\|/ deficits.

E v o lu tio n

Oo

Fluent language deficits; phonology and syntax are preserved in severe cases too; impaired verbal comprehension, spared repetition. In 22/86 major lex-sem deficits; in 19/86 major visuo-costr. deficits (11/86 only lex-sem, 4/86 only visuo-costr).

Language is impaired in 17/19 pts (89%): 8A, 6W, 2A/W, IB. Language disorder is more severe in pts. with later onset.

33AD

79AD; age:67.4±8; cognit. functions tested for 5 major n\jf aspects. 18AD; age: 82.5±7

86AD; age: 68±8

150AD; age: 73.5±5

19AD median age: 64 (range 54-78) 86AD

Bayles & Kaszniak, 1987

Huff et al., 1987

Murdoch et al., 1987

Becker et al., 1988

Faber-Langendoen & coli., 1988

Gavazzi et al., 1990

Bayles et al., 1991

+ (6-12 months)

36 ss. are Within mild AD, 11 % have moderate to severe language deficits; retested after 15, 33,& within moderate AD, 18% have minimal or no language deficits; within 50 months severe AD all pts. have severe language deficits.

56 pts. (1 year)

Com m ents

Disease length does not correlate with the severity of language disorder.

Language deficits in all patients.

An early language disorder predicts a more rapid evolution of AD.

There is no ^ in patterns of evolution.

Length of disease correlates only with the severity of articulatory disorder.

Half of the pts. with isolated deficit at the 1st exam, show multiple deficits at the retest.

78% of the patients have more than 80 years.

In 7/13 significant increase Pts. described only as a of language disorder, group. especially for NAM.

16/24 (67%); low correlat. of language & n\|f deficits with length of disease.

+

In 13 pts: all 6months for 18months.

E v o lu tio n

F o llo w -u p

In 32pts. Language deficits in 72%; deficit of retest after only one function 12%; of 2 functions 9-12months. in 15%; of 3 functions in 15% > 4 functions in 53%. Only sem-lex deficits in 3%. Sem-lex and memory deficits in 9%.

Deficit of propositional language but not of single linguistic rules; phonemic & syntactic judgements less damaged than semantic & pragmatic ones.

24AD in 8 groups Language deficits in 12 of 24 subjects by lang. & \\f (50%). deficits, & by pathology.

Neary et al., 1986a, b

Language

Subjects

A u th o r

TABLE 34.1 continued

Oo

Subjects

18AD with rapid and 15 with slow evolution 32AD+35 non-AD pts.

28AD (9M+19F) 20 consec. AD cases with pathology

647AD 127 pts. (47 AD, 83 SDAT) 52 pts. 17 minimal AD (age 72±7); 17 mild (age: 67±8); 18 moderates (age: 63±9)

A u th o r

Boiler et al., 1991

Lang et al., 1991

Binetti et al., 1993

Price et al., 1993

Henderson & Buchwalter, 1994

Jacobs et al., 1994

Hodges & Patterson, 1995

TABLE 34.1 continued

-

-

F o llo w -u p

-

All pts. have episodic and/or visuospatial memory deficits; 90% of pts. have LS deficits; pts. with mild LS deficits have very different patterns of impairment.

-

Early onset pts. (65) have major memory and naming deficits.

Females show a more severe naming deficit than males.

Language deficit in 17/20 pts. (severe 12 pts. deficit in 7); fluent deficits with anomia and no impairment in verbal comp (12 A, 4 W, 1C); only 1 function is involved in 7 pts (in 3 only language).

Two major n\|t clusters: C l: with major language deficits (n=6); C2: with major memory deficits (n=22).

AD: fluent language deficit with no dysarthria. COM & TT > REP. Clinical classification: A, W; never B; G in more severe cases only.

2 groups do not differ in age at onset. Within the pts. with rapid evolution, major language (mainly naming) deficits.

Language

-

Age: Cl 61±5;C2 72±7 C2 is quite heterogeneous.

'

C om m ents

All pts. have episodic memory deficits because it is a selection criterion of AD. Different age in different severity levels.

Pts. with early onset show more rapid evolution.

-

Fluent language deficits in all pts., often with comprehension disorders (5A, 6W, 1C).

-

Age at onset does not influence the rate of progress of the disease.

E vo lu tio n

818 LUZZATTI

rapid evolution of the AD symptomatology rather than earlier or later disease onset. The results as to the association between language deficits and other neuropsychological disorders are also relatively discordant. Della Sala et al. ( 1986) identified four major groups of patients: 56% showed extensive language, memory, and visuo-spatial deficits; 15% showed visuo-spatial and memory deficits with no impairment of language; 18% presented memory and language impairments but no visuo-spatial deficits; and the remaining 1 0 % showed only an isolated language disorder. Becker, Huff, Nebes et al. (1988) recorded similar findings: only 52% of their patients showed a uniform cognitive deficit, 26% presented prevalent language deficits, and 2 2 % prevalent visuo-constructive deficits; of the latter two groups approximately half the subjects (13%) presented a prevalence of language deficits only, and one quarter (5%) showed only visuo-constructive deficits. These findings were substantially confirmed by the study by Price, Gurvit, Weintraub, Geula, Leimkuhler, and Mesulam (1993) on a large sample of patients whose AD diagnosis had been confirmed by pathological and histological data. Once again, only 15% of the subjects showed homogeneous impairment of attention, memory, language, and visuo-constructive skills; the remaining subjects distributed almost proportionally along the various combination of symptoms: three or more cognitive domains were involved in 15% of the patients, two in 35%, and only one in a further 35%. Overall, language was impaired at least mildly in 85%, moderately in 35%, and severely in 10% of the patients. Such dissociation could be accounted for by initial focal cerebral atrophy where one hemisphere only or a single functional territory is affected. As a final remark, it should be stressed that the number of degenerative diseases with dissociated involvement is usually underestimated if it is considered that the majority of the authors selected AD patients using the DSM criteria (American Psychiatric Association, 1987,1994). These criteria require the co-existence of a memory deficit and damage of at least one other cognitive area (e.g. McKahn et al., 1984). Other studies insist on at least three affected cognitive areas (Puttman et al., 1992;

Stem et al., 1992). Therefore, the restrictiveness of these diagnostic criteria excludes a priori all subjects in whom only one cognitive area was affected.

Features of language deficits in AD As has been explained in the preceding paragraph, neuropsychological literature usually considers AD language deficits as being relatively homogeneous. For the sake of simplicity this will be accepted as a premise for the present and the clinical history of a standard case of AD will be described. The clinical data will be illustrated with examples taken from a study on Italian speaking patients (Gavazzi et al., 1986,1990). In the very early stage of AD, language deficits are usually described as a subjective symptom only and patients refer to them in terms of difficulty in concentrating on the topic of conversation or in remembering names they do not often use. Sometimes, during conversation, it is possible to recognise features that are typical of the language of normal elderly subjects, i.e. a mild impoverishment of the informative content and an increase in the use of pronominalised noun phrases (Obler & Albert, 1984; Stengel, 1964). However, such modifications are more marked than would be justified by the age of the patient. Typical aphasic symptoms are rare and the impairments appear to correspond to those described by Critchley (1964) as “ideatory inertia” and “concrete attitude” of AD patients. The rare anomia, the latencies, and some uncertainty in sentence structure are adequately compensated and spontaneously repaired, and do not impair communication. Impairment of generative naming (by category or on phonological cueing) and, less frequently, confrontation naming, may be an expression of ideatory inertia and of concrete attitude. The following is an example of conversation: Examiner: “Tell me how you spend your free time. ” F. G.: “I have a small piece of ground, there I take care, I take care o f the garden; we are two, two partners, you know ?Just to have some company, afterwards we gofor a while to the club, to play cards; I mean, I only watch, because ... well, my memory is not what it

34.

used to be a n d ..., and 1 make ..., now I am ... how can I explain it, well, my memory is not what it used to be and I uh, ... now I am, how can I explain it, he cards, ... in short, I make, I make mistakes: playing cards is a memory game, you have to know what has been played, and I ... no, no, I go and watch; maybe I sit there, yes, in front, in front, with them, you know, to watch if they make mistakes... I, uh, if they, if they..., you know, I still recognise the mistakes! " In the more advanced phase (after approximately 2-3 years from onset) spontaneous speech is impoverished, the lexicon is reduced, especially with regard to less frequently used words, anomia is more severe, cliché sentences and passe-partout words are more frequent (Nicholas, Obler, Albert, & Helm-Estabrooks, 1985). The expression of concepts is sometimes confused, as if there were no general plan to the sentence. The deficit may assume features similar to those of fluent (anomic or Wernicke’s) aphasia. A language examination may reveal a mild writing disorder, characterised particularly by the occurrence of perseverations or omissions of single graphemes; whereas the naming deficit may be more conspicuous on a confrontation or a fluency task. Examiner: “Could you explain why you prefer not to drive any more ? " L.A. : “uh yes, I don't remember the streets very well: I have a kind o f repulsion, Em a little ... a little afraid; the problem is that I get... almost... ; I avoid, I avoid .. because, if something happens ... Furthermore, while driving, you know, I ’m also ... also afraid, ... Em worried. Yes, because ... I don't ...To drive in areas I don 't know,... for instance, the parts o f Milan I don 't know very w ell... To go out, along streets I don’t know ...it's a lot more difficult than ... to do what 1 know .... I prefer the streets I know: the other, I don't like driving on them ... Well, I try to avoid them as much as possible... I f really I ca n n o t... I cannot avoid it, I go ... but if not, in general... You know, little by little, la m getting rid o f the car." Examiner: “Tell me how your disease started. "

LANGUAGE DISORDERS IN DEMENTIA

819

B.M.: “My work is ... to p la n ... th e... th e... what is the name o f it?... /e /... it is concerned with ecology, no, with/nelo/... naelology [-oenology] (...). It was just during ... during the holidays .. o f ..., th a t..., down in Pantelleria, I mean, toward Sicily ... And it's ... and there, because Pantelleria is on the sea, I mean, it’s an island, a n d ... Well, I was called in because a piece o f equipment did not work well, I m ean..., but I only had to go therefor one day, let’s say; whereas they only let me go after five days, because I w as... I had... to do another... something else tofix, I mean, and that, that ruined me... all the time I had to ... And m e,... then ... when I got home ..., you know, I cried. It must have been the turning point, let's say (...). " In the intermediate phase of the disease (for the majority of the patients this occurs between the third and fifth year from onset) language is more extensively damaged, often by salient inertia of the verbal initiative (the Spontanstummheit described by Kleist, 1934, in patients with frontal lobe lesions). Communication is severely reduced by the presence of automatisms, stereotyped utterances, and cliché sentences, and due to the lack of informative content words (empty speech; Benson, 1979). Anomia is progressively more severe, whereas compensatory strategies or circumlocutions are more and more inefficacious. Patients are no longer able to make turn-taking conversation and they communicate by means of egocentric language (Critchley, 1964) constantly returning to their own problems and needs. Articulatory disorders and phonemic paraphasias are rare. Language examination usually reveals moderate comprehension deficits, severe dysgraphia, and very severe naming disorders. Repetition and reading aloud, even of quite complex sentences, are still fairly well preserved. Examiner: “Tell me how you spend your day. ” R.N.: “In the morning I do ... the house-work, the cleaning a n d ... not the cooking, because I cannot, no, I don'tfeel..., my husband must do it, or we help each other, right, and then if there is something to wash, I wash, and i - ... iron, but I cannot work any more, I mean, sew, o r ... Iam bad at it, well, I have lost so many things, so many, I feel really better than

820 LUZZATTI

..., I mean, physically Em fine, yes, but not to ..., to do the things..., nor the house-work Examiner: R ) ”

d iffu s e c o r tic a l atro p h y

in c lu sio n s, se n ile p la q u e s.

( L > R ) ; c e lls b a llo n é e s, arg y r o p h ilic

te m p o ra l atro p h y (b ila t)

+

W /M u

?

B F A , a c a lc .

4

W

2

69

61

65

1

W .L .P

5

±

AAV

5

54

+

t e m p o r a l> p a r ie ta l atro p h y (b ila t)

fr o n to -te m p o ra l atro p h y ( L > R )

te m p o ral atro p h y ( L )

T S /M u

+

3

Mu

2

±

8

TS

±

te m p o ral atro p h y (b ila te r a l)

-

A

te m p o ra l atro p h y ( L > R )

±

W

3

VM , ±

4

th e d e g e n e r a tiv e d a m a g e

(y e a r s )

-

site , s e v e r ity a n d ty p e o f

o th e r n e u ro p s y c h o l. d e f ic its

ty p e o f a p h a s ia

f o ll o w - u p

o th e r n e u ro p s y c h o l. d e fic its

W /T S

2

57

K irsh n e r, et a l., 1 9 8 4

G o r d o n & S e in e s , 1 9 8 4

H e a t et a l., 1 9 83

B e n s o n et a l., 1 9 8 2

(c a s e 4 n o t in c lu d e d )

M e su la m , 1 9 8 2

S c h w a r tz et a l., 1 97 9

W e c h sle r et al. 1 9 8 2

1

A .C .

S te r tz , 1 9 2 6

W ec h sler, 1 9 7 7 ;

P.M . A .B .

M in g a z z in i, 1 9 1 4

57

54

E.N.

R o s e n fe ld , 19 0 9

A

5

D .B . 8

TS V D (? )

2

69 47

A .H .

P ic k , 1 8 9 2

S é r ie u x , 1 8 9 3

ty p e o f a p h a s ia

(y e a rs)

age

A u th o r s

ca se

le n g th

Major cases described in the literature with the clinical features of a primary progressive aphasia. (Age: age at onset; type of aphasia: A = Anomic aphasia, B = Broca’s aphasia, C = conduction, G = global aphasia, Gwad = global aphasia without articulatory deficits, Mu = mutism, APS = aphasic pseudostuttering, MiT = mixed transcortical, SA = speech apraxia, TMo = transcortical motor, TS = transcortical sensory, VD = verbal deafness, W = Wernicke’s aphasia; other neuropsychological deficits: acalc = acalculia, DA = dressing apraxia, BFA = buccofacial apraxia, CA = constructive apraxia, IA = ideatory apraxia, IMA = ideomotor apraxia, I = verbal and nonverbal intelligence deficit, VI = verbal intelligence deficit, M = verbal and nonverbal memory deficit, VM = verbal memory deficit, (*) = figure-to-colour and figure-to-sound association deficit; site, severity and type of the degnerative disease: L = left, R = right.

TABLE 34.6

CO

g

3

40 59 69 70 54 60

1 2 3 4 5 6

T y rre ll et a l., 1 9 9 0

58

2

62

1

G o u ld in g et a l., 1 9 8 9

1

2 .5

65

K a r t s o u n is et a l., 1991

4 1.5

67

1 2

S a p in et a l., 1 9 8 9

5

4

1.5

2

2

5

68

5

46

4

NV

53

HS

5

MW

63

B+SA

A /W

A /W

B+SA

A

A /W

A

B+SA

A /W

A

A

A

A

A

W /C

4

67

MH

1

B a s s o et a l., 19 8 8

P o e c k & L u z z a tti, 1 9 8 8

S c u lly et a l., 1 9 8 7

G w ad

4

60

2

A

A

W /B (? )

B

A /W

A

3

3

4

4

1.5

2

55

1

49

2

H a m a n a k a et a l., 1 9 8 7

51

1

C h a w lu k et a l., 1 9 8 6

66

M r. E

59

1

A s s a i et a l., 1 9 85

H o lla n d et a l., 19 8 5

56

5

69

6 1

A /W

8

5

A /W A /W

3

58 66

4

P o g a c a r , & W illia m s, 1 9 8 4

TABLE 34.6 continued -

3 2

_

3

1

0 .5

0 .5

1

3

7

6

0 .5

1

13

3

4

0 .5

-

-

IM A , B F A , V I

VM

-

_

-

VM

VM

-(*)

VM

VM

-

_

B F A , IM A , a c a lc .

VI

a c a lc .

V M , V I, a c a lc .

-

BFA

a c a lc .

C A , M , a c a lc .

IM A , D A , a c a lc .

B + S A /T M o

G /M u

?

A

A

A

A

W

G /M u

TS

+ (? )

A

SC + M

G

W

A /W

B F A ,V I , a c a lc

IM A , V I

+

VM

un ch an ged

V M , a c a lc . ±

VM , VI

V M , a c a lc .

+

+

a c a lc .

V M ,V I , ac alc .

± a fte r 10 y

(+ )

+

-

b ila te r a l fro n ta l atro p h y

fis s u r e

e n la r g e m e n t o f the le ft sy lv ia n

atro p h y o f the left te m p o ra l p o le

m ild d iffu s e atro p h y

d iffu s e left h e m isp h e re atro p h y

m ild left p e r isy lv ia n atro p h y

m ild le ft p e r isy lv ia n atro p h y

atro p h y

se v e r e fro n to -te m p o ro -p a rie ta l

le ft te m p o r a l atro p h y

m ild d iffu s e atro p h y

le ft te m p o ra l atro p h y

le ft te m p o ra l atro p h y

se v e r e te m p o ra l atro p h y ( L > R )

(L > R )

t e m p o r a l> fr o n to -p a r ie ta l atro p h y

n o a r g y r o p h ilic in c lu sio n s

se n ile p la q u e s , n o fib rilla ry t a n g le s,

( L > R ) ; c e lls b a llo n e e s, bu t n o

fro n tal 1-2 & su b c o r tic a l atro p h y

atro p h y ( L > R )

se v e r e fro n ta l, te m p o ra l & parietalam

m ild le ft te m p o ra l atro p h y

h y p o m e ta b o lism

C T : n e g a tiv e ; P E T : left

fissu r e

e n la r g e m e n t o f the left sy lv ia n

d iffu s e atro p h y

fis s u r e

b ila te r a l e n la rg e m e n t o f the sy lv ia n

fib r illa r y ta n g le s

p a r ie ta l lo b e ( L > R ) ; se n ile p la q u e s,

atro p h y o f the te m p o r a l> fr o n ta l an d

m ild d iffu s e atro p h y

m ild d iffu s e atro p h y

m ild fro n tal atro p h y

844

LUZZATT!

articulation disorders and agrammatism, six patients a fluent deficit, mainly lexical both in production and comprehension—the term semantic dementia has been used to designate these forms— while five other patients showed language symptoms that were intermediate to the two groups. During the following years, Mesulam et al. (Mesulam & Weintraub, 1992; Weintraub & Mesulam, 1993; Weintraub, Rubin, & Mesulam, 1990) partially modified the distinctive criteria for diagnosis of PPA. First of all the authors acknowledged that a large number of the cases in which the disease started with an exclusive or predominant language deficit develop into a widespread cognitive disorder. They suggested, however, that while this occurs fairly frequently in fluent language disorders, it is the exception where non-fluent language disorders are concerned. Therefore, while the authors acknowledged that a case of PPA may have fluent characteristics, they maintained that the most typical forms were non-fluent. This difference seems to be confirmed by the various underlying anatomo-pathological pictures: fluent language deficits may present histology typical of AD (senile plaques and neurofibrillary degeneration), of Pick's dementia (ballooned cells and argentophilic inclusions), of Creutzfeldt-Jakob dementia (vacuolar degeneration) or of an aspecific focal atrophy with gliosis, while only the histological pattern of the latter form corresponds exclusively to non-fluent language disorders. Such specificity of anatomo-

decrease. This relative deterioration of the nonverbal skills was interpreted as a late generalisation of the degenerative process with initial damage also to the extra-linguistic cognitive functions. Another problem that arises if slowly progressive language deficits are considered as a disease independent of the remaining diffuse degenerative diseases is the extreme variability of language disorders that emerge from the various studies (see Table 34.6). A wide spectrum of disorders, ranging from Broca’s aphasia with phonetic disintegration syndrome and agrammatism, to verbal deafness or Wernicke’s aphasia with semantic jargon, is distributed all along the aphasiological taxonomy (see Table 34.7). Almost all the cases reported suffer from focal cortical degeneration in the left hemisphere only, or from a predominant involvement of this hemisphere. The type of deficit is in turn related to the site of the focal degenerative process along the antero-posterior dimension: non-fluent language deficits with articulation difficulties and in certain cases agrammatism, are generally associated with left frontal degenerative forms; on the other hand, fluent deficits with progressive lexical-semantic breakdown and relatively intact phonological and syntactic skills are associated with left temporoparietal degenerative forms (see Table 34.6). A similar lack of homogeneity also emerges within the 16 patients described by Snowden, Neary, Mann, and Goulding ( 1992). Five of the patients showed a non-fluent language deficit associated with

TABLE 34.7 Features of the language disorders of the 40 PPA cases traced from the contemporary literature (1977-1991). F irs t ev a lu a tio n (n = 4 0 )

p a tien ts w ith fo llo w -u p (n = 2 4 )

first evaluation fo llo w -u p

flu e n t disorders (2 8 ) A

W

AAV

16

3

9

TS

11 7

B

G + MiT

6

flu e n t disorders (1 2 ) A

n o n -flu e n t disorders (7 )

W

AAV

TS

3 3

3 1

1

1

? or

F/nF 5

n o n flu en t disorders (8 )

? or

B

G/MiT/Mu

F/nF

4 2

6

3 4

A = anomia; W = Wernicke’s aphasia; A/W = fluent aphasia with mixed features (anomia vs. Wernicke’s); TS transcortical sensory aphasia; B = Broca’s aphasia; G = global aphasia; MiT = mixed transcortical aphasia; Mu = muteness; F/nF = not classifiable along the fluent/nonfluent dimension.

34. LANGUAGE DISORDERS IN DEMENTIA

pathological patterns for non-fluent language disorders is compatible with the prevalent aspecific neuronal loss and gliosis, and the absence of typical Pick’s or Alzheimer’s histological patterns within the frontal lobe atrophies (Brun, 1987).

Conclusions Alongside the classic cortical degenerative forms, a certain number of cases exist in which cerebral atrophy remains limited for a specific period of time to single cortical areas. This form, which was described by Pick at the end of the nineteenth century, was called partial cortical atrophy. An atrophy that is limited to the left perisylvian area is usually accompanied by a progressive language deficit. The language deficits may assume notably different characteristics along the taxonomy of aphasic disorders, from non-fluent deficits with dysarthria and possibly agrammatism to fluent forms with progressive lexical-semantic breakdown. There are very few studies that provide a detailed follow-up, but in point of fact most patients with fluent deficits appear to develop a generalised cognitive disorder, while the forms associated with degeneration of the frontal lobe appear to remain focal for a longer period of time and tend not to develop into generalised forms of AD.

GENERAL CONCLUSIONS The principal observations made in this chapter can be summarised by concluding that AD should not be considered as a single and homogeneous phenomenon but rather as a conglomerate of modifications which appear concurrently during the evolution of the progressive degenerative disease. Although the symptoms recorded differ quite significantly from patient to patient, which makes their grouping in a unitary cohort difficult, it was still possible to individuate some tendencies in the pattern of neuropsychological deterioration. A first form, which can be called early ageing, can be described as premature and rapid modifications that can be considered as close to the physiological process of normal ageing. In this form, language disorders are relatively slight and

845

are only evident in a fairly complex communication context and/or in tasks that require a constant effort of attention or concentration, or in tasks that bring to light limitations of verbal short-term memory. A second form of dementia, which can be defined as classic Alzheimer, is on the other hand characterised by prevalently lexical-semantic language disorders. This form is generally associated with impoverishment of the general cognitive and interactive skills, with verbal and psychomotor inertia. Finally there are a certain number of degenerative forms of focal origin, of which the clinical aspects are closest to those of neuropsychological disorders for focal vascular damages. These forms may sometimes show a circumscribed symptomatology (e.g. primary progressive apraxia, agnosia, or aphasia) which, however, frequently develops into a widespread cognitive disorder. In those cases in which a language deficit is the only or the dominant symptom over a prolonged period of time, it may assume various characteristics which may differ widely one from the other, from nonfluent forms with agrammatism to fluent forms with dominant lexical-semantic deterioration. The paradigm that opposes language disorders from focal lesion to degenerative disorders, and, on the other hand, the dissociation that can be found in these latter subjects between a more evident lexicalsemantic and a less obvious syntactic and phonological disorder, is open to a series of objections, which have been repeatedly discussed in this chapter. In certain individual cases the paradigm could be substantiated, but the extension of these conclusions to the language deficits that occur in each individual patient suffering from dementia cannot be justified.

