The Sensory Hand: Neural Mechanisms of Somatic Sensation 9780674275447

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The Sensory Hand

Two parietal lobes in contact. (From Kapinji, 1981.)

The Sensory Hand NEURAL MECHANISMS OF SOMATIC SENSATION

Vernon B. Mountcastle

Harvard University Press Cambridge, Massachusetts, and London, England

2005

Copyright © 2005 by the President and Fellows of Harvard College All rights reserved Printed in the United States of America Library of Congress Cataloging-in-Publication Data Mountcastle, Vernon B. The sensory hand : neural mechanisms of somatic sensation / Vernon B. Mountcastle. p. cm. Includes bibliographical references and index. ISBN 0-674-01974-1 (alk. paper) 1. Hand—Innervation. 2. Somesthesia. I. Title. QP334.M68 2005 612.97—dc22 2005050372

Dedicated to the memory of KENNETH O. JOHNSON, 1938–2005 Distinguished Scientist, Comrade in Research

Contents

Expanded Contents

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Acknowledgments xv

1 Perception and the World of Somesthesis 1 2 The Evolution and Structure of the Hand 27 3 General Features of Somatic Afferent Systems 51 4 Sensory Innervation of the Primate Hand 69 5 Large-Fibered Peripheral Interface 97 6 Dorsal Systems and the Dorsal Column Nuclear Complex 136 7 Small-Fibered Peripheral Interface 166 8 Ascending Spinal Cord Systems of Intrinsic Origin 187 9 Dual Functions of the Dorsal Thalamus 214 10 Postcentral Somatic Sensory Cortical Areas in Primates 260 11 Dynamic Neural Operations in Somatic Sensibility 301 12 Dynamic Neural Operations in the Sense of Flutter-Vibration 341 13 Parietal Lateral System and Somatic Sensibility 379

14 Parietal Frontal Sensory–Motor Transition 409 15 Adaptive Reorganizations of Central Somatic Sensory Networks 443 16 Haptic Sense as Substitute for Vision 468 References 493 Index 595

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Contents

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Acknowledgments xv

1 Perception and the World of Somesthesis 1 General Hypotheses 6

Special Cells of the Epidermis 45 Langerhans Cells 46 Melanocytes 46 Merkel Cell-Neurite Complexes 46

Neural Mechanisms in Somesthesis: A Brief Overview 8

The Dermis 47

The General Properties of Somesthesis 9

The Basement Membrane 48

Primary and Complex Varieties of Somesthesis 9 Attributes of Somesthesis 10 Somesthetic Modalities 12 Development of Psychophysics 15 The New Psychophysics and the Psychophysical Law 18

The Vascular Supply to the Glabrous Skin 48 Dermatoglyphics 50

3 General Features of Somatic Afferent Systems 51 On Naming 54

The Law of Correspondence 19 Single-Neuron Studies of the Somatic Afferent System 20 The Combined Experiment 21 Perceptual Neuroscience and the Philosophical Position 24 NOTES

25

2 The Evolution and Structure of the Hand 27

Somatic Afferent Systems Have Different Structural and Functional Properties 55 System Overlap and Embedding 58 Representation and Self-Organization 60 The Hebbian Elaboration of the Principle of Ariens-Kappers 62

Evolution of the Primate Hand 33

Modularity 63

Macrostructure of the Hand 34

Parallel Projections and System Convergence 64

Postures and Movements of the Hand 39

Localization in Somatic Afferent Systems 65

General Description of the Skin of the Hand 41

Localization vs Equipotentiality: The Cerebral Organ Concept of the Nineteenth-Century 65

The Epidermis 44

The Nineteenth-Century Triumph of the Cerebral Organ Concept 67

5 Large-Fibered Peripheral Interface 97 Skin Mechanics and Mechanoreception (by KO Johnson) 101

The Modern Synthesis: The Unit Module and the Distributed System 68

Contact Mechanics 102 Continuum Mechanics 103 Mechanoreceptor Models 104

4 Sensory Innervation of the Primate Hand 69

Molecular and Cellular Processes of Mechanical Transduction 105

The Innervation of the Skin: A Brief Overview 72 Definitions 75

Large-Fibered Mechanoreceptive Afferents Innervating the Primate Hand 107

Sensory Receptor 75 Threshold 75

Conduction Velocities, Innervation Densities, and Axon-Receptor Ratios 109

Sensory Unit 75 Peripheral Receptive Field 75

Peripheral Sensory Nerve Formations: “Sensory Organs” 113

Partially Shifted Overlap 76 Peripheral Innervation Density 76

Pacinian Corpuscle 114

Adaptation 76

Mechanical Transduction in the Pacinian Corpuscle

Modality 76 Polymodal 77

Meissner Corpuscle (RA) 121

Neural Code 77

Response Properties of Meissner Afferents 123

Merkel Cell–Neurite Complex (SA-I) 123

Primary Sensory Neurons 77

Response Properties of Merkel Afferents 125

Ontogenesis, Differentiation, and Migration 79

Ruffini Corpuscles (SA-II) 127

Axonal Projection and Target Recognition 80

Innervation of the Hairy Skin 129

Neurotrophins Control Sensory Neuron Survival and Death 82

Innervation of the Deep Tissues of the Primate Hand 132

General Principle of Stimulus Selectivity 85

Denervation and Reinnervation of the Glabrous Skin of the Primate Hand 133

Somatic Sensory Qualities Are Distributed in the Skin in a Punctate Fashion 86 Multicellular Sensory End-Organs of Large-Fibered Cutaneous Afferents Are Mechanical Filters 87

6 Dorsal Systems and the Dorsal Column Nuclear Complex 136

Different Modalities of Somatic Sensibility Are Dissociated by the Selective Block of Afferent Axons of Different Sizes 88 Modality Dissociation Is Produced by Differential Electrical Excitation of Afferent Fibers of Different Sizes 91 Somatic Sensory Modalities Are Dissociated by Disease Processes 91 Direct Evidence for Stimulus Selectivity Obtained by Recording from and Stimulating Single Somatic Afferents in Humans and Nonhuman Primates 92 Classifications of Somatic Sensory Afferent Fibers 93

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Response Properties of Pacinian Afferents 119

Expanded Contents

Dorsal Columns 139 Initial Mapping Rules in the Lemniscal System Are Set by Transformations in the Dorsal Ascending Systems 141 Re-Sorting for Modality and Topography 142 Dorsal Column Nuclear Complex (DCNC) 144 Functional Organization 145 Synaptic Operations in the DCNC 150 Dynamic Channeling Operation in the DCNC-Thalamic Transition 153 Postsynaptic System of the Dorsal Columns (PSDC) 153

Visceral Afferent Projections in the Dorsal System 155

Supraspinal Loops Control Nociceptive Transmission Through the Dorsal Horn 202

Spinocervicothalamic System 157

Descending Systems Have Integrative Functions 203

Loss and Retention of Somesthetic Capacities in Primates After Lesions of the Dorsal Ascending Pathways of the Spinal Cord 158

The Brain’s Own Opiate System 204 Ascending Systems of Intrinsic Origin 205

Defects in Motor Control and Dynamic Somatic Sensibility After Lesions of the Gracile and Cuneate Tracts 162 Concluding Remarks 164 NOTE

General Properties of Spinothalamic Systems in Primates 205 Input-Selective Channels of the Spinothalamic System 207

164

Convergent Channels of the Spinothalamic System 208

7 Small-Fibered Peripheral Interface 166

Does a Separate Ventral Spinothalamic Tract for Tactile Sensibility Exist in Primates? 210

Transducer Mechanisms at Small-Fibered Nociceptive Endings 169

Convergence of Somatic and Visceral Afferents in the Dorsal Horn: Referred Pain 211

Na+ Channels and Nociception 171 Proton Channels and Nociception 172

The Spinotectal and Spinomesencephalic Tracts 212

Correlations: Psychophysical Measures and First-Order Afferents 172

Propriospinal Systems 212

9 Dual Functions of the Dorsal Thalamus 214

Innocuous Warming and Cooling 175 Sensitization, Hyperalgesia, and Allodynia 181

The Two Modes of Thalamic Function 214

Chemical Activation of Nociceptive Afferents Innervating Injured or Inflamed Skin 184

Development of Ideas of Thalamic Function 215

The Neurosecretory Function of C-Fiber Nociceptive Afferents 185

Thalamic Cell Types and Their Connections 220

Thalamic Organization 218

Relay Neurons 220

“Sleeping” or “Silent” Nociceptive Afferents 185

Reticular Neurons 223 Interneurons 224

8 Ascending Spinal Cord Systems of Intrinsic Origin 187

Common Properties of Thalamic Nuclei 225 Synaptic Mechanisms at Thalamic Neurons 226

Dorsal Root Segregation and Lissauer’s Tract 189

Synaptic Structure 226

The Dorsal Horn as an Integrating Center 190 Sustaining and Guidance Mechanisms in the Development of Afferent Projections to the Dorsal Horn 194

Transmitters and Receptors 227 Multiple Conductances of Thalamic Neurons 230

Differential Projection of Sets of Dorsal Root Afferents to the Dorsal Horn 195

Voltage-Gated Channels Control the Transitions Between the Tonic and Bursting Modes of Thalamic Relay Cell Discharge 231

Representation of the Body Form in the Spinal Gray 200

The Channels 233

Neuronal Operations in the Dorsal Horn 200

Core and Matrix Model of Thalamic Organization 234

Suppressive Interaction Between Large- and Small-Fibered Afferents 202

Relay Functions of Somatic Sensory Thalamic Nuclei 235 The Relay Mode 235

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General Properties of Thalamic Relay Nuclei 236

Functional Organization of the Postcentral Somatic Sensory Areas 272

Modularity, Divergence, and Convergence in the Lemniscal Afferent System 237

Columnar Organization of Postcentral Somatic Sensory Areas 272

The Ventral Posterior Relay Nuclei 239

Extrinsic Connectivity of Postcentral Somatic Sensory Cortical Areas 277

Somatotopic Pattern: The Lamellar Model 239 Somatopic Pattern: The Core and Matrix Model 241

Thalamocortical Projections 277

Modality Segregation 242

Ipsilateral and Commissural Connectivity 278 Properties of Postcentral Neurons Determined with Methods of Single-Neuron Analysis 279

Dynamic Relay Functions 246 Trans-thalamic Relay of the Spinothalamic and Spinal Trigeminothalamic Systems 247

On Populations 279

Thalamic Projections of the Stimulus-Selective, Lamina I Axons 247

Peripheral Receptive Fields of Postcentral Cutaneous Neurons 281

Postcentral Neurons Are Specific for Place and Mode 280

Thalamic Projections of the Convergent Sets of ST/STT Axons from Deeper Layers of the Dorsal Horns 249

There Is a Somatotopic Representation of the Body Form in Each of the Four Postcentral Areas 283

Thalamocortical Control of Vigilant States and Sleep–Wakefulness Transitions 252

Neurons of Different Modalities Are Differentially Distributed in the Four Postcentral Areas 287

Brain Stem and Thalamic Mechanisms Maintain the Waking State 253

Imaging Studies of Postcentral Somatic Sensory Areas in Normal Humans 289

Transitions Between Waking and Sleeping: Thalamic Origin of Spindles and Delta Waves 254

Complexity of the Somatic Afferent System 292

Rapid Eye Movement Sleep 257

On Mapping 296

Evolutionary Development of Somatic Sensory Areas 293

Where Is the Sensory Blockade in Various Stages of Sleep? 257

Functional Implications of Cortical Maps 298

10 Postcentral Somatic Sensory Cortical Areas in Primates 260 Definitions of Somatic Sensory Cortical Areas 261 Location Determined by Studies of Humans with Brain Lesions 263

Summary: General Principles Predicted from Structure and Connectivity 299

11 Dynamic Neural Operations in Somatic Sensibility 301

Electrical Stimulation of the Postcentral Gyrus in Waking Humans Confirmed the Location of the Somatic Sensory Cortex 264 The Detailed Pattern of the Body Representation in the Postcentral Gyrus of Monkeys Mapped with the Evoked Potential Method 265

Experimental Sequence 304 Neural Coding in the Somatic System 304 Cutaneous Afferent Channels of the Lemniscal System 306 The Impact of Microneuronography 309 The Effect of Stimulus Movement 310 Tactile Thresholds on the Glabrous Skin 311

Symmetry in the Postcentral Areas 266

Rating of Pressure Stimuli on the Glabrous Skin 311

A Morphological Landmark of the Hand Representation 268 Cytoarchitecture of Postcentral Somatic Sensory Areas 268 Observer-Independent Method of Cytoarchitectonics 270

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Tactile Localization 317 Structure of Receptive Fields of Mechanoreceptive Afferents Innervating the Glabrous Skin of the Hand 318

Structure of Receptive Fields of Postcentral Neurons 320

Flutter and Vibration Can Be Dissociated 376

Representations of Complex Features of Tactile Stimuli in the Somatic System 322

Enhancement and Masking 376 Concluding Remarks 377

Curvature (Shape) 324 Orientation 325

13 Parietal Lateral System and Somatic Sensibility 379

Movement and Direction 326

Discovery of Multiple Cortical Sensory Areas 382

Tactile Texture 327

Structure and Connectivity of the Second Somatic and Insular Areas 383

Spatial Form and Pattern 330 Postcentral Processing of Complex Features of Tactile Stimuli 333

Cytoarchitecture and Connectivity 383

Stimulus Orientation 334

Direct Lemniscal Input to the Parietoventral and Second Somatic Areas Through the Ventral Posterior Lateral and Medial Nuclei 385

Spatial Form and Pattern Recognition 335

Posterior Thalamic Projections to SII and the Insula 385

Tactile Texture 334

The Manual Sensing of Three-Dimensional Form 337

Cortical Connections of SII Areas 386

Concluding Remarks 339

Dual Somatotopic Representation in the SII Areas 389 Functional Properties of Neurons of the SII Regions 391

12 Dynamic Neural Operations in the Sense of Flutter-Vibration 341

Properties of Insular Neurons 395

Psychophysical Studies of Flutter-Vibration in Humans and Monkeys 342

Defects in Mechanoreceptive Somatic Sensibility Produced by Lesions in the Sylvian Cortex 395

Threshold Functions for Flutter-Vibration Are Similar in Humans and Monkeys 345

The Cortical System for Pain and Temperature 397

Frequency and Amplitude Discrimination Thresholds for Flutter and Vibration Are Similar in Humans and Monkeys 346

Central Neuronal Mechanisms in Flutter and Vibration 353 Postcentral Cortical Mechanisms in the Sense of Flutter 354 Postcentral Cortical Mechanisms in the Sense of Vibration 360 Transcortical Neural Mechanisms in Flutter Discrimination: Postcentral Sensory to Contralateral Motor Cortex 362 Central Nervous System Lesions and Flutter-Vibration 367 Spinal Cord Lesions in Humans and Monkeys 367

Imaging Studies of the Cortical Pain System in Normal Humans 401 Thalamocortical Mechanisms for Innocuous Thermal Sensibility 404 The Convergent Problem 405 Hierarchical and Parallel Processing in the Somatic Afferent System 406 Hypotheses Concerning Synthesis in Somatic Sensory Systems 408

Cortical Lesions in Humans and Monkeys 368 Subjective Magnitude Estimation and the Primary Population Code for Stimulus Amplitude in Flutter-Vibration 371

Slowly Adapting Mechanoreceptive Afferents Innervating the Glabrous Skin Do Not Contribute to Flutter-Vibration 375

Posterior Thalamus and Cortex of the Lateral Fissure 400 Medial Thalamic Nuclei and the Frontal Cortex 401

Peripheral Transducer Mechanisms in Flutter and Vibration. Neural Coding in First-Order Afferents 349

Postcentral Neural Activity and the Atonal Interval 374

Thalamic Ventral Posterior Nuclei and Postcentral Somatic Areas 399

14 Parietal Frontal Sensory–Motor Transition 409 Cytoarchitecture and Connectivity of the Parietal Frontal System 414 The Parietal Lobe Syndrome in Humans 416 Disorders of Attention 418

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Disorders of Motor Control 419

Synaptic Modifications Occur at Each Level of the Somatic System 459

Disorders of Visual and Spatial Perception 420

Mechanisms of Adaptive Reorganizations in the Somatic Afferent System 460

Lesions of the Two Trans-Cortical Visual Streams Produce Different Behavioral Defects in Humans 420

Synaptic Divergence at Each Level of the System 460

The Parietal Lobe Syndrome in Monkeys 421

Dynamic Changes in Network Operations 460

Psychophysics of Reaching and Grasping in Humans 422

Synaptogenesis and the Formation of New Connections 463

Electrophysiological Studies of the Parietal Frontal Systems 426

Transneuronal Atrophy 465 Concluding Remarks 466

The Visual Grasping of Objects: The Lateral Intraparietal Area 427

NOTES

Reaching with the Arm: The Parietal Reach Region 429

16 Haptic Sense as Substitute for Vision 468

Grasping with the Hand: The Anterior Intraparietal Area 432

Direct Haptic-Tactile Substitution Systems 468 Tadoma 468

The Premotor Areas of the Frontal Lobe 433 Neural Signs of Cognitive Operations 434

Direct Tactile-to-Tactile Transmission of American Sign Language 470

The Coordinate Frame Problem 434

Direct Tactile-to-Tactile Transmission in Finger-Spelling 471

Automatic Regulation of Reaching Movements in Mid-flight 436 Sensory–Motor Mechanisms of the Precision Grip 437 Are Functions Localized in the Parietal Frontal Systems? 440

NOTES

Indirect Haptic-Tactile Substitutions: The Braille System 471 Braille Type 472 Manual Operations in Reading Braille 474 Speed of Reading Braille 475 Global Pattern or Textural Processing? 476

Concluding Remarks 440

Peripheral Neural Mechanisms in Braille Reading 477

441

Cortical Operations in Reading Braille 478

15 Adaptive Reorganizations of Central Somatic Sensory Networks 443

Does the Visual Cortical System Play an Essential Role in Reading Braille? 482 Indirect Systems Accessing the Vibratory Afferent Channels 483

The Microelectrode Mapping Method 445 Normal Variations of Representational Maps in the Somatic System 448 Adaptive Reorganization of Somatic Sensory Representational Maps in Monkeys After Peripheral Deafferentation 450 Adaptive Reorganization in the Human Somatic System After Central Lesions or Peripheral Deafferentation 452 Phantom Limbs 454 Phantom Limb Pain 456

A Pictorial System: The Optacon 483 Dynamic Spectral Displays with Abstract Coding 484 The Spatial Perception of the Blind 485 “Facial Vision” in the Blind: The Use of Reflected Sound 486 The Art of the Blind 486 What Do the Long-Blinded See When Sight Is Restored? 489 References 493

Experience-Dependent Modifications in Representational Maps in the Somatic Afferent System 458

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Index 595

Acknowledgments

While writing The Sensory Hand I have been fortunate to have daily interactions with the students and staff of the Krieger Mind-Brain Institute. In particular, institute member Takashi Yoshioka read each chapter as it was written, and his comments were of value in several revisions of the text. Three graduate students, Paul Fitzgerald, Sean Mikula, and Takashi Takama, each read the entire book, and I profited greatly from their special points of view. I express my gratitude to Professor Kenneth O. Johnson, Director of the Institute, who found time to share with me his knowledge of the neural mechanisms in somatic sensibility; he also contributed the essay on skin mechanics in Chapter 5. Professor E. R. Perl of the University of North Carolina agreed to review the chapters on the small-fibered interface, the functions of the dorsal horn, and the secondary ascending systems of the spinal cord. I am grateful for his advice. Likewise, I am indebted to Professor Harold Burton of Washington University for his critical review of Chapter 16 on the function of the somatic afferent system as a substitute for vision in blinded humans. The final products are my own responsibility. I appreciate greatly the help and guidance of Michael Fisher, Editor in Chief at Harvard University Press, as well as Sara Davis and other members of his staff, for editorial advice and patience during long delays.

The Sensory Hand

Perception and the World of Somesthesis All that we need notice here is, the extent to which in the human race a perfect tactual apparatus subserves the highest processes of the intellect. I do not mean merely that the tangible attributes of things rendered completely cognisable by the complex adjustments of the human hands, and the accompanying manipulative powers have made possible those populous societies in which alone a wide intelligence can be evolved. I mean the most far-reaching cognitions, and inferences the most remote from perception, have their roots in the definitely combined impression which the human hands can receive. H. Spencer, 1855

A nervous system faces the external world indirectly via the afferent input that reaches it over the first-order nerve fibers of the several sensory systems. A brain derives from that input ongoing, continually changing, slightly delayed images of the external environment. Our perceptual images are abstracted constructions of the events and objects in the world around us, constructions determined by the selective filtering and transforming functions of sensory nerve formations, by the intrinsic operating characteristics of central neural networks, and by the remembered residua of past perceptual experiences. The experimental neuroscientist seeks to discover the nature of the operations in the long, frequently parallel, and sometimes interacting chains of neural events that link afferent input and the perceptions that follow, and to seek explanations of the latter in terms of the former. The human hand is an organ of considerable virtuosity; with it we feel, point, and reach and determine the texture and shape of objects we palpate. We send and receive signs of approval, compassion, condolence, and encouragement, including the area of social touching comprising, among other things, expressions of friendship and love (Thayer, 1982). In different behavioral settings, we communicate signs of rejection, threat, dislike, antagonism; and in action, attack. Perhaps these latter are some of the “inferences the most remote from perception” Spencer had in mind; alternatively he might have had the idea that volition, intention, and the manipulation of abstract thoughts are akin to the operation of the hand in the manipulation of tangible objects.