NOTES 1. The nature of the visuo-perceptive deficit was not studied in greater depth; however, the absence of prosopagnosic difficulties and, in at least two of the five patients, of reading impairment, the absence of cortical atrophy in the occipital region, and lastly, the peculiarity of the naming errors (“snake”, for a hoover

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with a long tube; “propeller”, for a tin opener with a butterfly lever; “bowl”, for scales, etc.) suggests that the deficit should be interpreted as a “frontal” pseudoagnosie type deficit or as amorphosynthesis (Luria, 1966) rather than as a classic agnosie impairment. More information on visuo-perceptive deficits is given later in this chapter and in H. Spinnler’s Chapter 31 Part IX D e m e n tia ). 2. Some authors, however, have suggested the possibility of direct activation of the phonological representation from the structural representation, without passing

through semantic representation (Heilman, Tucker, & Valenstein, 1976; Kremin, 1986, 1988; Kremin & Koskas, 1984; Ratcliff & Newcombe, 1982). 3. The English language is characterised by a relative irregularity of phonemic/graphemic transcription, therefore homophone words, i.e. words with the same pronunciation (e.g. /nAn/) are written differently (e.g. n u n , none). 4. A speaker may use a personal pronoun such as he or she, or a determinate article as in “the boy”, only in the case that the reference is not ambiguous to the listener.

PartX

Recovery of Functions

Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

35 Recovery of Cerebral Functions Anna Basso and Luigi Pizzamiglio

on the other have clarified the conditions and mechanisms that make recovery possible. These studies will be described with the aim of clarifying the biological bases and general principles of neuropsychological recovery. A second area regards knowledge of the metabolic mechanisms that are released by the appearance of a cerebral lesion. Knowledge of both the toxic factors activated by the lesioned nervous tissues and the complex reparation responses put into effect by the organism represent a new and fascinating chapter in current neurology, which is now capable of increasing the possibility of therapeutic interventions, especially in the acute phases of nervous pathology. Current studies in this area, which are rapidly increasing, highly complex and very different methodologically from studies on behavioural disturbances, will be briefly summarised in this chapter. A third novel element is the increasingly frequent use of modem biotechnologies in the study of functional recovery. In particular, the various techniques for studying cerebral flow and the metabolic variations of cerebral areas in conditions of rest and specific activations have allowed a

The recovery of functions in patients with CNS lesions has always received attention, primarily because of the great social value attached to it. Interest increased further after the Second World War when systematic attempts were made to improve recovery of motor, sensory, and cognitive deficits through the development and use of specific rehabilitative procedures. Recovery has been studied in brain-damaged patients in the developmental years and in adults. In this chapter attention will be limited to pathology acquired in adulthood. In the broad panorama of studies on functional recovery, over the last 10 or 15 years new lines of research have developed, which have greatly increased knowledge in this area. An initial contribution regards the broadening of the concept of cerebral plasticity; the possibility of compensating in various ways for functional losses deriving from a lesion of nervous tissue can be observed over the entire life span and not only during the developmental period. These acquisitions, linked to a large number of experimental studies on various animal species, on one hand have proven the existence of functional recovery in adults and 849

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dynamic and more thorough look at the problem of identifying the nervous structures that intervene in recovery of functions compromised by the lesion. A demonstration of the mechanisms of compensation will be made when possible, also in light of these perspectives. Finally, the main elements for making predictions of functional recovery from the most important neuropsychological disorders will be discussed. A critical review of how much functional recovery in neuropsychology can be modified by specific rehabilitative interventions will be treated in subsequent chapters (see Chapters 36, 37, 38).

CEREBRAL PLASTICITY Recent literature shows that cerebral plasticity is not only observable in the case of lesions occurring in phases of cerebral development (Lenneberg, 1967; Webster et. al., 1997) but also in adults. Much experimental research in both primates and humans documents the possibility of observing massive cortical reorganisation following suppression of sensory input established during adulthood both following experimentally induced cortical destruction or occurring spontaneously. A second relevant concept is the importance of the environmental context in guiding processes of functional reorganisation of the brain. The structural changes that take place in the presence of a cerebral lesion or sensory deafferentation, begin and are defined if the environment provides an adequate and specific stimulation to compensate for sensory, motor, or cognitive deficits induced by the lesion.

Cortical reorganisation in adulthood following sensory deafferentation or cerebral lesions At the beginning of the 1980s many experiments showed how different forms of peripheral denervation in cats (Frank, 1980), in rats (Wall & Cusic, 1984), and in various species of monkeys (Merzenich et al., 1983a, b, 1984) produced considerable reorganisation of somatosensory representations in these adult animals. If a finger

on a monkey’s paw is immobilised for a long period of time it can be observed that in the somatosensory cortex 3b and 1 responses to stimulations of the deafferented finger are mediated by cells found in an area immediately adjacent to those originally responsive for the finger in question (Merzenich et al., 1983a). Already in these initial experiments it was noted that a very long time was necessary, even months, and a great deal of exercise, before this reorganisation could be shown. More recently Pons and others (1991) documented a reorganisation in the somatosensory cortex many years after amputation of the finger of an adult macaque. Unlike the restructuring described by Merzenich’s group, which was limited to the area contiguous with the original sensory representation, in the case of Pons and others (1991) the changes observed involved much larger cortical areas. Although cortical maps are unavailable, phenomena of functional somatosensory reorganisation have also been described recently in humans. Ramachandran, Rogers-Ramachandran, and Stewart (1992) studied a patient who had undergone amputation of an arm. In the postoperative period a precise somatotopical representation of the hand could be observed on the skin of the face homolateral to the amputation. When touched on very limited areas of the face, the patient had the subjective sensation of being touched on a point of the “phantom” hand. The correspondence among the various fingers or parts of the hand and facial areas was surprisingly precise and was easily replicated over time. In these cases it is evident that sensory areas anatomically contiguous to the cortical representation of the hand took control of the sensitivity of a new body district or, at any rate, one not functionally linked to it. Similar results were described by Aglioti and others (1994a) in patients with amputations of the lower limbs and in a large population of women who had had mastectomies (Aglioti et al., 1994b). In the latter study it is interesting to note that the new cortical representation could be observed very soon after the amputation (5-6 days). In patients with amputations of the upper limbs a modification has also been described in cortical

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representations of muscles near the amputations; these observations derive from studies on cortical evoked potentials following transcranial magnetic stimulations (Cohen et al., 1991) and more recently through the magnetoencephalograph (Flor et al., 1995). In a more recent study Ramachandran and Rogers-Ramachandran (1996) manipulated the proprioceptive sensations from the phantom by presenting visual input, therefore suggesting a possible interaction between vision and touch in the dynamic brain reorganisation. Conceptually similar results have also been observed in the field of vision, where deprivation of visual input provoked by mono or binocular retinal lesions produces a reorganisation of the cortical topography in adult animals (Gilbert & Wiesel, 1992; Kaas et al., 1990). Recently it has been possible not only to correlate a functional reorganisation of vision with structural changes in the striate cortex, but also to clarify the cellular mechanism supporting this reorganisation (DarianSmith & Gilbert, 1994). Bilateral retinal lesions have been produced in the adult cat. In the phase immediately following the lesion, enlargement of the receptive fields of the cells situated in the immediate vicinity of the deprived cortical area took place. After a period varying from three to nine months, an expansion of the representation of the retina adjacent to the lesion was observed in the cortical area initially silent following the lesion. From a structural point of view these functional readjustments were accompanied by phenomena of sprouting of cortical axons, which determined a lasting change in the architecture of the striate cortex; the extension of this reorganisation was approximately 7-8 mm in diameter. Darian-Smith and Gilbert (1994) suggest that this terminal sprouting together with synaptic proliferation represents a normal response of the adult cortex to extensive modifications of the sensory experience, whether visual or in other modalities. In a later study Das and Gilbert (1995) suggest that the functional reorganisation of the striate cortex may also be mediated by the potentiation of horizontal cortical connections which under normal conditions are activated below threshold.

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All of these studies have considered the cortical reorganisations occurring after deprivation of various types of sensory input. Analogous changes, associated with functional modifications, have also been observed following a cortical lesion. Jenkins and Merzenich (1987) determined the representation of the hand and digit in area 3b of adult monkeys. Successively, the area containing the cortical representation of a finger of the hand was removed. When examined after three to four months these animals showed that the cortical representation of the finger in question was again present in the sensory areas adjacent to the lesioned one and the entire topography of the cortical representation of the finger and hand was considerably modified. The authors generalise these results, hypothesising that in the presence of a cortical lesion in animals or in adult humans it is always possible to observe a reorganisation of the cortical representations in the saved areas functionally connected to them. They further hypothesised that recovery of the representations and functional recovery is greater the more extensive the cortical representation of a given function. The data just reported lead to the following conclusions: 1. It is possible to observe a structural reorganisation accompanied by changes in performance in the sensory and motor cortex of adult mammals. 2. In most of the cases described these changes require a long time for consolidation, even though data exist showing a very precocious beginning after the lesion (Kolarik et al., 1994). 3. The best documented structural changes are found at the level of the intracortical connections and within the functional areas linked to the lesioned or deafferented ones.

Changes in the environment modulate cortical representations in adulthood If a sensory surface, for example the skin of the finger of a hand, is repeatedly stimulated, an improvement in discriminative ability can be observed, which remains linked to the specifically trained surface (Recanzone et al., 1989).

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Jenkins and others (1990) trained adult primates to maintain constant pressure with a fingertip on a rotating surface containing in sequence stimuli in relief and in depression with respect to the surface of the moving disk. The cortical representation in the somatosensory area of the fingertip stimulated for a long time presented many changes when compared with that of the same finger before training. In particular, the representation of the stimulated area was enlarged about five times compared to the pretreatment finding (see Fig. 35.1). Further the receptive fields of the neurones in this area were remarkably smaller after the stimulation. These two adaptive changes induced by repeated training indicate that the sensory cortex was modified; on one side dedicating a larger area to the processing of those specific stimuli and, on the other modifying the properties of the single cells that reduce the receptive field in order to increase its discriminative ability (Garraghty & Kaas, 1992). Observations similar to those obtained with non-human primates were made on adult humans through use of functional Magnetic Resonance.

FIGURE 35.1

Outlines of the area 3b cortical territories representing the surface of the digits for 0M1 prior to differential stimulation (normal, top) and after stimulation (stimulation, bottom). Note that there was a substantial enlargement of the representation of digit 2 after stimulation.

Studying cerebral activation during the execution of an acoustic discrimination task, it was observed that repetition of the same task during an experimental session brought about a progressive reduction in the size of the sensory area activated (Ungerleider, 1994). In a different situation, normal individuals were trained to carry out a sequence of finger movements; in this case, training lasted about a month and the experimental subjects had to carry out the motor sequence every day for 15 minutes. At the end of this long learning period, the area of activation in the motor cortex was significantly enlarged compared to initial findings (Kami et al., 1995; Ungerleider, 1994). These two data, which need further verification, suggest that also in humans exposure to both short and long training periods produces significant, although opposite (concentration of sensory areas in the first case and enlargement of motor ones in the second case) cortical readjustments. Elbert et al. (1995) elegantly documented how the long and sophisticated use of the left hand by

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professional string players modified the cortical representation of the digits in the primary somatosensory cortex: furthermore the amount of such a reorganisation was correlated with the age at which the person had begun to play. All of these observations lead to the conclusion that both in animals and in humans it is possible to produce topographical modifications of cerebral representations through appropriate behavioural activation. These structural changes are probably the electrophysiological and/or metabolic manifestation of changes in synaptic effectiveness occurring at the cellular level, as a consequence of systematic exposure to environmental stimulations. This physiological information must constitute the explicative basis of the observable spontaneous changes in humans after a cerebral lesion, but even more of attempts to favour functional recovery through rehabilitative procedures. These acquisitions are not compatible with the notion that cerebral organisation remains immobile at the end of development; instead, they suggest the possibility of a continuous interaction between neural structures and the surrounding environment. It should also be noted that this interaction is possible only between adjacent cerebral areas and those previously connected functionally with the lesioned ones.

Metabolic modifications induced by a lesion After having examined the relation between neural structures and environmental modifications, it is interesting to look at recent knowledge on sequences of events connected with cerebral lesions that can be observed at the cellular and biochemical level. Direct cranial traumas, strokes, or cerebral ischemia produce an excess of excitatory amino acids, such as glutamic acid, which provoke a chain of events having toxic effects on the CNS, causing cell death. Figure 35.2, taken from Stein, Glasier, and Hoffman (1994) synthesises a sequence of events explaining the secondary damage released by the pathological event. The excessive production of amino acids, such as glutamic acid, and the alteration of calcium channels have destructive consequences on membranes of neurone and glial cells, and cells of

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the vascular endothelia. The latter, in turn, not only increase oedema and haemorrhage, but facilitate the release of auto-immune reactions; the hematic macrophages, which come into play, contribute toward increasing the production of free radicals, which determine the loss of neurones (for reviews of these mechanisms see Hall, 1991; Stein, Glasier, & Hoffman, 1994; Zevin & Choi, 1991). The foregoing has suggested the opportunity of activating biological mechanisms capable of interrupting or limiting these toxic effects. For example Stein and others (1994) report many studies that have shown the positive action of vitamin E on anatomical and behavioural recovery following experimental lesions in rats (Clifton et al., 1989; Stein, Halks-Miller, & Hoffman, 1991). The intracerebral administration of this substance in the lesioned area produced smaller neuronal loss and faster ability to learn new tasks. Preventive action was also observed when vitamin E was administered by injection before the destructive action on nervous tissue. Other examples of facilitation of functional recovery have involved the administration of antioxidant substances derived from a plant (Ginkgo biloba); these substances counteract the effects produced by the liberation of toxic substances on the hematoencephalic barrier, preventing development of cerebral oedema (Attella et al., 1989) and facilitating functional recovery in treated rats (see Brailowsky et al., 1991; Braquet et al., 1991 for a review of the literature). These acquisitions have stimulated the study of a series of pharmacological interventions to reduce the negative consequences produced by toxic factors released following lesions in humans (Lynch & Dawson, 1994; Stein, 1997; Teener et al., 1994). Neurotrophic factors and functional recovery Parallel to knowledge about toxic and destructive mechanisms released in lesioned cerebral areas, many studies have been carried out on the complex reparative mechanisms activated by the nervous system, in general indicated as the production of neurotrophic factors. In the period immediately following an experimental brain lesion, and with maximum intensity 7-8 days after the lesion (Cotman &

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Nieto-Sapedro, 1985) a great production of neurotrophic substances can be observed. This production is linked to specific activation of the glial cells (Gage et al., 1988) and, in particular, astrocytes (Fagan & Gage, 1990). The presence of large quantities of trophic factors favours in vivo dendrite regeneration through a sprouting terminal (Auburger et al., 1987; Hefti et al., 1989). The importance of neurotrophic factors is well illustrated by a complex series of experiments

FIGURE 35.2

Sequence of events after a brain lesion.

conducted on the plasticity of the visual cortex of varies species of animals. The binocular cells in rats, cats, and primates tend to be grouped in columns; within these columns, the neurones tend to respond more to one or the other stimulated eye (LeVay et al., 1980). Depriving an eye in a critical period of development (in the rat before the opening of both eyelids) important changes take place both at the level of the superior colliculus (reduction in diameter of neurones by about 30%.

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Maffei et al., 1991) and at the cortical level (great reduction of binocular cells and great increase of cells dominated by the undeprived eye; (Maffei et al., 1992). However, if rats with monocular deprivation in the critical period of development are treated with nerve growth factor (NGF) at the intracerebral level, none of the typical consequences of deprivation are observed. That is, at the cortical level, neither an alteration of ocular dominance nor the electric characteristics or selectivity for orientation that characterise the visual cortex of the deprived animal not treated with NGF are observed. Thus, the administration of neurotrophic factors, such as Schwann’s implantation of cells in the lateral ventricles that produce NGF (Pizzorusso et al., 1994) seem able to prevent both the anatomical and structural changes in the visual system and the functional deficits associated with them. Another line of research on functional recovery has been dedicated to studying the effectiveness of transplants of embryo tissue in the brains of animals that have undergone various types of lesions (for a summary of the literature, see Bjorklund, 1991). In the early 1980s several studies documented sensory, motor, and cognitive recovery in animals transplanted with embryo tissue. For example, Labbe and others (1983) produced lesions in the frontal lobes of adult rats and then implanted embryo tissue. The transplanted animals showed a lively production of cells that invaded the host tissue from the transplant and vice versa. The nervous tissue derived from the transplant had very different chitoarchitectonic characteristics from the original tissue (Mufson et al., 1986; Stein & Mufson, 1987); however, the treated rats were significantly more efficient than the control rats in learning a spatial task. Thus, the transplant seems to be able to promote good recovery (never complete) of cognitive abilities damaged by the lesion, even if this result is difficult to ascribe to anatomical reconstruction because of the dissimilarity of the original nervous tissue. In order to further study the link existing between tissue originated by the transplant and functional recovery, Stein (1988) reports an experiment with rats in which the transplanted tissue in the frontal area was successively removed

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together with part of the surrounding tissue. The rats still showed an advantage in solving spatial learning problems compared with the control animals. This result clearly confirms that the mechanism through which transplants act is not due to locally induced connectivity but to factors that can act even at a distance in the CNS. In particular, transplants can induce the production of a variety of neurotrophic factors which, in turn, promote neurone growth and favour the survival of cells that would otherwise regress due to their connection with the damaged tissue (Nieto-Sanpedro & Cotman, 1985). In the 1980s, the transplant technique was also extended to humans and in particular to the treatment of Parkinson’s disease. The neurosurgical treatment adopted consisted of the transplant of the striate body of surrenal tissue taken from the patient. The aim was to produce large quantities of dopamine precursors (Goetz et al., 1989). Other attempts were carried out by transplanting human foetal tissue at the cortical level (Backlund et al., 1985; Madrazo et al., 1987). Up until now the results obtained have been contradictory (see Freed et al., 1990; Lindvall & Odin, 1994 for a review) and have been evaluated by short follow-ups. Further, many bioethical issues (taking tissue from human foetuses) have emerged, making clinical use debatable.

Comments on results of biological research on cerebral plasticity The important acquisitions on the plasticity of the adult nervous system in many animal species and in humans guarantee an intact ability for structural and functional adaptation following various types of lesions over the entire lifespan, not only during critical periods of development. This plasticity manifests both spontaneously and in response to conditions of environmental stimulation which modulate times and characteristics. CNS recovery can be greatly stimulated by the presence of neurotrophic factors spontaneously induced by a reparative chain of events artificially administered to animals (for now, not to humans) or produced by tissue (foetal and non-foetal) transplanted in the CNS to stimulate cerebral regeneration and functional reorganisation.

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There is also better knowledge of the harmful and toxic factors released by the lesioned tissue. This knowledge has permitted the development of therapies to reduce the damage deriving from these secondary lesions, which are added to the primary one. Thus, the conditions are created for considering rationally justified pharmacological interventions with potential preventive value. However, to these positive considerations on recent advances in this sector of the neurosciences, other points must be made that show with greater precision their limits and their applicability to the clinical and neuropsychological area. It has already been noted that the important documentation on structural readjustments that can be observed after lesions or sensory deprivations are limited to the areas adjacent to the lesion and probably to those areas that formerly carried out a functional role analogous to the lesioned cells. None of this knowledge extends to structural changes distant from the lesion. This limitation is very important because the spontaneous lesions of most common clinical occurrence are large, sometimes very large, and very rarely limited to a restricted population of functionally homogeneous neurones. Moving on to consider the possibility of preventing the release and the perturbations linked to the chain of toxic events generated by the lesion, reference can be made to potential preventive interventions that must occur during the acute phase of the illness. This possibility, although very exciting, seems to have fewer effects on functional recovery of brain damage in sub-acute or chronic phases (Barbeau & Rossignol, 1994). Analogously, the spontaneous production of neurotrophic factors has its peak several days after the harmful event; however there is no documentation on possible effects in more advanced phases of the illness. Animal experiments on their effectiveness have only been conducted a short time after the lesion. The transplant technique still seems far from any real and documented clinical usefulness; in any case, its application has been slowed down by ethical issues. Even with these limitations, these ideas must be very critically compared with characteristics of the

complex neuropsychological disorders deriving from cerebral lesions and with the behavioural modifications observable during the course of their evolution.

NEUROPSYCHOLOGICAL DISORDERS The experimental neurology discussed so far has produced interesting results that must be integrated with observations on cerebral plasticity and functional recovery in humans. With regard to the precise and generally small lesions located in definite points of the brain and the experimentation on rather elementary performances, a very different reality is found when examining the neurological and neuropsychological consequences in human subjects. Spontaneous lesions, such as surgical or traumatic ones, often produce wide destruction of cerebral areas which do not respect precise functional anatomical limits as in the case of experimental lesions. Limiting attention to neuropsychological disorders, cerebral lesions in humans modify complex behavioural performances often not limited to a single cognitive domain; disorders are observed in reading, in the ability to recall everyday events or to recognise the physiognomy of familiar persons, etc. The size of structural lesions and the complexity of the resulting behavioural deficits make it imperative to formulate recovery models that involve broad cerebral areas and that anticipate complex adaptive readjustments. The microstructural processes of réadaptation in areas adjacent to the lesion are insufficient for representing phenomena of functional recovery that can be observed in the cognitive area due to spontaneous evolution of the CNS or to changes induced by therapeutic interventions. The description of cerebral plasticity in the neuropsychological area adopted here is based on a classification of functional disorders and, consequently, on the recovery mechanisms proposed by Poppel and Von Steinbuchel (1992). These authors propose four possible consequences of cerebral lesions:

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• the first consists of “partial destruction of a circumscribed area representing one or more specific functions”; • the second, a “complete loss” of an area in which one or more functions are represented; • the third, a general or partial reduction of the “activation” of cerebral areas; • the fourth, loss of the ability of “interaction” between various cerebral areas necessary for activating processes of functional integration. These four perturbations will be illustrated with examples taken from experimental and clinical studies. The first two types of cerebral lesions imply the acceptance of several theoretical assumptions. Several cognitive abilities do not derive from diffused brain activity, but are guaranteed by the functional efficiency of areas without which specific cognitive deficits can be observed with high statistical probability in different individuals. This formulation hardly predicts a correspondence between an area of the brain and a cognitive performance; this is a local function that interacts with wide activation of the entire brain. However, it is still necessary to postulate a relation between one or more populations of neurones, concentrated in a specific site, and the ability to carry out particular categories of information processing.