1

I deal in this book with the peripheral and central neural mechanisms of somatic sensibility, those varieties of perceptual experiences evoked by stimulation of peripheral tissues, particularly for the primate hand. The equivalent terms somatic sensibility and somesthesis indicate several readily identifiable more or less primary qualities, as well as more complex sensory experiences evoked by stimulation of peripheral tissues, in this case those delivered to or actively sought by the hand. The primary somesthetic experiences are contact or touch-pressure, form, texture, and flutter-vibration. Among the more complex aspects of somesthesis are the senses of spatial pattern, contour, and three-dimensional shape, and the senses of position and movement of the limbs at their joints. I focus on the afferent pathways linking the hand to central neural structures activated over those channels, structures that can be shown on the basis of other factors as well to play a role in these several aspects of somatic sensibility. My purpose is more general, for I wish by study of the brain mechanisms in somesthesis to probe those aspects of the cerebral operations in perception executed mainly by the distributed systems of the neocortex and its linked subcortical structures, subjects I explored in an earlier monograph (Mountcastle, 1998). Study of this problem requires, as the reader shall see, knowledge of peripheral sensory transductions and the neural operations in pathways leading to the cerebral cortex. I enter an immediate disclaimer: when I use the words cerebral cortex I implicitly include the large re-entrant systems of the forebrain with which the cortex is reciprocally connected. The proposition that the mechanisms of perception are to be understood in terms of brain function is now so widely accepted as to be almost a banal statement. This compelling idea, however, has for more than 2000 years been at the center of man’s attempts to understand himself and his relationship to the world around him. The idea was developed in a general way through purely intellectual effort, without any experimental base, by the post-Socratic Greek philosophers, notably Leucippus, Democritus, and Epicurus.1 The modern, experimentally based form of this idea is less than two centuries old, came directly from the discoveries of scientists of the early nineteenth century, and owes much to the discoveries and theoretical formulations of Hermann von Helmholtz in the period 1859–1879 (see Warren and Warren, 1968 for translations of Helmholtz’s essays). Helmholtz placed the theory of perception at the starting point of

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scientific knowledge, and it was Helmholtz who set the general empiricist proposition that dominates thinking about perception to the present day: that the perceptions we experience in everyday life are generated directly by primary afferent input and the patterns of neuronal activity that input evokes in the brain. Although Helmholtz’s knowledge of the brain was limited by that available in his time to its gross and histological structure, it is clear from his 1878 essay on “The Facts of Perception” that he had in mind a neuronal processing theory of perception. The long history of the development of ideas about perception has been dominated by interest in the sense of vision, from the time of Democritus (400 B.C.) through the Renaissance and the Enlightenment, through the revolution in thought in Helmholtz’s time, right up to the present day. Although the post-Socratic Greek natural philosophers recognized touch as one of the five cardinal senses, direct experimental study of somatic sensibility did not begin until 1834, in the hands of a persistent experimentalist, Ernst Weber. A central problem in understanding the neural mechanisms of somatic sensibility is that we perceive and identify separately a number of clearly different sensibilities evoked by stimuli delivered to an extended sensory surface. These perceptions differ in both quality and temporal patterns; some of the latter are themselves identifiable as separate qualities. The glabrous surface of the hand—the skin and the subcutaneous tissue—is innervated by at least eight identified sets of receptors and their linked primary afferent fibers: four lowthreshold mechanoreceptive afferent classes; two thermoreceptive sets, one responsive to innocuous warming and the other to cooling; and two nociceptive afferent classes. In addition, at least four sets of “proprioceptive” afferents terminate in subcutaneous tissue of the hand and may contribute to somatic sensibility.2 All of these terminate in overlaid distributions and differ in their stimulus sensitivities. The neuroscientist who takes this as his or her field of study must identify these several sets of primary afferents and draw correspondences between them and the several different qualities of somesthesis humans perceive, a field of experimental enquiry initiated by the work of Adrian in the 1920s (Adrian, 1931, 1932). The field was for a number of years handicapped by the hypothesis that no specificity at all exists in the peripheral neural apparatus, and that the identified modes of somatic sensibility depend on some pattern of central processing. It is difficult to overstate how much

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this vigorously argued hypothesis hindered the field, and for a dwindling minority of investigators, still does. The problem has been resolved by persistent laboratory investigation in primates, including waking human subjects. I summarize much of this new knowledge in the present volume. The neuroscientist who turns to the central brain mechanisms in somesthesis must attempt to answer questions such as: What are the dynamic central neural mechanisms in somesthesis? What are the mechanisms of the transitional interface between them and somesthetic perceptions? How do the several afferent pathways of the somatic system interact to produce a final integrated representation of the somatic sensory state? We have the advantage, in approaching these tasks, of a large fund of available information concerning the structure and connectivity of central somatic sensory systems, as well as increasing knowledge of the dynamic operation within these systems. The major problems can now be defined more precisely than was hitherto possible, even though their solutions are seen only dimly at the present time. The future promises progress in this endeavor, driven by the steady application of methods for observing both perceptual performance and the relevant brain activity in waking primates, including humans, as they work in somesthetic tasks. I follow several general ideas in this volume. The first is that dynamic and continually updated neural representations of our changing somesthetic experiences received or sought by the hand exist in the somatic afferent pathways of the brain and in the somatic sensory areas of the cerebral cortex. These dynamic representations of somesthetic events are embedded in the patterns of activity in large populations of neurons. After stimulus transduction by receptors and encoding, the parallel representations in the different sets of afferent fibers innervating the tissues of the hand are projected over parallel and sometimes interacting pathways of the somatic afferent system into the somatic sensory areas of the parietal lobe and the linked distributed systems of the homotypical cortex. These sets of neural activity interact at every synaptic level with neural activity in descending control systems, and with that in neural systems that deal with set or affect. The latter are important in somesthesis, for even trivial stimuli to peripheral tissues often evoke perceptions with intense affective overtones. The second is the general working hypothesis that both the private experience and its verbal description are initiated by these sets of

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neural activity. They are now studied directly in the brains of waking humans and nonhuman primates as these subjects perform somesthetic tasks with their hands. The third is a focus on the somesthetic performances and the relevant neural mechanisms in primates, particularly in humans and macaque monkeys. The densely innervated glabrous skin and deep tissues of the primate hand make it the sensory organ par excellence in somesthesis. In primates the tips of the fingers are backed with nails, a specialization that improves the tactile and manipulative capacity of the finger pads they cover. The palms and undersides of the fingers are marked by creases and covered with ridges called finger or palm prints that function to improve tactile sensitivity and grip. Moreover, although no one imagines that the human brain is a scaled-up model of the 80-gram macaque brain, many observations show that the sensory performances of the two primates are executed in much the same way in primary somesthetic tasks. The relevant peripheral and central neural mechanisms are similar in humans and monkeys, at least from the periphery to and through the initial somatic sensory areas of the cerebral cortex. This is an example of parallel evolution, for humans and macaques have followed different evolutionary trails for perhaps 60 million years. Fourth, descriptions are given of both the capacities of primates in the perceptual sphere of somesthesis, as measured with psychophysical methods, and of the peripheral and central neural operations evoked by identical sets of stimuli. The central idea is that these three sets of variables—stimulus parameters, the neural activity evoked by them, and the behavioral performances those stimuli induce—can be observed simultaneously, measured, and related to one another. It is my aim to relate these three sets of variables for several types of tactile and proprioceptive sensibilities, so far as present knowledge allows. I shall describe some of the motor as well as sensory functions of the hand and what is known of those seamless sensory–motor transitions executed at the level of the cerebral cortex through which central representations of sensory events flow through to motor actions, often at pre-conscious levels. Movements of the hand, like those of the eye, execute searching operations; through them we acquire the details of the physical structures we touch and manipulate. Without eye movements, vision fades, and the immobile hand is an impoverished sensory organ as regards the complex somesthetic

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5

perceptions, like three-dimensional form. Hand movements are guided by sensory input, an inflow that itself depends for precision in spatial and temporal summations on the movements of the hand that pan those sheets of nerve formations over objects examined. The sequence of events leading from a peripheral stimulus to relevant movement has been a dominant theme in neurophysiology for more than 100 years, reaching an apogee during the Sherrington era of study of spinal cord reflexes. I am not concerned here with these important aspects of behavior, but concentrate on the flow of activity that moves over the somatic afferent system into the posterior parietal lobe and parietal operculum, and from thence into the motor areas of the frontal lobe that link sensory to motor actions at the cortical level. We are seldom aware of activity in these distributed neocortical sensory–motor systems: we are conscious of outcomes, not processes. It may be possible from the many new discoveries at this level to shed some light on the even more complex question of how movements are generated de novo. The sequence of neural events that leads from willing to moving, the motivation to act, the satisfaction of intention, the choice of one sequence of movements over another—the brain mechanisms of all these seemingly effortless events still evade understanding. The initiation of movement is an internally generated and externally experienced act of will; it is one aspect of conscious behavior that will be studied directly.

General Hypotheses A general hypothesis I consider at several places in this book is that the small-fibered afferent systems, long known to contain the essential neural substrates for pain and temperature sensibilities, also contribute to the higher-order aspects of the several varieties of mechanoreceptive sensibility. They are activated under many conditions by the same mechanical stimuli processed in the large-fibered system, and carry signals to the forebrain that evoke the overall affective components of the sensory experiences. These small-fibered afferent systems activate many distributed areas in the frontal lobe, the limbic areas of the cerebral cortex, and the insula. At the same time signals in large-fibered afferents are processed in an elegant and quantitative manner and present to higher-order cortical systems signals that can be detected, discriminated, and rated with precision,

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in quantitative correspondence with the parameters of the stimuli that evoke them. Until now we have learned very little about the final “integration” of these varied inputs in producing overall somesthetic experiences. This integration and its varieties are obvious in everyday life—the touch of a loved one’s hand carries overtones not found in more ordinary tactile experiences. The hitherto perceived dichotomy of these two classes of systems has resulted in a parallel separation of investigators. Those talented individuals who have made such spectacular discoveries about the functions of the small-fibered systems in pain and temperature sensibilities now sense that the deepening knowledge of these systems, particularly the molecular aspects of the peripheral transducer mechanisms, will lead to chemical methods of blocking pain at its level of inception, with no effects on the function of the central nervous system. Yet only a few have taken full account of the broader—or perhaps I should say, other—meanings for behavior of activity in the small-fibered systems. Of course, the same is true inversely for those investigators involved in quantitative studies of the brain mechanisms in mechanoreceptive sensibility. They have because of the constraints of experimental design and execution not been able to take into account the accompanying activity in the small-fibered systems and the powerful contributions they make to the overall somesthetic experience. This division now ends, and concerted efforts are directed to study of the somatic system, complete. That such a dichotomy has not occurred, or at least not to the same extent, in studies of the visual and auditory systems is attributable to the relative simplicity of those systems. Compare, for example, the 12 different sets of first-order fibers innervating the primate hand with the much smaller number of afferent sets leaving the eye or the ear. The visual and auditory systems are by no means simple, but only appear so when compared with the somatic afferent system, in which a number of afferent sets with congruent peripheral distributions feed many ascending systems. Moreover, at several transition stations of these systems there is a complex interaction with motor mechanisms. I make here an effort to begin the process of unifying these two major fields of research. The reader will find in several chapters descriptions of the small-fibered systems, with some effort to show how they condition the overall mechanoreceptive sensory experiences.

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Neural Mechanisms in Somesthesis: A Brief Overview Nerve impulses generated in first-order somatic afferent fibers are projected into the nervous system and relayed to the cerebral cortex through the pathways of the spinal cord and trigeminal systems. Diagrammatic outlines of the somatic afferent system are deceptive, for they show somatic systems as if isolated completely from each other and from other brain systems. This is not the case, particularly not at levels of the thalamus and cortex, where somatic sensory systems partially converge and overlap, and where structures within them become nodes in distributed systems. The afferent activity projected into the large-fibered components of the somatic system is subject at every level to transformations imposed by (1) the processing characteristics of the network microstructure at each synaptic level, (2) the regulatory influence of descending systems that originate in the forebrain and project convergently upon each synaptic level of the system, and (3) the superimposed actions of afferent systems that arise from intrinsic neurons of the spinal gray and converge upon transition zones of the mainline components of the somatic afferent system. It is therefore an amazing observation, confirmed many times, that in spite of these converging modulatory systems, the lemniscal component of the somatic afferent system operates as a strong throughput system from periphery to postcentral gyrus, from hand to brain, in a waking monkey working in a somesthetic task. Under these circumstances, convergence and modulation appear to be trans-postcentral events, and do not challenge the primary perceptual operation. Afferent pathways of the somatic systems compose at each level maps that are distorted representations of the body form. A general description of mapping functions in the somatic sensory thalamic and cortical areas is given in Chapters 9 and 10. Somesthetic system maps are distorted by intermittencies and discontinuities distributed spatially in a manner determined in general but not always by peripheral innervation density, not actual body form. Stimulus parameters, and thus specific sets of afferent fibers, are often mapped through these somatotopic representations in an intermittently recursive manner; that is, over and over again in each small geographic compartment such as a set of cortical columns. Neural activity evoked in the postcentral somatic sensory areas is further relayed into the several somatic sensory areas of the parietal operculum, and into

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areas of the posterior parietal cortex and their linked connections. Mapping parameters in these trans-postcentral areas of the distributed somatic sensory cortical system may differ, so that dynamically constructed properties form the mapping rules with bodily form only loosely mapped, if at all.

The General Properties of Somesthesis Primary and Complex Varieties of Somesthesis The equivalent terms somesthesis and somatic sensibility include the several varieties of perceptual experiences evoked by stimulation of the tissues of the body. These subjective experiences vary greatly, especially in the emotional overtones that sometimes accompany them. Mechanoreceptive perceptual experiences are evoked by stimulation of the skin, muscles, joint capsules, and ligaments. Pain, warmth, and coolness are evoked by qualitatively different modes of stimulation, and are readily identified as unique by human observers. The peripheral afferent fibers serving cutaneous pain and temperature perception are interdigitated with those serving mechanoreceptive sensibilities, and the afferent pathways for pain and temperature are integral parts of several, ascending somatic systems. The primary features of the mechanical stimuli impinging upon the skin and deep tissues of the hand are selectively transduced at the peripheral ends of primary afferent fibers and by the multicellular receptor organs innervated by some terminals. The terminals and receptors differ greatly in their selective transducer functions and are arranged in overlapping spatial mosaics. The glabrous skin of the hand is a filter for stimulus quality; different sets of fibers respond at lowest threshold to some particular parameters of mechanical stimulation. I shall from place to place consider the importance of pain and temperature, with special reference to how these sensory inputs influence mechanoreceptive sensibility. Several components of somatic sensibility are classed as primary, for they can be evoked by afferent input restricted to a single set of first-order afferent fibers. While observers identify other mechanoreceptive modes as equally unique, they are thought to be more complex because they are generated by combinations of afferent input in two or more sets of primary fibers. I call these different qualities of somesthesis modalities, defined here in a restricted sense as the sensory

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experiences evoked by stimulus parameters that activate selectively a particular set or sets of primary afferent fibers. In this sense the term is in many but not all cases identical with Helmholtz’s more general definition of modality as composed of a class of sensations connected along a qualitative continuum. The singularity of some qualities of somesthesis can be demonstrated in the constrained environment of the combined psychophysical–neurophysiological experiment; several examples are given in later chapters. Somesthetic experiences of everyday life are produced by blends of those regarded as primary, evoked by simultaneous activity in several sets of primary afferent fibers. The inferred convergence between neural signals in different sets of specific afferent fibers has not been observed in the major superhighway of the system, its lemniscal component, which is composed of parallel, modality-segregated channels that project to and through the primary somatic sensory cortex of the postcentral gyrus. Present evidence indicates that the convergences and integration of several primary qualities to produce more complex ones like stereognosis occur in trans-postcentral areas of the parietal lobe and the Sylvian fissure.

Attributes of Somesthesis The different features of the mechanical stimuli that impinge upon us or that we ourselves generate by movements and postures are selectively transduced at the terminals of sensory nerve fibers innervating the skin and the deep tissues of the body. This filtering process is accomplished by transducer mechanisms located either in the nerve terminals themselves or in the sensory “organs” in which those nerve fibers terminate, such as the Meissner’s corpuscles of the glabrous skin of the primate hand (Malinovsky, 1996). Under normal conditions in peripheral tissues, sensory receptors are narrow filters often selectively tuned to special features and to limited quantitative ranges of stimulus parameters. The total input pattern evokes sensory experiences with several general properties or “attributes.” The idea that sensations have general attributes is an old one in experimental psychology. Several somesthetic modalities share the same attributes. Prominent among these is local sign, which is associated with spatial extension and duration in time. A stimulus delivered to the hand of a waking human is readily localized to the spot stimulated. Errors in spatial localization

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vary from a few millimeters for the densely innervated hand and face to several centimeters for the least densely innervated regions, the trunk, and proximal limbs. A local or spatially extended mechanical stimulus to the skin evokes a local or extended zone of increased neural activity propagated through the somatic afferent system to a spatially appropriate location in the map of the body surface in the somatic sensory areas of the postcentral gyrus. How such local or extended zones of incremented neural activity are interpreted in terms of the location and extent of the stimulated site on the body surface is unknown. This relates to the more general problem of the meaning for function of place in the sensory and motor systems of the brain. The quality of a stimulus is signaled with some certainty, and that quality is the same no matter how a particular set of afferent fibers is excited. The attribute of quality obtains for each of the varieties of somesthesis. This principle of the labeled line derives from Muller’s 1838 doctrine of specific nerve energies (see Chapter 4), now combined with the principle of stimulus selectivity of sensory nerve endings. These principles have been confirmed and extended in studies of the peripheral and central components of the somatic afferent system in nonhuman primates. This large body of knowledge has been extended for the first-order fibers by recording from single primary afferent fibers in the peripheral nerves of waking humans. A question of special interest is the association of particular patterns of activity (“neural codes”) with particular labeled lines. Mechanical stimuli delivered to the body are distributed along intensive (prothetic) and extensive (metathetic) continua. Contrast, for example, the series of sensations evoked by mechanical stimulations of different forces delivered to the skin (intensive) as opposed to a series of positions of the fingers at their joints (extensive). More complicated stimuli, the most common, may of course possess both intensive and extensive properties. The afferent signals evoked by two stimuli of different amplitudes allow humans to discriminate precisely between them when the two can be compared directly. We perform poorly when asked to rank the intensities of a number of stimuli along a prothetic continuum by subjective magnitude estimation. The capacity of humans to discriminate between somesthetic stimuli was the subject of the original studies of Weber (1834; translated, 1978), which led Fechner (1860) to the science of psychophysics. Weber studied the judgment of lifted weights, which is

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now thought to be a complex matter that depends on both the pressure of the weight on the skin of the hand and on a central judgment of the effort required to lift the weight, called the “sense of effort.” The latter is defined as an internal perception of the intensity of the motor commands emitted, and is often incommensurate with the force produced by those commands, for example, during fatigue (Burgess and Jones, 1997; Gandevia, 2001). In addition to signals of these attributes of place, spatial extent, temporal duration, quality, and intensity of stimuli that impinge on the surface of the skin, the cutaneous mechanoreceptive afferents provide population signals of the form and the surface microstructure of spatially extended stimuli. In brief, population coding means that information about a particular sensory attribute is signaled by the temporal and spatial relationships between the trains of impulses in elements of the active population, and can be derived neither from the pattern in any single neural element nor by any simple summation of the activity in many elements. Mechanoreceptive, cutaneous afferent fibers play important roles in the haptic appreciation of threedimensional form called stereognosis, in combination with signals in afferent fibers innervating the deep tissues of the hand.

Somesthetic Modalities Sensory attributes and modalities differ, for several attributes apply to all modalities of somesthesis that are themselves connected along different qualitative continua. The most obvious of the somesthetic modalities is that of light touch, or pressure. The quintessence of tactile sensibility is achieved by the moving hand, particularly by the rapid, successive palpations of objects we explore. How these temporally successive and spatially changing afferent inputs are integrated to generate a perceptual whole remains an intriguing and difficult problem in neuroscience. The sensory apparatus of the glabrous skin of the hand endows it with a capacity for mechanical sensitivity and differential discrimination matched only at the lips and at intraoral structures innervated by the trigeminal nerve. Tactile sensations are evoked by mechanical stimulation of the skin everywhere on the body surface, but nowhere in the hairy skin with the precision or variety as found on the hands and face. Patterns of nerve impulses evoked in the mechanoreceptive afferents innervating the glabrous skin as the hand moves over a two-dimensional tangible substrate,

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or equivalently, as the substrate is moved under the stationary hand, allow identification of the spatial structure, mechanical consistency, roughness or smoothness, and texture and pattern in the substrate with thresholds for detection and differential discrimination at the micrometer level (Chapter 11). The unmoving hand palpating a stationary substrate is by comparison to the moving hand relatively insensitive. It is through movement that the rich variety of tactile experience is unveiled; hence, movement is a facilitating agent for more complex tactile experiences. The continuous flow of rapidly changing somesthetic input produced by the differential movement between substrate and hand (or, e.g., by the moving tongue) is integrated in space and time to yield a perceptual whole. One example is the capacity to store in sequential order a series of tactile inputs evoked by tracing with a forefinger a two-dimensional outline, and then immediately generating from memory the complete outline. It was David Katz (1925, translated by Krueger, 1989) who emphasized that what is retained is the total tactual outline, but little of the movement sequences that generated it. Katz termed movement the “elementary formative factor in tactual phenomena,” derived from the much earlier studies of E. H. Weber. Measurements made in tasks such as the reading of Braille type by skilled blind readers or the tactile perception by one pair of hands of the American Sign Language generated by another indicate the capacity to integrate successive patterns of input to create a perceptual whole, with intracortical processing times of 80–100 msec for each pattern. The spatial sequence in which first-order afferent fibers are activated by the movement of light mechanical stimuli across the surface of the skin, as well as the temporal pattern of the evoked neural activity, allows identification of the location, direction, speed, and extent of the movement. Moreover, the spatial relationship of the activity in the population of afferents signaling the outline of a two-dimensional stimulus is preserved in the population discharge as such a stimulus moves. A variant of motion sensitivity is flutter-vibration, a dual sense evoked by local mechanical oscillations delivered to the skin. Humans sense such stimuli over a frequency range from about 5 to about 600 Hz; higher frequencies are perceived as constant. Frequencies in the range of 5–50 Hz evoke a fluttering sensation localized to the stimulus site. As stimulus frequency increases, with constant subjective magnitude, the sensory experience gradually changes to the deep, spreading, and poorly localized hum we call vibration.

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This duality of the sensory experience is produced by activity in two different sets of primary afferents with partially overlapping frequency sensitivity curves (Chapter 12). The important role of fluttervibration lies not only in detecting purely sinusoidal mechanical oscillations, which are seldom encountered in ordinary life, but also in showing that the somatic system is equipped with acute detectors of temporal transients over a considerable frequency range. Moreover, it is the sensitivity to vibration that converts the normally local sense of touch into a distant sense, for we can detect vibrations at considerable distances from the sources that generate them, sometimes for hundreds of meters. The terms kinesthesis and position sensibility designate a group of sensations that include the senses of the position and movements of the limbs and the body, the sense of force we encounter when contracting muscles against weight, and the internal sense of effort we experience when we do so. I discuss in Chapter 13 the more complex questions of the body schema and the internal image we have of the posture, form, and size of the body. The use of the moving hand to explore and identify the location, surface microstructure, size, and three-dimensional form of objects, traditionally called stereognosis, is sometimes called “haptics,” and these many complex aspects of somesthesis are collectively referred to as the haptic senses. There are no specific sets of primary afferent fibers that serve haptics, per se. The complex aspects of somesthesis called haptics are served by various combinations of afferent input in the sets of mechanoreceptive afferent fibers innervating the glabrous skin and deep tissue of the hand, which, under simpler circumstances, serve the primary aspects of somesthesis. These combinations are projected and processed within the afferent pathways and cortical areas devoted to somesthesis, simple or complex, but with particular emphasis for the latter upon the trans-postcentral areas of the parietal lobe, the several somatic sensory areas in the parietal operculum, and the further projections of these two pathways. Among these “haptic” sensibilities are those of the texture or surface microstructure of objects grasped by the hand, their roughness/smoothness, hardness/ softness, warmth/coolness, weight, global shape and volume, and detailed three-dimensional contour and form. The salient feature of all these is movement of the hand, and particular classes of movement appear adapted to seek particular classes of sensory information (Klatzky and Lederman, 1995).

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A comparison of passive tactile perceptions with those we derive from haptic explorations of objects in the local environment reveals a unique duality of somesthesis, one described by Katz in his monograph of 1925, The World of Touch (translated by Krueger, 1989). That is, we quickly identify the several varieties of somesthesis imposed upon us passively in terms of location, quality, intensity, and so forth, and signaled by activity in primary afferents. We use the same system of peripheral and central neural mechanisms in the haptic mode of the exploring hand to examine and identify the nature, form, size, and other properties we project to the objects palpated. These latter we perceive as objects, not as passively received tactile experiences. The neural mechanisms of this subtle cognitive difference are unknown.

Development of Psychophysics The quantitative study of somatic sensation began in the early nineteenth century when the German physiologist E. H. Weber (1834, translated 1978) made systematic studies of several sensory continua, including estimation of weights placed on the resting finger or lifted by the hand, of auditory pitch, and of the lengths of lines inspected visually.3 Weber discovered that over a considerable range of stimulus amplitudes the fractional increment of stimulus amplitude (∆Θ) required to produce a just detectable increment in subjective sensory magnitude is a constant fraction (c) of the starting intensity of the stimulus. This is Weber’s law:   + c ; or,   = c  The constant c is characteristic of the sensory domain under study. Weber’s law was later modified by adding a second constant, a, thought to account for the spontaneous activity in sensory systems; it allowed a better fit to the empirical data:   = c; or   = c ( + a) +a Nearly three decades later Gustav Fechner of Leipzig established psychology as an experimental science by creating psychophysics. Fechner believed that sensation magnitude could not be measured directly. He sought a method of indirect scaling as a

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way to measure the subjective magnitudes of sensations in terms of the stimuli that evoke them. He had the idea that an arithmetic series of sensation magnitudes might correspond to a geometric series of stimulus magnitudes. Fechner used Weber’s findings, and made the assumptions that since a just noticeable difference is a minimal sensory change, that all these sensory changes measured along any given intensity sensory continuum must be equal, and that such minimal sensory changes could be further reduced and treated as differentials. Fechner integrated Weber’s equation to obtain the general relationship that sensory magnitude increases as logarithmic function of stimulus magnitudes, the Weber–Fechner law that dominated experimental psychophysics for nearly a century: S = κ log Θ where S is sensation magnitude, Θ is stimulus intensity in units above threshold, and κ is a constant characteristic of the sensory modality and dimension measured. For a detailed description of the history and present status of psychophysics, see Gescheider’s monograph of 1997. We now know that while Weber’s law is correct over the central range of stimulus magnitudes, it is incorrect at the low and the high ends of many sensory continua. However, the importance of Fechner’s work was not in the faulty assumption leading to his logarithmic law, but rather in the introduction of measurements into experimental psychology, particularly his demonstration that careful, quantitative measurement could lead to general inferences about perception. Fechner’s methods of constant stimuli, limits, and adjustment form the basis for present-day designs for measuring the human capacity to detect and to discriminate between stimuli, and for their classification. His additional contribution was to use statistical methods to analyze experimental results; the mathematics of normal distributions used by him are one part of those used in modern decision and signal detection theories. Scarcely before or since has a single contribution transformed a scientific field so completely, or has had such a profound and lasting effect, as that produced by the publication of Fechner’s Elemente der Psychophysik (1860). There followed more than 70 years of measurement

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of virtually every sensory capacity humans possess. Controversy followed quickly during this time, and many modifications of the Weber–Fechner law were proposed, for it was clear from early on that over many ranges and for many sensory continua the law is simply incorrect, just as Weber’s law on which it is based is incorrect over any wide range of stimulus intensities. This detracts little from the contributions of Weber and Fechner, for the surge of interest they generated dominated experimental psychology for several generations. Interest in physical measurement reached a plateau in the 1920s–1930s, so that Boring lamented in his history of sensation and perception (Boring, 1942): “The two dreary topics in the history of experimental psychology, so convention has it, are nativism and empiricism, on the one hand, and psychophysics on the other.” Boring’s comment was written only a few years before several new advances energized perceptual neuroscience. The first was the development and validation by Stevens (1957) of the method of direct scaling over many sensory continua; the second was the development of the theory of signal detection, which provided a framework for analyzing the task of perceptual detection by observers seeking maximal performance in the face of unpredictable variability and unknown, nonsensory factors (Tanner and Swets, 1954; Green and Swets, 1966). These major events occurred just as the electrophysiological study of sensory systems gained momentum, from 1940 on. The new discoveries in both neurophysiology and psychophysics during this period set the stage for the development of the combined experiment in which both behavior and brain activity relevant to it are observed simultaneously. Since 1960–1965, this has been the most productive means of studying brain mechanisms in both humans and in nonhuman primates, particularly for the central nervous mechanisms in sensation and perception. It has opened for study the black box of Fechner’s “inner” psychophysics, the brain mechanisms of perception, and many other aspects of brain function as well. It is obvious that the correlation between psychophysical measures of sensory performance and the peripheral and central neural activities evoked by identical stimuli used in the two cases is a difficult theoretical and practical experimental problem, but one whose solution is essential for the progress of perceptual neuroscience.

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The New Psychophysics and the Psychophysical Law Although the Weber–Fechner logarithmic law achieved canonical status in the half-century after Fechner, cases accumulated in which it did not reflect reality; however, it was not until the 1930s that viable alternatives were put forward in the form of direct scaling. It was in the rating of loudness by acoustic engineers that the Fechner scale failed to reflect the growth of the sensation of loudness as sound intensities were increased. Churcher (1935) summarized the work of several engineers, particularly that of Richardson (Richardson and Ross, 1930), who measured loudness of sounds by the direct, quantitative estimation of human subjects who were asked to set a test tone as a fraction or a multiple of a standard tone in terms of relative loudness. Stevens and his colleagues modified this method of fractionation to one they called magnitude estimation, in which subjects are asked to report directly on the intensities of sensations by assigning numbers to them. The data obtained by Stevens and Galanter (1957) in a study of a dozen sensory continua showed that subjects did this reliably, and that the functions relating magnitude estimations to stimulus intensities are power functions of the general form S = κΘa + c, where S is the numerical report of the sensation magnitudes evoked by the stimuli, Θ; a is the slope parameter of the function plotted in double logarithmic coordinates; and c is the intercept. The exponent a varies for different sensory continua, from 0.33 for brightness to 3.5 for electrical shock to the finger (Stevens, 1957, 1959a, 1960, 1961, 1970; Marks, 1974; Galanter, 1984). Some researchers assigned an exponent of 3.5 to pain on the basis of the sensations evoked by electrical stimulation of the skin. This is incorrect because electrical stimulation of the skin activates in synchrony many classes of afferent fibers, including at highest intensities nociceptive ones, a combination that evokes a series of equally confusing sensory experiences. Later studies of the warmth–pain continuum using changes in the temperature of the glabrous skin of the hand, produced by a laser-powered radiant heat stimulator, showed that over the narrow range of 2–1 from the pain threshold to the level of severe pain the subjective magnitude estimates of human subjects are fitted with power functions with exponents slightly above 1.0 (LaMotte and Campbell, 1978). For the glabrous skin of the hand of the monkey this transform is set at the level of the C-fiber afferents whose intensity functions are fitted

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with power functions with exponents of about 1.2; see Chapter 7. These correlated studies confirm in another modality the law of correspondence described below, derived originally from studies of mechanoreceptive sensibility. The concept that equal stimulus ratios produce equal ratios of sensation magnitudes originated in the studies of visual perception by Plateau (1872). It was used to derive what is now usually called Stevens’s law, based on the widely confirmed observation that magnitude estimations measured for a variety of sensory continua increase in proportion to the physical value of the stimulus raised to a power. Many publications have appeared over the last 50 years supporting either Fechner’s or Stevens’s law, and many describe efforts to reconcile the two (MacKay, 1963; Krueger, 1989; Norwich, 1993; Norwich and Wong, 1997).

The Law of Correspondence It has now been shown for the somesthetic continua of touch, roughness, texture, warming, cooling, flutter-vibration, and pain, and much earlier for taste, that the value of the exponent p is set by the initial transduction and encoding phase at the peripheral interface. The governing influence of the transformation at the stage of peripheral transduction is especially clear for several mechanoreceptive somesthetic modes, in which the frequency of impulses in primary mechanoreceptive afferents, and in the population signals generated by the stimuli, are power functions of stimulus intensities, with an exponent identical to that characterizing the psychophysical relationship for the identical sets of stimuli. These observations support the general hypothesis that relations between the physical values of stimuli and our perceptions of their magnitudes are set at the level of peripheral induction and encoding (Mountcastle, 1966, 1967, 1984, pp. 367–369; Stevens, 1970). A comparison of the input, defined as activity in first-order fibers, with the subjective perceptual experience or behavioral response, reveals no transformations over a range of stimulus values for which the functions relating the two are uniformly consistent. This means that central neural mechanisms follow in correspondence their primary afferent drive; and, as Johnson has emphasized, this consistency is the critical test for any neural coding hypothesis (Johnson et al., 1999, 2002).

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This general proposition is independent of whether transformations intervene at one or another stage of the central processing mechanisms, so long as their overall sum is in correspondence with the firstorder afferent input. In general, the proposition to be tested is that peripheral sensory mechanisms set the psychophysical relation between sensation and stimulus values over a considerable range of the latter. If non-correspondences are found, the experimental task is to determine where in the central neural networks those transformations take place. The measurement of behavior with quantitative methods that originated in psychophysics has now become a standard method in much of experimental neuroscience—in experimental venues broader than measurements along sensory intensive continua that occupied Fechner and those who followed him.

Single-Neuron Studies of the Somatic Afferent System The first era of cortical mapping with the evoked potential method was followed by one in which microelectrode recording of the electrical activity of single neurons in the system was used as a mapping tool (1950–1970). This produced a series of new discoveries described more fully in later chapters, and listed here in abbreviated form. 1. Somatic sensory areas of the neocortex are organized in a columnar manner. 2. The postcentral gyrus, previously thought to contain but a single geographic map of the body surface, contains four, one in each of the cytoarchitectural areas of the gyrus. 3. Somatic sensory cortical maps can be changed by changing their afferent inputs by suitable peripheral manipulations, and this plasticity persists in adult life. (Chapter 15) 4. Differences in the sizes and detailed patterns of representation in the somatic sensory areas of conspecifics are attributable in part to differences in life experiences. 5. Specificities for place and modality of the A-beta mechanoreceptive afferent fibers, for example, those from the hand, are preserved in their projection into the primary somatic receiving areas of the postcentral gyrus with limited spatial convergence within modalities. Convergence between the

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mechanoreceptive modalities occurs to any significant degree only in trans-postcentral cortical areas. 6. More complex properties of peripheral somatic sensory stimuli are signaled at all levels by the activity in neural populations, and are seldom derived by analysis of the discharge pattern in any single neuron. 7. The temporal precision and modality specificity of the lemniscal system is maintained through the system to the somatic sensory area of the cortex in spite of the nuclear convergence of small-fibered afferent systems at several levels.

The Combined Experiment A continuing effort in neuroscience has been to measure the perceptual behavior of primates, observe simultaneously the activity in their brains during those perceptions, and correlate the two, beginning with the development of methods for recording the electroencephalogram (EEG) by Berger, three-quarters of a century ago (for Berger’s 14 papers, see Gloor, 1969). Berger proposed that explanatory correlations be sought between the oscillatory wave patterns of the EEG and human behavioral states. During the following decades Berger’s program was expanded by investigators who sought those correlations in almost every conceivable state, including psychotic conditions. Leaving aside important discoveries of the EEG patterns that characterize sleep, coma, anesthesia, and epilepsy, the hope that the EEG might be used to characterize the brain operations in relation to normal behavior has not been fully realized. One reason may be that the EEG patterns as traditionally recorded are ambiguous reflections of the neural activity in the brain. New methods of recording and analysis give hope for resolving this dilemma. The development of the EEG led to the evoked and event-related potential methods for the study of cortical mechanisms in somesthesis, particularly for mapping the somatic sensory areas of the cortex, described in Chapter 10. A major development in perceptual neuroscience of the last several decades has been the union of neurophysiology and psychophysics— the latter expanded to include many aspects of behavior, as well as perception. The simultaneous recording of behavioral performance

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and of brain events in humans and nonhuman primates is now the most successful approach to the problems of the brain mechanisms in the many varieties of perceptions, especially somesthesis. An important step was the demonstration that methods for measuring sensory performances in humans could be adapted, by operant conditioning methods, to measure similar behavior in nonhuman primates (Stebbins, 1970; Stebbins et al., 1984). A second pivotal discovery was that humans and nonhuman primates have virtually identical capacities over a wide range of somesthetic domains. A third was the demonstration that the electrical signs of the activity of cortical neurons could be recorded under stable conditions in waking monkeys as they executed behavioral tasks. The method was introduced by Herbert Jasper and his colleagues (Jasper et al., 1960), and elaborated by Edward Evarts for his studies of the motor cortex (Evarts, 1966). Many studies of the central neural mechanisms in somesthesis are made using this combined experimental approach. Experiments are made in waking nonhuman primates as they execute somesthetic tasks that vary from the simple ones of detection, discrimination, and rating to those with greater cognitive demands, including attention. Several methods of recording the relevant neuronal activity are used. Perhaps the most productive continues to be the recording of the electrical signs of neuronal impulse discharge with microelectrodes inserted into areas of the cerebral cortex and into connected subcortical structures. The method has now been expanded by the introduction of multiple microelectrode recording from large numbers of chronically implanted microelectrodes. This allows the study of patterns of activity in neuronal populations simultaneously, and will shortly be incremented to permit recording from many neurons in nodes of widely distributed systems of the cortex and its connected structures. This is particularly promising for study of neocortical mechanisms in the somatic–motor interfaces, for example, that between the somatic areas of the parietal lobe and the premotor areas of the frontal lobe that are densely interconnected and simultaneously active in the complex cortical operation of reaching and grasping. The method depends on the careful selection of the perceptual tasks and training of monkeys to execute them, and on stable and long-time recording in brain regions selected on other grounds as putatively related to the behavioral task under study. A third requirement is the correlation on a trial-by-trial basis of behavioral and

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neural events observed, with particular attention to trial failures. The method has been elaborated to allow tests of hypotheses concerning candidate neural codes, including population codes, and the covariations between elements within a population that appear to be important for the detection–discrimination process (see Parker and Newsome, 1998). It is recognized by many investigators in the fields of perception that the tasks used in the laboratory setting of the combined experiment are pale images of the perceptual operations of nonhuman primates operating freely in a natural environment. The next and difficult step will be to study brain mechanisms in perceptual operations occurring naturally in humans and nonhuman primates with telemetered signals of intracranial neural events. Equally important experiments are made in waking humans as they execute somesthetic tasks. Several methods are used to measure brain activity, including evoked and event-related changes in electrical activity recorded from the scalp with either electroencephalography or magnetoencephalography. Intensive use is now made of a number of rapidly evolving methods of brain imaging based on changes in local cerebral blood flow and oxygen consumption that occur in and around active neuronal populations (Roland, 1993; Paulesu et al., 1997; Raichle, 1999; Vanzetta and Grinvald, 1999). These studies have revealed that when humans perform somesthetic tasks, regions of the cerebral cortex are activated that could not be predicted from prior knowledge. Some of what has been learned with these methods will appear in later chapters. Until now, imaging methods have yielded valuable new geographic information, and the central problem of the relationship of these changes to the patterns of activity in the related populations of neurons can now be attacked directly. One method is to record simultaneously in nonhuman primates the activity of large numbers of cortical neurons, and the light emitted from those neurons by reflectance or that emitted by voltage-sensitive membrane molecules that may occur naturally or be embedded in neuronal membranes experimentally (Grinvald et al., 1988, 1991; McLoughlin and Blasdel, 1998). The solution of this problem will add great power to the imaging methods. All of these methods appear to be constrained for the present to the range of the pre-conscious processes leading to perception. Until now, only a few experiments have been designed to target the neural processes of conscious perception, somesthetic or otherwise, and

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if that pattern of neural activity has ever been recorded it has not been recognized, beyond the well-known electroencephalographic patterns of the waking, attending brain in contrast to those of the sleeping brain. Intermediate levels of cerebral mechanisms in somesthesis remain the subjects of intensive research. I believe this is just the right level at the present time, sustained by the conviction that a better understanding of these intermediate processes will lead to direct experimental studies of the conscious perception of somesthetic events (Tononi and Edelman, 1998).