A partial lesion of a functional area Returning to the concept of the partial lesion of an area, several functional recoveries can be attributed to the intervention of spared neurone populations. This involves reorganisation within the same functional module allowing for the same performances, using the same processing modalities. From the examples illustrated in the first part, the somatosensory areas surrounding the lesion of the cerebral cortex, in a certain period of time and following repeated stimulations, produce a cortical reorganisation able to guarantee analogous processing of sensory information (Jenkins & Merzenich, 1992). A similar interpretation can be applied to the examples of reorganisation observed by Darian-Smith and Gilbert (1994) and Maffei and others (1992). In humans, an example of this

recovery mechanism through reorganisation in the same functional module can be seen in the partial recovery of the visual field in a scotoma (Kasten & Sabel, 1995; Zihl & Van Cramon, 1979). The latter authors observed that stimulation repeated for a long time in the peri and intramacular areas, derived from striate lesions or retrogeniculate visual projections, permitted patients to extend their ability to detect luminous stimuli even in the blind area. Perhaps several recent attempts to recover linguistic ability can be conceptualised according to this model. Modem neurolinguistics allows us to analyse complex behavioural deficits as deriving from a selective perturbation of a specific cognitive module that interrupts a complex chain of processing (Caramazza & Hillis, 1993). In several carefully selected patients it was possible to identify precisely the specific cognitive impairment. Hillis and Caramazza (1994) describe two patients with deficits functionally localisable at the level of the mechanisms of lexical production, in one case phonological and in another orthographical. In these two cases, the precise definition of the functional deficit made it possible to orient the therapies of these patients so as to favour the reacquisition of the mechanisms of lexical production. Using a method of study with a multiple baseline, good improvement was observed in deficient performances in both patients which was even generalised to lexical production of items not used in the training. However, the same authors describe another case showing functionally similar deficits, in which the same procedures did not produce analogous results. The authors conclude that the use of a therapy based on a neuropsychological cognitive approach produces significant and generalisable results, unlike other therapeutic interventions where results are observable only for the material used during the training (Behrmann, 1987). On the other side they conclude that the use of neurocognitive models is not sufficient for developing appropriate treatments. The negative results of several patients, who were apparently similar, do not permit making therapeutic rules valid for all.

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Returning to the problem of the partial lesion of a cerebral area, it is possible, at least at the hypothetical level, to suggest that if a specific cognitive module preserves at least partially the neural substrate that allows for its functioning, the repetition over time of computational operations appropriate to that linguistic process will be able to provide for reacquisition of the original competencies; the latter will be carried out with modalities identical to those used prior to the lesion. If, instead, the neural substrate is completely destroyed, either functional reacquisition will be impossible, or the individual will have to resort to compensation mechanisms based on processing strategies different from the pre-disease ones. With our current state of knowledge, there are no instruments available for predicting whether it is possible to effect complete recovery.

Total lesion of a functional area When considering the second case, that is, a total lesion of a functional area, it is important to know whether the CNS has the capacity to organise complex behaviours using different cognitive pathways. These characteristics are certainly observable in very different functional areas, in both animals and in humans. Finger and Stein (1982) discuss an old experiment of Honzik (1936) in which a group of mice learned the route of a spatial labyrinth. After initial learning, from time to time the animals underwent a series of surgical manipulations to remove the visual, olfactory, tactile, acoustic, proprioceptive, etc. afferences. After each of these lesions the animals, with progressively less facility, showed they were still able to relearn the route of the labyrinth. Evidently the animals had to substitute the most natural learning strategy, for example the visual one, with processing strategies based on the sensory capacities that had remained uninjured. It could be said that the animals were able to reconstruct the spatial representations necessary to guide them through the labyrinth, using informative elements derived from different sensory modalities. Split-brain studies document the existence of many ways of reaching an analogous result. The isolated right hemisphere is not able to carry out

operations of phonological coding or of decoding (Zaidel, 1986). In the absence of these competencies, the hemisphere is not able to read using operations of phonological and orthographic input. However, the right hemisphere of patients studied by Zaidel (1983) is able to comprehend the meaning of written words presented in the left visual hemifield; this result must be supported by the existence of an ability to analyse written words that is independent from phonological competencies. Zaidel (1988) hypothesised the possibility of reading by this hemisphere through a configurational analysis of written information. This mechanism does not allow for the same speed and accuracy of phonological-orthographical mechanisms, but it is sufficient to guarantee a discrete capacity to comprehend a written text. Functional réadaptation through the use of alternative strategies implies the intervention of cerebral areas that are different from the original one; these areas can be logistically near or rather far from the lesioned areas. Also, we should not speak of recovery but of substitution of functions. Documentation of recovery linked to the activation of cerebral areas far from the lesioned ones was initially provided by a series of observations on patients who had become aphasie following left hemisphere lesions. After a more or less long interval, during which improvements in the capacity to communicate were observed, the same patients had a second stroke in the right hemisphere; their aphasia seriously worsened. This sequence of events was interpreted by Nielsen (1946), Lee and others (1984), Levine and Mohr (1979), and Basso and others (1989) as due to a compensatory action by structures of the contralateral hemisphere, which was demonstrated by linguistic regression when a second lesion in the opposite hemisphere followed the first. Indications on the importance of the right hemisphere for language recovery also come from studies using different methods (for a review see Cappa & Vallar, 1992). By injecting carotid sodium amytal, temporary inactivation of the homolateral hemisphere occurs (Wada’s test) and thus it is possible to correlate the compromised cognitive activities during this period with the inactivated hemisphere. Czopf (1972) used Wada’s test with a

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group of aphasic patients and found that inactivation of the right hemisphere produced an arrest of language which was more evident the greater the distance from the harmful event. The author interprets this finding as indicative of the fact that language recovery is the work of the right hemisphere and that it does not occur rapidly but requires a relatively long period of time. Kinsbourne (1971), again with Wada’s test, obtained an arrest of language following inactivation of the right hemisphere, but not of the left, in three aphasic patients. In a dichotic listening test with verbal stimuli, Moore and Weidner (1975), Johnson, Sommers and Weidner (1977), and Pettit and Noll (1979) found a superiority of the left ear/right hemisphere in aphasics; this is contrary to what occurred in control subjects who showed superiority of the right ear/left hemisphere for the same stimuli. Finally, Papanicolau and others (1984, 1988) used evoked potentials to study recovery from aphasia. During a verbal task, these authors showed attenuation of evoked potentials in response to a click in the left hemisphere of normal subjects and in the right hemisphere of aphasic subjects. This attenuation shows less neuronal availability for responding to the click, due to greater involvement of the corresponding hemisphere in the verbal task. Today, these phenomena of substitution at a distance can be better documented through longitudinal studies of cerebral flow or metabolism carried out in patients whose behavioural changes are also described. Using single photon tomography (SPECT), Pantano and others (1992) documented the activation of left prefrontal areas (contralateral to the lesions) in six patients with right focal lesions after a period of re-education for visuospatial neglect. In this study the increase in perfusion of the frontal lobes between the first and second measurement was significantly correlated with the degree of functional recovery observed. Vallar and others (1988) used the same SPECT technique with six aphasic patients and two patients with neglect due to unilateral and subcortical vascular lesions. In all patients the almost complete improvement of neuropsychological symptomatology, 2-3 months after the stroke,

accompanied a significant increase in cortical perfusion at the second observation. Perani and others (1993) described two patients with visuospatial neglect due to right hemisphere focal lesions; both of these patients had experienced spontaneous regression of symptomatology associated with functional metabolic recovery tested using the PET (with the Desossiglucose method) in both the hemisphere contralateral to the lesion and in the unharmed ipsilateral areas. A similar technique (PET with Desossiglucose) showed metabolic improvement and lesion reduction in two patients with visual field deficits in the presence of lesions in the striate area (Bosley et al., 1987). These improvements were associated with a reduction of the visual field deficit; three other hemianoptic patients, whose field deficits remained unchanged, presented no appreciable changes in cerebral metabolism. The contribution of the hemisphere contralateral to the lesion in the recovery of motor deficits has recently been documented in vascular patients through the use of PET studies (Chollet et al., 1991; DiPiero et al., 1992) and by measuring flow velocity with the transcranial Doppler technique (Silvestrini et al., 1993, 1995). Although these studies clearly illustrate the intervention of areas associated with functional recovery either contiguous with or far from the lesion, none of these studies appropriately analyses the cognitive strategies through which this recovery took place. It seems very likely, as Pantano and others (1992) hypothesise, that alternative strategies were adopted, but this problem must be faced more systematically by research that documents the substitution of neural structures as well as the operative modalities adopted. On the purely behavioural side, there are numerous examples, in many neuropsychological areas, that clearly describe the substitution of resolution strategies for different cognitive problems. Wilson and Moffat (1992) and Thone (1996) describe many ways adopted by patients with amnesic disorders to face everyday life situations (see Chapter 38). Grossi (1991) described the return to work of a glass worker struck by serious constructive apraxia following a right posterior lesion. These results were obtained

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through the development and activation of a series of verbal instruments used for representing spatial relations and for planning the appropriate motor responses. In part, recovery from visual-spatial neglect takes place through the development of conscious verbal and nonverbal strategies to increase the exploration ability of the neglected space (Antonucci et al., 1995; Pizzamiglio et al., 1990, 1992; Seron et al, 1989; Weinberg et al., 1977). Luria (1970) proposed using visual and proprioceptive afferences in patients with verbal apraxia. Verbal apraxic patients are no longer able to articulate fluently; their production is syllabised, difficult, and slow; articulated movements no longer occur unconsciously, but must be controlled intentionally by the patient who can use visual afferences (controlling the various articulative positions in a mirror) or proprioceptive afferences, for example, controlling the position of the articulative organs with a hand. At a more abstract level, Hatfield and Shewell (1983) suggested the use of lexical compensation procedures for the re-education of agrammatism. For example, when a patient is not able to correctly use the various verb declensions because of agrammatism, he/she can be re-educated to express the same concept based on other elements of the language. In place of “I will go” he/she is taught to say “tomorrow I am going”, thus communicating the idea of a future action without having to resort to verb parts. Also for deep agraphia, Hatfield (1983) has suggested alternative compensation procedures. For example, patients with deep agraphia are not able to write grammatical function words. Therefore, they are taught to associate the various grammatical function words, for example “on” and “over”, to nouns relevant to them containing the same sounds. Two patients with deep agraphia chose the name “Don” for “on” and the name of a town they knew, “Over” for “over”. When the patient has to write the function word, he/she must then learn to think of the word chosen for that function word and to write it; in this way he/she will be able to write function words. The increased ability to cognitively analyse the functional architecture of neuropsychological

competencies and to dynamically document the changes that occur at the neurological level will allow for a profitable deepening of these mechanisms of cerebral plasticity already generally indicated at the beginning of this century by Von Monakow, such as cerebral diaschisis. Poppel and Von Steinbuchel (1992) have indicated two other categories of deficits and two other mechanisms of neuropsychological recovery. As long as activities such as perception, memory, emotions, language, etc. can manifest and fill up the content of consciousness, there must be several functional prerequisites that make this development possible. In particular, the CNS must be kept in a state of general activation and must be able to maintain a more or less diffused or focalised level of attention for a necessary period of time to permit cognitive processing. In the second place, there must be the ability to coordinate a series of cognitive operations temporally and hierarchically, to allow for effective integration. These functions of activation and integration are less localisable at the level of cerebral structures but are dependent on neurological circuits involving very extended parts of the NS and probably on widely distributed neurotransmitting systems.

Reduced activation of functional areas Thus, a third type of cerebral lesion can determine a lack of or an excess of activation. An elegant experimental model illustrating the mechanism of excitation and inhibition between the superior colliculus and the cortex is provided in an experiment by Sprague (1966). Subsequent to a lesion in a striate area, the animal presented visual deficits relative to stimuli coming from the field contralateral to the lesion. Following a second lesion, consisting of removal of the contralateral superior colliculus or the sectioning of the intercollicular commissure, the animal’s visual behaviour improved instead of worsening. The interpretation is based on the equilibrium of excitation and inhibition between these structures. In normal conditions the occipital areas exercise an excitatory action on the ipsilateral colliculus and the two colliculi inhibit each other. The first lesion of the striate area

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decreases activation of the ipsilateral colliculus; its activity is further inhibited by the contralateral colliculus, which maintains a normal connection with the ipsilateral striate cortex. If this inhibitory state is modified, by removing the contralateral colliculus or interrupting the transcollicular connections, visual performance based on the ipsilateral colliculus improves. In humans, primarily in cranial traumas with diffused lesions, rather frequently both decreases in attentive capacity, tiring, inability to concentrate, and disorders of the opposite sign, such as passing rapidly from one idea to another and losing the initial idea, can be observed (Levin et al., 1991; see also Chapter 24). Some experimental clinical situations illustrate rather spectacularly the existence of alterations in the state of activation. Visual-spatial neglect, both in the acute and in the chronic phase, can undergo transitory regressions following specific stimulations. A strong caloric stimulation (cold water) that acts on the vestibular system ipsilateral to the neglected side (Cappa et al., 1987; Rubens, 1985), an optocinetic stimulus that moves in the ipsilateral direction (Pizzamiglio et al., 1990; Vallar et al., 1993a, 1995), a transcutaneous electric or vibratory stimulation applied to the neck muscles ipsilateral to the neglected side (Biguer et al., 1988; Karnath et al., 1991, 1993, 1994) result in a regression of the symptomatology. Concretely, the patient, who omits checking off a series of targets placed on the neglected side of space or who omits parts of a sentence when reading, shows normal or clearly improved performance on the same tasks during the appropriate stimulations. This advantage disappears shortly after the end of the stimulation. Even when different physiological presuppositions were made, Butter and others (1990, 1992, 1995), at variance with Walker et al. (1996), obtained similar results through presentation of luminous stimuli that moved randomly in the hemifield contralateral to the lesion. These observations indicate that the behaviour of a patient with neglect cannot be described as a total loss of the ability to attend to events displaced in one part of space, but rather as a phenomenon of inhibition or subactivation, asymmetrically produced by the

cerebral lesion. When this functional disequilibrium is reduced with the appropriate stimulations that cause reflex responses, strong remissions in the attentive or representative disorder can be observed. In this case we are faced with the precise identification of a deficient activation of an operative system; these observations have important implications for organising a therapeutic intervention to rebalance spatial processing systems

Reduced integration among functional areas A fourth type of lesion hypothesised by Poppel and Von Steinbuchel (1992) causes a perturbation of the ability to organise temporally and, more generally, to integrate multimodal information. The first point, temporal organisation, concerns those processes, such as language, that require a rapid succession of processes in order to interpret the incoming message or to produce a verbal response. Some research has specifically documented a selective loss in the speed of verbal processing and in particular in the production of sentences in aphasies with anterior lesions and with non-fluent production (Friederici & Kinbom, 1989; Swinney, Zurif & Nicol, 1989). Together with other elements, this type of observation was conceptualised into an interpretative model that describes aphasia as a deficit in the procedures for accessing linguistic knowledge in real time (Bates & MacWhiney, 1989; Bates & Wulfeck, 1989). Accent on the access deficit has suggested more frequent use of “on-line” trials in the study of various aphasie disorders. Independent of the problem of temporal organisation, it is possible that a cerebral lesion involves missing integration of multisensory information or of interconnected computations. Examples of these perturbations have recently been described by Vallar and others (1995) and Pizzamiglio and others (1995, 1997) in patients with unilateral spatial neglect. Besides gravitational information, the organisation of responses to visual stimuli in space requires the use of visual, proprioceptive information on the position of the eyes, head, and

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trunk. This multisensory information generates intermediate spatial representations; and the responses of the organism that has to act in space depend on integration between these different representations (Andersen et al., 1993). Patients with neglect show disequilibrium between retinotopic representations of space and one or more egocentric representations based on nonsymmetrical processing of extravisual information. The missing correspondence between the egocentric (altered) representations and the retinotopic (preserved) ones determines a strongly incomplete representation of external space. The asymmetrical egocentric representation is documented by the previously discussed possibility that external, vestibular, visual, or proprioceptive stimulations transitorily rebalance the behaviour of the neglect patient. The hypothesis that neglect is the manifestation of an interaction between various spatial representations is further documented by an experiment in which a reduction of neglect symptoms is again obtained not by stimulating the patient but by putting him/her in the position of basing judgements on only visual data, in the absence of gravitational information (Pizzamiglio et al., 1995; 1997). In this experiment, the neglect patients had to indicate the midpoint of a segment both in a seated position and when lying down. In the supine condition the gravitational information was virtually abolished and in the seated condition it interacted with the visual information (Marendaz et al., 1993). The elimination of the conflict between visual and gravitational input causes a significant reduction of asymmetry in the spatial processing of neglect patients. These examples of integrative disorders produced by a lesion suggest the need to base recovery of spatial abilities on the transfer of integrative functions to compensatory functional structures still partly existing in the CNS. Following this illustration of various mechanisms observable in patients with neuropsychological disorders, it is necessary to analyse the factors that can interfere positively or negatively with functional recovery. As much as possible these factors will be discussed in light of the previously described

neurobiological acquisitions regarding cerebral plasticity.

THE PROGNOSIS For many years aphasia was the most studied cognitive disorder; however, in the past 10-20 years other cognitive disorders such as spatial hemineglect or memory disorders have provoked great interest, and publications on these topics are probably more numerous than those on aphasia. However, the problem of recovery has been studied primarily in the area of language disorder, so this topic will receive greater attention. An important issue requiring immediate clarification is the difference between the concept of “improvement” and that of “final outcome”. Improvement refers to the difference between two successive moments. Some patients can present discrete or relatively good improvement even when they still show serious aphasia or serious amnesia; in other cases improvement can be infrequent or null in patients who do not present cognitive disorders at a distance from the harmful event. The final outcome refers simply to the seriousness of the disorder presented by the patient at a time sufficiently far from the beginning of the disorder, independent of whether or not there was improvement. It is obvious that the final outcome depends essentially on the initial seriousness of the disorder, which in turn is an important factor in determining the degree of improvement. In the following pages we will essentially treat improvement; trying, where there may be confusion, to distinguish the effect of various factors on initial gravity of the disorder from that on improvement. The factors that will be treated are certainly not the only ones that influence recovery, but they are the ones that have been studied experimentally. There is an important exception regarding rehabilitation; this will be dealt with in another chapter. Other obviously important factors either have not been or cannot be verified experimentally; these are general factors such as motivation (difficult to evaluate and quantify) or the general capacity for attention (which, on the contrary, could

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be studied experimentally). It is obviously true that a motivated patient with a good level of attention has greater possibilities of improvement than a scarcely motivated patient with a low level of attention; but we do not know of experimental studies on the effect of these factors on improvement. Other factors, such as cultural level or the way the disorder starts— slow in tumours, more or less instantaneous in traumas and in vascular pathologies—have been studied in terms of their influence on the initial frame of the disorder but not, with rare exceptions, in terms of their effect on possible subsequent improvement. Before reviewing the studies on prognostic factors, an important point must be emphasised: these factors are not always independent; they often interact, as in the case of the type and the seriousness of aphasia, and this makes studying their specific effects on recovery difficult. Finally, a warning must be made about the level of reliability of the various works reported. Although an effort has been made to choose, these studies are extremely heterogeneous. The populations studied and the experimental designs are different from one study to another; in several cases the dependent variable of the research was the factor being analysed; in other cases several factors were considered together; and still in others, the groups were simply matched for factors not under observation and, therefore, the results cannot be extrapolated to different populations.

Prognostic factors The prognostic factors studied naturally form two groups: those relative to the patient’s personal data and those relative to the lesion and the neuropsychological disorder. Regarding the former, we will discuss the effect of age at the time of onset of the harmful event and sex and manual dominance; regarding the latter, we will treat the etiology (vascular or traumatic), size, and site of the lesion and, finally, type and seriousness of the cognitive disorder. Age With regard to the possible effect of age on improvement, it is customary to consider children

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(up to a maximum of 16 years) and adults separately. The literature on aphasia in children is full of statements about greater recovery in children than in adults; however, this statement has only rarely been subjected to experimental verification. Basso and Scarpa (1990) compared the recovery of two groups of cranial trauma aphasic patients. The patients in the first group were between 5 and 16 years of age (average: 11.2); the patients in the second group, between 35 and 65 years of age (average: 48). The two groups were the same for sex, left-handedness, and lesion site (right, left, bilateral). The improvement of the two groups was compared in an oral comprehension test (Token Test) and in two production trials (naming and narrating an event). A four-way analysis of covariance (the concomitant variables were duration of illness, age, and level of schooling) did not reveal significant differences, even after adjusting the score on the second Token Test based on the score on the first test, that is, not even considering the initial gravity of the aphasia. Even if we consider this with great caution, the result indicates that if there are differences in recovery between children and adults with traumatic etiology they are not very evident. However, it is possible and even probable that improvement is greater in children under 5, but we do not know of any supporting data. With regard to aphasic adults, it is frequently stated that younger patients improve more than older ones. As happens for almost all factors considered, it is difficult to directly compare the effect of age because older patients often differ with regard to other factors, which may also be important for recovery. In particular, it is much more frequent that there are more lesions, lower schooling, scarcer motivation, etc. Thus, a positive result should be attributed to age only with caution. However, a review of the work that has considered the effect of age on improvement of the aphasic disorder leads to rather reductive conclusions. While Vignolo (1964), Sands and others (1969), Gloning and others (1976), and Marshall and others (1982) found, in one way or another, that younger subjects improve more than older ones, this result was not confirmed by Samo and Levita (1971), Keenan and Brassel (1974),

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Messerli and others (1976), Kertesz and McCabe (1977), Basso and others (1979), and Sarno (1980) who did not find differences attributable to patients’ age. In the 1970s and 1980s many studies demonstrated that type of aphasia in vascular subjects is associated with age of onset: fluent aphasies are significantly older than nonfluent ones. However, it is difficult to establish with certainty that there is no interaction between effect of age and type of aphasia, even if a comparison of improvement in fluent and nonfluent aphasie patients revealed no significant between group differences (Basso et al., 1979). As for most of the factors studied, it can be concluded that it is difficult to isolate the effect of age from that of other factors; however there are indications (but no strong experimental evidence) that younger subjects have relatively greater chances for recovery. Sex The effect of sex has been studied most in terms of incidence and initial gravity of aphasia rather than improvement (De Renzi et al., 1980; Miceli et al., 1981; Obier et al., 1978). However, sex has been considered in some studies on recovery, and in a small number of studies the issue of sex in recovery is treated directly. The conclusions are practically the same as those for age. In most studies, no differences in improvement were found between the two groups (Gloning et al., 1976; Kertesz & McCabe, 1977; Samo et al., 1985); however, a significant difference was sometimes found for women, or for improvement in comprehension (Pizzamiglio et al., 1985) or production (Basso et al., 1983). Manual dominance Since Broca affirmed in 1865 that in left-handed subjects the dominant hemisphere for language is the right one (and the left one in right-handers), the conviction arose that the functional organisation of the brain is different in left-handed subjects, because it was noted that left-handed braindamaged subjects became aphasie following both right- and left-hemisphere lesions. With a single exception (Newcombe & Radcliff, 1973), in all

works prior to the 1980s the importance of manual dominance and family left-handedness for recovery was stressed; it was held that left-handed subjects or even right-handed subjects with family lefthandedness, had greater chances for recovery (Gloning etal., 1976;Luria, 1970; Subirana, 1969). Actually, strong right handers and strong left handers form the two extremes of a continuum of subjects who use one or the other hand preferentially; here we are not dealing with a binary quality, such as sex, but with a continuum; therefore it is always arbitrary to decide to separate the population into two, three, or more groups according to the relative dominance of one hand. Besides, it must be said that in terms of methodology the early works were not very correct: comparisons were only clinical, with a low number of left-handed subjects. In more recent and methodologically more correct studies good improvement has not been found in left-handed subjects (Borod et al., 1990) and no differences have been found between the two groups (Basso et al., 1990). However, these conclusions are not valid for left-handed aphasic subjects with right hemisphere lesions; these are very rare in the literature and their improvement has not been compared to that of right-handed subjects. Basso and Rusconi (1998) were able to compare four left-handed aphasic patients with right lesions with four right-handed aphasic patients with comparable left lesions; subjects were matched for age, schooling, sex, etiology, and distance from the harmful event. All patients underwent re-education and had a second evaluation. Even though much less numerous, these data seem interesting because the left-handed/right-handed pairs were matched for many of the factors that can influence improvement. Initially, the four left-handed subjects presented a less serious, but qualitatively not very different, picture of aphasia than that presented by the righthanded subjects. However, when checked, the recovery of the left-handed subjects was inferior in all cases, even if not significantly, to that of the righthanded subjects. Also in this case, the only thing that can be said is that the effect of manual dominance on cerebral organisation has been over-evaluated in the past; more accurate investigations tend to show that the differences are actually minimal.

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Etiology Data on etiology are rare, but for once they agree. Aphasic disorders of traumatic origin have a better prognosis that aphasic disorders of vascular origin (Alajouanine et al., 1957; Basso et al., 1980; Kertesz & McCabe, 1977; Luria, 1970). In the area of vascular etiology it is very difficult to find equal groups of patients with ischemic or hemorrhagic pathology because the lesion sites are generally different. Therefore, even when a difference in improvement is found in the two pathologies, it is difficult to state with certainty that it depends on the type of vascular disorder and not on the different lesion site. Data in the literature are scarce and conclusions very heterogeneous. Other types of pathologies, for example infectious illnesses, are somewhat rare and the hypothesis that as such they can have a different effect on the patient’s improvement has not been verified experimentally. Naturally things are different in the case of tumour pathologies. A tumour can remain silent for a long time, even when it occupies a relatively large space; and the type of language disorder found in tumour patients presents characteristics in part different than those found in vascular patients. In almost all cases the first symptom to appear is anomia and the forms of fluent aphasia (in the sense that the positive symptoms of the nonfluent forms of aphasia are not present, such as verbal apraxia or agrammatism) are more frequent even if the speech production is often greatly reduced. With regard to recovery, however, it is obvious that this depends on the course of the basic illness and cannot be considered without evaluating this as well. The difference between stroke entry lesions or slow and progressive ones, as in the case of tumours, has been studied experimentally by systematically manipulating the temporal variable of entry of the lesion. The same lesions produced in frontal areas (Patrissi & Stein, 1975) or on the entorhinal cortex (Scheff et al., 1977) in adult rats, had very different consequences if the lesion was obtained with only one or with two interventions. There were less effects in lesions executed in two stages and they were reduced considerably if the time interval increased between the first and the second intervention.

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In a general sense it can be hypothesised that an interval between two different times of a lesion (or between the beginning and the proceeding of a slowly developing illness) permits the establishment of mechanisms of reparation or of functional substitution which make the functional consequences less marked. It can also be thought that smaller and repeated lesions (or lesions slowly becoming more serious) produce less toxic factors that increase the extent of damages due to the lesion. In humans the study of the effects of temporal factors on recovery are for now limited to nonsystematic observations. Lesion size Above all when speaking of lesion size and site, discussions on the effects of these factors on initial gravity of the disorder and on chances for improvement intersect and become confused. This is also due to the fact that in the literature in English the word “recovery” is used and is often interpreted as improvement; but it actually corresponds to what we previously called “final outcome”. In language pathology the most important factor in determining the final aphasic picture is not given by neurological factors such as etiology, size, or lesion site, but almost exclusively by initial gravity of the disorder, which in turn is determined primarily by the site and size of the lesion. As Mega and Alexander (1994, p. 1817) stated “the gravity of the language profile depends on the extent of damage...Temporal evolution and extent of improvement depend, in turn, on gravity”. All the authors, without exception, agree on the importance of lesion size for determining the gravity of the disorder. Before, initial gravity was considered separately, so very few and rather ambiguous data exist on the effect of lesion size on chances for improvement. Studying a group of 10 patients, Demeurisse et al. (1985) did not find significant correlations between lesion size and recovery three months after the harmful event in subcortical lesions; in cortical-subcortical lesions the same authors found a significant (negative) correlation between improvement in oral production and lesion size, but not between improvement in

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comprehension and lesion size. Seines and others (1983) subdivided 39 patients into two groups according to lesion size: large lesions and smaller lesions. They found a significant negative correlation only in the first group; improvement in oral comprehension in patients with very large lesions was inferior to that of patients with large, but not very large, lesions. Kertesz and others (1979) report a paradoxal result: the larger the lesion, the greater the chances for improvement in oral comprehension. These authors interpret this result as the “ceiling” effect; given that subjects with small lesions have a slight disorder in comprehension, they obtain high scores even at the first evaluation and thus do not have the possibility of obtaining much higher scores in a subsequent examination. Instead, patients with large lesions and serious language disorders initially have scores at the lower levels of the evaluation scale and thus have greater space for improvement. In a subsequent work, Kertesz, Lau, and Polk (1993) obtained a different result in a study with 22 Wernicke’s aphasics, who were first examined within 45 days of the stroke, at 3 months, and then at 12 months from the harmful event. On CT scans, patients with good recovery show less compromission of the posterior part of the superior temporal gyrus; the lesion in this area is greater in patients with poor recovery. As is evident from this study, it is difficult to separate the effects of lesion site from those of lesion size. In patients with unilateral spatial neglect a moderate correlation has been shown between lesion size and gravity of disorders (Cappa et al., 1991; Hieret al., 1983; Levine etal., 1986). On the other side, lesion size does not seem to have predictive value for extent of functional recovery obtained with rehabilitative interventions (Cappa et al., 1991; Gordon et al., 1985). These considerations lead us to believe that neuroradiological information about the lesion is not of great value in formulating prognoses of major neuropsychological disorders. Does the presence of two or more lesions have a negative effect on improvement? No research has specifically considered the effect of a plurality of lesions, once the effect of lesion size (and site) is subtracted. In other words, whether a lesion of

the same size has different effects according to whether it is continuous or subdivided into two or more lesions has not yet been studied. With regard to apraxia, Basso and others (1987) found no differences in recovery in patients with bilateral lesions compared to patients with only left hemisphere lesions. However, this result may be due to the fact that the right hemisphere does not have great possibilities for substituting the left hemisphere in the control of intentional gestures; whereas it could have a greater capacity to assume several linguistic functions (or, obviously, other cognitive functions). Lesion site As we have already seen in the discussion on lesion size, there is a great deal of literature that agrees about the effect of site on type and initial gravity; however, data on the effects of this factor on chances for improvement are almost totally lacking. By the end of the 1970s it was known that a lesion limited to Broca’s area does not produce complete Broca’s aphasia, but only slight and transitory disorders (Mohr et al., 1978) and a lesion in Wernicke’s area generally accompanies complete and lasting Wernicke’s aphasia (Brunner et al., 1982; Ludlow et al., 1986; Naeser et al., 1987). Naeser and others (1987) found no differences when they compared the improvement of five patients with Wernicke’s aphasia and the preservation of at least half of Wernicke’s area, with the improvement of five patients with larger lesions in Wernicke’s area (it is not known whether the lesions were generally larger in these patients or only with regard to Wernicke’s area). Recently, Goldenberg and Spatt (1994) demonstrated that the presence of mediobasal temporal lesions, which did not change the spontaneous recovery of 18 aphasic patients, seemed instead to cause minor recovery following language therapy. These authors interpret the result by hypothesising that mediobasal lesions produce a disconnection between the hippocampus and presylvian areas; this disconnection would make a process of language relearning, stimulated by therapy, difficult.

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Type and gravity o f aphasia Type of aphasia and gravity are not independent factors because in some clinical syndromes the level of gravity of the disorder is one of the defining factors (see, for example, global aphasia, which is grave by definition, or Broca’s aphasia, which is not grave by definition). Thus, it is impossible to study the effect of type of aphasia on improvement apart from gravity. When only fluent and nonfluent patients were compared (Avent & Wertz, 1996; Basso et al., 1979; ) were no significant differences found. As we have already said, the effect of initial gravity of aphasia on chances for improvement is recognised by all authors and is certainly by far the most important factor in determining the point of arrival. Thus, we can conclude with another citation from Mega and Alexander (1994, p.121): “initial performance on language tests—in particular, those for verbal-auditory comprehension—is strongly correlated with final outcome while neuroradiological measures are not”. There are no analogous studies available for other neuropsychological disorders such as amnesia, neglect, or the apraxias. Functional type methods, such as single photon emission tomography (SPET) and positron emission tomography (PET) have been used in the study of the recovery of cognitive functions with different modalities. Investigations in resting conditions have permitted demonstration that recovery of the diaschisis, or the effects of functional compromission in structurally uninjured areas, correlates with clinical improvement in patients with aphasia and unilateral spatial neglect. For example, one SPET study showed that in patients with aphasia or unilateral spatial neglect following a subcortical lesion, a correlation exists between the gravity of the neuropsychological disorder, its evolution over time, and regression of effects at a distance (Vallar et al., 1988). Also with the PET, the existence of a correlation between regression of functional depression in structurally uninjured areas and recovery from aphasia has been shown (Cappa et al., 1991, 1997; Metier et al., 1992).

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Studies of activation, which consist of measuring regional cerebral perfusion during the execution of spatial exploration and language tasks in patients who have shown recovery, constitute the most recent, still limited approach for relevant technical problems connected with procedure and data analysis. A recent study on activation in six patients showing recovery from Wernicke’s aphasia (Weiller et al., 1995) has shown the recruitment of frontal and temporal areas of the right hemisphere, specular to the language areas of the left hemisphere, during tasks of repetition and lexical searching. With the same approach, three patients with neglect following subcortical lesions were studied before and after a specific training of 60 days. The interaction between the two PET exams and the increased perfusion during the performance of the spatial task showed a significant activation of several ipsilesional structures specifically involved in visual reorientation and attention (Pizzamiglio et al., 1998).

CONCLUSIONS We have primarily dealt with the improvement of linguistic functions and the factors that may have a specific effect on language recovery, but not with other cognitive functions. For example, for a long time manual dominance was considered very important because it was held that there was a relationship of causality between dominance for language and dominance for handedness; and at the end of the nineteenth century it was proposed that, as a rehabilitative technique for language, the left hand should be trained to perform fine movements (Buzzard, 1882 cited by Goodglass & Quadfasel, 1954). However, we have seen that manual dominance is not a good predictor of recovery. Actually, none of the personal factors (age, sex, lefthandedness) seems to have a real effect on recovery. Neurological factors seem to be much more important, but their effect on recovery is not direct; it passes indirectly through the initial gravity of the neuropsychological disorder; the site and extent of the lesion determine the initial picture

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which, in turn, is the only true predictor of chances for improvement. This is true both for aphasia and for visuospatial neglect. As for other cognitive disorders, obviously each one has a temporal curve

and a greater or lesser chance for recovery; but it is probable that for all, or almost all, the importance of prognostic factors is more or less similar to what we have reported in this chapter.

36 Aphasia Rehabilitation Anna Basso

patients can at times produce some correct and adequate sentences which they cannot produce in different, less natural, situations. This led to the belief that aphasics had not lost their linguistic capacities, they were only unable to access them. Speech therapy consisted in having the patient initially produce language in more automatic situations that were rendered more and more voluntary. Many different methods are generally included in the classic approach; they all have in common the idea that aphasia is a unitary process and that language must not be re-taught because it has not been lost; it is not easily accessible and its use must be facilitated.

A BRIEF HISTORY Classic school

Rehabilitation of aphasia became common practice approximately 50 years ago, but single-case studies and brief descriptions of therapeutical interventions had occasionally been published earlier. After the Second World War many countries, mainly Englishspeaking, were confronted with the problem of veterans with head trauma and language disorders. At that time many rehabilitators were psychologists with a specific interest in aphasia. As no theory of aphasia rehabilitation existed, they could only follow suggestions from pedagogics and theories of second-language teaching. In that climate grew what today is generally called the classic school, with Wepman (1951) and Schuell (Schuell et al., 1964) as its most well known exponents, whose teaching is still alive in the United States. In those years, knowledge about aphasia was less detailed than it is nowadays. Aphasia was often considered as an unitary central disorder involving all aspects of language, varying from patient to patient only because of its severity and associated disorders. The classic school made an important observation for aphasia therapy, that is, the dissociation between the automatic and the voluntary use of language. Some

Pragmatics Aphasia rehabilitation was not carried out in a vacuum, isolated from the rest of the scientific world. It utilised knowledge from similar disciplines, particularly linguistics. With spreading of pragmatics (see Levinson, 1983), speech therapists acknowledged that in the process of speaking/listening there is more than the capacity to name, describe pictures, and match words and sentences to pictures. First of all, when one speaks, a large part of what one communicates is not verbalised. It is not sufficient to understand the linguistic content of a message in order to 869

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understand what we have been told; we must understand why we have been told that message and we are supposed to behave accordingly. If we are asked something, we should answer the question; if it is an order, obey it; if we are told something, we should store it, and so on. Speech therapists understood that linguistic competence is not sufficient and that communicative competence is also needed. Many functional communication evaluations appeared at that time (Functional Communication Profile; Taylor, 1965; Communicative Abilities in Daily Living; Holland, 1980) as well as therapeutic techniques based on communication rather than linguistic capacities (Promoting Aphasic Communicative Effectiveness; Davis & Wilcox, 1985).

Cognitive rehabilitation As always happens, with time these methods also became less used and other therapeutic approaches appeared. Similar to the oscillations of a pendulum, speech therapists recognised that without the support of language, communication is extremely poor. The scene was set for cognitive neuropsychology with its interest in the functional structures of the different components of language. Today we speak of rehabilitation of the phonological lexicon, of buffer reduced capacity, of rehabilitation of thematic roles, and so on. The debate on the utility and limitations of cognitive rehabilitation is rich and variegated (see Caramazza & Hillis, 1993) and this is not the place to analyse it. I will only add that cognitive neuropsychology made therapeutic interventions progress, as had already happened for previous approaches, but the last word has still to be said. Parallel to the advancement of language rehabilitation, the question has been raised as to whether rehabilitation is effective or whether changes seen in aphasic patients are due to spontaneous recovery.

EFFECTIVENESS OF REHABILITATION We have seen that in the field of language rehabilitation different therapeutic methods have

predominated in different periods. Similarly, different methodological approaches have been used in the study of aphasia rehabilitation effectiveness. In the earliest studies only groups of rehabilitated patients were considered and their initial level of severity was compared to outcome. Later, rehabilitated and nonrehabilitated patients were compared; more recently, different methods or groups of patients rehabilitated by speech therapists and volunteers have been compared. Today, clinical studies are generally discarded and rehabilitation is evaluated in single cases. We will rapidly summarise these four approaches.

Only rehabilitated patients The earliest researches on aphasia rehabilitation effectiveness generally studied groups of traumatic patients, veterans of the Second World War. Those patients had some characteristics—they all were male, relatively young, with head trauma—that made them differ from today’s aphasics. These are generally older, most with vascular diseases, and include women as well as men. All authors (Broida, 1977; Butfield & Zangwill, 1946; Leischner & Linck, 1967; Marks et al, 1957; Wepman, 1951) agreed that rehabilitation was effective. However, there was no control group and one cannot know whether the patients would have shown the same degree of recovery without rehabilitation. Moreover, the amount of rehabilitation varied greatly from patient to patient, and in the different studies; in Butfield and Zangwill’s paper, for instance, the number of rehabilitation sessions varied from a minimum of 5 to a maximum of 290. It is therefore difficult to maintain that recovery was due to rehabilitation, and we are compelled to conclude that these researches do not demonstrate that rehabilitation is effective.

Control groups Once it was realised that there was a serious methodological drawback in previous researches, in later studies comparison was made between rehabilitated and nonrehabilitated patients. Unfortunately results were rather equivocal. A significant difference between rehabilitated and nonrehabilitated patients has been found in some

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studies (Basso et al., 1975, 1979; Gloning et al., 1976; Hagen, 1973; Mazzoni et al., 1995; Poeck et al., 1989) but not in others (Levita, 1978; Samo et al., 1970; Vignolo, 1964; for a thorough bibliography on studies on aphasia therapy effectiveness see Robey, 1994). However, this group of studies also showed some methodological weaknesses. First of all, the control group was not random; secondly not all the variables influencing recovery had always been taken into account, and length and frequency of rehabilitation greatly varied from one study to the other. We will come back to this later.

Therapists and volunteers The major criticism raised against the previous group of studies is that a control group is still lacking. They do not allow one to explain the difference in recovery between rehabilitated and nonrehabilitated patients by the effect of rehabilitation; the difference can be due not to the techniques employed but to the fact that rehabilitated patients have had someone speaking to them for a certain number of hours. In other words, the difference can be an aspecific effect and not the direct consequence of the therapeutic methods employed. In order to test this hypothesis, some researchers have compared the effect of rehabilitation by speech therapists with that of rehabilitation by volunteers (David et al., 1982; Hartman & Landau, 1987; Meikle et al., 1979; Wertz et al, 1986). Unfortunately for the speech therapists, no significant difference between the groups of patients has ever been found in these studies. It must, however, be added that also these researches present methodological drawbacks that we will not examine in detail. It must, however, be stressed that the aim of these studies was not to evaluate aphasia therapy effectiveness but rather to evaluate effectiveness of treatment available in the UK. In all these studies the length and the frequency of treatment was small and this is also true for all the previously considered researches that did not find any significant effect of rehabilitation. On the contrary, in all those studies that demonstrated a significant effect of rehabilitation on recovery, rehabilitation continued for longer periods (at least 6 months) or was very intensive (6/8 hours per day).

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We decided to study the effect of length of rehabilitation (Basso, 1987) and found a significant effect: a 6-month rehabilitation programme is significantly more effective than a 3-month rehabilitation programme, which was approximately what was offered to patients in the English studies that compared speech-therapists and volunteers.

Meta-analysis Robey (1994) intended to conduct a valid and convincing synthesis of researches on the efficacy of aphasia therapy and to try to put an end to this debate. He gleaned all previously published researches on aphasia therapy effectiveness and selected those that reported sufficient data to be subjected to a meta-analysis; 21 studies met this requirement. Robey calculated the difference between a first and a second evaluation in nonrehabilitated aphasic subjects, the difference between a first and a second evaluation in aphasic rehabilitated patients, and the difference between the two differences. He also considered separately acute and chronic patients. He reached the following conclusions: • The effect of a rehabilitation treatment starting in the acute period is approximately double the effect of spontaneous recovery. • A rehabilitation treatment starting in the chronic period has a significantly lower effect but it remains noticeable. • The difference in recovery between acute rehabilitated and nonrehabilitated patients approaches the criterion for what Cohen (1988) consider a large-sized effect for the t statistic. • The difference for chronic patients corresponds to a small-to-medium sized effect. Robey also attempted to calculate the effect sizes for therapy provided by volunteers. He analysed in detail David et al.’s (1982) study, which has probably been the most read and cited among this group of studies. His conclusion were that the statistical procedure adopted by the authors did not allow them to study the main hypothesis (whether there is a significant difference between the effect

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sizes for therapists and volunteers) and only allowed conclusions about a series of irrelevant hypotheses. The paper by Robey furnishes a thorough analysis of the published papers and it is statistically well conducted. I am confident that we can retain his conclusions: aphasia therapy is efficacious and it is more efficacious if it starts relatively early after onset.

Single cases Cognitive neuropsychologists were critical about group studies, the main reason being that there is no a priori certainty that the functional damage is the same in all patients and the mean value cannot be taken as indicative of the group performance. Studies on the efficacy of aphasia therapy have been frequently criticised because neither the functional damage nor the treatment were sufficiently detailed. Group studies were replaced by single-case studies (Byng, 1988; Byng & Coltheart, 1986; de Partz, 1986; Hatfield, 1983; Jones, 1986) where the functional damage and the therapeutic tecniques were described in detail. All these studies agreed that aphasia rehabilitation was effective. Unfortunately, although these results agree on aphasia rehabilitation effectiveness, the question remains open. If a speech therapist rehabilitates a patient who does not recover he/she will probably not publish the results. I am afraid that there is a bias in the selection of published cases: positive results have a higher chance of being published than negative results. To conclude, data on effectiveness of aphasia therapy indicate with sufficient certainty that there are patients who take advantage of rehabilitation, particularly if it is intensive, prolonged, and precocious. For the moment, however, this conclusion is only true for groups of patients: we can expect that a higher number of patients will recover in a group of rehabilitated patients than in a group of nonrehabilitated patients but we cannot know beforehand whether rehabilitation will be effective for a specific patient. The time for clinical studies on aphasia therapy effectiveness has elapsed; we now must try to answer more specific questions, such as which disturbances can be effectively treated and how.

A THEORY OF REHABILITATION Recently single-case studies of patients rehabilitated with cognitive methods have been published, and cognitive neuropsychologists have sustained that only a therapy based on the principles of cognitive neuropsychology is rationally based, and this applies to any kind of cognitive deficit. Cognitive neuropsychology has had the undoubted merit of studying language (and other cognitive functions) disturbances from a point of view that previously had been rather neglected: the point of view of the normal processing. Starting from a model of the processing in normal subjects, cognitive neuropsychology aims to identify the damaged components in the single patient. It also assumes the hypothesis of modularity (each function can be analysed in subfunctions that are functionally independent) which allows one to consider separately all aspects of the cognitive function under investigation. These models, particularly the model of the lexical/semantic system—the most detailed aspect of language processing—allow diagnostic hypothesis much more accurate than those allowed by classic aphasiology which was essentially based on observation of the verbal behaviour of the patient. An accurate diagnosis is a necessary starting point for any motivated therapy. The contribution of cognitive neuropsychology, however, is limited to diagnosis; it does not give any indication about what to do once the functional damage has been ascertained, nor whether the damage can be recovered. It is up to the speech therapist, with his/her clinical experience, to choose rehabilitation procedures that do not ignore what is known about the damaged functional component but which are not clearly specified by the simple identification of the functional damage. We can illustrate this with an example. If a patient has a deficit of the output phonological buffer we know that there is no logical ground for asking him/her to name items chosen among a single semantic category, even if this can be helpful for other patients with a deficit of the semantic system, but the precise diagnosis—deficit of the output phonological buffer—does not dictate what exercises will be the best ones.

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CONCLUSIONS In this chapter the story of aphasia rehabilitation and of the studies on its effectiveness have been rapidly sketched and the conclusion has been reached that aphasia therapy can be effective. As a last comment

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I want to underline that advances in aphasia therapy are mainly due to the fact that it has always taken into account advances in other disciplines— psycholinguistics, cognitive psychology, learning theories. Future advances in aphasia rehabilitation techniques will be made possible by therapists’ ingenuity and the gathering of new knowledge.

Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

37 Visual, Visuospatial, and Attentional Disorders Pierluigi Zoccolotti

the heminattentive disorder (see later). It is clear that knowledge of the spontaneous development of symptoms is essential for evaluating the actual impact of the rehabilitative treatment. The frequency of appearance of visuospatial disorders is very variable. For example, it is believed that the agnosias, at least in their pure forms, are very rare. In recent years the use of standardised tests has revealed a rather large number of patients with milder but equally reliable agnosic disorders. For example, it has been observed that patients with focal lesions in the right hemisphere perform below the norm on tests of perceptual matching of unknown faces (Benton, 1980); however, an “acclaimed” deficit in recognising famous or familiar faces (prosopagnosia) is generally rare in these patients. In evaluating this differentiation it must be considered that the two recognition disorders are qualitatively different: in one case, this involves perceptual operations on faces with which the patient has no internal reference for comparison; in the other case, a comparison operation of an internal trace, with information stored in the “semantic” visual memory is required (see Bruce & Young, 1986). Coherent

INTRODUCTION If we examine the attempts made in neuropsychology to treat cognitive disorders following a cerebral lesion, we see that much of the literature concerns the treatment of language disorders (see Basso & Cubelli, Chapter 9 this volume). However, following a right hemisphere lesion, patients may also show a variety of visuospatial and attentional disorders (e.g. De Renzi, 1982). The consequences of these disorders on the relational life of patients may be particularly incapacitating, especially if other motor and/or sensory-type symptoms are associated with them. Research on rehabilitation in this area is complicated by the fact that there is relatively little knowledge of information critical for planning treatment. For example, information on the frequency of appearance and the spontaneous development of disorders is particularly important. The spontaneous development of nonlinguistic disorders has been studied systematically only in recent years. This is the case with ideomotor apraxia (Basso, Capitani, Della Sala, Laiacona & Spinnler, 1987). More information is available in the case of 875

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with this idea, patients presenting a dissociation between these two disorders have been described; for example, they show a clinical profile of prosopagnosia but retain spared or almost unaltered their ability to associate unknown faces (e.g. Benton, 1980). This example indicates that there are visuospatial disorders, such as prosopagnosia, with severe and obvious consequences on the relational life of the patient. Alternatively, there are disorders that can be shown only with standardised psychometric testing. In the latter case, the functional impact of the disorder on the patient’s relational life is less clear. In fact, the majority of experimental studies concentrate on the implications provided by a given cerebral disorder for the comprehension of cerebral functioning (e.g. the importance of various areas of the right hemisphere in perceptual tasks requiring a global evaluation of a perceptual stimulus). These observations underline the dichotomy present in the literature between a formal examination of the visuospatial competencies of a patient and the study of the impact of these disorders on everyday life. It is important to be aware of this distinction when examining the potential of rehabilitative intervention. In fact, the most general aim of treatment is to help the patient increase or regain a sufficient degree of autonomy in relational life. This view underlines the importance of a functional evaluation of visuospatial disorders. To return to the previous example, observing that a patient has a score under the normal cut-off on a test of perceptual matching of unfamiliar faces tells us relatively little about the impact this deficit will have on relational life. It should be noted that these observations do not refer exclusively to the problem of evaluating visuospatial disorders but also of evaluating linguistic abilities (Holland, 1980). This chapter will consider the relatively limited number of studies that up until now have examined the effectiveness of specific training to compensate for visual, visuospatial, and attentional disorders. A number of isolated studies exist in the literature with very specific aims which at present cannot be organised into an articulated perspective; vice versa, today it is possible to carry out a significant synthesis of rehabilitative interventions only in a

very limited number of areas. The first of these areas to be considered is the recovery attempt for disorders relative to reductions in the visual field. A rather large number of studies on the rehabilitation of patients with a heminattentive disorder will be considered. A limited but interesting group of studies has been carried out on constructive apraxia. Finally, studies evaluating the possibility of recovery o f basic attentional mechanisms in patients with head trauma lesions will be examined.

DISORDERS INVOLVING REDUCTIONS OF THE VISUAL FIELD A reduction of the visual field affects an individual’s ability to orient him/herself in the surrounding environment. To alleviate the disorders resulting from this deficit, two different rehabilitative approaches have been undertaken. On one side several studies have examined the possibility that systematic exercise might reduce the size of the visual field deficit. On the other side there has been an attempt to teach patients compensation strategies which permit them to maximise their exploration of the visual field.

Recovery of visual functions in cases of reductions of the visual field of a central origin In a fascinating series of studies (Zihl, 1981; Zihl & Von Cramon, 1979, 1982), the possibility of increasing the visual field of patients with retrigenicolate lesions of the visual pathways was examined. In general, Zihl and Von Cramon (1979) start from the hypothesis that these lesions do not necessarily produce an absolute and permanent visual field defect. In particular, according to these authors, the transition between the intact parts and the “blind” parts of the visual field can be gradual or clear-cut. A zone of gradual transition may indicate the presence of portions of cerebral tissue which, if stimulated adequately, can recover the visual function either completely or in part. In an initial investigation (Zihl & Von Cramon, 1979), it was demonstrated that the stimulation of these areas

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produces an improvement in contrast sensitivity and an increase in the size of the visual field. Coherent with the central nature of the deficit, an inter-ocular transfer of improvements obtained with rehabilitation was present. In a second investigation, similar results were obtained through exercises of saccadic localisation (Zihl, 1981). These data were strongly criticised by Balliet, Blood, and Bach-y-Rita (1985), who obtained no improvement following an intensive treatment evaluating visual functions with very careful procedures. However, it should be noted that some investigations have confirmed Zihl and Von Cramon’s original results (e.g. Kerkhoff, Munssinger, & Meier, 1994). Overall, it seems prudent to conclude that, although recovery of reduction of the visual field due to retrogenicolate lesions seems possible, the conditions in which these improvements occur are not well understood. Zihl, in a heated exchange with Balliet et al., admitted that these effects are present in a limited number of patients and that only the positive cases were included in the originally reported case histories. In any case, from the rehabilitative point of view, it is important to observe that, with rare exceptions, the observed widening of the field regards only a few degrees of visual angle; therefore, the patient must still learn to compensate for the residual visual field deficit.

Optimisation of visual exploration Up until a few years ago, it was held that patients with visual field reductions were able to develop a series of compensatory strategies over time to make up for the perimetric deficit (e.g. Gassel & Williams, 1963; Meienberg, Zangemeister, Rosenberg, Hoyt, & Stark, 1981). More recent investigations have shown the presence of residual exploration deficits that produce disabling outcomes for the patient (Kerkhoff etal., 1994). Reading behaviour that is slow, tiring, and involves errors warrants particular attention. These effects are much more marked in patients with a deficit in the right visual field (e.g. Kerkhoff, Munssinger, Eberle-Strauss, & Stogerer, 1992). This appears to be linked to the importance of the right parafovea for the programming of ocular movements in reading (for a review, see Rayner,

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1989). Consistently with this idea, it was seen that patients with right hemianopia present more (Eber, Metz-Lutz, Strubel, Vetrano, & Collard, 1988) and less wide (De Luca, Spinelli, & Zoccolotti, 1996) rightward saccades compared to control subjects and patients with reductions of the left visual field. In recent years, various investigations have shown the possibility of improving the patient’s ability to orient him/herself toward the hemianopic side (Kerkhoff et al., 1994; Zihl, 1995; Zoccolotti, Judica, & Di Pace, 1992) as well as the possibility of increasing reading fluency (Kerkhoff et al., 1992; Zihl, 1988).

HEMINATTENTIVE DISORDER Heminattention (or hemineglect) disorder is the inability (or reduced tendency) to attend to events taking place in the side of space contralateral to the side of the cerebral lesion (see Bisiach, Chapter 21 this volume). The patient with this disorder tends to ignore objects or persons in the neglected hemispace. In a rehabilitative view, the heminattentive disorder assumes particular significance for a variety of reasons. Above all, it is very frequent. Almost half of the the patients with right hemisphere lesions have more or less marked symptoms of heminattention at least in the first phases following stroke (Heilman, Valenstein & Watson, 1985). Further, this disorder has very negative general effects on the patient’s everyday life. They seem to live in a “h alf’ world; they tend to shave only half of their face, read the information on half of the page, interact only with the people who are on one side of space. Work activities requiring reading and writing become impossible; the patient has difficulty in moving autonomously (also in cases in which locomotion is not impaired by a paretic disorder) due to the consistent tendency to bump into objects in the side of space contralateral to the hemispheric lesion. A characteristic aspect of the disorder is that very often patients do not seem to be aware of their impairment (anosognosia). In other words,

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not only is there an inability to find objects on one side, but the patient is not aware of this inability and, on request, formulates incoherent or minimising explanations of the disorder. The great majority (if not all) patients with a relatively severe and stabilised symptomatology, for whom rehabilitative intervention is more important, show an alteration in degree of awareness of the state of their illness; this has important implications for the course of rehabilitative treatment.

Spontaneous course of heminattentive disorder Several studies have shown that in the first weeks after a stroke a consistent proportion of patients seem to have a remission of symptomatology (Gainotti, 1968a; Hier, Mondlock, & Caplan, 1983a). Other investigations, although observing a clear developmental course in the symptomatology, have underlined the presence of a remaining, more or less consistent, disorder even long after the pathological event (e.g. Campbell & Oxbury, 1976a; Colombo, De Renzi, & Gentilini, 1982). Colombo and others (1982) also observed that although there may be a correlation between performance on the first trial and a trial carried out six months later, the individual amount of recovery is not clearly associated with initial severity of the disorder. The relative stability of the heminattentive disorder in time is confirmed by cross-sectional studies that have examined case histories of chronic patients in rehabilitation clinics. The absence of a correlation between duration and severity of the illness is noted. Stability of the disorder in time was also confirmed by observations of patients with a clear heminattentive disorder many years after stroke (Zarit & Kahn, 1974; Zoccolotti, Antonucci, Judica, Montenero, Pizzamiglio, & Razzano, 1989). Overall, these results confirm the clinical impression of a clear improvement in the heminattentive disorder, particularly in the initial post-stroke phases, but they also indicate that many patients have a consistent disorder even months or years after stroke, suggesting the importance of rehabilitative intervention.

Treatment of heminattentive disorder The first results on the effectiveness of rehabilitative intervention were reported by Lawson (1962), who analytically described the evolution of two patients with heminattention. After several weeks of concentrated training in reading, the two patients showed remarkable improvements. Lawson’s (1962) method seems to be that of trying to provide the patient with direct compensation for his/her explorative inability. At times, a flashlight was used to draw attention to the left edge of the stimulus, thus providing “strong” sensory stimulation. In other cases, semantic-type suggestions were used; in particular, the patient was shown that whenever the portion of the text read made no sense it was necessary to look more to the left to recover the lost material. The relative effectiveness of these two different types of interventions was not examined by Lawson (1962). Most of the training that developed subsequently is an extension and systematisation of the observations presented by Lawson (1962). More often, the choice of successive authors has been to use sensory cues (e.g. Seron & Tissot, 1973).1 The most articulated and complex training in this sense was developed by Diller and colleagues (Diller & Gordon, 1981; Diller & Weinberg, 1977; Diller etal., 1980; Gordon etal., 1985; Weinberg et al, 1977). Their treatment procedure involves “anchoring” the patient at the left margin of the stimulus, from where the exploration must begin. In a preliminary investigation, Diller, Ben-Yishay, Gerstman, Goodkin, Gordon, and Weinberg (1974) observed that a red line placed to the left of the stimulus containing the targets to be cancelled had the effect of reducing the asymmetry of the patients’ response. This same procedure was applied in tasks in a rehabilitative perspective (Diller et al., 1980). In the attempt to favour a generalisation of learning, these principles were applied to a variety of rehabilitative procedures, such as searching for coloured stimuli presented with the use of a “scanner”, cancellation of target stimuli, and reading and copying linguistic material. In general, the reported results are positive. After four weeks of treatment patients with right hemispheric lesions and heminattention showed great improvements in a series of exploration tasks,

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particularly barrage tasks (Diller & Weinberg, 1977; Weinberg et al., 1977). Equally positive results were reported in another series of studies with similar treatment procedures (Antonucci et ah, 1995; Carter, Caruso, Languirard and Berard, 1980; Carter, Howard, & O’Neil, 1983; Ladavas, Menghini, & Umiltà, 1994; Pizzamiglio, Antonucci, Judica, Montenero, Razzano, & Zoccolotti, 1990; Pizzamiglio et al., 1992). However, other results must be noted where relevant changes in patients’ behaviours were not observed. Very limited changes were observed in a group study using a single procedure of computerised stimulation (Robertson, Gray, Pantland, & Waite, 1990). In two other studies it was found that the changes obtained did not extend to the patient’s other behaviours even though they were present in the learned tasks (Gouvier, Bua, Blanton, & Urey, 1987; Wagenaar, Van Wieringen, Netelenbos, Meijer, & Kuik, 1992). These negative results have been underlined by some authors (Halligan, Donegan, & Marshall, 1992; Robertson, Halligan, & Marshall, 1993) to indicate the ineffectiveness of the procedure proposed by Diller and colleagues to stably and substantially modify the explorative behaviour of patients with heminattention. On the other side, Antonucci and colleagues (1995) observed that the studies reporting negative results used very brief treatment periods (1-2 weeks). Vice versa, the studies that obtained a more consistent generalisation of learning normally used more prolonged treatment periods (4-8 weeks). It seems reasonable to expect that a generalisation occurs only in the case in which the patient is brought to a high level of overlearning (Antonucci et al., 1995). Extension o f improvemen ts to everyday life situations The description of several single cases provides indications consistent with the idea that patients manage to apply the results of rehabilitative training to their everyday life (Diller et al., 1980; Diller & Weinberg, 1977; Rao & Bieliauskas, 1983). A more direct way of verifying the degree of generalisation obtained by patients consists in examining their behaviour in semi-structured situations that reproduce everyday life situations

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before and after rehabilitative training (Wilson, Cockburn, & Halligan, 1987; Zoccolotti, Antonucci, & Judica, 1992; Zoccolotti & Judica, 1991). Using this procedure remarkable individual consistency was observed in recovery after rehabilitative training in standard tests and that shown on a semi-structured evaluation scale (Pizzamiglio et al., 1992; Zoccolotti et al., 1992). Information on the functional impact of rehabilitative training also derives from the analysis of behaviours affected by the heminattentive disorder which are particularly important in the patient’s everyday life, such as driving a wheelchair. Using the paradigm developed by Diller and colleagues (1980), Webster, Jones, Blanton, Gross, Beissel, and Wofford (1984) were able to document an increase in the precision of driving the wheelchair in three patients with heminattention. Similar results were reported by Stanton, Pepping, Brockway, Bliss, Frankel, and Waggener (1983). Overall, this information indicates that the acquisitions obtained are not limited to standard tests for measuring heminattention but are also present in more natural situations, witnessing to the functional significance of the rehabilitative treatment. Rehabilitative treatment and spontaneous recovery It is important to evaluate whether the improvements just described must be specifically ascribed to the role of rehabilitative treatment or are simply the expression of the spontaneous evolution of the disorder. At least in some investigations, the role of spontaneous recovery has been accurately tested. For example, Weinberg and colleagues (1977) examined only patients with a relatively stabilised symptomatology, and the treated patients’ improvements were compared with those obtained from control patients with the same degree of initial severity. At a distance from stroke, changes in the explorative behaviour of treated patients were present, but not in that of the control patients; this result is consistent with the idea that the improvements found cannot be ascribed to a spontaneous evolution of the heminattentive

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disorder. These results were recently replicated by Antonucci and colleagues (1995); they showed the ineffectiveness of a general cognitive stimulation to change patients’ explorative behaviour. The observations of patients examined many months or years after cerebral damage are in the same direction. For these patients it does not seem reasonable to expect spontaneous changes in behaviour (Pizzamiglio et al; 1990, 1992; Rao & Bieliauskas, 1983; Seron & Tissot, 1973). These studies indicate that significant improvements in explorative behaviour are possible even in patients who have undergone rehabilitation a long time after cerebral damage. Persistence o f changes over time A fundamental aspect in evaluating rehabilitative treatment is examination of the persistence over time of the changes obtained. In a limited number of investigations, patients were re-examined with a follow-up after treatment was interrupted. After about a year of non-treatment, Weinberg and colleagues (1977) observed that the patients’ behaviour was not substantially changed. A similar result was observed by Pizzamiglio and colleagues (1990, 1992), who observed that the patients’ performances were also substantially stable in exploration tasks in semi-structured situations. Training selectivity An important aspect in evaluating the impact of a rehabilitative therapy is to establish whether the observed changes are specific to the disorder in question or whether they can be attributed to general improvements in the patient’s behaviour. Lawson (1962) underlined the selectivity of observed improvements, noting that the reading exercises do not modify the ability to draw a figure. However, much successive research has not been informative with respect to this problem. In fact, in some cases it has been limited to the examination of the explorative functions as the subject of training (e.g. Carter et al., 1980, 1983). In other cases the improvement in exploration tasks was not clearly distinguished from that in tasks involving other visual-spatial abilities, and the broadness of the impact of rehabilitative training on

the patient’s overall performance was underlined instead (e.g. Weinberg et al., 1977). In some studies, the problem of selectivity has been tackled in a specific way. Ladavas and colleagues (1994) observed that, after visual training, explorative improvements were confined to this sensory modality and did not extend to the tactile one. Pizzamiglio and colleagues (1990, 1992) observed that with marked improvements in a variety of situations requiring a complete exploration of space, patients showed small changes (even if sometimes significant for the group as a whole) in a variety of visual-spatial tasks, such as recognition of faces or figures presented in an incomplete way or in unusual perspectives. This dissociation is particularly clear in the copying of drawings task. In this case, the patients showed a persistent apraxic deficit after therapy; however, their drawings extended correctly toward the left side of the sheet of paper (Pizzamiglio et al., 1990, 1992). Recently, Pizzamiglio and colleagues (1997) examined patients showing both hemineglect and deficits in position sense; after rehabilitation training, scanning behaviour improved while the position sense deficit remained unchanged. These findings indicate a dissociation between the internal representation of the position of body segments and that of objects in extrapersonal space. Changes in awareness and mood as a function o f the rehabilitative treatment Most of the investigations considered up until now have not particularly emphasised the possible modulatory role of disorders in awareness and mood on the patient’s behaviour during rehabilitative training. Consistent changes in the patients’ attitudes toward their deficit during rehabilitative training have been reported by Pizzamiglio and colleagues (1990,1992). Initially indifferent to or surprised by the attention given them, the patients changed their behaviour substantially during the course of the first weeks of training. To the extent to which exploration toward the neglected side began to improve, substantial changes were also observed in the patient’s attitude toward his/her disorder (e.g. “Today I want to find all the numbers by myself— don’t help me”). This change represents an

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important point in the training; the patient begins to take an active part in the rehabilitation, often begins to build personal compensation strategies (for example, guiding his/her own search with a pen), and is more lucid and cooperative. Vice versa, some patients have crises of depression when they perceive the severity of their symptomatology. A change from an attitude of indifference to one of desperation to greater contact with reality has also been described in the spontaneous evolution of patients with heminattention (Gainotti, 1968b). The presence of this complex evolution during training suggests that the comparison of the pre- and post-therapy affective state may not be critical, and accounts for the scant results obtained by Gordon and colleagues (1985). Other approaches in the rehabilitation o f heminattention As stated before, almost all studies have tried to tackle the heminattentive problem with a direct approach, that is, using a series of sensory suggestions that lead the patient to orient his/her attention toward the neglected side in order to correctly process the target stimulus. Recently, this approach has been severely criticised both on a theoretical and empirical basis (Halligan et al., 1992; Robertson et al., 1993; Seron, Deloche, & Coyette, 1989). Seron and colleagues (1989) observed that a patient followed with procedures similar to those proposed by Diller’s group showed a drastic dissociation between automatic and voluntary behaviour. In other words, the patient displayed explorative improvements only in situations in which he was able to concentrate explicitly on identifying stimuli in the left hemispace. In more spontaneous situations, the patient did not try to compensate for the deficit and large omissions of elements placed in the left hemispace reappeared. On the basis of this observation they proposed an alternative paradigm defined as “mental prothesis”. A brief sound was presented to the patient at random intervals; following sound onset the patient had to orient his/her exploration toward the left and successively interrupt the sound by pressing a button. The interesting aspect of this procedure is that the explorative cue is disconnected by the

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timing and by the perceptual characteristics (size, orientation) of the target stimuli. According to Seron and colleagues (1989), these characteristics should permit a reacquisition of a complete exploration of the space that has characteristics of automaticity. Partly on the basis of these criticisms, in recent years alternative approaches to the rehabilitation of heminattention have been proposed. The basis for these new proposals is the observation that, through a series of various types of stimulations, it is possible to obtain a partial, even if temporary, reduction of the heminattentive deficit. In this vein, it was observed that the explorative asymmetry of patients with heminattention is markedly reduced in the presence of vestibular (Cappa, Sterzi, Vallar, & Bisiach, 1987; Rubens, 1985), opto-kinetic (e.g. Pizzamiglio, Frasca, Guariglia, Incoccia, & Antonucci, 1989) or transcutaneous electrical stimulation (e.g. Vallar et al., 1996). Significant changes in the degree of heminattention are also obtained in the case of motor activation of the limbs contralateral to the lesion; in this way it was observed that a patient tends to execute better line bisection if, during the task, he or she moves the contralateral leg (e.g. Robertson & North, 1992). This literature is summarised extensively in Robertson and colleagues (1993). It seems clear that some of these techniques (e.g. vestibular stimulation) cannot be easily adapted to rehabilitative-type situations for general reasons and because of the presence of an adaptation in the subject’s response. In other cases, however, it is possible to think of a systematic use of this type of stimulation for rehabilitation. For example, it has been seen that visual exploration is favoured by the presence of a background moving toward the left producing a typical opto-kinetic response (Zoccolotti, Guariglia, Judica, Pantano, Pizzamiglio, & Razzano, 1992). After about two months of training, the difference between the presence and absence of optical-kinetic stimulation had disappeared and the patient showed a very clear exploration of the entire visual field. Partially positive results have also been reported in the case of motor activation by Halligan and colleagues (1992), even if the degree of generalisation obtained

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was limited (probably because of the brevity of the training used). It is important to observe that the repetitive use of sensory stimulation by itself is unlikely to produce significant improvements in explorative behaviour. Thus, Pizzamiglio, Vallar, and Magnotti (1996) found very little changes in scanning when the transcutaneous stimulation of the neck muscles was given for two months together with a non-specific cognitive therapy; the same patients showed significant improvements when they were successively submitted to a specific training for neglect (as in Pizzamiglio et al., 1990, 1992) . In general, it can be said that the use of rehabilitative procedures alternative to the direct approach proposed by Diller and colleagues is still at the beginning stages, and the results obtained in a limited number of single cases, although suggestive, cannot be considered conclusive. Also the statement of some authors (Robertson et al., 1993) that this type of intervention has a more solid theoretical base than that proposed by Diller seems dubious. In fact, in this case the reliability of the effects obtained with the various techniques of stimulation is confused with the presence of an exhaustive theoretical explanation. Vice versa, the debate over the significance to be attributed to the effect of the various techniques of stimulation in reducing the heminattentive disorder still appears to be at an early stage and there does not seem to be an accepted unitary interpretation of these effects (see Gainotti, 1993 for a discussion of the possible interpretation of these effects). According to one view, all these sensory inputs (vestibular, visual, and somatosensory-proprioceptive) contribute to the dynamic balance of egocentric representations of space; thus, lateralised stimulation can counterbalance the distortion of representation toward the side of the lesion present in neglect patients (Pizzamiglio et al., 1996). Alternatively, it has been proposed that these stimulations can directly or indirectly affect the arousal level of the patient (Gainotti, 1993). Interactions between basic attentional problems and neglect symptoms have been underscored by some authors (e.g. Robertson & Frasca, 1992). Interestingly, it has been recently reported that a training focusing on sustained attention can ameliorate hemineglect symptoms,

even in the absence of any explorative exercise (Robertson, Tegner, Tham, Lo, & Mimmo-Smith, 1995). In any case, the formulation of new paradigms of intervention in the case of heminattentive disorder seems to be a relevant objective for increasing the effectiveness of rehabilitative training. At least two aspects of these techniques are of potential interest. On one side, it seems important to develop procedures that increase the automatisation of exploration (Seron et al., 1989). On the other side, the use of techniques that permit obtaining a remission of symptomatology in a passive way (as in the case of optical-kinetic stimulation) can be particularly useful at the beginning of the rehabilitative intervention and/or with those patients showing the greatest lack of awareness of the deficit.

CONSTRUCTIVE APRAXIA Still today, only very fragmentary information is available about the possibility of a rehabilitative intervention of the disorders of constructive apraxia. This disorder is generally defined in terms of a reduced ability to copy drawings, geometric figures, to build or to place objects in space (De Renzi, 1982; De Renzi and Faglioni, Chapter 18 this volume). In general, it should be observed that both elements of constructive apraxia and of heminattention can be found in the performance of these tasks. The association between these two disorders is confirmed in the large case studies by Hecaen (1962, 1969). In particular, a constructive apraxic disorder was shown in almost all (95%) patients with heminattention and in about half of patients without heminattention. The presence of this frequent association is important in the planning of a rehabilitative intervention, even if the mechanisms underlying the two disorders are different (Ettlinger, Warrington, & Zangwill, 1957). The influence of the apraxic disorder in everyday activities, such as eating and driving a car, can be easily imagined. However, also in this case, it should be observed that most of the diagnostic instruments developed by the various authors

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relative to this disorder are “formal” and do not offer direct information on the functional impact of the disorder.