Perceptual Neuroscience and the Philosophical Position In earlier decades, the neuroscientist working in the field of somesthesis could pursue his or her experimental objectives unconcerned with whether the results he or she obtained had philosophical implications. That situation has changed in a dramatic way, for now philosophy takes a place on stage. This is a sign of the success of the brain sciences over the last half-century, during which we have moved from the study of the reflex activity of the spinal cord to the study in realistic terms of the brain mechanisms at the highest level, those aspects of human behavior commonly labeled cognitive. Few proponents of the classical dualistic position remain on the scene, at least not among neuroscientists. The vast majority have as a working hypothesis some form of objective realism—that things mental, indeed minds, are emergent properties of brains (Bunge, 1980, 2003; Bunge and Ardila, 1987). The central idea is that the general properties of a complex system like the brain are emergent, and may be understood in terms of the elements of the system and their couplings. System properties are not the simple sum of similar properties over the elements of a population, but emerge from the dynamic interactions between elements of the system that yield general system properties not displayed by any single element in the system. It is possible to postulate on this principle that every “mental” process is generated by a brain process, but that mind and brain are not identical; the former emerges as a product of the function of the latter. The emphasis is that the brain is not a machine, but a biological system with its own evolutionary and ontological history, with properties that appear to be unique among all known systems in the universe. While all conscious mental states are produced by brain states, the reverse is not true. Only the results of those complex operations

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flow seamlessly across some vaguely defined and continuously changing threshold to conscious perception. Consider, for example, the mechanisms guiding the projection of the arm and shaping of the hand in reaching for a target. Here the highest-level interactions between the parietal and frontal lobe functions are involved in generating the proper motor output—all of which proceed outside conscious experience. They can be brought to conscious experience by attention, but then the reaching movements may be less accurate! How operations such as these and others of everyday perceptual experience may reach conscious awareness is a formidable experimental task in neuroscience. The word “consciousness” designates a class of phenomena with different properties that have awareness in common. We are aware of self; of internal operations such as thinking, remembering, and planning; and of sensory stimuli. We are aware when we intend to act and when we do so. Without some unpredictable discovery, I believe it is not yet possible to study “awareness” directly. What we can study now at the level of brain mechanism is the chain of brain events set in motion by sensory stimuli, and follow them through the processing operations of the distributed systems of the neocortex; to mechanisms for efferent action; and, it is surmised, to those that do flow through to conscious experience. Confidence is strong among neuroscientists that the steady accumulation of knowledge of these high-level operations in the cerebral cortex will ultimately allow them to close in on the problem of the neural mechanisms of consciousness itself. N OTES 1. According to Esolen and other historians this ancient idea came originally from Leucippus (?460–370 B.C.). It is put powerfully in several places in Lucretius’s long poem De rerum Natura (Esolen’s translation, 1995). Lucretius is thought to have lived from about 99 B.C. to 55 B.C., but the date of publication of De rerum Natura is unknown. 2. The eight sets innervating the glabrous skin of the monkey hand are: the A-beta large mechanoreceptive afferents that terminate in Pacinian, Merkel, and Meissner’s “sensory organs”; the C-fiber innocuous warming; C-fiber noxious heat; C-fiber polymodals; A-delta cooling; and A-delta nociceptive afferents. Further divisions of some of these based on differences in functional properties

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can be made, but multiplication of classes serves little useful purpose, particularly because the functional properties observed for some classes, for example, the C-fiber nociceptive afferents, depend on the condition of the peripheral tissues such as presence of hyperalgesia. In some studies of the innervation of the human hand a fourth large slowly adapting mechanoreceptive afferent set terminating in Ruffini end organs has been identified, but whether its activation evokes any conscious somesthetic perception appears to be unlikely; such a set does not exist in the innervation of the monkey hand. The large fibered stretch afferents from the short muscles of the hand and long muscles of the forearm should also be included, for they may play a role in position sensibility (Chapter 13). 3. It is rarely given to any investigator to establish through his own direct experimentation an entire field of science. That is what E. H. Weber did in the period 1830–1850, described in two classic essays written in Latin; their abbreviated titles are De Tactu (1834) and Der Tastsinn (1846). These foundation publications of somatic sensory psychophysics have been translated into English several times, most recently by Ross and Murray. Weber lived from 1795 to 1868; he was successively Professor of Anatomy and then Physiology in Leipzig. He is most widely known for his— not quite correct—law stating that the discriminable increment in the value of a stimulus is always a constant fraction of the base stimulus strength, and so forth. The law holds over the midrange of values, but deviates for weak and strong stimuli. Nevertheless, this generalization energized Fechner, who went on to establish psychology as a scientific discipline, largely through his monograph of 1860. The advantage of hindsight allows us to say that Weber’s most significant contributions were in his studies of cutaneous sensibility, made in a long series of detailed experiments carried out mainly on himself, in which he created the field of tactile psychophysics.

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Perception and the World of Somesthesis

The Evolution and Structure of the Hand

The descent from the trees; the assumption of the bipedal stance and way of going; and the delayed, postnatal enlargement of the brain are salient features of hominid evolution. Hands are ancient structures, the mammalian continuance of a morphology of reptilian origin. Over the history of the primate radiation from the paleocene–eocene period, 65–55 mya, hands retained many primitive characteristics, but also evolved changes as primates adapted to different environmental niches and used different modes of stance and locomotion. Among living species, these modes vary from the vertical climbing, clinging, and leaping of euprimates and prosimians; to the horizontal quadrupedalism and intermittently upright posture of Old World monkeys when sitting; to the scrambling and brachiation of gibbons and orangutans; to the terrestrial quadrupedalism with knucklewalking of the African great apes; to the upright posture and bipedal locomotion of hominids, including humans. Each of these postures and modes of traveling was enabled by adaptive changes in hands, feet, and limbs and by the elaboration of the motor control systems of the brain (Lewis, 1977, 1989; Skelton et al., 1986; Beard, 1991; Godinot and Beard, 1991, 1993; Linscheid, 1993; Gebo, 1996). Two changes in the course of hominid evolution were the transition of the functions of the hand from weight-bearing and progression to manipulation, when the early australopithecines assumed the bipedal mode of progression, and the enlargement of the brain in the successive species of the genus Homo. The Hominidae are thought to have arisen from the stem Hominoidea about 7 million

2

years ago by a split from an uncertainly identified ancestor that yielded the australopithecines and the pongids. Which of the australopithecines first assumed the mode of bipedal stance and progression is uncertain. Several species of this genus have been identified, with sometimes overlapping dates of origin and extinction in the critical transition period. Figure 2–1 gives one example of a branching

Fig. 2–1 Time line showing a scheme of the possible relationships between various hominoidea, with starting point at the conjectured emergence of bipedalism. (The drawing was prepared by Ian Tattersall and is reprinted from Wilson, 1998.)

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tree to show the lifelines of the australopithecines, from some of the earliest identified: Australopithecus ramidus and A. afarensis, dated to 4.3–4.5 mya. It is unlikely that these species can be arranged in any linear order of descent, and many paleoanthropologists favor the branching tree rather than the linear ladder model of hominid evolution. The former are diagrams of proposed evolutionary trees derived from analyses of features shared and derived between different species (Skelton et al., 1986). The tibia of A. anamensis suggests that he was bipedal (Leakey et al., 1995); however, the footprints discovered by M. Leakey in volcanic tuft at Laetoli, dated to about 3.5 mya and assigned to A. afarensis, provide evidence for bipedalism in this species (Leakey, 1981). Regardless of which of these hominids (or some unknown predecessor) was the first to stand and walk erectly, and whether he did so intermittently while still retaining some arboreal habits, the assumption of bipedalism initiated the evolutionary path leading to the genus Homo and eventually to ourselves. It freed the hand. Although the earliest known australopithecines were committed bipeds, they retained some skeletal adaptations for arboreal life. Adaptations for bipedalism led to more rapid changes in the hindlimb for action in the upright position, while more primitive characteristics were retained in the forelimb (McHenry, 1982). A reliable sign of a retained adaptation to arboreal life is curvature of the phalanges of hand and foot. Measures of this curvature in terms of the “included angle” are given in Fig. 2–2 (Stern and Susman, 1983; Susman et al., 1984; Stern et al., 1995). The results place A. afarensis within the range of the African apes, the chimpanzee, and the gorilla, with much less curvature than that in the hands of the brachiators, but more than that in the hands of humans. The hand of this early australopithecine was as much a branch-grasping as a manipulative organ, and for this reason he is regarded by some authorities as transitional between earlier quadrupedal hominoids and the genus Homo. At this time, the pelvis, legs, and feet were adapted for bipedal progression with changes efficient for running, which may have been the only means of escape for weaponless early hominids aground in a hostile environment filled with aggressive, toothed carnivores. The first australopithecines to assume bipedalism did so with a brain size of 425–450 g, no weightier than those of ancient or modern pongids. The hand of A. afarensis shows no sign of having been

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Fig. 2–2 Box and whisker plots show the normalized curvature movement arm (above) and the included angles (below) calculated for the hand proximal phalanges for humans and selected nonhuman primates. The lowest plot is for A. afarensis. Each box represents the interquartile range, and the vertical line the median. Numbers in parentheses = number of phalanges examined in each taxon. Increased phalangeal curvature is interpreted as adaptation for life in the trees. (From Stern et al., 1995.)

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used in quadrupedal locomotion, but retained some characteristics suitable for arboreal life: long fingers with curved metacarpals and phalanges; a short, stout thumb with only pseudo-opposability; carpals resembling those in living chimpanzees; limited forearm rotation; lack of individual control of the fingers; and a cranially directed glenoid fossa of the scapula, which allowed a degree of shoulder abduction suited to arboreal life (Stern and Susman, 1983). There followed a period of what may have been evolutionary stasis, which, absent new evidence, lasted nearly a million years after the adoption of bipedality by the australopithecines. It was broken by the appearance of a new species of a new genus. The newcomer was Homo habilis, who appeared about 1.6–2.3 mya, with important new equipment and capacities (Leakey et al., 1964). He possessed a brain enlarged by 50 percent to 650 g, and the ability to make and use stone tools—hence his name. It may be that the more advanced australopithecines, A. boisei and A. robustus, form a link from the early australopithecines to H. habilis, for they lived contemporaneously with him (Fig. 2–3), and there is some evidence that they used stone tools; for descriptions of the development of tool use, see Berthelet and Chavillon (1993). Tobias summarized the evidence for the hypothesis that H. habilis possessed the cerebral machinery for verbal communication: a remarkable increase in brain size; the presence of protuberances in regions of the endocasts appropriate for Broca’s cap and Wernicke’s area; a frontal lobe sulcal pattern resembling that of H. sapiens; and cultural activity including tool-making which Tobias suggests is required for generational transmission, a more efficient method of communication than imitation (Tobias, 1991, 1995). Whether this inferred capacity for verbal communication arose de novo in H. habilis is uncertain, for there is some evidence that the brain of the robust australopithecines contained rudimentary Broca caps and Wernicke areas. H. habilis possessed a strong and heavily muscled hand with curvature of both proximal and middle phalanges, adapted for grasping. He was the most ancient hominid to possess the expanded first metacarpal head characteristic of hands capable of precision grips (Stern et al., 1995; Susman, 1994). A rudimentary saddle joint at the 1st carpometacarpal joint and expansions of the tips of the distal phalanges allowed him to maneuver objects between thumb and fingertips, while holding them firmly. The habilis hand shows

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Fig. 2–3 The progress of encephalization in hominids, indicated by the encephalization quotient (E. Q.—circles). Trend initiated with H. habilis, accelerated in the time of H. erectus, and into the early times of H. sapiens. Absolute endocranial capacity (A. E. C.) and mean body size are indicated for each taxon. (From Tobias, 1997.)

significant advance toward the human condition over that of the australopithecines, but retained some adaptations for arboreal climbing (Godinot and Beard, 1993). It is conjectured that the simultaneous development of the hand and a further refinement of an acute stereoscopic vision occurred in step with increasing brain size, and that together these enabled tool-making in H. habilis. Napier has emphasized tool-making over tool-using, for the manufacture of a tool is a creative event, and the manufacture of any tool more complex than a simple stone chip may require that the image of the tool be conceived by the tool-maker before manufacture begins (Napier, 1993). The development of manual dexterity in tool design and use as well as increase in brain size are believed to have been interdependent processes.

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Evolution of the Primate Hand The line of evolution in the genus Homo leads from H. habilis to H. erectus, who appeared about 1.3 mya. It remains uncertain whether H. habilis, H. erectus, and H. sapiens evolved in succession by phyletic trend, or whether they represent the results of separate cladistic events. Regardless of that uncertainty they compose a sequence characterized by enlargement of the brain and the successive evolution of primate culture and technology. It is unfortunate that in the midst of a large fossil collection of H. erectus, there does not exist a complete hand. The otherwise nearly complete skeleton of an adolescent male H. erectus discovered by Walker and Leakey (1993) contains only two phalanges and two metacarpals. A single wrist bone was recovered with the Peking hominids. While there are few fossilized hands of H. erectus to examine, there is evidence of what those hands produced in the increasingly sophisticated stone tool cultures that characterize the more than 1.5 million years of his life before the appearance of H. sapiens. It is commonly said that the human hand is a primitive organ, a representative of one that emerged early in the long history of primate evolution. This is astonishing, if true, given the skilled movements humans execute with their hands. These functional capacities are frequently and perhaps correctly attributed to the central neural mechanisms controlling the hand, but it is worth asking whether any derived structural features of the human hand itself may have contributed in an enabling way to the operations of those central neural mechanisms. It appears certain that the evolution of the powerful and opposable thumb, the high density of sensory innervation of the glabrous skin of the hand, and the central control of skilled and independent finger movements have contributed to the development of the skilled hand operations of humans. The history of primate hands reveals that many transformations of structure and function in the motor sphere preceded the evolution of the hand in modern humans. The human hand shows, in addition to some retained signs of a primitive structure, the recent acquisition of new motor capacities. What is so startling is that the repeated adaptation of hands to different functional niches that primates occupied occurred without significant changes in the sensory apparatus of the hand. Fossils provide no information about that sensory

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apparatus. We can only make comparisons between the sensory innervation of the human hand and those of extant African monkeys and apes. It is a remarkable example of convergent evolution that the sensory innervation of the hand of the macaque monkey is similar to that of man, with one exception, the presence of skin-stretchsensitive slowly adapting type II (SA-II) afferents in man, which contribute to the control of finger position and movement. Similarities are shown by the structure of the afferent innervation of the two hands, and by the functional properties of the myelinated afferent fibers that terminate in those receptors, paralleled by the identical performances of monkeys and humans in somesthetic tasks. Little is known of the functional properties of the afferent fibers innervating the hands of the great apes, but their histological structure is so similar to those in macaques and humans that one can predict with reasonable certainty that their functional properties are similar. The classical description of the structure of the human hand is that of Sir Charles Bell (1811, 1840). For an entertaining monograph, see The Hand by Charles Wilson (1998).

Macrostructure of the Hand On casual inspection, the hands of monkey and man appear remarkably similar. A few moments’ observation of those hands in action reveals the adroit manipulative capacity of the human, a skill of a different order from that which any monkey displays. This capacity for motor control enables the elegant sensory function of the hand in haptic perceptions. An important feature of the human hand is its long and powerfully muscled thumb (see that of the mother’s in the frontispiece photograph), the movements of which are essential to all skilled manipulations. The most obvious of these essential movements is the opposition of thumb and fingertips, which anthropologists regard as an important structural adaptation in human evolutionary history. Opposition is a finely controlled combination of flexion, adduction, and rotation that moves the thumb to meet the approaching, flexing finger movements, so that the pulp surface of the distal phalanx of the thumb is placed squarely in contact with one or all of the other digits (Fig. 2–4). This movement is permitted by a nearly perfect saddle at the first carpometacarpal joint and by the partial freedom of the fingers to rotate and move from side to

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Fig. 2–4 Contact areas in precise grasping: a = human, b = gorilla, c = chimpanzee, d = bonobo, e = orangutan, f = gibbon, lar = moloch. Darker areas are more often used than the lighter areas. (From Christel, 1993.)

side at their metacarpophalangeal joints when flexing (Koebke, 1983). Movements and positions of the hand, such as those shown in Figs. 2–5 and 2–6, are produced by the actions of 35 muscles (or 44 if one takes into account the three muscles that each have four insertion tendons) that control the movements of the 27 bones of the

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Fig. 2–5 Four positions of the human hand commonly used. From above, divergence, convergence, prehensibility, and opposability. The elegance and exactness of the last is unique to humans. (From Napier, 1993.)

hand at their joints. The hand has about 25 degrees of freedom, in contrast to the 6 degrees of freedom of the objects it grasps. Some of the muscles operating at the thumb are uniquely developed in humans, and contribute to their capacity to oppose. These are a fully developed flexor pollicis longus, a separate extensor pollicis brevis, a

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The Evolution and Structure of the Hand

Fig. 2–6 The human hand writing, one of the most elaborate manual exercises. (From Jouffroy et al., 1993.)

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separate abductor pollicis longus, and a fully developed opponens pollicis. These muscles are weakly developed and frequently absent in pongids. Some degree of opposability may have been possible in early primates, perhaps in what Napier called pseudo-opposability, a form with limited thumb rotation seen in living monkeys (Napier, 1993). Apes have a more elegant capacity for opposition, as shown in Fig. 2–4, but are handicapped by their short thumbs in making true opposition to the finger pads. These developments allow humans a number of power grips well adapted for the use of tools at high forces, as well as a wide variety of precise operations such as those shown in Figs. 2–5 and 2–6. It seems likely that it was with the evolution of these precision grips and the central neural mechanisms to generate and control them that man could progress to the artistic accomplishments of the neolithic period, and to the highly evolved cultures that followed with the synthesis of manipulative and intellectual skills. In Landsmeer’s words: In man, with a full-fledged thumb, a functional universe or continuum has emerged, not impaired by any specific functional demand. The thumb as a most versatile component provides an opposing force to the fingers which are paired II-III and IV-V. Varying magnitude and direction of opposing forces yield specific data on qualities of objects held. Because of the setting of metacarpals II-V and the presence of a fullfledged thumb, the human hand is capable of a continuous perception of the universe it can hold, and of a unique encoding of each discrete situation. The quality of the hand finds its corollary in development of cortical structures and areas involved in processing this information. (Landsmeer, 1992)

While the invention of tools was a factor in encephalization, it is the capacity of the hand for making small, precise movements that is of interest as regards its sensory capacity. Movements pass the sensory receptor sheets of the hand over and around objects palpated. These movements occur in rapid succession and evoke sequential sets of afferent input that are integrated in time and neural space within the somatic areas of the cortex to create a dynamic, ongoing, neural image of the texture and three-dimensional structure of the object palpated. Moreover, there is some evidence that the central neural signals driving the movements of the hand provide central re-entrant signals of hand positions and movements. Finger movements are carried on precisely controlled movements of the hand as

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The Evolution and Structure of the Hand

a whole, as well as on movements of the wrist, elbow, and shoulder. When all are considered, there is scarcely a muscle in the body that is not active in one or another manual operation. The combination of all these yields a large number of degrees of freedom of the hand in palpating and sensing of shape, in contrast to the limited number of degrees of freedom of the objects palpated. The result is that many movement trajectories are open to the sensing hand.

Postures and Movements of the Hand The posture of the hand at rest varies between individuals and in single persons from time to time, but those shown in Fig. 2–5 are commonly seen. In the rest posture, the elastic components of tendons and ligaments are at minimal tensions, and the intrinsic muscles of the hand are as near as ever to rest lengths, with minimal afferent discharge from their stretch and tension receptors. The rest position is maintained in part by the low-level, continuous action of the flexor digitorum profundus, a muscle with four neuromuscular regions and a complex common tendon that then divides to serve digits II–V (Schreiber et al., 2001). A wide variety of skilled movements of the hand can be initiated from this posture. Consider, for example, the movement of the hand in prehension; from this position of rest forward to surround and grasp a three-dimensional object. The initial movements of the hand on the extending arm are extensions and fanning abductions of the digits, which, while moving toward the target, form a spatial contour to fit its size and threedimensional shape derived from visual inspection of the target, or a learned spatial image recalled from memory. This spatial spread and the curving apposition of the fingers to the object about to be grasped, the wrist rotation in anticipation of object orientation, and closure at the moment of the grasp itself, generate patterns of afferent nerve impulses essential for three-dimensional form detection and discrimination. Stereognosis depends on simultaneous afferent inputs from the skin, joints, and muscles of the hand. Which of these sets of afferents is of cardinal importance in stereognosis is uncertain, and perhaps no one more than the other. Alternatively, from this rest position any of a multitude of small, skilled movements can be initiated, as in writing or in using small tools. In contrast, from this same position the hand suddenly may be converted to a fist and, carried on a stabilized and rigid wrist, used for aggressive action.