Treatment of constructive apraxia Several studies have examined the possibility of improving the performance of patients with cerebral lesions in the Block design test, borrowing from Wechsler’s scale (Diller et al., 1974; Young, Collins, & Hren, 1983). It should be observed that as well as visuo-motor abilities, this test requires complex abilities of perceptual structuring; therefore, it does not seem ideal in measuring constructive apraxia. However, this use is part of clinical and experimental practice (e.g. Hier, Mondlock, & Caplan, 1983b) in that performance on the Block design test is strongly correlated with the more frequently used copying of complex drawings (Hier, & Kaplan, 1980). With this in mind, the cited studies offer several indications about the possibility of intervening in a positive way on the constructive disorder. Diller and colleagues (1974) followed patients with right hemispheric lesions and heminattention with a four-week training during which different versions of the Block design test were presented. After training significant improvements were present in performance on standard tests. The performance changes were relatively specific; in particular, training with the Block design test did not significantly change the explorative ability of these patients (measured with a letter cancellation test). Vice versa, there were several indications that the improvements obtained extended in some way to the patients’ behaviour. Diller and colleagues (1974) concentrated their attention in particular on eating behaviour. Overall, the treated patients showed greater organisation in their behaviour at table than the untreated controls. In particular, there were fewer inappropriate manoeuvres and accidents. The possibility of modifying performance on the Block design test was confirmed in a study by Young and colleagues (1983). These authors chose to use Diller and colleagues’ procedures for constructive apraxia and heminattention. They observed that the patients treated with both procedures showed more sensitive improvement in

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cancellation tasks than those treated only with training for the heminattentive disorder. Unfortunately, this study does not offer any indication about the degree of generalisation of the acquisitions observed in everyday life situations. Very significant indications about the functional importance of systematic training for constructive apraxia come from a case studied analytically by Angelini (1991). The patient, a 30-year-old glassworker, with a severe form of constructive apraxia and slight heminattention, was followed-up for about a year with training to develop alternative solution strategies in visual-motor tasks, in particular taking advantage of the patient’s remaining undamaged verbal abilities. The results were very encouraging both regarding performance on standard tests (copying geometric figures, figures with cubes) and regarding work recovery. At the end of therapy the patient was again able to carry out most of his glassworking tasks without supervision. Partly on the basis of this experience, an articulated procedure for diagnosis and treatment of constructive disorders was developed (Terapia razionale dei disturbi costruttivi or TeRaDiC (Rational Therapy of Constructive Disorders), (Angelini & Grossi, 1993). Overall, there is still very incomplete information about the possibility of intervening effectively on the constructive apraxia disorder. In any case, the research that has been carried out indicates that it is possible to significantly reduce the constructive apraxia disorder presented by patients and that the improvements observed to some extent involve patients’ everyday life activity. The potential influence of this training on patients’ everyday life suggests the importance of further studies to more thoroughly investigate this area of research.

BASIC ATTENTION DISORDERS In recent years, very few areas in psychology have experienced the same theoretical and experimental development as the examination of attentional processes. Today there is a broad consensus that attention is not a unitary phenomenon but rather a

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group of processes that are relatively independent from each other (for a broad review, see Van Zomeren & Brouwer, 1994). In particular, a distinction is made between processes that change the intensity of the subject’s response and processes that permit selecting the stimulus and the attributes of the stimulus that the observer intends to process. With regard to the former, it is possible to distinguish more rapid or phasic (alert) components and slower or tonic ones (vigilance). With regard to the latter, Van Zomeren and Brouwer (1994) distinguished between situations of selective attention, in which one stimulus or its attribute must be processed and others ignored, and situations of divided attention, requiring that the subject execute more than one task simultaneously. In a neuropsychological-rehabilitative view, the interest of researchers is centred particularly on the examination of patients with a head trauma. Even many months or years later these patients frequently report a variety of symptoms such as irritability, inability to concentrate, scarce memory, easy tiring (McKinlay, Brooks, Bond, Martinage, & Marshall, 1981; Oddy, Humphrey & Uttley, 1978; Van Zomeren & Van Den Burg, 1985). Van Zomeren & Van Den Burg (1985) have proposed that these symptoms can be traced to underlying disorders in different attentional processes; that is, the various attentional components would be affected to a different degree in patients with traumatic damage producing the described behavioural picture (Gronwall & Sampson, 1974). The consequences of these deficits are particularly important for the patients’ job recovery. It is important to consider that job recovery is closely correlated with the severity of the trauma (in terms of post-traumatic amnesia) and the aforementioned cognitive disorders (Van Zomeren & Van Den Burg, 1985).

Treatment of attentional disorders A first systematic attempt to develop a specific rehabilitative procedure for the attentional deficit was made in a series of investigations by Ben-Yshay and colleagues (Ben-Yshay, Diller, & Rattok, 1978; Ben-Yshay, Piasetsky, & Rattok, 1987). The Orientation Remedial Module (ORM), proposed by the authors, comprises of five tasks that require paying attention and reacting to environmental

signals, measuring the length of the responses in relation to signs of environmental changes, being actively vigilant, estimating temporal length, and synchronising responses with complex rhythms. The ORM was administered to a sample of patients with stabilised symptomatology (more often examined 2-4 years after cerebral damage). The results showed significant improvements in performance on all tasks. Positive results were also reported for the generalisability of these improvements, obtained both by evaluating the patients’ performances on standard psychometric tests and observing patients’ behaviour during particular everyday life activities. Positive results were also reported by other studies both on patients with traumas (Gray, Robertson, Pentland, & Anderson, 1992; Sohlberg & Mateer, 1987) and on patients with vascular damage (Sturm & Willmes, 1991). For example, Sohlberg and Mateer (1987) reported that the behavioural changes extended significantly to the patients’ everyday life activities; before treatment none of them lived independently and at the end of treatment all lived independently. Further, they had all resumed their work activity in varying degrees. Finally, the observed changes (both on standard and functional tasks) remained stable after the end of therapy for as long as it was possible to follow up the patients (for eight months). Overall, the various trainings that have been investigated show a certain degree of effectiveness. However, it must be underlined that, presumably to increase the probability of effectiveness of the intervention, all cited treatments used rehabilitative procedures that cover a broad spectrum of attentional processes. However, it remains to be clarified whether the effectiveness of these treatments derives from the complex of paradigms used or whether it is possible to obtain specific results with trainings that intervene only on one single attentional process (e.g. selective attention). A first attempt to verify this hypothesis provided discouraging results. Using a treatment programme focused exclusively on deficits relative to speed of information processing, Ponsford and Kinsella (1988) obtained results that do not seem greater than those due to spontaneous recovery. A more articulated attempt in this direction was made by

37. VISUAL, VISUOSPATIAL, AND ATTENTIONAL DISORDERS

Sturm and collegues (Sturm, Hartie, Orgass, & Willmes, 1994; Sturm, Willmes, Orgass, & Hartie, 1997) in patients with vascular damage. In particular, these authors reported specific improvements in alertness and vigilance after specific trainings in these areas; a greater degree of cross-over was present in the case of treatments relative to selective attention and divided attention. It seems particularly important that studies in this direction also be carried out on patients with head trauma.

GENERAL CONCLUSIONS As already stated, the development of research in the area of neuropsychological rehabilitation of visual, visuospatial, and attentional disorders is relatively recent. As a consequence, the overall picture that emerges is still very incomplete from many vantage points. For example, we have seen that many trainings are effective in reducing heminattentive disorder. These rehabilitative successes as a function of very different treatments underline the importance of examining more

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analytically the mechanisms that actually act in producing the observed changes. The same can be said with regard to attentional deficits in patients with head injuries. At the same time, the results presented illustrate well the potential of a rehabilitative intervention in improving the relational life of patients with cerebral pathologies. At least in some investigations it has been possible to show that the results obtained do not bring about an improvement limited to standardised laboratory situations, but represent significant and stable acquisitions in patients’ behavioural repertoire. Considering the number of individuals with cerebral problems, it is easy to appreciate the importance of research developments in the area of neuropsychological rehabilitation.

NOTE

1. A n exception is Stanton and co lleag u es’ approach w hich is based on the use o f sem antic recall (Stanton, Y orkston, K enyon & B enkelm an, 1981).

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38 The Rehabilitation of Memory Giovanni A. Carlesimo

associated with disorders in other cognitive areas (attention, language, abstract reasoning, etc.) is a serious cause of disability (Levin, 1989). The increase in the number of patients with severe memory disorders has led to the development of rehabilitative approaches directed toward alleviating the disabling consequences of this deficit. However, as often happens in the rehabilitative field, therapeutic practice developed as a direct response to requests for assistance well before reliable experimental evidence was able to demonstrate its theoretical soundness and, above all, its practical effectiveness. In order to respond to the need for scientific validation of rehabilitative approaches to memory disorders, a line of research has been developing since the early 1970s directed toward the elaboration of rehabilitative strategies founded on explicit theoretical assumptions with verified experimental effectiveness. The aim of this chapter is to provide a critical review of the evidence deriving from this type of study.

INTRODUCTION A disorder in the ability to acquire and/or recall new information is probably the most frequent cognitive deficit following cerebral damage. Harris and Sunderland (1981), for example, report that in the various rehabilitation centres in Britain a percentage of patients varying from 34 to 100% show significant memory disorders. In most cases (for example, in degenerative demential syndromes or in severe closed head injuries), the memory deficit occurs together with diffused impairment of cognitive functions. More rarely, the difficulty of retaining new information manifests as an isolated disorder, outlining the picture of a pure amnesic syndrome (for example, Korsakoff’s disease, herpes simplex encephalitis, surgical removal of mesiotemporal structures, etc.; see Vallar, Chapter 15 of this volume). Undoubtedly, the most frequent cause of memory disorder today in patients with a nonprogressive illness (thus, excluding the demential syndromes) is severe head traumas. The development of methods of assistance in the acute phases of post-traumatic coma has produced a population of patients with residual neuromotorand neurocognitive-type disorders; therefore, a memory deficit that is isolated or more often

A BRIEF THEORETICAL FRAMEWORK Today, memory, understood as the ability to acquire, retain, and recall experiences and/or information, is 887

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no longer considered a unitary function. Functional dissociations in healthy subjects and neuropsychological dissociations in brain-damaged patients have suggested that memory is fractionated into a series of systems and subsystems which obviously interact but, at the same time, are relatively independent. As extensively discussed by Vallar (Chapter 15), the first distinction generally made is the one between short- and long-term memory. In the context of long-term memory, today a distinction between explicit and implicit memory is widely recognised. Explicit memory is involved in the recall and intentional recognition of experiences and information. Implicit memory, on the contrary, manifests as a facilitation, a performance improvement in perceptual, cognitive, and motor tasks in the absence of conscious reference to preceding experiences. Based on Tulving’s (1983) theoretical position, a further distinction is generally made between an episodic and a semantic memory system. Episodic memory is responsible for the storing and recall of information, mostly autobiographical facts and experiences, which can be placed precisely in a temporal-spatial context. Instead, semantic memory is involved in the acquisition and recall of the complex of information that constitutes our semantic-lexical patrimony, our cultural experience, and which, even though intentionally accessible, is not necessarily linked to the spacetime context in which it was acquired. The most convincing demonstrations of the functional and neuroanatomical independence of memory subsystems derive from neuropsychological evidence. The documentation of brain-damaged patients who show a selective longterm episodic memory deficit and normal functioning of short-term memory (Baddeley & Warrington, 1970), of semantic memory (Weingartner et al., 1983), and of implicit memory (Squire, 1992) is accompanied by descriptions of patients with selective deficits of short-term verbal memory (Basso et al., 1982) or semantic memory (De Renzi et al., 1987). In clinical practice, the most frequent memory disorder observed, which also presents the most disabling characteristics, is the inability to acquire and/or retain new information (anterograde episodic amnesia). Less frequent is the

case of patients who complain of great difficulty in recalling autobiographical events that occurred prior to the pathological event (retrograde episodic amnesia) or semantic-type information learned previously (semantic amnesia). Finally, patients with selective short-term memory deficits are very rare. For this reason (and because the experimental literature has only been interested in this type of patient), this chapter will review the experimental evidence regarding disorders of anterograde episodic memory.

METHODS OF MEMORY REHABILITATION The final goal of every rehabilitative approach is to render the patient as able as possible to adapt functionally to environmental conditions. In effect, an impairment of the ability to retain and/or recall relevant information constitutes a severe maladjustment to environmental requests (whether family, work, or social). With respect to this functional deficit, the most frequently used rehabilitative strategies can be traced back to three main models of intervention: 1. Training in the use of external aids, conceived of as a sort of “cognitive prothesis”, to remedy the reduced functioning of physiological memory processes. Mazzucchi et al. (1990) proposed a distinction between passive external aids, such as changes in the home environment (signs, use of different colours on different levels of the building, etc.) to improve patients’ spatial and temporal orientation (Reality Orientation Therapy; Holden, & Woods, 1988), and active external aids, primarily training in the use of memory books and/or agendas (Sohlberg & Mateer, 1989) which require the patient’s direct management. In spite of the great diffusion of these methods (and the recent attempts to computerise active external aids), it is clear that their possible effectiveness remains circumscribed by improvement of spatial-temporal orientation and facilitation of prospective memory (for example, remembering appointments). The intrinsic limitation of these

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objectives has led to the development of other types of strategies. 2. Methods aimed at reinforcing residual learning abilities (Patten, 1972). These strategies, which will subsequently be described in detail, are based on the hypothesis that it is possible to “reeducate” memory, thus rendering the amnesic patient able to reduce his/her disorder through improvement in the quality of processing of incoming information. 3. Methods fo r teaching information and/or useful procedures fo r carrying out specific tasks (domain-specific knowledge; Glisky et ai, 1994). This approach springs from the conviction that, primarily in patients with severe amnesic syndromes, it is not possible to restore autonomous learning of new information either directly or through alternative strategies. For this reason, a more realistic aim is to provide these patients with a set of knowledge and procedural abilities through specific methods in order to improve their adaptation to environmental requests.

EFFECTIVENESS OF REHABILITATIVE METHODS General methodological considerations Just as with any other therapeutic approach, in evaluating the effectiveness of a rehabilitative method a first aspect to consider is the clear characterisation of the sample of patients whom the therapeutic procedure is aimed at. For the rehabilitative techniques of memory disorders, this problem takes on particular importance due to the great heterogeneity of patients in need of this type of treatment. First of all, the severity as well as the qualitative characteristics of the memory deficit vary greatly from subject to subject. A review of the literature on the topic shows extremes that go from patients with light and isolated verbal memory disorders (for example, Patten, 1972) to patients with severe impairments of visual-spatial and verbal anterograde memory (Glisky & Schacter, 1987; Heinrichs, 1989). Further, as mentioned earlier, the memory disorder is rarely found in an

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isolated form; most often it is accompanied by a more or less marked impairment of other intellectual functions (for example, attention, language, logical-conceptual reasoning, and psychomotor initiative). The severity as well as the characteristics of this cognitive involvement vary from subject to subject and are, at least in part, dependent on the phase of evolution of the disorder (with greater possibilities of spontaneous improvement for deficits of recent onset). A final factor of variability, certainly able to influence the effectiveness of the rehabilitative programme, is the patient’s degree of awareness of his/her memory disorder. The presence of anosognosia (not rare in patients with extensive cerebral lesions) is an obstacle to the patient’s full involvement in the rehabilitative process and poses serious difficulties for the therapist in effecting any treatment strategy. The difficulty, if not the practical impossibility, of procuring groups of patients who are sufficiently homogeneous, has resulted in most of the experimental studies reported in the literature being based on the treatment of single subjects or very small groups of patients. On one side, this type of approach has the limitation of reducing the possible generalisation of experimental results. On the other, it has the advantage of showing how every rehabilitative process (and particularly the one directed toward cognitive impairments) must be individualised, that is, turned toward the solution of specific problems posed by the single patient; these range from the characteristics of the disorder and the evaluation of possible associated cognitive deficits to the analysis of specific requests for environmental adaptation (Mazzucchi et al., 1990). A second aspect to consider in judging the reliability of an experimental study concerning the effectiveness of a rehabilitative method is the availability of an adequate control condition. This condition (generally represented by the absence of any rehabilitative intervention or by the proposal of alternative methods of intervention) excludes the possibility that functional improvement observed following therapy is really simple spontaneous recovery or the result of a general cognitive stimulation. In light of the great qualitative variability in memory disorders, the most reliable control condition is not the examination of other

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amnesic patients but the repeated evaluation of patients who are receiving the experimental treatment and who, prior to treatment, were followed without any therapy or with other types of cognitive treatment (for a detailed discussion of this experimental approach, see Wilson, 1987). A final methodological problem to consider in evaluating the effectiveness of a rehabilitative intervention is the type of instruments used for measuring the possible functional variations occurring following the intervention. The most immediate measure of this variation is improvement in carrying out the procedure that was the main object of the rehabilitative intervention (for example, frequency in use of agendas for treatments centred on external aids, or learning lists of words for treatments centred on visualimaginative or semantic encoding of verbal items). Improvements in performances on other neuropsychological memory tests are indicators of a generalisation of the effectiveness of the therapeutic intervention. However, it seems obvious that the real aim of the rehabilitative intervention (and thus the basic parameter for evaluating its effectiveness) is improvement of the patient’s functional autonomy in everyday life situations, as measured by scales of functional evaluation or questionnaires on effectiveness of memory in daily living. From this point of view it is interesting to note that many neuropsychological tests commonly used for evaluating anterograde memory are hardly predictive of memory effectiveness in everyday life. For example, Sunderland and colleagues (1983) reported low correlation coefficients between performances on visual memory tests (such as a test of face recognition) and verbal memory tests (short-story recall, word-pair learning) and scores on a questionnaire of memory effectiveness in everyday life in a large sample of patients with outcomes from severe closed head injuries of recent onset (four months on the average). Correlations were also low between performances on visual memory tests and scores on the questionnaire in a subgroup of patients evaluated at a greater distance from the injury (four years and eight months on the average). However, in the same subgroup a significant association was

shown between scores on the questionnaire of subjective evaluation and performances on verbal memory tests. The artificiality of the memory requests on many neuropsychological tests has led to the development and clinical use of the so called “ecological memory tests”; these tests simulate real-life situations in which learning and recall of new information is necessary (Wilson et al., 1985). However, the true reliability of these instruments in predicting the effectiveness of the memory function in everyday life has not yet been demonstrated either in cross-sectional studies or in rehabilitative-type follow-up studies. Linked to the measurement of results of rehabilitative intervention is the problem, recently raised by Robertson (1993), of the “open” or “blind” nature of these studies. It is well known that “open” studies (that is, in which the person making the functional evaluations is aware of the type of treatment the individual patient has undergone) generally report more positive results than “blind” studies (in which the examiner does not know whether he/she is evaluating a patient who has undergone the experimental treatment or the control procedure). In fact, with very few exceptions (e.g.Godfrey & Knight, 1985), the studies reviewed in this chapter have used open procedures for evaluating results of the treatment.

Methods aimed at optimising the use of external aids Very few experimental studies have evaluated the effectiveness of rehabilitative interventions in stimulating the use of external aids and the real impact of these aids on patients’ functional autonomy. Godfrey and Knight (1985) report that rehabilitative group sessions centred on the training to use environmental facilitations, according to Reality Orientation Therapy, produced improvements in spatial-temporal orientation in a sample of patients with diffused cognitive impairments. Evans and Wilson (1992) described improvements in the use of active external aids (calendars, agendas, etc.) in four out of five amnesic patients who attended a cycle of rehabilitative group sessions. Given the generic description of rehabilitative methods, it is difficult to judge the validity of the results obtained by the two studies just cited.

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Instead, Sohlberg and Mateer’s (1989) report of their attempt to train a young patient with severe post-traumatic amnesia to use a memory book is more detailed. In this case, the initial phase of the training was centred on rehearsal exercises aimed at memorisation of the different sections of the memory book. In the successive phases, the patient was conditioned to use the instrument by means of simulation games and in real-life situations. With respect to observations made during the pre-therapy month, the patient showed completely autonomous use of the memory book after a six-month period of training and a clear improvement in social and work adaptation. Successful attempts to train severe amnesic patients in the use of memory notebooks by means of individual or group rehabilitative sessions have also been reported by Schmitter-Edgecombe et al. (1995), Squires et al. (1996), and Wilson et al. (1994). In all of these studies, the treatment was effective in improving subjects’ adaptation to specifically targeted real-life situations (e.g. remembering appointments, reducing repetitive questioning). However, in no case was improvement generalised to neuropsychological memory test performance.

Methods aimed at reinforcing residual learning abilities Since the end of the 1960s, theories about the functioning of memory have changed their focus of interest from a structural approach (to single out the systems involved in the various functional expressions of memory) to one centred on the modalities of information processing to learn (for a review, see Baddeley, 1990). The most noteworthy result of this approach has been the demonstration that the level of learning in a memory task is not of the “all or nothing” type, but that it varies greatly as a function of the quality of the coding processes during the acquisition of information and the relations existing between learning conditions and contextual conditions in the information recovery phase (Tulving, 1983). Proposals for rehabilitative interventions centred mostly on improving visual-imaginative or semantic coding of information have derived from these theoretical studies.

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Rehabilitative methods centred on visual imagination Since antiquity (Yates, 1966) it has been known that verbal information (lists of words, passages of a discourse) can be much better remembered if they are associated with visual-imaginative mental representations when they are acquired. These methods (termed mnémotechniques) were rediscovered around the 1960s and their effectiveness in improving processes of memorisation in normal subjects has been confirmed experimentally (Delin, 1968). A theoretical justification for the use of visual imagination to improve processes of memorisation was provided at the same time by cognitive psychology studies reporting better learning of lists of figures than lists of words (Paivio, 1971) and of concrete words than abstract words (Paivio, 1969). The most common interpretation of this phenomenon is that of multiple coding, that is, exposure to information can evoke different mental representations (verbal, visual, etc.) and recall is easier the more numerous the representations. From the rehabilitative point of view, spread of the use of mnémotechniques among normal subjects and experimental evidence that amnesic patients are able to improve their level of recall when induced to form visual images of words they must recall mentally (Jones, 1974) has stimulated experimentation of rehabilitative interventions to improve these patients’ retention ability through the visual-imaginative coding of material to be learned. In the first experimental study published on the topic, Patten (1972) reported anecdotally the case of four patients with left hemisphere lesions and primarily verbal memory deficits who improved their performances on tests of recalling lists of words after being trained to relate single words to “vivid and paradoxal” mental images (for example, to memorise the words “dog” and “newspaper”, the patient was induced to create a visual image of “a dog reading the newspaper”). No control condition and no generalisation of improvement shown with the rehabilitative procedure to other neuropsychological or behavioural parameters was reported in the study.