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Goal-directed movements such as the reach to grasp are now studied intensively with a variety of methods, in both humans and nonhuman primates. The dual nature of the action has been confirmed by many since its description from film studies by Jeannerod (1984, 1988). The subject includes both general and specific aspects of motor control. A more general question is the nature of what are called motor programs and how they are formed, stored, and emitted by the nervous system. It is thought that the two phases of the reach and grasp movement are driven by independent “programs.” How then are the two sequenced so smoothly to achieve the seamless transition from the high-velocity projection of the arm to the second phase with its in-flight molding of the hand to match the target? Perhaps the most difficult of all is the coordinate transformation problem, the change from the initial retinocentric coordinates of the visual fixation of the target to a representation in an appropriate set of joint angles at the shoulder, elbow, and wrist to specify the arm rest position, and then in another coordinate set oriented at shoulder or on the object itself to select a particular arm and hand trajectory to the target (see Soetching and Flanders, 1992; Lacquiniti et al., 1995; Soetching et al., 1996). While many skilled movements of the hand can be executed by actions of the muscles of the hand and arm alone, many others depend on coordinated action in virtually the entire body musculature. The hand can be brought accurately to any reachable point in surrounding space as well as to any location on the surface of the body, except the upper back, and act with precision at all points. Consider, for example, the motor control of the hand of a baseball pitcher as he releases a 90 mph (144 km/h) fastball accurately to a small target 60.5 ft (18 m) away. His hand speed at the point of release is at least 132 feet/sec (40 m/sec). The manual release occurs within the last foot (30 cm) of hand movement and frequently includes imparting spin to the ball, all within no more than 8–10 msec. Moreover, accurate placement of the forward striding foot within a range of no more than a few inches is essential for throwing strikes. Precise movement of the hand in this case depends on the coordinated action of the entire body musculature, including those of trunk, leg, and foot. These movements are learned over many years of practice, and are thought to be preprogrammed (Hore et al., 2001), but they are emitted on each occasion under direct conscious control, for any wavering of attention to the details of the movements

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may lead to errors. The release action depends on a continual afferent input from the hand; even a slight disruption of the sensory function of the hand (e.g., a small blister) renders it useless for pitching. Leaving aside the limited sensory capacity of the passively receptive, unmoving hand, it is clear that the complex somesthetic capacities of the hand are sensory–motor in nature, as indeed are the precise motor functions of the hand that depend critically on this linkage. It is through manual explorations of the objects around us that we gather detailed information of their shape, size, and quality. The sensory capacity of the immobile hand is limited, for example, the insentient hand of the congenital hemiplegic. The nature of the central neural mechanisms generating and controlling hand functions in humans is a central theme in the field of motor control. For reviews, see Elliott and Connolly (1984), Preuschoft and Chivers (1993), Bennett and Castiello (1994), Wing et al. (1996), and Bizzi and Mussa-Ivaldi (1998); for a review of the ontogenesis of the hand, see Christ et al. (1986).

General Description of the Skin of the Hand The skin is a large and functionally diverse organ. It makes up 10–16 percent of body weight, covers an average of 2 m2 of body surface, and generally varies from 1.5 to 4.0 mm in thickness, but is exceptionally thin in the eyelid (0.2 mm) and thick on the sole of the foot (6 mm). The skin is a protective and an interpretive interface between the body and the environment, regulates fluid and electrolyte balance, and is an essential organ in temperature regulation. Through its appendages (nails, hair, etc.) the skin plays roles in functions so diverse as prehension and sexual identification. The general properties of the skin vary not only with age, race, and sex, but in any single individual they may also vary from the skin at mucocutaneous borders; to the hairy skin which covers most of the body; to the hairless (glabrous) skin on the ventral surfaces of the palms, fingers, and soles of the feet (Fig. 2–7). Hairy skin contains pilosebaceous units; and both hairy and glabrous skins are densely supplied with sweat glands. The distribution of hairs and the associated structures varies in different regions of the body, but the hairy skin serves everywhere as both a protective surface and as a sensory interface (Montagna and Parakkal, 1974; Odland, 1991).

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The Evolution and Structure of the Hand

The glabrous skin is characterized by the alternating papillary ridges and grooves. The lower levels of the epidermis are arranged in alternate folds, or ridges. The limiting ridge is fixed to the underlying collagenous structure of the dermis; the intermediate ridges are free to swing laterally in the dermis, a motility that may play a role in sensory function. The sensory functions of the glabrous skin of the hand are served by an interdigitated mosaic of afferent nerve fibers that terminate in the skin directly; or, in some cases, in multicellular receptor organs within or beneath the skin. The dermis and epidermis are flooded with the unencapsulated endings of the thinly myelinated and unmyelinated fibers. This neural interface provides filtered signals of the locations, intensities, qualities, and spatial and temporal patterns of the stimuli impinging on the surface of the skin of the hand. These patterns include sensitivities to the many varieties of mechanical force, to heat and cold, and to stimuli that tend to destroy tissue. The skin is a viscoelastic, virtually incompressible medium possessing physical properties that contribute importantly to the mechanical transducer mechanism; these physical properties are mass, stiffness, and resistance. The skin consists of two major tissue layers, each further divided into sublayers. The outer layer is stratified epithelium, the epidermis, which is 50–150 µm thick in hairy skin and twice that in glabrous skin. The inner layer is a dense fibroelastic matrix called the dermis, which makes up the principal mass of the skin. The dermis consists of fibroblasts and the extracellular collagen and elastic fibers arranged in a variety of orientations and immersed in a gel-like matrix, all of which the fibroblasts synthesize and excrete. It contains the vascular, nervous, and lymphatic networks of the skin and encloses the

Fig. 2–7 Drawing by Ms R Crosby of a section of glabrous skin, cut across the papillary ridges. Three networks of nerve fibers correspond generally to the vascular plexuses: subcutaneous, dermal, and subpapillary. The limiting ridge is tightly adherent to dermal collagen, may be fixed to underlying bone, and contains few nerve endings; the intermediary ridge tends to lie free in papillary dermis, is relatively mobile, and its inner surface is rich in nerve endings with tapered or expanded tips, the Merkel’s discs. Pacinian corpuscles lie in deep dermis or subcutaneous tissue. Meissner’s corpuscles occupy uppermost reaches of papillary dermis. Recent evidence indicates there are no Ruffini or Krause organs in the glabrous skin. Tapered tip or free endings occur throughout all layers, and may cross the basement membrane to terminate the lower layers of the epidermis. (From Jabaley, 1981.)

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cutaneous excretory and secretory glands. These layers are well defined in both the glabrous and hairy skin. Beneath the skin proper is a subcutaneous layer, sometimes called the hypodermis, composed of fatty connective tissue that varies in thickness between individuals.

The Epidermis The epidermis consists of four overlapping layers of cells that differ in morphology and biochemical markers. From inside to outside the layers are in sequence the basal (or germinative), spinous, granular, and the corneum. The epidermis is a renewal system; its cells are constantly replaced as the stem cells of the basal layer produce progeny cells that move upward through the overlying layers, dividing again two or three times in the spinous layer, changing morphology and biochemical markers as they go, finally to die and be desquamated from the outer surface of the corneum. The transit time varies from 26 to 42 days. The epidermis generates derivative nails, glands, and so forth, but keratinocytes account for 80–85 percent of all epidermal cells. The single-celled basal layer is applied closely to the basement membrane at the dermal–epidermal junction. Its cells are called keratinocytes with the characteristic structural proteins, the epithelial cell intermediate filaments, and the keratins, which account for 30 percent of the mass of these cells. At the cell peripheries the filaments dock with the desmosomes that fix the keratinocytes together and provide tensile strength to the surface skin. Postmitotic keratinocytes move upward from the germinal layer into a layer called spinous because of the polyhedral shape of its cells. Keratinocytes of the spinous layer express a changing pattern of proteins of the keratin family. The function of these proteins remains obscure, but their actively changing biochemical composition suggests a dynamic function in addition to providing structural stability for the keratinocytes. Cells of the upper layer express different proteins of the keratohyalin family in the form of dense, granular-like, amorphous masses without plasma membranes, but surrounded by filaments. These masses of keratohyalin are the cellular markers of the granular layer of the epidermis. The function of this class of proteins is unknown. The terminal phase follows in the life cycle of the keratinocyte. Mitochondria and ribosomes disappear, the nucleus is degraded,

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and the flattened cells of the corneum are filled with masses and filaments of dephosphorylated derivatives of keratohyalin. The corneum consists of many layers of progressively more flattened cells, without nuclei, stacked in orderly arrays. Protein filaments fill the interstices between corneal cells and provide an amorphous matrix in which the cells are embedded; the cells and matrix together are thought to account for the resistance of the corneum to mechanical or chemical injury. Finally, the intercellular matrix breaks down and the remnants of the corneal cells are desquamated. The layers of the skin and several of its cell types differ in embryological origin (Holbrook, 1991; Holbrook and Wolff, 1993). The epidermis is present within 10 days of conception in humans, when ectoderm and endoderm are first defined in the implanted blastocyst. It consists then of a single layer of early keratinocytes of ectodermal origin, a layer soon covered over much of the fetal surface by a second layer called the prederm, which is at first one cell but later two cells thick. Prederm cells are linked to each other by desmosomes, which suggests that the layer plays a role in osmoregulation. When epidermal differentiation nears completion, the prederm is sloughed into the amniotic fluid. The epidermis is fully differentiated and several cellular layers thick by the end of the second trimester, which in humans is the time at which the keratinocytes become spinous. The cerebral cortex and the epidermis have common embryological origins. Each is organized horizontally into layers and transversely (vertically) into columns. It has been shown at many sites in many species that the keratinizing cells of the epidermis are arranged in columns that extend across the epidermal layers. Cells migrating from the basal layer are aligned beneath previously migrated cells, and flatten to compose a roughly hexagonal surface area about 10 times that occupied by the 8–10 cells of the germinal layer at the base of the column. These columns are regarded as discrete epidermal proliferative units (Mackenzie, 1969; Menton and Eisner, 1971; Potten, 1976).

Special Cells of the Epidermis Two classes of cells invade the epidermis from other tissues: the Langerhans cells from the mesenchyme and the melanocytes from the neural crest.

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Langerhans Cells Langerhans cells are dendritic leukocytes found in many stratified epithelia, only in mammals. In the skin, they are located mainly at suprabasal levels in the epidermis, where they account for about 10 percent of the epidermal cells. Langerhans cells initiate the protective immune response to antigens introduced into the skin, for example, in the allergic reaction, by their specific activation of T-cell lymphocytes, and in this way are important links in the surveillance function of the immune system. There is some evidence that a part of the Langerhans–T-cell interaction occurs in the regional lymph nodes, in which case it is postulated that the Langerhans cells are transported to and from the regional nodes via the cutaneous lymphatic channels (Hauser et al., 1991).

Melanocytes The melanocytes migrate from the neural crest to the epidermis, where they account for about 2 percent of epidermal cells. They remain in the basal layer, in contact with the basal lamina, but their dendrites project into the spinous layer of proliferating keratinocytes. Melanocytes contain large numbers of intracellular organelles called melanosomes that contain the synthetic apparatus for several classes of melanin proteins. Melanosomes are formed from the endoplasmic reticulum, migrate to the dendritic extensions of the melanocytes, and are extruded into the extracellular space and engulfed by the surrounding keratinocytes. In this way all the germinative cells of the basal and spinous layers are provided with light-protecting melanin. The melanocytes are under several extrinsic control mechanisms, chiefly by the melanocyte-stimulating hormone of the adenohypophysis.

Merkel Cell–Neurite Complexes The Merkel cell–neurite complexes are present in large numbers among the basal layer of keratinocytes in the intermediate ridges of the glabrous skin, and in the hair follicles, of mammalian skin. In some regions of hairy skin, Merkel cells are clustered in specialized regions called touch-domes, located between the hairs. Merkel afferents in each of these locations adapt slowly to maintained stimuli delivered

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to the skin. The ultrastructure of the Merkel cell–axon complex suggests that the two are related by an excitatory synapse, with polarity from Merkel cell to axon terminal. The evidence for this hypothesis and for that favoring a direct activation of the terminals is considered in Chapter 5. The origin of Merkel cells is not established with certainty, but recent evidence suggests that they differentiate from keratocytes within the epidermis itself, where they are present in large numbers before nerve fibers reach the skin (Morohunfola et al., 1992a). Epidermal appendages, nails, hair follicles, and sebaceous and sweat glands develop during the second trimester in humans, and are of adult form and distribution at birth.

The Dermis The dermis lies between the epidermis and the underlying subcutaneous tissue. It consists of two layers. The upper papillary layer is tightly molded to the underside of the basal lamina, conforming to the undulations of the overlying epithelium. The lower, reticular layer of the dermis contains relatively few cells, predominantly fibroblasts, dense collagen fibers that account for the tensile strength of the skin, and elastic fibers that tend to restore the normal spatial array of structure after deformation of the skin. The development of the dermis lags behind that of the epidermis. It is initiated by the dermal fibroblasts from the underlying mesoderm and mesenchyme. Fibroblasts synthesize and secrete the collagen, elastic, and glycoprotein extracellular elements of the dermis, and in the process convert the dermis from a cellular to a fibrous matrix as the extracellular material accumulates. By the fifth month of ontogenesis in humans the dermis contains the complex vascular apparatus described below. Nerve fibers invade the dermis at about 8–9 weeks of life, and by 13–14 weeks innervate the entire skin. Gentle cutaneous stimulation anywhere on the body surface elicits reflex movement. The vascular and nervous plexuses extend upward through the dermis to reach the dermal–epidermal border just beneath the basal lamina. Unencapsulated nerve endings, penetrate the basement membrane to end among the epidermal keratinocytes. These endings are partially enclosed by Schwann cell processes, and in some cases contain clusters of vesicles (Kruger et al., 1981; Messlinger, 1996). They are the terminals of nociceptive afferent fibers thought to serve pricking pain (Kruger, 1996).

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The Basement Membrane The basement membrane is a thin (30–150 nm), multilayered, extracellular matrix structure that forms the interface between dermis and epidermis. This scaffold consists of type IV collagen, laminin, and several proteoglycans and is virtually acellular. It is anchored to the dermis by microfibrillar bundles, and to the basal cells of the epidermis by hemidesmosomes. The basement membrane may function as a semipermeable filtration barrier, controlling the movement of cells and foreign material from epidermis to dermis. During development it allows passage from dermis to epidermis of morphogenetic signals that control the generation of epidermal appendages of mesenchymal origin (Krieg and Timpl, 1984), as well as the movement of cells that migrate from the mesenchyme and the neural crest to the developing epidermis.

The Vascular Supply to the Glabrous Skin The radial and ulnar arteries enter the hand and are linked there by the deep and superficial palmar arches and by a single dorsal arch. The palmar and dorsal metacarpal arteries arise from these arches, project distally through the hand, and divide at the bases of the fingers to generate the phalangeal arteries which supply the blood flow to the fingers. Branches of these arteries reach the subcutaneous layer of the glabrous skin, divide into arterioles and then capillaries, and generate the double capillary loops that follow the line of the papillary ridges of the glabrous skin (Fig. 2–8). The long descending capillaries of these loops flow into the venules and veins that drain the glabrous skin. It has been suggested that this arrangement of capillary loops explains how the skin can be vertically mobile without vessel injury, and why normal blood flow is maintained even during the application of mild pressure vertically to the skin surface (Umeda and Ikada, 1988; Ikada and Matsumoto, 1993; Ikada and Umeda, 1993). These properties are important for the continued sensory functions of the hand under a variety of conditions of pressure, distortion, and movement. Arteriovenous anastomoses are common in the circulation of the hand and fingers, where they are surrounded by muscle coats under autonomic vasomotor control. When relaxed these function to divert blood away from the superficial plexus and so reduce heat loss; they are commonly active in the circulations of the hands and feet.

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Fig. 2–8 Scanning electron micrograph of the microvasculature in the glabrous skin of the finger pad of a macaque monkey. Skin prepared by vascular injection of acrolate monomer, and digestion of other tissue. The palmar skin has a double capillary loop along the lines of the dermal ridges. The capillary loops link the subpillar arterial network and the subpillar venules. This structure may provide an explanation for how it is possible for blood flow to continue when external pressure is applied vertically to the surface of the glabrous skin. Bar = 100 µm. (From Ikada and Umeda, 1993.)

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Dermatoglyphics The pattern of the ridges in the human glabrous skin of hand and foot is formed during the fourth month of intrauterine life. That pattern is unique for each individual, and absent severe injury and scarring, remains unchanged for life, an observation documented many times in single individuals over periods lasting 70 years. The afferent innervation of the skin plays an important, though not exclusive, role in determining the dermatoglyphic pattern and the time of its appearance (Dell and Munger, 1986; Moore and Munger, 1989; Morohunfola et al., 1992a,b). Ridges begin to form only after the earliest Abeta fibers reach the skin and make contact with the previously resident Merkel cells in the epidermis. The ridge pattern in the skin thus reflects the genetically determined pattern of outgrowth and cutaneous termination of the dorsal root afferents, and this relationship is thought to determine the phenotypic specificity of each pattern. Consequently, the dermatoglyphic pattern will also reflect any genetically determined abnormalities of central nervous system (CNS) development. Study of those patterns is an aid in the diagnosis of many such conditions. The most firmly established is the unique ridge pattern in trisomy 21, Down’s syndrome; less certain correlations have been described for a large number of conditions determined by genetic abnormality, including some forms of schizophrenia.

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General Features of Somatic Afferent Systems

The numbers and the variety of the afferent nerve fibers innervating the peripheral somatic tissues are matched by the number and complexity of the somatic afferent pathways of the spinal cord and brain into which they project. Somatic afferent systems serve many functions in addition to somatic sensibility. They provide the afferent drive for spinal reflex actions, and the peripheral afferent input for such nonperceptual functions as the vegetative and homeostatic mechanisms of the subcortical regions of the forebrain, for example, in temperature regulation. It has been the continuing task of experimentalists and clinical neurologists to winnow out from these many systems those that contribute directly to somatic sensibility. In a general sense they all do, for perception, like other high-level functions, depends critically on such brain states as the general level of excitability. Nevertheless, it is possible to define a somatic sensory system as one activated by stimulation of peripheral tissues, and that can be shown to be important for somatic sensibility by the defects in somesthesis produced by local lesions in the systems, and by the reports of waking human subjects when the candidate systems are stimulated electrically. A schematic outline of the somatic sensory system is shown in Fig. 3–1. This outline is a spare extraction from a rich database of knowledge derived from classical neuroanatomy, from studies of connectivity, and from the results of electrophysiological experiments designed to answer anatomical questions. The results of such experiments provide the details of somatic representations

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Fig. 3–1 A box diagram of the somatic afferent system, from the level of primary afferent input to the somatic sensory areas of the parietal lobe and the lateral Sylvian cortex. (Courtesy of Dr. Takashi Yoshioka.)

in the pathways, nuclei, and cortical areas of somatic afferent systems. Systems are defined in various ways in different fields of science, for example, as “a collection of interacting functional units combined to achieve a purposive behavior” (Regan, 1999, p. 16), or “an

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integrated assembly of interacting elements designed to carry out cooperative or predetermined functions” (White and Tauber, 1969, p. 3). These are unsuitable in the present context, for each carries a tone of purposive design. I define in a general way a neural system as a group of neurons synaptically linked together in partial isolation from surrounding neural elements, and which can be shown to serve a particular function or functions preferentially but in some cases not exclusively. Each of the components grouped together in the somatic afferent system outlined in Fig. 3–1 is linked by its afferent pathways with sets of peripheral receptors and first-order afferent axons segregated from those projecting into other systems. This segregation is maintained from the peripheral level through the transition nuclei of the large-fibered afferent systems of the dorsal and dorsolateral funiculi of the spinal cord. Different sets of elements defined by modality, particularly for those innervating the glabrous skin of the hand, are processed in parallel. The two major sets of somatic afferent systems are not completely isolated from each other or from other systems within the brain. System interaction increases from lower to higher levels of the brain, and culminates in the cross-coupling between components of the distributed systems of the neocortex. At those levels the initial quasiisomorphic representations of stimulus qualities at the input levels of sensory systems are abstracted to forms not obvious in the firstorder input. The result is modified by interactions between somatic systems and other systems of the brain, including, it is assumed, signals of past experience. The result is the dynamic activity in cortical distributed systems proposed to be the neural basis of perceptual experience. Studies of humans with disease or injury to the nervous system were early combined with traditional anatomical methods to produce much of the anatomical knowledge of the somatic afferent systems. Many results in humans with lesions of the brain were obtained in the golden age of clinical neurology; see Head and Holmes (1911); Head (1920); Critchley (1953); Semmes et al. (1960). For studies in humans with lesions of afferent pathways of the spinal cord, see Nathan et al. (1986), and its references to the older neurological literature. Lesions of a somatic afferent system may degrade its function severely if placed at a critical input funnel of the system. Lesions of central projection pathways or cortical targets seldom

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eliminate somesthetic function completely. What is revealed is the remaining capacity of the lesioned brain for somesthesis that often improves with time and sensory training, an adaptative process now generally thought to be plastic in nature (see Chapter 15). The shortterm negative losses and the long-term positive signs of the remaining capacity are seldom exactly reciprocal. Nevertheless, studies of humans with brain or spinal cord lesions have continued to produce new information right up to the present time. They have now been expanded by the application of electrophysiological methods in waking humans (Desmedt et al., 1987; Nunez, 1995; Gevins et al., 1996) as well as by methods for imaging the brain in both humans with lesions and in normal individuals as they work in somesthetic tasks (Roland and Mortensen, 1987; Toga and Mazziotta, 1996; Paulesu et al., 1997).

On Naming The sets of afferent systems of the spinal cord and forebrain I describe in the following chapters differ from one another in their functional properties, but with considerable overlap. This makes system labeling difficult, and in the long history of study of the somatic system no pair of antonyms has come into general use. Recall, for instance, protopathic–epicritic, nonspecific–specific, anterolateral–lemniscal. The latter is used to designate both pathways and properties, but the term anterolateral does not include the several ascending pathways of intrinsic origin that ascend in other quadrants of the spinal cord. For want of a better pair, I choose the noncommittal terms large-fibered and small-fibered. These terms derive from the review of GH Bishop (1959), who summarized the evidence then available supporting the division of peripheral afferent systems and their central projection pathways as small- and largefibered. Bishop emphasized also the increasing acquisition of large fibers and the development of those systems in mammalian phylogeny, and used the terms integrative (primitive) and elaborative (analytic) for the two classes, small- and large-fibered. Even here, overlap exists between the projections of the two system sets, particularly for the myelinated fibers in the range of 3–4 µm diameter. I define the large-fibered systems as those composed of the medium to large myelinated fibers entering through the dorsal roots and

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the trigeminal nerve, and serving, in general, the discriminative aspects of mechanoreceptive sensibility. Some project directly via the dorsal columns and others indirectly via the dorsolateral columns to the dorsal column nuclear complex, which in turn projects to the dorsal thalamus. The term is not exactly equivalent to either lemniscal, specific, or epicritic. I define the small-fibered systems as those composed of the small myelinated and unmyelinated fibers that enter through the dorsal roots to terminate in the segmental gray, from which second-order systems ascend toward the forebrain in each of the funiculi of the spinal cord, including those in the lateral and ventral funiculi that serve the discriminative aspects of pain and temperature. The term small-fibered is not exactly equivalent to either anterolateral, nonspecific, or protopathic.

Somatic Afferent Systems Have Different Structural and Functional Properties The somatic sensory pathways of the spinal cord differ in the sets of peripheral afferent fibers that project into them; in their cells of origin; in security of synaptic transmission and dynamic operations; and in the roles they play in somatic sensibility, described in Chapters 6 and 8. This variety has led to attempts to classify the systems according to contrasting sets of properties. I shall describe two sets of differing properties, and so far as possible characterize each system in terms of the properties that it possesses, making clear in the process the group to which the system belongs, or if it belongs to neither. A principle emerging from studies of somatic afferent systems is that one group of pathways and transition nuclei, which I label large-fibered, deals with the discriminative–sensory aspects of somesthesis, and a second group, which I label small-fibered, deals with the affective–vegetative components of the perceptions evoked by all but the blandest of somatic stimuli (Millan, 1999). Jones called these two classes of systems core and matrix according to the degree of their interdigitation at thalamic and cortical levels (Jones, 1998a,b). The discriminative–sensory systems include those of the dorsal and dorsolateral columns that deal with the mechanoreceptive aspects of somesthesis. The affective–vegetative systems flood all

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the ascending columns of the spinal cord, surrounding and converging on the transition nuclei of the discriminative–sensory systems (not necessarily on the same cells) but also diverging from them at thalamic and cortical levels to engage the frontal, lateral, and limbic cortical circuits, which, among other things, deal with affect and emotional reactions. The affective–cognitive systems have wider functions, for they also project upon the regions of the brain stem and other subcortical structures important for the control of vegetative and homeostatic functions (Craig, 1996). Discriminative– sensory systems have medium to large myelinated fiber spectra with medium to rapid conduction velocities, secure synaptic transmission, preservation of modality specificity, a precise topography, peripheral inputs of large and medium-sized myelinated fibers, and functional roles in discriminative operations. The affective–cognitive systems have fiber spectra of medium to small axons with medium to slow conduction velocities, relatively insecure synaptic transmission with considerable divergence and convergence, loss of modality specificity by cross-modality convergence, peripheral input from small myelinated and unmyelinated afferent fibers, and less precise topography. The antonyms “large-fibered–small-fibered” make no commitment in relation to other properties, which may vary considerably between different components in each of these large classes. While the large-fibered ascending systems dealing with mechanoreceptive sensibility are more or less confined to the dorsal and dorsolateral columns, the small-fibered intrinsic ascending systems are found in all spinal quadrants, but are especially concentrated in the ventral and ventrolateral columns. Systems of the two classes show a degree of convergence and overlap, with frequent segregation of their projections upon different classes of cells in transition nuclei. For example, elements of the spinothalamic system project selectively upon the calbindin-labeled neurons of the ventral thalamic posterior nuclei, in contrast to the axons of the medial lemniscus, which project selectively upon the parvalbuminlabeled relay cells. Nevertheless, it is useful to classify systems in terms of their properties, although when viewed in these terms there are some systems that can be classified in neither of the two groups. The systems for pain and temperature are the clearest examples of those with mixed properties. They provide centrally projected signals that allow precise detections, discriminations, and ratings of noxious and thermal stimuli. Neurons of the large- and small-fibered

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systems are identified at the thalamic level by different intracellular calcium-binding proteins—parvalbumin for the large-fibered systems, calbindin, or calretinin, for the small-fibered system. On this score, the pain and temperature systems qualify as small-fibered systems, but they provide specific, discriminable signals for pain and temperature. There are three large-fibered somatic afferent pathways. The first is the dorsal column–medial lemniscal system whose axons arise from large neurons of the dorsal root ganglia, enter the spinal cord, and project directly through the dorsal columns to the dorsal column nuclear complex (DCNC), and from there to the thalamic ventral posterior lateral nucleus. The second is the trigeminal lemniscal system, whose axons arise from neurons in the principal nucleus of the trigeminal nerves, and project to the thalamic ventral posterior medial nucleus. The third is the spinomedullothalamic tract, whose axons arise from neurons within the spinal gray and project through the dorsolateral column to the DCNC, and from there to the thalamic ventral posterior lateral nucleus. These large-fibered systems serve the discriminative aspects of somatic sensibility, particularly mechanoreceptive ones, and play important roles in the control of movement. Three other large-fibered systems arise from neurons within the spinal cord and project through the dorsolateral columns to the cerebellum: the dorsal, ventral, and cuneocerebellar tracts. They receive large-fibered inputs from skin, muscle, and other deep tissues. Spinocerebellar systems play no direct roles in somatic sensibility, but like other components of motor systems do so indirectly by influencing the movements of the hand in acquiring sensory input. Thinly myelinated and unmyelinated axons of the smaller dorsal root afferents project upon neurons of the local segmental spinal gray, and from there, small-fibered systems project cephalad in all quadrants of the spinal cord. This group includes the postsynaptic dorsal column system, the spinothalamic systems of the anterolateral columns, the spinocervicothalamic system of the dorsolateral column, and other ascending systems of the ventral and lateral columns, described in later chapters. Each spinal funiculus also contains a number of propriospinal fibers that arise and terminate within the spinal cord (Nathan and Smith, 1959). The propriospinal systems serve local and multisegmental reflex functions, and may also function as interneuronal processing systems linking signals

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for movement from the forebrain to the spinal motor apparatus, with their final expression in the patterns of motoneuronal discharge.

System Overlap and Embedding Discoveries made with axoplasmic tracer anatomical methods have led to a reformulation of some concepts of the functional organization of somatic afferent systems. A new feature is that the largefibered afferent pathways of the dorsal and dorsolateral columns of the spinal cord and their target transition nuclei in the medulla and thalamus are converged upon by significant numbers of smallfibered elements within and surrounding the neuronal clusters and axons of the large-fibered system. The evidence suggests, however, that this convergence is to nuclear formations, and has not yet been shown to be to individual cells. Neurons activated by large-fiber input project selectively to parvalbumin-labeled cells in the DCNC, to the ventral posterior lateral nucleus of the thalamus (the core), and to layers IV and III of the postcentral gyrus. Small-fiber inputs project selectively to smaller neurons of those transition nuclei that are selectively labeled with calbindin or calretinin (the matrix), and project to the superficial layers of the postcentral cortex and adjacent areas. I describe the functional properties of these two classes of systems in Chapters 6 and 8. The projections of the small-fibered system are not constrained by cytoarchitectural boundaries or by the defined projection zones in the somatic sensory cortex of the thalamic sensory nuclei in which they relay. The small-fibered systems are parts of the thalamocortical loops that regulate the state of excitability of the cerebral cortex, and of the related behavioral states. An important generality has evolved from the work of the last decades, that the small-fibered systems are activated by sensory stimuli that excite sets of primary afferent fibers, many of which are polymodal in their sensitivity to mechanical, noxious, and thermal stimuli. However, some of these afferent systems appear to play no essential role in the sensations of pain and temperature under normal circumstances, but serve more general functions of controlling the excitability of the forebrain and of regulating the subcortical systems of the brain stem and forebrain concerned with homeostatic functions, as Craig has emphasized (Craig, 1996). One important

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fact for the experimentalist is that afferent fibers and central neurons activated by noxious stimuli are not necessarily directly involved in pain perception. A central system activated by noxious stimuli must be shown to be essential for the perception of pain on evidence obtained by other means before it is considered to be a part of the central pain system. The degree to which the large-fibered and small-fibered elements of the somatic afferent system are intermeshed differs among animals of different radiations. Of those studied sufficiently to allow generalization, it is greatest in rodents, less in carnivores, and perhaps still less in primates. The distinctive properties of the largefibered dorsal column–medial lemniscal pathway are clear in the central cores of the dorsal column nuclear complex, in the thalamic transition nuclei, and in area 3b of the somatic sensory cortex. The functions of the small fibered systems in this nuclear convergence are still uncertain, but whatever they may be this convergent action does not normally disrupt the precise neuronal processing actions of the large-fibered elements. The functional independence of the large-fibered systems is more marked in nonhuman primates than in carnivores. The inference from work in monkeys, combined with direct experimental and clinical evidence, is that a similarly precise neuronal processing exists in humans as well. Several of the major components of the somatic afferent system overlap with one another, a generality I shall support with evidence in later chapters. Briefly stated, the ascending, large-fibered, mechanoreceptive components of the system are partially embedded within the small-fibered systems. This is clear at the levels of the brain stem and thalamus, where the modular arrays of the largefibered system are embedded within distributed sets of neurons of the small-fibered system that have functional properties that differ from those of the large-fibered elements they embrace. The smallfibered systems compose a “diffusely projecting matrix” (Jones, 1998a,b). These neurons are distributed thinly within the largefibered projection targets in the dorsal column nuclear complex and in the ventrolateral nucleus of the thalamus, and are densely clustered in the surround. This concept derives from both anatomical and physiological observations, and appears to resolve many of the uncertainties that formerly accompanied ideas of what is a diffuse and what is a specific system. The degree of interaction between systems increases from lower to higher brain levels, and culminates in

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the cross-coupling between components of the distributed systems of the neocortex discussed in later chapters. At these levels, the initial quasi-isomorphic representations of stimulus qualities present at earlier levels of the somatic systems are replaced by abstracted features not obvious in the first-order input. The result is modified by interaction between the somatic system and other systems, and by the intrinsic processing operations in the distributed systems of the brain including, it is assumed, neurally embedded records of past experience. The result is the dynamic activity in cortical distributed systems, conjectured to be the neural basis of perceptual experiences. With further progression into those distributed systems of the cerebral cortex there is a further convergence between the major afferent systems. This is particularly so for the visual and somatic sensory systems that converge onto areas of the posterior parietal cortex discussed in Chapter 14.

Representation and Self-Organization The word “representation” as used in the present context conveys the idea of a central neural reflection of a particular event in the external world, or internal bodily condition, transduced by sensory receptors and projected into the brain over afferent pathways. It is the density distribution of the peripheral sensory end-organs that is mapped, not the body form. Representations in the discriminative somatic systems are somatotopic, by which is meant that neighboring locations in the peripheral sensory fields are mapped to neighboring locations in the central projection fields, with occasional breaks and discontinuities. These maps reflect the anisotropic nature of the density and distributions of the primary afferent fibers innervating these sensory fields. It has long been assumed that a local zone of increased neural activity within such a central neural representation provides the perceptual attribute of local sign, but how that may be so is unknown, and the meaning of place in the nervous system remains an enigmatic problem. It is believed that genetic factors set the gross trajectories of somatic representational systems through the spinal cord, medulla, thalamus, and into the somatic sensory cortex. In rodents, carnivores, and New World monkeys, the gross layout of maps in the sensory cortex is present at birth (Krubitzer and Kaas, 1988), and thus,

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presumably, so are maps at thalamic and medullary levels of the system. A major discovery is that the synaptic relationships at the level of microstructure can be modified by afferent input; that is, by experience broadly defined, an example of the general property of plasticity described in Chapter 15. The elaboration of map details, the distribution of synaptic strengths, the segregation of neurons by place and modality, and differential gene expressions—all are influenced in a dynamic way by ongoing activity generated in the periphery (Jones, 1990). How early in ontogeny this dynamic mechanism becomes effective in determining the details of somatic sensory maps is uncertain, but it is possible that activity generated by body movements in utero play a role before birth. This dynamic control mechanism is called self-organization (von der Malsberg, 1973; von der Malsberg and Willshaw, 1976; Willshaw and von der Malsberg, 1976; Kohonen, 1997; Kohonen and Hari, 1999). Its major features are that (1) the temporal correlation between pre- and postsynaptic activities strengthens the linking synapses while asynchronous activity weakens them and (2) synchronous temporal correlations between the inputs from adjacent locations in a sensory field, like the skin, strengthen their synaptic engagements on single neurons and small groups of neurons simultaneously. Since the activity evoked from adjacent regions in the sensory field is more likely to be synchronous than that evoked from nonadjacent fields, a somatotopic map of adjacencies results. Lateral interactions between single neurons, and between small groups of neurons in the cortex, are excitatory at short range and inhibitory in the slightly wider surround. Modeling experiments have shown what is seen regularly in afferent systems, notably the formation of local group segregations especially characteristic of sensory systems and the cerebral cortex. This pervasive adjacency and minimization of local axonal projection distances allows for rapid local interaction, which is an organizing principle for cortical maps, particularly for those that map several variables to a single two-dimensional surface (Durbin and Mitchison, 1990; Mitchison, 1995). The convergent afferent input on central neurons achieves mutual strengthening and stabilization by activating postsynaptic N-methyl-D-aspartate (NMDA) glutamate receptors. These require both ligand binding of transmitter and membrane depolarization, a combination that opens their Ca2+ channels, initiating a Ca2+-dependent cascade of molecular events leading to changes in synaptic strength.

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The Hebbian Elaboration of the Principle of Ariens-Kappers Synaptic modification was the theme developed by Ariens-Kappers and other comparative anatomists more than half a century ago to explain the phenomenon of neurobiotaxis (Ariens-Kappers et al., 1936, chapter 1, pp. 73–94). They wrote: “The final connection always takes place in a territory or with a cell which has correlated activity; that is, which exhibits just previous or simultaneous electric phenomena. Non-stimulated centers are equally indifferent to it.” and “—the relationships which determine connections are synchronic or immediately successive functional activities.” This general idea was elaborated by Hebb in the context of neuronal cell assemblies (Hebb, 1949, chapter 4B). It is uncertain how central processing mechanisms undergo these adaptive changes while still maintaining long-term stability in perceptual operations and spatial representations in sensory systems. Central maps are idiosyncratic, reflecting to some degree the differences in the sensory experience of each individual. This may account for the differences in size and mapping details between otherwise homologous sensory cortical areas in primates of the same age, sex, and species. Radical changes in central representations are produced in the somatic afferent systems by digit or limb amputation, as well as by peripheral denervation, or, conversely, by intense and sustained activity in a spatially restricted afferent channel, particularly if that activity is used for learning or to control complex motor patterns (Weinberger, 1995; Buonomano and Merzenich, 1998). Well-known examples are the changes in representation of the reading finger in the postcentral gyrus in long-term Braille readers (Chapter 16), or in players of stringed instruments. The general conclusion is that dynamic mechanisms of self-organization are determining factors in the development of maps in the somatic system and other sensory systems, and that they are the basis of the continuing susceptibility to change in those maps during life experience. The discovery of the general process of plasticity, particularly with reference to cortical maps, ranks as a major event in the recent history of systems neuroscience (Chapter 15). The two-dimensional spatial parameters that define maps in the somatic system from the level of entry through to the primary sensory cortex are combined with and in some cases replaced at more

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central levels of the system by extracted features not present in the primary afferent input. Some of these are called computational maps in which derived or extracted (“computed”) features vary across the cortical surface. Computation is defined in this case very broadly as “any transformation in the representation of information” (Knudsen et al., 1987); by that definition there is scarcely a map in any nervous system that is not computational! Some computational maps are partially, and in some cases completely, independent of peripheral spatial topography and from any other simple, ordered, spatial projection from a sensory field to a brain area. They are place-coded distributions such that increased activity at a local site in the map defines the intersection of the mapped parameters. The word “computation” is used with different meanings by neuroscientists. Some modeling studies are directed at how neural networks might operate in complex functions such as perception, and how these might help to explain those higher brain functions; these are termed “computational” by Hildreth and Koch (1987). These ideas and the results of synthetic modeling led to the hypothesis that the coupling together by mutual re-entry of high-level feature maps might form the distributed systems of the cortex in which the dynamic neural mechanisms of perception are played out (Edelman, 1993; Wray and Edelman, 1996).

Modularity Modularity is a widely documented principle of design that applies to both vertebrate and invertebrate brains (Leise, 1990; Mountcastle, 1997). The central theme is that the larger entities of brains we call cortical areas, or subcortical nuclei, or the discrete lobes of neuropil in the nervous systems of the higher invertebrates, are composed of smaller units consisting of hundreds of cells. These local neural circuits are repeated iteratively throughout the larger entities. Modularity is particularly well documented for the somatic afferent system, in terms of the columnar organization of the somatic sensory areas of the neocortex, the modality-specific longitudinal rods of neurons in the transition nuclei of the lemniscal system in the dorsal thalamus, and the modality-specific rods in the center of the dorsal column nuclear complex. Some evidence suggests that the principle of modularity applies also to the small-fibered components of the somatic afferent system, as it does to other regions of

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the mammalian brain (Mantyh, 1983; Szentagothai, 1983; Rethelyi, et al., 1989). The importance of the modular concept, in terms of the functional organization of the somatic system, is discussed in several chapters that follow.

Parallel Projections and System Convergence The components of the somatic afferent system differ in their degree of parallel processing for modality and space in the synaptic transitions from periphery to cortex. Several classes of large, myelinated mechanoreceptive afferent fibers innervating the glabrous skin of the hand project through parallel components of the dorsal column–medial lemniscal system. These parallel lines remain virtually free of cross-modality convergence from dorsal root entry through areas 3b and 1 of the postcentral gyrus. Minimal cross-modality convergences occur in area 2 and are full blown in areas 5 and 7b of the posterior parietal cortex. By contrast, convergence between the different modality sets of thinly myelinated and unmyelinated fibers is prevalent in many components of the small-fibered systems into which they project, from the first transition nucleus in the spinal gray onward. Spatial convergence in the large-fibered, dorsal column–lemniscal system is largely restricted to neurons of the same modality class. The receptive fields of the rapidly adapting and slowly adapting neurons of area 3b are three to five times larger than are those of the relevant sets of first-order fibers innervating the glabrous skin of the hand, but modality cross-convergence within those larger fields is rarely observed. Even this relaxed degree of spatial restriction is maintained dynamically, first, by a contributing factor arising from physical properties of the glabrous skin, the edge effect described in Chapter 11. Second, a powerful feed-forward inhibition is present that is generated from receptive fields that superimpose upon, surround, or flank excitatory receptive fields on the glabrous skin. Inhibition occurs in each transition nucleus of the system and in the postcentral gyrus, depending in each case upon the action of γ-aminobutyric acid-ergic (GABAergic) inhibitory interneurons (Alloway and Burton, 1991). Third, converging small-fibered systems have been shown in some cases to control the properties of the largefibered systems upon which they project. For example, anesthesia of neurons of the dorsal horn that project upon the dorsal column

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nuclear complex produces an immediate enlargement of the receptive fields of the topographically related large-fibered relay neurons, without an accompanying modality change (Dykes and Craig, 1998).

Localization in Somatic Afferent Systems Localization is a pervasive property of somatic afferent systems from their levels of inception in peripheral tissues to the distributed somesthetic system of the cerebral cortex. There is no dispute concerning the locations of the afferent pathways of the spinal cord, of thalamic “relay” nuclei of the system, or the whereabouts of the somatic sensory cortical areas to which they project, described in later chapters. There have been long-standing disputes over whether complex functions such as the perception of somesthetic or other sensory events, or of higher cognitive functions, are localized within the brain, and especially to what degree they are “localized” within the cerebral cortex. A short essay on the historical roots of this long-standing controversy follows here; it gives what I believe is the modern synthesis.