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Following this pioneering study, a series of other rehabilitative attempts centred on techniques of visual imagination were reported. Crovitz and others (1979) described improvement in learning lists of words in three patients who had been trained to use these words to create a short story with paradoxical characteristics and endowed with strong imaginativeness (“The Airplane List”). Analogous to the preceding study, no control condition was provided for, and improvement seemed strictly limited to the rehabilitative procedure, without any benefit for other neuropsychological or behavioural measures. In two studies (Glasgow et al., 1977; Wilson, 1982) a technique based on visual imagination was used to facilitate the learning of proper names of unknown faces. Positive results were reported for the rehabilitative procedure in the second study but not in the first and, also in this case, there was no control condition and no generalisations were made. Finally, positive results in the learning of prose passages through rehabilitative procedures centred on visual-imaginative coding (again without parallel improvement on other neuropsychological measures or adaptation to everyday life conditions) were reported by Malec and Questad (1983) and Crosson and Buenning (1984). Rehabilitative methods centred on verbal processing In 1972, Craik and Lockhart reported results of a study that showed unquestionably that the level of learning of lists of words is a function of the “semantic” quality of the processing of stimuli. In particular, it was shown that “deep” encoding of words (centred on their semantic meaning) produced levels of recall significantly greater compared with “superficial” encoding (centred on phonological or perceptual aspects). In the following years, a rather popular interpretation of the amnesic syndrome proposed that memory disorders actually derive from inadequate encoding of incoming material (Cermak et al., 1974). According to this theory, amnesic patients tend to encode stimuli on the basis of their phonological or perceptual characteristics and this explains both their poor performances on free recall tasks and improvement when they are provided with

phonological facilitations (for example, the first letters of words) at the time of recall (Warrington & Weiskrantz, 1970). Although this interpretation of the amnesic syndrome has never received definite confirmation, and various ad hoc studies have not been able to obtain performances in amnesic patients comparable to those of controls after inducing semantic encoding of stimuli (see Vallar, Chapter 15, for a detailed discussion of this line of research), various rehabilitative approaches to memory have aimed at potentiating processes of semantic encoding in amnesic patients. The first technique, proposed by Gianutsos and Gianutsos (1979), consisted of training patients to relate the words they had to remember in a brief story. Of the five studies that used this rehabilitative method with partial modifications, three found an improvement in learning of lists of words by amnesics (Gianutsos & Gianutsos, 1979; Kovner et al., 1983; Malec & Questad, 1983), and in two cases the rehabilitative procedure did not produce any appreciable results compared to a base condition (Gianutsos, 1981; Heinrichs, 1989). Further, in no case did the rehabilitative procedure produce clinically important behavioural changes. Glasgow et al. (1977) obtained positive results in rehabilitating a young and very scholarly patient to retain prose passages using a method (PQRST), which had already been used successfully with normal individuals (Robinson, 1970). With this technique, the subject is first asked to read the passage (Preview), then to ask him/herself questions about the passage (Question) and to look for the answers by rereading (Reread). These answers are consolidated using exercises involving looking over again and rereading (State) and self-examination (Test). At the end of the training period, the patient was able to use the technique autonomously to improve retention of newspaper articles and book passages. In spite of these encouraging results, no subsequent work has used this method with other amnesic patients. Instead, negative results were reported by Benedict and colleagues (1993) in a study in which a severely amnesic patient was trained to encode a list of words on the basis of semantic category. Results of the neuropsychological evaluation at the

38. THE REHABILITATION OF MEMORY 893

end of the training period did not show any improvement in tasks involving free recall of word lists compared to a pre-therapy control condition. Substantially negative results have also been reported by Berg and co-workers in a study comparing performance on neuropsychological memory tests of a group of amnesic patients trained to semantically encode incoming verbal material and a group of amnesics trained by means of generic cognitive exercises. The better memory performances obtained by the first group immediately following the end of rehabilitative training (Berg et al., 1991) were not confirmed at a follow-up evaluation performed four years later (Milders et al., 1995) when levels of memory performances exhibited by the two amnesic groups were indistinguishable. Finally, Schacter and colleagues’ (1985) study must be cited, in which improvement in learning word lists was found in four amnesic patients trained to use the spaced retrieval method. This method is based on the phenomenon, extensively investigated in cognitive psychology (Landauer and Bjork, 1978), in which recall of information following its initial presentation improves subsequent retrieval more effectively than other presentations of the information. In spite of the good results obtained by the four patients when the “spaced retrieval” method was induced by the therapist, only two of the four were able to continue to use this method autonomously and none showed improvement in mnesic effectiveness in everyday life conditions. To summarise, the studies that have attempted to re-educate amnesic patients by reinforcing their ability to process the memorandum have produced mostly unsatisfactory results. Some of these studies, which are completely lacking in control conditions, furnish anecdotal type data that are of little help in evaluating the effectiveness and applicability of the techniques studied (for example, Crovitz et al., 1979; Patten, 1972). On the other side, studies with control situations also mostly report improvements limited to the execution of the specific rehabilitative procedure, such as learning word lists (for example, Gianutsos & Gianutsos, 1979) or prose passages (for example, Malec & Questad, 1983). In many cases, from the data available it is not clear whether

patients have acquired the ability to autonomously use the processing strategy and, in any case, with sporadic exceptions (Glasgow et al., 1977) the rehabilitative practice does not seem to consistently improve the deficit in everyday life autonomy. In conclusion, these rehabilitative techniques have two major limits. The first is that they are aimed in many cases at re-educating the ability to carry out memory tasks (for example, learning word lists) which have very low application in the ecological situations involving memory every day. The result is that the possible improvement in carrying out the rehabilitative procedure seems essentially sterile compared with the disability shown by the patient in the natural environment. The second limit of these rehabilitative techniques is that learning strategies of processing that facilitate the acquisition of new information often encounters an insurmountable obstacle in these patients’ memory deficit. Often they do not remember the strategies they are supposed to use for remembering. One has the definite impression that these rehabilitative procedures may be useful in patients with milder forms of amnesia and with good preservation of the remaining cognitive abilities but that they are difficult, if not impossible, to apply in severely amnesic patients or in memorydisordered patients with deficits involving other cognitive domains such as selective or sustained attention, logical-conceptual reasoning, and imaginative abilities.

Rehabilitative methods based on teaching specific domains of knowledge Due to the practical impossibility of improving the active processes of acquisition and retrieval of new information in most amnesic patients, Glisky and colleagues (1994) proposed that a more limited (and more realistic) objective of the rehabilitative approach is to teach patients specific information and/or procedures useful for improving their social or work adaptation. Two methodological aspects characterise the long series of studies carried out by Glisky and co-workers to verify the applicability of this rehabilitative hypothesis: the first is that, with very few exceptions, lexical information and rehabilitative procedures have involved the use of the personal computer; the second is the method

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used for teaching the individual information units, known as the vanishing cues technique. In practice, in teaching the individual commands necessary for use of the computer, first the entire command (SAVE) is provided upon completion of the specific definition (If you want the computer to store data, press...). In successive learning attempts, the number of letters is progressively reduced (SAV_, SA__, S___ ) and the patient is encouraged to complete the lexical fragment until, in the final phase of training, the patient is able to produce a correct response without any orthographic facilitation. The rationale for this technique derives from a great deal of experimental literature reporting that amnesic patients often perform similarly to healthy control subjects when they are facilitated by the availability of phonological fragments in the word retrieval task (Warrington & Weiskrantz, 1970). This facilitation is particularly effective when the completion of the fragment is tested implicitly, that is, without the patient being aware that he/she is carrying out a memory task (procedures of Repetition priming; Carlesimo, 1994; Graf et al., 1984; Vallar, Chapter 15 of this volume). In the first two studies (Glisky et al., 1986a, b) using the vanishing cues technique, patients with amnesic syndromes of varying severity learned a small vocabulary of computer terms, which enabled them to carry out simple programs in “basic”. Although learning occurred much more slowly in amnesic patients than in healthy control subjects, all patients were able to use the commands learned appropriately at the end of the training phase, and this learning still held in a test carried out from one to three months later. The positive results of this study were confirmed and extended in a successive study (Glisky & Schacter, 1988a) in which the procedure was able to train eight amnesic patients of variable etiology (head injury, herpes encephalitis, hypoxia, cerebral haemorrhage) and severity of memory impairment (Wechsler’s Memory Quotient variable between 61.5 and 89) in the computer programming language, with good retention of procedures learned even 7-9 months later. Strengthened by the experience acquired in these first studies, Glisky and Schacter concentrated their

attention on a single patient (H.D.) afflicted by a severe amnesic syndrome resulting from herpes encephalitis. H.D.’s employer had expressly requested that he learn specific procedures on the computer in order to facilitate work reintegration. In three successive studies, Glisky and Schacter (1987, 1989) were able to train the patient in progressively more complex procedures of dataentry by first simulating application in the laboratory, then following the first phases of work reinstatement. At the end of the training phase, H.D. had reached a speed of execution of the taught procedures comparable to that of normal subjects. Also in this case, the training procedure was primarily centred on the vanishing cues technique, integrated depending on need by reinforcements based on repeated presentation of the material to be learned. In a final work (Glisky, 1992), the same procedure of data-entry used in the first study with H.D. was taught with success to 10 amnesic patients with varying severity and etiology, and with variable preservation of other cognitive functions (IQ between 77 and 130). The encouraging outcome of these studies raises important questions regarding the quality of the processes of memorisation activated by the vanishing cues technique. It has been known for some time that even in the most severe amnesic patients some forms of learning are maintained (see Vallar, Chapter 15). For example, these patients are able to learn motor procedures (e.g. the Pursuit Motor Tracking Task; Corkin, 1968) or cognitive procedures (e.g. Mirror Reading; Cohen & Squire, 1980) at the same speed and with the same accuracy as normal subjects. Further, when learning of lexical or perceptual information is evaluated implicitly by means of repetition priming procedures such as Stem Completion (Graf et al., 1984), Perceptual Identification (Carlesimo, 1994), or Free Association (Shimamura & Squire, 1984), amnesic patients show normal levels of retention of the material studied. These experimental data have given rise to a series of interpretative hypotheses of the amnesic disorder centred on the distinction between an explicit or declarative memory, which is impaired in these patients, and an implicit or nondeclarative memory, which functions normally (Squire, 1992; Vallar, Chapter 15).

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In effect, the type of learning obtained with the vanishing cues technique has characteristics in part, but not completely, comparable to those observed in repetition priming experiments. In fact, learning the single lexical units that form programming language takes place thanks to the availability of orthographic fragments, a common situation in many repetition priming procedures (Graf et al., 1984; Schacter & Graf, 1986; Warrington & Weiskrantz, 1970). Further, analogously to what happens for priming (Kirsner et al., 1983; Schacter & Graf, 1989), Glisky and Schacter (1986a, b, 1988a) have repeatedly shown how learning produced by the vanishing cues technique has characteristics of hyperspecificity, in the sense that it becomes evident above all when the contextual conditions present during the learning phase are recreated in the test phase (even small variations in the definition of the command brought about a significant decrease in accuracy in amnesic patients’ responses). Finally, as a confirmation that the learning of computer terms and procedures by means of the vanishing cues technique is at least partially dissociated from processes of explicit memory, Glisky and Schacter cite the case of patients who, although progressively improving their performances on the rehabilitative procedure, do not show any memory of the many rehabilitative sessions to which they have been subjected. In spite of the fact that these results suggest a parallelism between processes of memory underlying the repetition priming and the type of learning resulting from use of the vanishing cues technique, other data are incompatible with the hypothesis of a purely implicit genesis of this learning. First of all, unlike what is generally reported in the literature about the complete normality of procedural learning in amnesic patients, lexical information and procedures of the rehabilitative intervention are learned much more slowly by amnesic patients compared to normal subjects. Further, at the end of the training phase, patients are able to recall the command or the specific procedure without any orthographic facilitation. Finally, in clear contrast to the phenomenon of repetition priming, which declines in minutes or hours (Squire et al., 1987), amnesic patients

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rehabilitated with the vanishing cues technique are able to recall single commands even months after the end of the training phase (Glisky & Schacter, 1988a). In conclusion, the results of this research suggest that learning evoked by the vanishing cues technique is based on an interaction between processes of declarative and procedural memory. However, the way in which the two types of memory and the intrinsic characteristics of this rehabilitative method interact toward rendering severely amnesic patients able to intentionally recall a complex set of information, even after a long time, must still be clarified In conclusion, the results of these studies document the possibility of teaching amnesic patients a system (even a complex one) of information and procedures able to considerably improve functional adaptation (above all in the work area), even though the functional bases of the learning processes have not yet been clarified. The most obvious limits of this type of approach are the hyperspecificity of the learning, so that information is stored in a rather rigid way, making recall in a changed context difficult, and the fact that attempts up until now regard a rather narrow area of application, essentially linked to the use of the personal computer. Finally, it should be emphasised that positive results in the use of this technique all come from the same laboratory. Recently, Hunkin and Parkin (1996) failed in an attempt to replicate the positive results obtained by Glisky and Schacter (1986a) in their very first study using the vanishing cues technique to teach computer language on a different group of amnesic patients. A different approach to effectively teaching new domain-specific knowledge to severe amnesic patients has been proposed by Wilson and coworkers and is mainly based on preventing patients from making mistakes during the learning process. In a first study, Baddeley and Wilson (1994) compared word list learning by a group of amnesic patients in a condition in which patients were required to guess the words by the first two letters (ierrorful condition) and a condition in which guessing was prevented by the examiner who provided the right word after presenting the first two letters (errorless condition). Results demonstrated significantly greater learning in the

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errorless than in the errorful condition by the group of amnesic patients. The application of the errorless principle as a rehabilitative technique for memory disordered patients has subsequently been experimented both on single-cases (Squires et al., 1996; Wilson et al., 1994) and group studies (Wilson & Evans, 1996), demonstrating its effectiveness in a number of different conditions, ranging from training in the use of a notebook to the learning of word pairs or face-name pairs. According to Wilson and Evans (1996), the errorless condition should be particularly fruitful in amnesics in that the implicit memory processes, which are the only way these patients acquire and retain new information, are particularly sensitive to the proactive interference possibly arising from the trial-and-error way of learning. It should be noted, however, that also in this case attempts to replicate or extend the use of this technique to other domains of knowledge have not been consistently effective. In fact, in the same group study in which amnesics took advantage of the errorless technique to learn face-name pairs, the errorless condition was no more effective than the errorful condition in teaching these patients a diagrammatic route (Wilson & Evans, 1996).

CONCLUSIONS In recent years, requests for rehabilitation of memory disorders have increased together with the increase in the number of patients with cognitive deficits resulting from severe head injury. Other pathologies, which contribute less to this rehabilitative intervention request, are the alcoholic Korsakoff’s syndromes and sporadic cases of cerebral ischemia, brain hypoxia, herpes simplex encephalitis, and surgical resection of the temporalmesial regions. The first attempts to scientifically validate rehabilitative approaches for memory disorders go back more than 20 years. Initially, these attempts were centred primarily on the improvement of visuo-imaginative coding of information. Over time, the types of intervention have been modified, on one side pushed by the low success of the

methods tried and, on the other, by the increase in knowledge about the normal functioning of memory and the cognitive characteristics of the amnesic syndrome. In general, affirmations about the presumed effectiveness of one or the other rehabilitative approach have not received sufficient experimental validation. Training in the use of memory books, for example, is without a doubt the most frequently used intervention in rehabilitation centres for alleviating disabilities following memory deficit. However, only few experimental studies, mostly centred on the rehabilitation of a single patient, have been published up until now regarding the effectiveness of this method. Contrasting results regarding the effectiveness of methods for improving visuo-imaginative or semantic processing of stimuli are probably due to the scarce methodological trustworthiness of many of the studies published, besides the heterogeneity of the patients treated. The lack of an adequate control condition to compare to the experimental treatment condition is, from this point of view, the most outstanding limit of many of these studies. Finally, the encouraging results obtained by Glisky and Schacter using the vanishing cues technique and by Wilson and co-workers using the errorless technique in teaching domain-specific knowledge to severely amnesic patients await replication by other research groups and possible extension to the teaching of further domains of knowledge. In this regard, the results of several recent experimental works must be noted; they have documented that severely amnesic patients are able to learn (even though slowly and after a very high number of exposures to the information) and retain new semantic-type information for long periods of time (Hayman et al., 1993; Tulving et al., 1991; Verfaellie & Cermak, 1994). In conclusion, research on the most effective rehabilitative methods to remedy memory disorders is rapidly expanding. The results of recent years, even though essentially disappointing with respect to initial expectations, have contributed toward outlining on one side the limits of the results obtainable and on the other the methods of intervention with the widest applicative potential and therefore worthy of further theoretical and experimental study. Attention to the concrete

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needs of patients and the use of adequate experimental designs that give validity to the results obtained are necessary so that in the next few years

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rehabilitative programmes for memory can be developed according to criteria of effectiveness and rationality.

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References A.P.A. (1994).

Ackerman, P.T., Dykman, R.A., & Oglesby, D.M. (1994). Visual event-related-potentials of dyslexic children to rhyming and nonrhyming stimuli. J o u r n a l o f C lin ic a l a n d E x p e r im e n ta l N e u r o p s y c h o lo g y , 16, 138-154. Ackermann, H. (1985). M e h r d im e n s io n a le n ic h t-

D ia g n o s tic a n d S ta tis tic a l M a n u a l o f

(IV Edition). Washington DC: American Psychiatric Association. Aaltonen, O., Tuomainen, J., Laine, M., & Niemi, P. (1993). Cortical differences in tonal versus vowel processing as revealed by an ERP component called mismatch negativity (MMN). B r a in a n d L a n g u a g e , 4 4 , 139-152. Abbruzzese, M., Bellodi, L., Ferri, S., & Scarone, S. (1995). Frontal lobe dysfunction in schizophrenia and obsessive-compulsive disorder: A neuropsychological study. B r a in a n d C o g n itio n , 2 7 , 202-212. Aboitiz, F., Scheibel, A.B., & Zaidel, E. (1992a). Morphometry of the sylvian fissure and the corpus callosum, with emphasis on sex differences. B r a in , 1 1 5 , 1521-1541. Aboitiz, F., Scheibel, A.B., Fisher, R.S., & Zaidel, E. (1992b). Fiber composition of human corpus callosum. B r a in R e s e a r c h , 5 9 8 , 143-153. Abramson, R., & Katz, D.A. (1989). A case of developmental right hemisphere dysfunction: Implications for psychiatric diagnosis and management. J o u r n a l o f C lin ic a l P s y c h i a t r y , 5 0 , 70-71. Absher, J.R., & Cummings, J.L. (1993). Noncognitive behavioural alterations in dementia syndromes. In F. Boiler & J. Grafman (Eds.), H a n d b o o k o f N e u r o p s y c h o lo g y , vol. 8 (pp.315-338). Amsterdam: Elsevier Science Publisher B V. Ackerly, S.S. (1964). A case of paranatal frontal lobe defect observed for thirty years. In J.M. Warren & K. Akert (Ed.), T h e f r o n t a l g r a n u la r c o r te x a n d b e h a v io r (pp. 192-218). New York: McGraw-Hill. M e n ta l D is o r d e r

p a r a m e tr i s c h e N o r m b e r e ic h e . M e t o d o lo g is c h e u n d m e d iz in is c h e A s p e k te . Berlin: Springer Verlag. Acredolo, L.P. (1976). Frames of reference used by children in unfamiliar spaces. In G. Moore & R. Gooledge (Eds.), E n v ir o n m e n ta l k n o w in g : th e o r ie s , re se a r c h , a n d m e th o d s (pp. 165-172). Stoudsberg, PA: Dowden, Hutchinson, & Ross. Adams, E.W., Fagot, R.F., & Robinson, R.E. (1965). A theory of appropriate statistics. P s y c h o m e tr ik a , 3 0 , 99-127. Adams, R.D., Fisher, C.M., Hakim, S., Ojemann, R.G., & Sweet, W.H. (1965). Symptomatic occult hydrocephalus with “normal” cerebrospinal fluid pressure. A treatable syndrome. N e w E n g la n d J o u r n a l o f M e d ic in e , 2 7 3 , 117-126. Adams, R.D., & Victor, M. (1994). Syndromes due to focal cerebral lesions. In K.J. Isselbacher, E. Braunwald, J.D. Wilson, J.B. Martin, A.J. Fauci, & D.L. Kasper (Eds.), H a r r is o n ’s p r i n c i p l e s o f in te r n a l m e d ic in e , ed. 13 (pp. 153-156). New York: McGrawHill. Adler, A. (1944). Disintegration and restoration of optic recognition in visual agnosia. Analysis of a case. A r c h iv e s o f N e u r o lo g y a n d P s y c h ia tr y , 4 1 , 243-259. Adler, A. (1950). Course and outcome of visual agnosia. J o u r n a l o f N e r v o u s a n d M e n ta l D is e a s e s , 111, 41-51. Adler-Grinberg, D., & Stark, L. (1978). Eye movements, scan-paths and dyslexia. A m e r ic a n J o u r n a l o f O p to m e tr y & P h y s i o l o g i c a l O p tic s , 5 5 , 557-570. 899

90 0

H A N D B O O K O F CLIN IC AL A N D EXPER IM EN TA L P S Y C H O L O G Y

Adolph, R., Tranel, D., Damasio, H., & Damasio, A.R. (1994) . Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. N a tu r e , 3 7 2 , 669-672. Adolph, R., Tranel, D., Damasio, H., & Damasio, A.R. (1995) . Fear and the human amygdala. J o u r n a l o f N e u r o s c ie n c e , 75,5879-5891. Adrian, E.D., & Matthews, B.H.C. (1934). Berger rhythm: Potential changes from occipital lobes, J o u r n a l o f P h y s io lo g y , 5 7 , 355-385. Aggleton, J.P., & Sahgal, A. (1993). The contribution of the anterior thalamic nuclei to anterograde amnesia. N e u r o p s y c h o lo g ia , 3 1 , 1001-1019. Aglioti, S., Berlucchi, G., Pallini, R., Rossi, G.F., & Tassinari, G. (1993). Hemispheric control of unilateral and bilateral responses to lateralized light stimuli after callosotomy and in callosal agenesis. E x p e r im e n ta l B r a in R e s e a r c h , 9 5 , 151-165. Aglioti, S., Berlucchi, G., & Tassinari, G. (1996). Spatial stimulus-response compatibility in callosotomy patients and subjects with callosal agenesis. N e u r o s c ie n c e a n d B io h e h a v io u r a l r e v ie w s , 2 0 ( 4 ) , 623-629. Aglioti, S., Bonazzi, A., & Cortese, F. (1994b). Phantom lower limb as a perceptual marker of neural plasticity in the mature human brain. P r o c . R . S o c . L o n d . B ., 2 5 5 , 273-278. Aglioti, S., Cortese, F., & Franchini, C. (1994b). Rapid sensory remapping in the adult human brain as inferred from phantom breast perception. N e u r o r e p o r t, 5 , 473-476. Aglioti, S., Dall’Agnola, R., Girelli, M., & Marzi, C.A. (1991). Bilateral hemispheric control of foot distal movements: Evidence from normal subjects. C o r te x , 2 7 , 571-581. Aglioti, S., DeSouza, J.F.X., & Goodale, M.A. (1995). Size-contrast illusions deceive the eye but not the hand. C u r r e n t B io lo g y , 5 ( 6 ) , 679-685. Aglioti, S., & Fabbro, F. (1993). Paradoxical selective recovery in a bilingual aphasic following subcortical lesions. N e u r o r e p o r t, 4 , 1359-1362. Aglioti, S., Smania, N., Manfredi, M., & Berlucchi, G. (1996) . Disownership of left hand and objects related to it in a right-brain-damaged patient. N e u r o r e p o r t, 8 , 293-296. Agnetti, V., Carreras, M., Pinna, L., & Rosati, G. (1978). Ictal prosopagnosia and epileptogenic damage of the dominant hemisphere. A case history. C o r te x , 1 4 , 50-57. Ahem, G.L., & Schwartz, G.E. (1979). Differential lateralization for positive versus negative emotion. N e u r o p s y c h o lo g ia , 17 , 693-698.

A hlfors, S.P., U m oniem i, R .J., H àm alainen, C.N. (1992). E stim ates o f v isually evoked co rtical currents. E l e c tr o e n c e p h a l o g r a p h y

and

C lin ic a l

N eu ro-

p h y s i o l o g y , 8 2 , 2 2 5 -2 3 6 .