Localization vs Equipotentiality: The Cerebral Organ Concept of the Nineteenth Century It is now almost banal to say that the brain is the organ of the mind. This was not always seen to be so, for two centuries ago it was a matter of intense debate. It is now generally accepted that the brain processes afferent input leading to perceptual experience; generates intentionality to act upon the external world, and at choice the efferent activity to execute it; provides for the store and recall of what Locke called reflections—thinking (Locke, 1690, 1959); is responsible for affective and cognitive states; and maintains homeostasis by its control of other body systems. These concepts of brain function so apparent to us now—even though our understanding of them is limited—were a major contribution of the Age of the Enlightenment to Western civilization. At the transition from the eighteenth to the nineteenth centuries, however, the idea of the brain as the organ of the mind provoked controversies among philosophers, neuroscientists, and theologians. And, going beyond this debate, those who accepted the brain–mind proposition were further divided over the question of localization of function in the brain, particularly whether this is true for the cerebral cortex. The theory of localization was/is

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that a local region of the cortex contains the neural processing mechanisms for a particular function, spatially separate from other areas controlling other functions, and is more or less invariant from brain to brain. This was/is opposed by the idea of equipotentiality, that each of the various functions attributed to the cerebral cortex is processed throughout the full extent of the cortex, seamlessly overlaid conjointly with the mechanisms for all other cortical functions. The modern synthesis represents a synthesis of the two ideas. The concept of localization was at that time not new. Reports that brain lesions in humans produce isolated, contralateral defects in movement or sensation appeared during the course of the eighteenth century, and several neurologists observed that stimulation of the brain could provoke contractions of contralateral muscles. The idea of cortical localization can be traced to the clinical–pathological correlations of Thomas Willis (1664). A widely unknown contribution was made by the Swedish religious mystic Swedenborg (1669–1672; see translation, 1938). Swedenborg described in a general way the somatotopic patterns in some unknown cortical area that controlled movement. He had it right, but kept it to himself! All these prescient observations were swept away by the influence of von Haller (1754, English translation, 1936), who supported the concept of equipotentiality in the mode of action propre, a mode vigorously argued by Flourens in the nineteenth century (Flourens, 1846). Equipotentiality of cortical function was the dominant theme in European neurological circles right up to and overlapping for half a century the first publication of Gall in 1791 (see Gall, 1822–1825). For extended reviews of these tumultuous years and the intense controversy between Gall and Flourens, see Young (1970) and Clarke and Jacyna (1987). It was Gall who generated the theme of organology, that different local areas of the cerebral cortex process the central neural activity for different functions, for example, for love, hatred, thinking, selfesteem, and so on for at first two and then three dozen “functions.” Gall’s localization of psychological faculties differs from the ideas of sensory–motor localization that followed later. His list contained only higher psychological faculties, none for sensation, thought by him to be a subcortical operation. Moreover, Gall and Spurzheim proposed that when one of these functions is developed to an unusual degree in an individual the relevant local region of the cortex increases in size (it may, e.g., the pre- and postcentral finger areas of players of

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stringed instruments!), and that this increased local brain area generates a bump on the overlying skull (it does not!) that could be identified by palpation and measured by craniometry (Gall, 1822–1825; Gall and Spurzheim, 1835). For reviews of Gall’s importance in the history of neuroscience, see Temkin (1947); Young (1970); Critchley (1965); Clarke and Jacyna (1987); Zola-Morgan (1995); and Gross (1997); Prejudiced as we are by the discredited idea of Phrenology, the term coined and used by Spurzheim, never by Gall, it is easy to overlook the positive contributions Gall made to neuroscience: first, to the anatomy of the nervous system, and to the unity of form and function in the nervous system; second, to the idea that the brain is the organ of the mind; and third, to the concept of the localization of function in the cerebral cortex. The latter was directly opposed to the concepts of Gall’s most effective and eventually destructive critic, Pierre Flourens (1846), who claimed that each large division of the nervous system, for example, the spinal cord, cerebellum, cerebral cortex, and so forth controls a certain set of functions, and that these functions are distributed in a completely overlapping manner throughout their related major brain divisions. In the long run, it was Gall’s idea that formed the basis for the spectacular “localizations of function” that characterize the golden age of clinical neurology in the latter half of the nineteenth century.

The Nineteenth-Century Triumph of the Cerebral Organ Concept The discoveries of Broca (1861), Fritsch and Hitzig (1870), and Ferrier (1875) that different local regions of the cortex control different aspects of behavior, in these cases the motor production of speech and control of the peripheral musculature, combined with Spencer’s (1855) application of the Darwinian theory of evolution to the nervous system, led to Jackson’s general working paradigm of correlating the results of study of patients with brain lesions or disease with the state of the brains of those patients, obtained at death. The application of evolutionary theory to the brain led to Jackson’s theme of sensory–motor localization in the cerebral cortex. He applied the theme of “sensory–motor” quite broadly, including under that rubric many aspects of abnormal behavior we now would classify otherwise. The Spencer–Jackson idea of sensory–motor localization differs remarkably from Gall’s idea of the localization of psychological faculties

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in the cortex. Those in the English-speaking world attribute this explosive development in brain science to Jackson and to those who followed him, but it is fair to say that the development went on at an equal pace in France (Charcot, 1881), Germany, and Italy. This development began well before evidence accumulated supporting the neuron theory. It was known that axons conducted activity at finite velocities, but virtually nothing was understood of synaptic transmission. The general method of observing the effect of natural lesions of disease in humans, or those produced experimentally in nonhuman primates, on various aspects of behavior including motor and sensory performance, has continued to dominate research in brain science right up to the present day, including much of that in cognitive science. For extended reviews of this period, see Young (1970) and Clarke and Jacyna (1987).

The Modern Synthesis: The Unit Module and the Distributed System If we now move to a somewhat different formulation of these matters, it is worth emphasizing what Gall’s ideas and the century of discoveries by clinical neurologists contributed to our understanding of brain function. The present synthesis takes advantage of all the facts of cerebral localization, but regards local regions as specialized processing units, not sites of function per se, except for certain highly stereotyped cortical reflexes (Evarts et al., 1984). Examples of these are the several nodes processing different aspects of somatic sensory stimuli are linked together in distributed cortical arrays consisting of those nodes and their interconnections, and the fact that a particular function depends upon—the perception is generated by—the dynamic activity within that distributed system of interlocking nodes (Mountcastle, 1978). Examples of this “multiple-nodesembedded-in-a-distributed-system” idea in somesthesis are given in several chapters that follow. It is now a dominant theme in concepts of the organization of the visual areas of the neocortex (Zeki, 1993), but it is necessary to point out that the distributed system concept does not solve the so far impenetrable problem of how we know— the bridge to the subjective experiences of perception.

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Sensory Innervation of the Primate Hand

Variety and complexity characterize the neural mechanisms of somatic sensation from the level of their inception in peripheral tissues to that of somesthetic experiences. Peripheral tissues are innervated by many classes of afferent fibers that differ in the stimulus qualities to which they are sensitive, and in the targets and distributions of their central projections and peripheral terminations. The several sets of sensory fibers innervating the hands of monkeys and humans vary from the largest, A-alpha fibers that innervate the muscle spindles of the short hand muscles, to the unmyelinated, Cfiber, polymodal nociceptive fibers that flood all tissues of the hand except bone (Table 4–1). In all but the simplest circumstances, the stimuli of ordinary life activate simultaneously several of these different afferent fiber sets in a variety of spatial and temporal patterns. This poses the problem of how to unravel the contributions of different groups of fibers to complex somesthetic experiences. For example, how can one determine the relative contributions to the total sensory experience of the several sets innervating the glabrous skin and deep tissues of the hand, all activated in a temporally driven dynamic during the haptic identification of the textural nature and threedimensional form of an object grasped by the hand? A similar difficulty obtains in studies of the central neural mechanisms in somesthesis, for the diversity of the many afferent fiber sets feeding the system is matched by the many ascending pathways, subcortical targets, and cortical areas of the central somatic system (see Fig. 3–1). These ascending systems differ in the sets of fibers from

4

Table 4–1

Classification and General Properties of Afferents Innervating Glabrous Skin in Human and Macaque Axon con. vel.

Adequate stimulus

Receptive field

Adaptation rate

Sensory experience evoked

RaI Meissner corpuscle

A-beta,* 25–75 m/sec, myelinated

Moving, displacement, velocity

Spots distinct borders

Rapid

Velocity, horizontal movement contact, flutter best at 20–30 Hz

RAII Pacinian corpuscle

A-beta,* 25–75 m/sec, myelinated

Contact, vibration, lateral movement

Single area, indistinct borders

Rapid

Contact, movement vibration, best at 250 Hz

SAI Merkel cell–neurite complex

A-beta,* 25–75 m/sec, myelinated

Contact, pressure, lateral movement

Several spots, distinct borders

Slow

Contact, pressure, texture, two-dimensional form

SAII Ruffini corpuscle subcutaneous (humans only)

A-beta,* 35–75 m/sec, myelinated

Contact, displacement, skin stretch

Single area, indistinct borders

Slow

None, when stimulated in humans (?Motor control)

Cooling, unencapsulated

A-delta, 5–30 m/sec, mean 15 m/sec, thinly myelinated

Mild thermal cooling, range 15–45°C

Single spot, distinct borders

Slow

Sense of cooling

Warming, unencapsulated

C-fibers, 0.5–2.0 m/sec, mean 1.2 m/sec, unmyelinated

Mild thermal warming, range 20–40°C

Single spot, distinct borders

Slow

Sense of warming

Polymodal, unencapsulated**

C-fibers, 0.5–2.0 m/sec, unmyelinated

Noxious heat, Heat > 45°C, Chemical

Multiple spots, distinct borders

Intermediate

Slow, burning pain, heat pain

High-threshold, unencapsulated**

A-delta, 5–40 m/sec, thinly myelinated

Destructive mechanical, heat > 52°C

Multiple spots, distinct borders

Slow

Mechanical, intense heat pain, hyperalgesia

Cold nociceptors, unencapsulated**

C-fibers, 0.5–2.0 m/sec, unmyelinated

Extreme cooling

One–two spots

Slow

Cold pain

Class Mechanoreceptors

Thermoreceptors

Nociceptors

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Table 4–1

(continued)

Class

Axon con. vel.

Heat nociceptors, unencapsulated

C-fibers, 0.5–2.0 m/sec, unmyelinated

Adequate stimulus

Receptive field

Adaptation rate

Sensory experience evoked

Extreme heating

Multiple spots

Slow

Heat pain

*In many classifications these fibers are labeled “A-alpha” or “A-alpha/beta,” following Gasser’s original grouping. They are similar in size distributions, with rare exceptions, to that of Group II afferents from muscle. **These were originally called “bare” because of their appearance at the magnification level of the light microscope. It is now known from ultrastructural reconstructions (Messlinger, 1996) that the terminal regions are partially covered with Schwann cell membrane, and that some areas of axolemna are directly exposed to the tissue surround.

which they receive afferent input, in their intrinsic processing functions, in the degree of overlap and interaction between them, and in their functional roles in somesthesis and in somatic–motor control. These latter vary from segmental reflex actions to perceptual experiences of the highest order. I have chosen for special emphasis one important segment of somesthesis: the afferent input from the hand, the several components of the somatic system it activates, and the sensory experiences we derive from it. The functions served by the hand in somesthesis reach an epitome of quantitative and discriminative elegance, matched elsewhere in the body only by those perceived on the face, lips, and tongue. In some contexts I have inserted facts obtained from study of the hairy skin of mammals, but these are not comprehensive descriptions of the innervation of hairy skin. I include in Chapter 13 abbreviated descriptions of the peripheral and central neural mechanisms serving the sensations of pain and temperature because of their relation to complex sensations evoked by the simultaneous activation of several afferent pathways. The hypothesis considered is that the afferent pathways of the spinal cord responsible for the affective component of the experience of pain are also important for other modalities of somesthesis, including especially tactile ones. How important these combinations are is shown when one or two are absent. Patients with bilateral anterolateral cordotomy, carried out for the relief of intractable pain, report normal sensitivity to mechanical stimuli delivered to their genitalia, but that these sensations are no longer accompanied by the affective overtones they normally induce (White and Sweet, 1969, pp. 734–745).

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Much of the new information about the small-fibered somatic afferents and the intrinsic ascending systems of the spinal cord they drive has come from studies of the hairy skin of rodents and carnivores, much less from study of the primate hand. I shall extrapolate from the former to the latter only when no other information is available, with the caveat that structures and patterns of innervation and projection may differ substantially between species, and between types of skin, and that these may determine different functional properties.

The Innervation of the Skin: A Brief Overview The tissues of the body are innervated by about 2 million or so afferent nerve fibers whose neuronal cell bodies lie in dorsal root ganglia (DRG) or cranial sensory ganglia (CSG). A large proportion of those afferents innervate the skin and subjacent tissues. These can be divided into four groups. The first consists of afferents sensitive at low thresholds to non-noxious mechanical stimulation of the skin; they provide signals to the brain concerning the form, texture, location, intensity, movement, direction, and temporal cadence of mechanical stimuli, forms of somesthesis highly developed on the hand. A second group of fibers is selectively sensitive to minimal warming of the skin, and a third to minimal cooling. The fourth class consists of several sets that are relatively insensitive to ordinary mechanical or thermal stimuli, but have in common a sensitivity at high threshold to stimuli that tend to or do destroy tissue; they are nociceptors. The large majority but not all of these nociceptors are sensitive to tissuedestroying stimuli regardless of the form of stimulus energy, whether mechanical, chemical, or thermal—they are polymodal nociceptors; others are differentially sensitive to particular classes of noxious stimuli. Useful schemes for classifying afferent fibers combine their stimulus selectivities with axon diameters and conduction velocities as well as other differences in structure and functional properties. Within each of the four classically defined groups, other variables may lead to further separate classifications. These include differences in dorsal root ganglion neuronal size, neurotropic dependencies, biochemical particulars, and peptide content as well as differences in central projections and modes of central termination. Classifications of afferent fibers innervating the glabrous skin of primates and the hairy skin of furred mammals are given in Tables 4–1 and 4–2. They are based on both axon diameters/conduction

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Table 4–2

Classification and General Properties of Afferents Innervating the Hairy Skin of Mammals

Class receptor type

Axon size c.v.

Adequate stimulus

Receptive field

Adaptation rate

Experience evoked

Mechanoreceptors G-1 Hair hair follicle

A-beta* 35–75 m/sec myelinated

Contact movement

Hair follicle

Rapid

Contact, movement

G-2 Hair hair follicle

A-beta* 35–75 m/sec myelinated

Contact moving displacement

Hair follicle

Rapid

Contact, movement flutter

Field skin surface

A-beta* 35–75 m/sec myelinated

Contact movement

Many spots distributed

Rapid

?Contact, movement

SA-I Merkel cell-axon complex Touch-domes

A-beta* 35–75 m/sec myelinated

Contact pressure

Single spot, distinct borders

Slow

None, when stimulated in humans

SA-I I Ruffini corpuscle Subcutaneous

A-beta* 35–75 m/sec myelinated

Contact pressure

Single area, indistinct borders

Slow

Touch, pressure

Pacinian corpuscle (PC) Subcutaneous

A-beta* 35–75 m/sec myelinated

Transient; mechanical oscillation

Single area, indistinct borders

Rapid

Vibration, ?tickle

D-“Hair” hair follicle

A-delta 5–30 m/sec myelinated

Slowly moving displacement

Single area, distinct borders

Slow

?Movement ?contact

C-mech, C-fiber skin surface unencapsulated**

0.5–2.0 m/sec unmyelinated

Low-threshold distortion

Several local spots

Intermediate

?

Cooling thermo. unencapsulated**

A-delta 5–30 m/sec thinly myelinated

Decrease in skin temp.

Single spots

Slow

Cooling of the skin

Warming thermo. unencapsulated nociceptors

C-fibers 0.5–2.0 m/sec, unmyelinated

Increase in skin temp.

Single spots

Slow

Warming of the skin

Polymodal unencapsulated**

C-fibers 0.5–2.0 m/sec, unmyelinated

Noxious heat, mechanical or chemical stimuli (can be sensitized)

Single spots

Slow

Burning pain

Thermoreceptors

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Table 4–2

(continued)

Class receptor type

Axon size c.v.

Adequate stimulus

Receptive field

Adaptation rate

Experience evoked

Heat-mechanical unencapsulated**

A-delta 5–30 m/sec thinly myelinated

Noxious heat, mechanical stimuli

Single spots

Slow

Pricking pain

Cold nociceptors unencapsulated**

C-fibers 0.5–2.0 m/sec, unmyelinated

Very low skin temp.

?

?

Cold pain

Heat nociceptors unencapsulated**

C-fibers, 0.5–2.0 m/sec, unmyelinated

Very high skin temperature

?

?

Heat pain

*In some classifications these fibers are labeled “A-alpha” or “A-alpha/beta,” following Gasser’s original groupings. They are similar in size, with rare exceptions, to the Group ii afferent fibers in muscle nerves. **These endings were orignally called “bare” because of their appearance at the magnification of the light microscope. Reconstructions at the ultrastructural level (Messlinger, 1996) show that the nerve terminals are partially covered with Schwann cell membrane, but that indeed some portions of the axolemna are exposed directly to the tissue surround.

velocities and stimulus selectivities. A more detailed classification of nociceptive afferents, based on membrane receptor and other molecular characteristics, is given in Table 7–1. Some scholars designate the largest cutaneous afferents A-alpha, as Gasser and Erlanger (1929) did in their original descriptions. Others restrict the A-alpha term to the Group I class, as Lloyd and Chang (1948) did in their studies of afferent fibers from muscle. The equivalencies between the two systems are these: A-alpha fibers occur in muscle nerves; fibers of this size rarely occur in cutaneous nerves; A-beta fibers of cutaneous nerves are, with few exceptions, equivalent in size distribution to the Group II afferents from muscle; A-delta fibers in cutaneous nerves are equivalent to the Group III afferents from muscle; the unmyelinated C-fibers to Group IV. I shall indicate the equivalent terms when needed for clarity, but in general will use the terms A-beta, A-delta, and C-fibers to refer to afferents from peripheral tissues other than muscle. B-fibers are, by definition, the preganglionic efferents in autonomic nerves. Although they match in size the thinly myelinated A-delta cutaneous and muscle afferents, they are classed differently because they have some unique membrane properties. For further classification of afferent fibers, see Perl (1992); Light and Perl (1993), and Birder and Perl, (1994).

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Definitions Sensory Receptor The terms sensory receptor and ending are used interchangeably. The true somatic sensory receptors are the nerve endings themselves. Nerve terminals of large myelinated mechanoreceptive afferents, innervating the glabrous skin of the hand, are frequently enclosed in multicellular sensory corpuscles, defined by Halata and Munger (1983) as “a sensory axon terminal and associated cells and/or associated tissue components that appear to be structurally demarcated from the general connective tissue with or without a capsule.” In every case examined, these organs function as filters that determine the particular parameters of mechanical stimuli reaching the nerve terminals they cover, where transduction takes place.

Threshold Sensory axon terminals have thresholds; that is, of stimuli of the same quality but different magnitudes, some never, and others always, excite nerve endings. Stimuli of increasing magnitudes between these values are increasingly likely to excite, and are usually defined by a statistical estimator. The thresholds for human somatic sensations under optimal conditions of observation approach and are often equal to thresholds of the relevant set of first-order fibers.

Sensory Unit A sensory unit is a single primary afferent nerve fiber and all its peripheral branches and central terminals. The term is often used to refer to a single neuron of a central sensory structure; for example, a sensory unit of the postcentral gyrus is a single postcentral neuron.

Peripheral Receptive Field A peripheral receptive field is that area in space within which a stimulus of sufficient magnitude and adequate quality will evoke a discharge in a sensory unit, for example, the area of skin within which a cooling stimulus will excite an A-delta cooling afferent fiber.

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Partially Shifted Overlap The peripheral branches of adjacent afferent nerve fibers innervating the skin are successively intertwined in the X–Y dimensions. The overlap shifts gradually across the skin. It is unlikely that any stimulus of normal life ever engages a single afferent fiber alone. This principle of partially shifted overlap is important for understanding central neural mechanisms in spatial discriminations.

Peripheral Innervation Density The peripheral receptive fields of primary somatic afferents vary greatly in size, inversely with the number of innervating fibers per unit surface area. The volume of central nervous tissue given to the representations of various parts of the body surface varies directly with this peripheral innervation density, as does sensory acuity.

Adaptation Sensory afferents differ in their rates of adaptation to a continuing stimulus. Some are detectors of transients, discharging only a few impulses on the application of a stimulus and again on its removal; they are quickly or rapidly adapting afferents. Others respond to stimulus onset with a high-frequency discharge determined by the rate of stimulus application and its final magnitude, and continue to discharge during stimulus application at a frequency determined by the steady stimulus magnitude. They are slowly adapting afferents.

Modality Modality is defined as a group of perceptual experiences distributed over a qualitative continuum. In the field of somesthesis, modality is defined in a more restricted way as that experience evoked by afferent activity in a particular set of sensory fibers, or by a particular temporal pattern of activity in a set of afferent fibers. For example, vibration is defined as that perception evoked by high-frequency, periodic activity in the set of afferents terminating in Pacinian corpuscles.

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Polymodal Polymodal indicates the stimulus sensitivity of groups of C-fiber nociceptive afferents and cells of origin of the spinothalamic systems to two or more of either mechanical, thermal, or chemical stimuli that tend to destroy tissue.

Neural Code Neural code refers to complex concepts of how information is transmitted in neural systems, peripheral and central. The word “code” is used in somatic sensory physiology to indicate a pattern of nerve impulses in single or populations of elements that evokes a specific sensory/perceptual experience, from which one can predict the perceptual experience evoked by it. Peripheral stimuli, the neural code, and sensory experience vary in correspondence. Ancillary to this is the code of the labeled line.