A im ard, G., B oisson, D., Trouillas, R, & D evic, M . (1979) E ncéphalites et encéphalopathies aigues am nésiantes. R em arques à propos de 16 o b servations. R e v u e N e u r o lo g iq u e , 1 3 5 , 6 7 9 -6 9 2 . A itkin, M ., A nderson, D., Francis, B., & H inde, J. (1989). S t a t i s t i c a l m o d e llin g in G L IM . O xford: O xford S cience P ublications. A jax, E.T. (1964). A cq u ired d yslexia: A co m p arativ e study o f tw o cases. A r c h iv e s o f N e u r o lo g y , 2 . A ju riag u erra, J. de, & H écaen, H. (1959). L e C o r te x C é r é b r a l. Paris: M asson. A ju riag u erra, J. de, H écaen, H ., & A n g elergues, R. (1960). L es apraxies, v ariétés clin iq u es et la té ra lisation lésionelle. R e v u e N e u r o lo g iq u e , 1 0 2 , 5 6 6 -5 9 4 . A juriaguerra, J., M uller, M ., & T issot, R. (1960). A p ropos de quelques p roblèm es posés par l ’apraxie dans les dém ences. E n c é p h a le , 4 9 , 275—401. A juriaguerra, J., & Tissot, R. (1969). T he apraxias. In P.J. V inken, & G.W. B ruyn (Eds.), H a n d b o o k o f C lin ic a l N e u r o lo g y , v o l 4 (p p .4 8 -6 6 ). A m sterdam : N orth H olland. A juriaguerra, J. de, & T issot, R. (1975). Som e aspects o f language in various form s of senile dem entia. In: E.H. L en n eb erg & E. L enneberg (E ds.), F o u n d a tio n s o f L a n g u a g e D e v e lo p m e n t, vol. 1 (p p .3 2 3 -3 3 9 ). N ew York: A cadem ic Press. A kelaitis, A .J. (1941a). P sy ch o b io lo g ical studies follow ing section o f the corpus callosum . A prelim inary report. A m e r ic a n J o u r n a l o f P s y c h i a t r y , 9 7 , 1147-1158. A kelaitis, A .J. (1941b). Studies on the corpus callosum . II. T he higher visual functions in each hom onym ous field fo llo w in g co m p lete section o f the corpus callosum . A r c h iv e s o f N e u r o lo g y a n d P s y c h ia tr y , 4 5 , 7 8 8 -7 9 6 . A kelaitis, A .J. (1942a). Studies on the corpus callosum . V. H om onym ous defects for color, o bject and letter re c o g n itio n (h o m onym ous h e m iam b ly o p ia) b efo re and after section o f the corpus callosum . A r c h iv e s o f N e u r o lo g y a n d P s y c h ia tr y , 4 8 , 108-118. A kelaitis, A .J. (1942b). S tudies on the corpus callosum . VI. O rientation (tem poral, spatial-gnosis) follow ing section o f the corpus callosum . A r c h iv e s o f N e u r o lo g y a n d P s y c h ia tr y , 4 8 , 9 1 4 -9 3 7 . A kelaitis, A .J. (1943). Studies on the corpus callosum . V II. Study o f language functions (tactile and visual lex ia and graphia) u n ilaterally fo llo w in g section o f the corpus callosum . J o u r n a l o f N e u r o p a th o lo g y a n d E x p e r im e n ta l N e u r o lo g y , 2 , 2 2 6 -2 6 2 .

REFERENCES

Akelaitis, A.J. (1944). A study of gnosis, praxis and language following section of the corpus callosum and anterior commissure. J o u r n a l o f N e u r o s u r g e r y , 1 , 94-102. Akelaitis, A.J. (1944-45). Studies on the corpus callosum. IV. Diagonistic dyspraxia in epileptics following partial and complete section of the corpus callosum. A m e r ic a n J o u r n a l o f P s y c h ia tr y , 1 0 1 , 594-599. Akelaitis, A.J., Riesteen, W.A., Herren, R.Y., & Van Wagenen, W.R (1942). Studies on the corpus callosum. III. A contribution to the study of dyspraxia and apraxia following partial and complete section of the corpus callosum. A r c h iv e s o f N e u r o lo g y a n d P s y c h ia tr y , 4 7 , 971-1007. Akert, K. (1964). Comparative anatomy of frontal cortex and thalamo-frontal connections. In J.M. Warren & K. Akert. (Eds.), T h e f r o n t a l g r a n u l a r c o r t e x a n d b e h a v i o r (pp.372-396). New York: McGraw-Hill. Alajouanine, T. (1948). Aphasia and artistic realization. B r a in , 77,229-241. Alajouanine, T. (1956). Verbal realization in aphasia. B r a in , 1-28. Alajouanine, T., Castaigne, R, Lhermitte, E, Escourolle, R., & Ribaucourt, B. (1957). Etude de 43 cas d’aphasie post-traumatique. E n c é p h a le , 4 6 , 1^-5. Alajouanine, T., & Lhermitte, F. (1965). Acquired aphasia in children. B r a in , 8 8 , 653-662. Alajouanine, T., Lhermitte, F., Ledoux, M., Renaud, D., & Vignolo, L.A. (1964). Les composants phonémiques et sémantiques de la jargon aphasie. R e v u e N e u r o lo g iq u e , 110, 5-20. Alajouanine, T., Ombrédane, A., & Durand, M. (1939). L e sy n d r o m e d e d é s in té g r a tio n p h o n é tiq u e d a n s V a p h a s ie . Paris: Masson. Alajouanine, T., Sabouraud, O., & de Ribaucourt, B. (1952). Le jargon des aphasiques. Désintégration anosognosique des valeurs sémantiques du langage, I: Analyse des aspects principaux. J o u r n a l d e P s y c h o lo g ie , 4 5 , 168-180. Alajouanine, T., & Thurel, R. (1933). La diplegie faciale cerebrale. Forme corticale de la paralysie pseudobulbaire. (Contribution à l’etude de la dissociation des activités volontaire et réflexe). R e v u e N e u r o lo g iq u e , 4 0 , 441-458. Alberoni, M., Baddeley, A., Della Sala, S., Logie, R.H., & Spinnler, H. (1992). Keeping track of a conversation: Impairments in Alzheimer’s Disease. I n t e r n a tio n a l J o u r n a l o f G e r i a t r i c P s y c h i a t r y , 7, 639-646.

901

Alberoni, M., Della Sala, S., Pasetti, C., & Spinnler, H. (1988). Problem solving ability of Parkinsonian patients. I ta lia n J o u r n a l o f N e u r o lo g ic a l S c ie n c e s , 9 , 35-40. Albert, M.L. (1973). A simple test of visual neglect. N e u r o lo g y , 2 3 , 658-664. Albert, M.L. (1976). Short-term memory and aphasia. B r a in a n d L a n g u a g e , 3 , 28-33. Albert, M.L., & Bear, D. (1974). Time to understand: A case study of word deafness with reference to the role of time in auditory comprehension. B r a in , 9 7 , 373-381. Albert, M., Butters, N., & Brandt, J. (1981). Patterns of remote memory in amnesic and demented patients. A r c h iv e s o f N e u r o lo g y , 3 8 , 495-500. Albert, M.S., Butters, N., & Levin, J. (1979). Temporal gradients in the retrograde amnesia of patients with alcoholic Korsakoff’s diseas A r c h iv e s o f N e u r o lo g y , 3 6 , 211-216. Albert, M., Feldman, R., & Willis, A. (1974). The ‘subcortical dementia’ of progressive supranuclear palsy. J o u r n a l o f N e u r o lo g y , N e u r o s u r g e r y a n d P s y c h ia tr y , 3 7 , 121-130. Albert, M.L., Goodglass, H., Helm, N.A., Rubens, A.B., & Alexander, M.P. (1981). C li n i c a l A s p e c t s o f D y s p h a s i a . Wien: Springer-Verlag. Albert, M.L., & Milberg, W. (1989). Semantic processing in patients with Alzheimer’s disease. B r a in a n d L a n g u a g e , 3 7 , 163-171. Albert, M.L., Reches, A., & Silverberg, R. (1975). Hemianopic colour blindness. J o u r n a l o f N e u r o lo g y , N e u r o s u r g e r y a n d P s y c h ia tr y , 3 8 , 546-549. Albert, M.L., Soffer, D., Silverberg, R., & Reches, A. (1979). The anatomical basis of visual agnosia. N e u r o lo g y , 2 9 , 876-879. Albert, M.L., Yamadori, A., Gardner, H., & Howes, D. (1973). Comprehension in alexia. B r a in , 9 6 , 317-328. Aldrich, M.S., Alessi, A.G., Beck, R.W., & Gilman, S. (1987). Cortical blindness: Etiology, diagnosis and prognosis. A n n a ls o f N e u r o lo g y , 2 1 , 149-158. Alemà, G., & Donini, G. (1960). Sulle modificazioni cliniche ed elettroencefalografiche da intro-duzione intracarotidea di iso-amil-etil-barbituratodi sodio nell’uomo. B o lle ttin o d e l l a S o c ie tà I ta lia n a d i B io lo g ia S p e r im e n ta le , 3 6 , 900-904. Alexander, D., & Money, J. (1966). Turner’s syndrome and Gerstmann’s syndrome: Neurological comparisons. N e u r o p s y c h o lo g ia , 4, 981-984. Alexander, G.E., Crutcher, M.D., & DeLong, M.R. (1990). Basal ganglia-thalamocortical circuits: Parallel substrates for motor, oculomotor, "prefrontal" and "limbic" functions. In H.B.M. Uylings, C.G. Van Eden, J.P.G. De Bruin, M.A.

902

H A N D B O O K O F C LIN IC AL A N D EXPER IM EN TA L P S Y C H O L O G Y

Corner, & M.G.P. Feenstra (Eds.), c o r te x :

its

s tr u c tu r e ,

f u n c tio n ,

T h e p r e f r o n ta l and

p a th o lo g y

(pp. 119-146). Amsterdam: Elsevier. Alexander, M.P. (1989). Clinical-anatomical correlations of aphasia following predominantly subcortical lesions. In F. Boiler & J. Grafman (Ed.), H a n d b o o k o f N e u r o p s y c h o lo g y , vol. 2. Amsterdam: Elsevier. Alexander, M.P., Baker, E., Naeser, M.A., Kaplan, E., & Palumbo, C. (1992). Neuropsychological and neuroanatomical dimensions of ideomotor apraxia. B r a in , 1 1 5 , 87-107. Alexander, M.P, Fischette, M.R., & Fischer, R.S. (1989). Crossed aphasia can be mirror image or anomalous: Care reports, review and hypothesis. B r a in , 1 1 2 , 953-973. Alexander, M.P, Fisher, R.S., & Friedman, R.B. (1992). Lesion localization in apractic agraphia. A r c h iv e s o f N e u r o lo g y , 4 9 , 246-251. Alexander, M.P, & Freedman, M. (1984). Amnesia after anterior communicating artery aneurysm rupture. N e u r o lo g y , 3 4 , 752-757. Alexander, M.P, Friedman, R.B., Loverso, F., & Fischer, R.S. (1992). Lesion localization in phonological agraphia. B r a in a n d L a n g u a g e , 4 1 , 83-95. Alexander, M.P, Hiltbrunner, B., & Fischer, R.S. (1989). Distributed anatomy of transcortical sensory aphasia. A r c h iv e s o f N e u r o lo g y , 4 6 , 885-892. Alexander, M .P, & Loverme, S.R. (1980). Aphasia after left hemispheric intracerebral hemorrhage. N e u r o lo g y , 30,1193-1202. Alexander, M.P, Naeser, M.A., & Palumbo, C.L. (1987). Correlations of subcortical CT lesion sites and aphasia profiles. B r a in , 1 1 0 , 961-991. Alexander, M.P., Naeser, M. A., & Palumbo, C.L. (1990). Broca’s area aphasias: Aphasia after lesions including the frontal operculum. N e u r o lo g y , 4 0 , 353-362. Alexander, M.P, & Schmitt, M.A. (1980). The aphasia syndrome of stroke in the left anterior cerebral artery. A r c h iv e s o f N e u r o lo g y , 3 7 , 97-100. Alexander, M.P., Stuss, D.T., & Benson, D.F. (1979). Capgras syndrome: A reduplicative phenomenon. N e u r o lo g y , 2 9 , 334-339. Alho, K., Woods, D.L., Algazi A., Knight, Naatanen R. (1994). Lesion of frontal cortex diminish the auditory mismatch negativity. E l e c tr o e n p h a l o g r a p h y a n d C lin ic a l N e u r o p h y s io lo g y , 9 1 , 353-362. Alivisatos, B. (1992). The role of the frontal cortex in the use of advance information in a mental rotation paradigm. N e u r o p s y c h o lo g ia , 3 0 , 145-159. Alivisatos, B., & Milner, B. (1989). Effects of frontal or temporal lobectomy on the use of advance information in a choice reaction time task. N e u r o p s y c h o lo g ia , 2 7 , 495-503.

Alivisatos, B., & Petrides, M. (1997). Functional activation of the human brain during mental rotation. N e u r o p s y c h o lo g ia , 3 5 ,

111-118.

Allamano, N., Della Sala, S., Laiacona, M., Pasetti, C., & Spinnler, H. (1987). Problem-solving ability in aging: Normative data on a non-verbal test. I t a l J. N e u r o l. S c i .,8 , 111-119. Allen, L.S., Richey, M.F., Chai, Y.M., & Gorski, R.A. (1991). Sex differences in the corpus callosum in the living human brain. T h e J o u r n a l o f N e u r o s c ie n c e , 1 1 (4 ), 933-942. Allison, T., Ginter, H., McCarthy G., Nobre, A.C., Puce, A., Luby, M., Spencer, D.D. (1994). Face recognition in human extrastriate cortex. J o u r n a l o f N e u r o p h y s io lo g y , 71, 821-825. Allison, T., Hume, A.L., Wood, C.C., Goff, W.R. (1984). Developmental and aging changes in somatosensory, auditory and visual evoked potentials. E l e c tr o e n c e p h a l o g r a p h y a n d C lin ic a l N e u r o p h y s i o l o g y , 58, 14-24. Allport, A.D. (1983). Language and cognition. In R. Harris (Ed.), A p p r o a c h e s to L a n g u a g e , Oxford: Pergamon. Allport, A. (1992). Attention and control: Have we been asking the wrong questions? A critical review of twenty-five years. In D.E. Meyer & S. Kornblum (Eds.), A tte n tio n a n d p e r f o r m a n c e XIV, s y n e r g ie s in e x p e r im e n ta l p s y c h o lo g y , a r tif ic ia l in te llig e n c e , a n d c o g n i t i v e n e u r o s c ie n c e (pp. 183-218). Cambridge, MA: The MIT Press. Allport, A.D. (1985). Distributed memory, modular system and dysphasia. In S.K. Newman & R. Epstein (Eds.), C u r r e n t p e r s p e c t i v e in d y s p h a s ia (pp.32-60). Edinburgh: Churchill Livingstone. Allport, A.D., & Funnel, E. (1981). Components of the mental lexicon. P h i l o s o p h ic a l T r a n s a c tio n o f th e R o y a l S o c ie ty o f L o n d o n , B 2 9 5 , 397-410. Allport, D.A. (1979). Word recognition in reading. In P.A. Kolers, M.E. Wrolstad, & H. Bouma (Eds.), P r o c e s s i n g o f v i s ib l e la n g u a g e , vol. 1. New York: Plenum Press. Allport, D.A. (1984a). Auditory-verbal short-term memory and conduction aphasia. In H. Bouma & D.G. Bouwhuis (Eds.), A tte n tio n a n d p e r f o r m a n c e X . C o n tr o l o f la n g u a g e p r o c e s s e s (pp.313-325). Hove, UK: Lawrence Erlbaum. Allport, D.A. (1984b). Speech production and comprehension: One lexicon or two? In W. Prinz & A.F. Sanders (Eds.), C o g n itio n a n d m o t o r p r o c e s s e s (pp.208-228). Berlin: Springer-Verlag. Alpers, B.J. (1936). The mental syndrome of tumors of the corpus callosum. A r c h iv e s o f N e u r o lo g y a n d P s y c h ia tr y , 3 5 ,

911-912.

REFERENCES

Alpers, B.J. (1937). Relation of the hypothalamus to disorders of personality: Report of a case. A r c h iv e s o f N e u r o lo g y a n d P s y c h ia tr y , 3 8 , 219. Alpers, B.J., & Grant, F.C. (1931). The clinical syndrome of the corpus callosum. A r c h i v e s o f N e u r o lo g y a n d P s y c h ia tr y , 2 5 , 67-86. Altman, J.A. Balonov, L.J., & Deglin, V.L. (1979). Effects of unilateral disorder of the brain hemisphere function in man on directional hearing. N e u r o p s y c h o lo g ia , 17, 295-301. Alvarez, R, & Squire, L.R. (1994). Memory consolidation and the medial temporal lobe: A simple network model. P r o c e e d i n g s o f th e N a t i o n a l A c a d e m y o f S c ie n c e s , U S A , 9 1 , 7041-7045. Alvord, M.L. (1971). The pathology of parkinsonism: Part II. An interpretation with special reference to other changes in the aging brain. R e c e n t A d v a n c e s in P a r k in s o n 's d is e a s e . Philadelphia: Davis. Alzheimer, A. ( 1911 ). Ueber eigenartige Krankheitsfaelle des spaetern Alters. Z b la t t g e s . N e u r o l P s y c h ia t, 4 , 356-385. Amaral, D.G., & Insausti, R. (1990). Hippocampal formation. In G. Paxinos (Ed.) T h e h u m a n n e r v o u s s y s te m (pp.711-755). San Diego: Academic Press. Amaral, D.G., & Price, J.L. (1984). Amygdalo-cortical projections in the monkey ( m a c a c a f a s c i c u l a r is ) . J o u r n a l o f C o m p a r a tiv e N e u r o lo g y , 2 3 0 , 465-496. Amassian, V.E., Cracco, R.Q., Maccabee, P.J., Cracco, J.B., Rudell, A., Eberle, L. (1989). Suppression of visual perception by magnetic coil stimulation of human occipital cortex. E le c tr o e n c e p h a lo g r a p h y a n d C lin ic a l N e u r o p h y s io lo g y , 74, 458^162. American Academy of Neurology AIDS Task Force (Working Group). (1991). Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection. N e u r o lo g y , 4 1 , 778-785. American Psychiatric Association. (1980). D i a g n o s t i c a n d S ta tis tic a l M a n u a l o f M e n ta l D is o r d e r s , (D S M

I I I ) . Washington, DC: American Psychiatric Associ-

ation. American Psychiatric Association. (1987).

D ia g n o s tic

a n d S t a t i s t i c a l M a n u a l o f M e n ta l D i s o r d e r s , ( D S M

Washington, DC: American Psychiatric Association. American Psychiatric Association. (1989). D i a g n o s t i c IIIR ).

a n d S t a tis tic a l M a n u a l o f M e n ta l D is o r d e r s . 3 r d E d. ( D S M - 3 -R ).

Association M a n u a le M e n ta li.

Washington, DC, American Psychiatric [ T r a d u z io n e

D ia g n o s tic o

e

Milano: Masson.]

ita lia n a : S ta tis tic o

D S M -3 -R dei

-

D is tu r b i

American Psychiatric Association (1994).

903

D ia g n o s tic

a n d S t a tis tic a l M a n u a l o f M e n ta l D is o r d e r s , (D S M -

Washington, DC: American Psychiatric Association. Amit, D.J. (1995). The Hebbian paradigm reintegrated: Local reverberations as internal representations. B e h a v io r a l a n d B r a in S c ie n c e s , 1 8 , 617-657. Amouyel, P., & Richard, F. (1996). Epidemiology of frontotemporal dementia. In F. Lebert, & P. Scheltens (Eds.), F r o n to te m p o r a l d e m e n tia , 11-17. Dordrecht, The Nederlands: ICG Publications. Andersen, R. (1978). Cognitive changes after amygdalotomy. N e u r o p s y c h o lo g ia , 1 6 , 439-4-51. Andersen, R.A. (1989). Visual and eye movement functions of the posterior parietal cortex. A n n u a l R e v ie w o f N e u r o s c ie n c e , 1 2 , 377^103. Andersen, R.A. (1995). Coordinate transformations and motor planning in the posterior parietal cortex. In M.S. Gazzaniga (Ed.), T h e C o g n itiv e N e u r o s c ie n c e s (pp. 519-532). Cambridge, MA: MIT Press. Andersen, R.A., Essick, G.K., & Siegel, R.M. (1985). Encoding of spatial location by posterior parietal neurons. S c ie n c e , 2 3 0 , 456-458. Andersen, R.A., Snyder, L.H., Li, C-S., & Stricanne, B. (1993). Coordinate transformations in the representation of spatial information. C u r r e n t O p in io n in N e u r o b io lo g y , 3 , 171-176. Anderson, B. (1996). A mathematical model of line bisection behaviour in neglect. B r a in , 1 1 9 , 841-850. Anderson, D.C., Bundlie, S., & Rockswold, G.L. (1984). Multimodally evoked potentials in closed head trauma. A r c h iv e s o f N e u r o lo g y , 4 1 , 369-374. Anderson, J.R. (1978). Arguments concerning representations for mental imagery. P s y c h o lo g ic a l R e v ie w , 8 5 , 249-277. Anderson, S. (1982). Where’s morphology? L in g u is tic In q u ir y , 1 3 , 571-612. Anderson, S.W., Damasio, A.R., & Damasio, H. (1990). Troubled letters but not numbers. B r a in , 1 1 3 , 749-766. Anderson, S.W., Damasio, H., Jones, R.D., & Tranel, D. (1991). Wisconsin Card Sorting Test performance as a measure of frontal lobe damage. J o u r n a l o f C lin ic a l a n d E x p e r im e n ta l N e u r o p s y c h o lo g y , 1 3 , 909-922. Anderson, S.W., Damasio, H., & Tranel, D. (1990). Neuropsychological impairments associated with lesions caused by tumor or stroke. A r c h i v e s o f N e u r o lo g y , 4 7 , 397-405. Anderson, T.J., Jenkins, I.H., Brooks, D.J., Hawken, M.B., Frackowiak, R.S.J., & Kennard, C. (1994). Cortical control of saccades and fixation in man. A PET study. B r a in , 117, 1073-1084. IV ).

904

H A N D B O O K O F CLIN IC AL A N D EXPER IM EN TA L P S Y C H O L O G Y

Andreasen, N.C., Harris, G., Cizadlo, T., Arndt, S., O’Leary, D.S., Swayze, V., & Flaum, M. (1994). Techniques for measuring sulcal/gyral patterns in the brain as visualized through magnetic resonance scanning: BRAINPLOT and BRAINMAP. P r o c e e d in g s o f th e N a tio n a l A c a d e m y o f S c ie n c e U S A ,

9(9, 93-97. Andreassi, J.L. (1980).

P s y c h o p h y s i o lo g y :

b e h a v io u r a n d p h y s io lo g ic a l re sp o n se .

Appleton-Century-Crofts. Andreassi, J.L. (1995). P s y c h o p h y s i o lo g y : b e h a v io u r a n d p h y s io lo g ic a l

H um an

New York:

re sp o n se ,

H um an

3rd ed.

Hillsdale, NJ: Lawrence Erlbaum. Andrews, E., Poser, C.M., & Kessler, M. (1982). Retrograde amnesia for forty years. C o r te x , 1 8 , 441-458. Angelelli, P, De Luca, M., & Spinelli, D. (1996). Early visual processing in neglect patients: A study with steady-state VEPs. N e u r o p s y c h o lo g ia , 34, 1151-1157. Angelergues, R., de Ajuriaguerra, J., & Hécaen, H. (1960). La négation de la cécité au cours des lésions cérébrales. J o u r n a l d e P s y c h o lo g ie , 4, 381^404. Angelergues, R. (1969). Memory disorders in neurological disease. In P. J. Vinken & G. W. Bruyn (Eds.), H a n d b o o k o f c l i n i c a l n e u r o lo g y . D i s o r d e r s o f th e n e r v o u s a c tiv ity , Vol. 3 (pp.268-292). Amsterdam: North Holland. Angelergues, R., Hecaen, H, & De Ajuriaguerra, J. (1955). Les troubles mentaux au cours des tumeurs du lobe frontal. A n n a le s M e d i c o - P s y c h o g i q u e s , 1 1 3 , 577-642. Angelini, R. (1991). Ilcaso di S.C. InD. Grossi (Ed.),L