Primary Sensory Neurons Neurons of the DRG and CSG have round cell bodies enveloped by peripheral glial cells. Each of these monopolar neurons emits a single unmyelinated process that divides after a few hundred microns into two branches; one projects to a peripheral target, the second enters the spinal cord or brain stem. The two neurites have the structural attributes of axons. The centrally projecting axon is somewhat smaller, with lower conduction velocity and rate of axoplasmic flow. Action potentials generated in the periphery and propagating over the dorsal root conduct directly into the central branch, and also invade the DRG cell bodies. Neurons of the DRG and CSG are unique in the nervous system, for they receive no synaptic terminals from other neurons. Dorsal root ganglion neurons differ in cell size over a range of 3 to 1, in optical density in Nissl sections, and in their molecular profiles. Twenty percent appear large and translucent in Nissl stains (“light”); they have myelinated axons of the A-alpha and A-beta mechanoreceptive afferents that innervate the skin and deep tissues. Forty percent of DRG neurons are small and “dark,” contain many peptides, and are supported by neurotrophin growth factor (NGF). They emit unmyelinated afferents that innervate all peripheral

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tissues. The remaining 30 percent are also small and dark, but do not express peptides, and are supported by glial cell line–derived neurotrophic factor (GCDF), described below. These two sets of Cfiber afferents have different dorsal horn targets. It is likely that a group of DRG cells of intermediate size emits the thinly myelinated nociceptive and thermoreceptive afferents, but such a set has not been clearly defined. Similar variations in cell sizes and staining properties have been described in rat, guinea pig, cat, and humans. The large cells average 50–60 µm in diameter, the small cells about 40 µm, in humans (Lawson, 1992; Holford et al., 1994). DRG cells contain a number of peptides, hormones, enzymes, and other proteins, with a relative segregation of peptide molecules to the group of the small-dark cells with C-fiber afferent axons (McCarthy and Lawson, 1989; Lawson et al., 1997). A survey tabulated 46 molecular species; those in DRG cutaneous cells are listed in Fig. 4–1 (Lawson, 1996b). Substance P is the most prevalent peptide in the group of the small-dark cells colocalized with calcitonin gene–related peptide, found without substance P in a significant proportion of the large-light cells as well. Whether different subclasses of dorsal horn cells, defined in terms of peptide content, serve different aspects of pain, thermal, or mechanoreceptive sensibilities is uncertain, but some have different forms of terminal aborizations and different target zones in the laminae of the dorsal horn, and in the spinal trigeminal nucleus (Hunt et al., 1992; Lawson, 1995, 1996a,b). Combined intracellular recording and cell marking studies have been made of DRG neurons in dissociated cell culture, in intact ganglia in vitro, and in vivo in mice, rats, and cats. Large-light cells with peripheral A-alpha and A-beta axons have rapidly rising and falling tetrodotoxin (TTX)-sensitive Na+ action potentials, with minimal after-hyperpolarizations. Those with myelinated mechanoreceptive axons innervating the skin have different concentrations of three K+ channels: sustained Ik; fast inactivating IA; and slowly inactivating ID (Everill et al., 1998). Smaller light cells with peripheral A-delta axons and dark cells with C-fiber axons have both TTXsensitive and TTX-resistant Na+ channels, and the action potentials of these neurons are slowed in the repolarization phase by a surge of Ca2+ current, followed by a prolonged hyperpolarization (Harper and Lawson, 1985a,b; Koerber et al., 1988; Waddell and Lawson, 1990).

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Fig. 4–1 Diagram illustrating the approximate percentages of retrogradedly labeled cutaneous afferent neurons also labeled by each of the peptide and other markers indicated; the dotted lines in each column represent 100 percent. The small, dark filament-poor neurons are dorsal root ganglion cells with afferent C-fibers; the large, pale, filament-rich neurons are dorsal root ganglion cells with myelinated afferent fibers. Abbreviations: trkA, trkB, and trkC— neurotrophin receptors. BSA-IB4—lectin; CA—carbonic anhydrase; SSEA3/4— globoseries oligosaccharides; CALB— calbindin; TMP—tyrosine monophotase; SBA—soybean afflutinin; CGRP—calcitonin gene–related peptide; PNA—peanut agglutinin; 2C5—anti-lactoseries carbohydrate antibody; SP—substance P; SOM—somatostatic; NF—neuofilament. (From Lawson, 1996a.)

Ontogenesis, Differentiation, and Migration Neurons of sensory ganglia develop through stages of neuroblast migration and differentiation, axonal projections, trophic interactions with peripheral targets, and local circuit formation in their spinal cord and brain stem projections. These events are controlled

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by several structural factors and a variety of molecular species. DRG neurons are derived from the neural crest. Some neurons in the ganglia of cranial nerves V, VII, VIII, and X are generated in the neural crest, others in the ectodermal placodes. These two sets of cranial sensory ganglia neurons occupy separate zones in mature cranial nerve ganglia (Davies and Lumsden, 1990; Le Douarin and Smith, 1988). Crest founder cells can potentially produce cells of the sensory and autonomic ganglia, the adrenal medulla, and the Schwann cells of peripheral nerves. Crest cell migration is driven by linkage between proteins of the extracellular matrix and the cell surface receptors, the integrins, which attach cells to the matrix and mediate mechanical and chemical signals from it. Migration is disordered when the linkage is blocked by specific antibodies (Bronner-Fraser and Lallier, 1988). Dorsal root ganglion neuroblasts become progressively more restricted in phenotype specificity as they migrate from the crest into their target locations on the lateral side of the developing neural tube. They continue to divide as they move as well as after they reach their target location, where they cluster into small groups in which some neurons are linked transiently by gap junctions. These neuroblasts pass through a stage of dual sensory–autonomic precursors to their final restricted phenotypes as one or the other. After the last cell cycle, DRG neuroblasts differentiate through a bipolar phase into their final monopolar form, and display the characteristic diversity in the central and peripheral targets of their axons, in the structure and stimulus selectivity of their peripheral terminals, and in the variety of the molecules they synthesize.

Axonal Projection and Target Recognition Emerging axonal growth cones of DRG and CSG neurons move through the extracellular environment to reach their targets in skin and other peripheral tissues. Growth cone membrane receptors recognize a variety of molecules that provide a sticky substrate and either promote or repel growth cone extension and axon elongation. Some neurotrophic molecules are fixed to the surfaces of tissue cells, others to the extracellular matrix, and still others are synthesized and secreted from target cells and diffuse freely through the extracellular space. Receptor linkage to a positively neurotropic molecule leads via a transmembrane linkage to second messenger systems that increase intracellular Ca2+, and to activation of the synthetic

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and transport systems that deliver membrane and cytoskeletal proteins to the growth cone over the fast and slow transport systems, respectively. This supplies the needs for axon growth, and may also control the polymerization of actin within the growth cone and its pseudopodia (Lasek and Katz, 1987; Sheetz et al., 1992). The filapodia are filled with actin microfilaments and dispersed myosin. Although the molecular mechanism of the forward movement is uncertain, destruction of the actin filaments arrests that movement. Several families of adhesive glycoproteins have been identified on the surfaces of emerging growth cones and in the extracellular matrix of the tissues they invade; among them are the immunoglobulins, the cadherins, and the integrins. Cell adhesion molecules control cell surface to cell surface interactions during the growth of DRG and CSG axons, and regulate adhesion, growth cone advance, and fasciculation. The most widely distributed cell adhesion molecule of the immunoglobulin family is a large glycoprotein, N-CAM, present on the surfaces of neuron and tissue cells from the time of induction. It links neurons to other neurons and to other cells in a non-Ca2+-dependent manner (Edelman and Cunningham, 1985). N-CAM on axonal surfaces is highly sialylated during the period of axonal growth, and the arrival of the growth cone in the local target regions is correlated with the selective elimination of some sialic acid residues, after which the N-CAM molecule is more adhesive. Highly sialylated N-CAM promotes both neurite adhesion and growth (Doherty and Walsh, 1994). N-cadherin is present on most neurons and links cell-to-cell surfaces in a Ca2+-dependent manner. Integrins are receptor molecules expressed on axonal cone membranes; they mediate the adherence of neurons to the glycoproteins of the extracellular matrix, such as limonene, over which growth cones readily migrate. After binding with ligands, the integrins interact with cytoskeletal proteins and regulate the levels of second messengers, and in this way promote axon outgrowth. The molecular extracellular matrix provides a receptive and positive substrate for axon outgrowth, but the evidence is scanty on how it provides directional information for specific targets. Other molecular families function as negative guidance cues for extending axons. Among them are the semaphorins and netrins, families of proteins conserved from insects to mammals; they exert repulsive or inhibitory actions on growth cones by eliminating branches or synapse formation, or by inducing growth cone collapse.

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Semaphorins repel or induce collapse of emerging growth cones of DRG neurons in tissue culture (Messersmith et al., 1995; Kolodkin, 1996; Tessier-Lavigne and Goodman, 1996). Although a number of molecules have been identified as either promoting or repelling axonal growth, little is known of the signals read by the extending growth cone to account for the specificity of target acquisition. Growth cones integrate their positional information in three dimensions, and upgrade it continuously in time as they move, correct for false leads explored, and find the correct trajectory to target. Some evidence now supports the idea of neurotropism, that target cells secrete substances that diffuse through the tissue to provide concentration gradients along which the appropriate set of axons, and no other, will home (Lumsden and Davies, 1986). The problem of distance remains, for analysis suggests that the spatial limit over which neurotropic substances provide detectable concentration gradients is about 1 cm for substrate-bound molecules and only 1 mm for diffusible ones (Goodhill, 1998). Goodman has emphasized that the molecular guidance system is multiple, and that several neurotrophic molecules overlap in their spatial locations in the projection pathway, and perhaps also in their functions (Goodman, 1996). The guidance system has a robust redundancy that provides a safety factor for axon migration and target acquisition. DRG cells are specified for target location and modality from the time they emit axons. Microdissections of the peripheral nerves innervating the glabrous skin of the monkey hand reveal that fibers with similar properties for place and mode are segregated in nerve fascicles. A similar segregation has been described in human peripheral nerves (Hallin et al., 1991).

Neurotrophins Control Sensory Neuron Survival and Death The neurotrophin theory is derived from discoveries made in the 1950s by Buerker, Cohen, Hamburger, and Levi-Montalcini (for reviews, see Levi-Montalcini, 1987; Bothwell, 1995; and Levi-Montalcini et al., 1996). The central ideas are that neuronal cell death is a normal feature of the development of vertebrate nervous systems and that survival of developing sensory and sympathetic neurons depends on a continuing supply of a sustaining neurotrophic substance, nerve growth factor (NGF) (Cowan et al., 1985; Oppenheim, 1991). Target tissues such as the skin produce a limited amount of NGF for

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which innervating nerve terminals with the appropriate membrane receptors compete. When terminals that achieve effective contact with target cells and make ligand–receptor binding, the NGF–receptor molecular complex is transported in the retrograde direction to their cell bodies, where it supports gene expression, cell survival, and growth. Cells whose terminals do not compete successfully die. The process yields a quantitative match between the sizes of surviving neuronal populations and the target tissues they innervate, and plays a critical role in shaping the innervation patterns of peripheral tissues by first-order sensory and motor axons. Neurotrophins can be defined more generally as molecules that sustain the development of neurons and their innervation patterns. In addition, they regulate the long-term survival, functional properties, and in some cases the distinguishing phenotypes of fully differentiated neurons of the dorsal root and trigeminal ganglia. Many neurotrophins can be grouped in two families: the nerve growth factor family with NGF as its prototype, and the glial cell line–derived family, with GCDF as the prototype (McMahon et al., 1994; McMahon and Bennett, 1999). The NGF family contains NGF itself, brainderived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Four of these act by binding to high-affinity tyrosine kinase receptors: NGF to Trk-A; BDNF and NT-4 to Trk-B, and NT-3 to Trk-C; they also bind to p-75, a low-affinity neurotrophin receptor present in many classes of DRG neurons, which appears to facilitate binding to the high-affinity receptors. Binding of the NGF receptor, Trk-A, with NGF at its extracellular domain leads to homodimerization and autophosphorylation of its intracellular kinase domain (Barde, 1992; Barbacid, 1994). The ligand–receptor complex is internalized and incorporated into vesicles that are transported via microtubules to the soma, where it initiates a train of protein phosphorylations that stimulate the synthetic and expressive activities of the cell. It is uncertain whether the receptor molecule is then recycled to the nerve terminal. NT-3 and BDNF are thought to have similar modes of action. NT-3 and Trk-C are expressed earlier than is NGF, and NT-3 exerts a mitogenic effect on sensory neuroblasts. During this early period, BDNF can bias precursor cells toward the sensory phenotype. DRG/CSG cells are sustained by NT-3 and BDNF during axon outgrowth and target acquisition. It is only after innervation that epidermal cells express NGF, and nerve terminals the matching Trk-A, a

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switchover to NGF support for major subsets of nociceptive and thermoreceptive neurons (Ruit et al., 1990; Wyatt et al., 1990; Lewin and Barde, 1996; Davies, 1997). Large, light cells of the sensory ganglia are supported by NT-3 and BDNF from neurogenesis to the adult form. During the immediate postnatal period in mice, the dependency of small-fibered nociceptive afferents on NGF fades rapidly, but NGF is essential for preserving the phenotype identity of the A-delta nociceptive afferents. Thereafter, and throughout life, NGF stimulates the synthesis of substance P in the peptidergic C-fiber afferents, and is a molecular key in the mechanisms of peripheral inflammation and hyperalgesia, described in Chapter 7 (Lewin and Mendell, 1993; Levi-Montalcini et al., 1996; Mendell et al., 1999; Shu and Mendell, 1999). Neurotrophins have changing and frequently combinatorial relations with the sets of primary sensory neurons that depend on them for survival. Those relations are frequently multiple, and change in the transition from developmental to adult life. Whether any species differences occur is unknown, for the majority of the experiments have until now—necessarily—been made in mice (Lewin, 1996; Lewin and Barde, 1996; Lindsay, 1996). Some specific relationships between neurotrophins and different classes of DRG neurons have been documented in studies of mice genetically altered by homologous recombination to be defective in a neurotrophin or its receptor (Crowley et al., 1994; Snider, 1994; Snider and SilosSantiago, 1996), and in other studies in which a neurotrophin is eliminated by specific antibodies (Ruit et al., 1990). For example, in adult mice the peptidergic C-fiber nociceptive afferents are supported by NGF, the nonpeptidergic set of C-fibers by GCDF (Molliver et al., 1997; Bennett et al., 1998). The first set of these terminate in lamina I and outer lamina II of the dorsal horn, the second in the inner layer of lamina II. It is not known whether these two have different peripheral innervation patterns. A complex, combinatorial relationship governs the neurotrophin support of the large myelinated, slowly adapting afferents innervating the skin, the Merkel afferents. In BDNF-deficient mice, the afferents remain structurally intact, but lose their dynamic sustained responses to steadily maintained mechanical stimuli, even though there is no loss of the Merkel cells themselves (Carroll et al., 1998). However, the Merkel cells are lost completely in mice lacking NT-3 (Airaksinen et al., 1996). Experiments of the same sort have shown that NT-3 is especially

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important for sustaining the large proprioceptive afferents from deep tissues (Liebl et al., 2000), but it appears unlikely that other specific and unique relationships exist between individual neurotrophins and single sets of afferent nerve fibers.

General Principle of Stimulus Selectivity Different sets of sensory fibers are selectively sensitive to different stimulus qualities; signals in those different sets evoke somesthetic experiences that can be identified as different by human observers. An alternative “pattern theory” was strongly argued in the 1950s by Weddell (1955) and Sinclair (1955, 1967); see also Melzack and Wall (1962). It was based on the observation that several varieties of somatic sensibility can be evoked from a tissue, such as the cornea, in which histological study with the limited methods available at the time revealed only unencapsulated nerve endings. The speculations of Weddell and his colleagues were also based on their studies of the furred skin of the rabbit’s ear. Later, Rice and Munger (see Munger and Ide, 1988, pp. 10–11) showed that the ear in the rabbit is almost unique among that in furred animals in that the piloneural complex of its hairy skin lacks Ruffini receptor organs, and the lanceolate terminals do not form the regular palisades seen in other mammalian hairy skin; that is, the furred skin of the rabbit’s ear has few if any organized sensory receptors. The conclusion reached by Weddell was that the sensitivities of all primary afferent fibers are as uniform as the structure of the endings in the cornea and the rabbit’s ear appeared to be, and are not stimulus selective. Weddell and his colleagues formulated the hypothesis that different somatic sensations are produced by different patterns of activity in several sets of simultaneously active, otherwise nonspecific, fibers, that is, that our specific sensory experiences are evoked by specifically different spatial patterns of neural activity in afferent fibers. How those patterns could ever be specific, given the continuous variations of frequencies and spatial distributions of afferents activated, was never explained. It has since been shown that in many instances different sets of unencapsulated nerve endings, though they appear identical on histological and ultrastructural examination, show clearly different stimulus selectivities—facts not known when the pattern theory was formulated. For example, the different sensitivities of the low-threshold warming and C-fiber

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nociceptive afferents innervating the skin are properties of unencapsulated endings of otherwise structurally similar sets of C-fibers. It now appears likely that these specific sensitivities are produced by the presence of qualitatively different receptor proteins in peripheral nerve terminals, and by differences in the concentration of different Na+ channels. Although the mechanisms producing specificity are still imperfectly known, that it exists is beyond reasonable doubt (for reviews, see Perl, 1984, 1992; Stevens and Green, 1996). The principle of stimulus selectivity is supported by convincing evidence, both old and new, obtained in a variety of experiments, including direct observations of first-order somatic afferents in humans. Some of that evidence is presented here, and more in following chapters. It is generally agreed that somatic afferents are specific; that is, they are differentially sensitive to one or another form of impinging energy. Our somesthetic experiences are determined by the spatial and temporal patterns of activity in the many sets of specific afferent fibers and in the activity patterns of the central neurons upon which they project.

Somatic Sensory Qualities Are Distributed in the Skin in a Punctate Fashion It has been known for a century that stimulation of single small spots on the surface of the skin evokes only one of the four somesthetic qualities of touch, warmth, coolness, or pain. This discovery was made independently by Blix (1884), Goldscheider (1884a, b), and Donaldson (1885); it extended to somatic sensation Mueller’s (1840) doctrine of specific sense energies, which was later elaborated by Helmholtz for vision and hearing (Helmholtz, 1860). For historical review, see Norsell et al. (1999). Von Frey (1897) confirmed these discoveries and used quantitative methods to show that modespecific spots were distributed independently in an interdigitated fashion on the skin. Sensory spots are more dense on the hand and face than on the more thinly innervated proximal body parts. What is now called the law of specific nerve energies has been confirmed in a host of experiments since the time of Blix, Goldscheider, and Donaldson, and in an especially powerful way by the results obtained by microelectrode stimulation of identified single axons in the peripheral nerves of waking human subjects described below and in Chapter 11.

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Multicellular Sensory End-Organs of Large-Fibered Cutaneous Afferents Are Mechanical Filters It was discovered almost at the same time that the terminals of many myelinated cutaneous nerve fibers are enclosed in multicellular structures then called “sensory receptors” or “sensory organs.” They were named eponymously: Vater-Pacinian, Merkel, Ruffini, Meissner, and so forth, and these designations persist to this day. Von Frey and others attempted to correlate the modality type identified in a sensory spot with a sensory organ type searched for in that same spot by histological study of the excised patch of skin; that is, the hypothesis was that different multicellular end-organs served the modalities of touch, pain, warmth, and coolness. This effort was partially successful, for von Frey correctly identified hairs and Meissner corpuscles as tactile organs in the hairy and glabrous skin, respectively (von Frey, 1897). He mistakenly assigned the thermal senses to the subcutaneous Krause and Ruffini receptor organs, but correctly observed that the terminals of fibers in pain spots are unencapsulated, and this is true for both the C-fiber and A-delta nociceptive afferent fibers. These endings are not completely bare, as they appear at the level of the light microscope, but are partially covered by a thin sheath of Schwann cell membrane. The electron microscopic, three-dimensional reconstructions by Messlinger (1996) in Fig. 4–2 show that for both the A-delta and C-fiber nociceptive afferents some surface areas of the terminal axolemna are exposed directly to the intercellular space. The terminal segments are frequently beaded in local enlargements that contain large numbers of mitochondria and both clear and dense vesicles. These uncovered areas of the terminals are thought to contain membrane receptor proteins that are targets for external ligands, and also to be the sites of vesicular release; they may be the locations of chemoreceptive and perhaps efferent functions as well. Cutaneous myelinated afferents with multicellular, organized endings are mechanoreceptive afferents. The multicellular organs serve as mechanical filters in the transfer of different quantitative properties of mechanical stimuli to the terminal; for example, contrast the rapidly adapting Pacinian and Meissner afferent sets of the glabrous skin with the slowly adapting Merkel set (see Chapter 5). Three important generalizations followed from these and other discoveries made at about the same time, that: (1) cutaneous sensibility consists

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of several identifiable, separate modalities—touch, pain, warmth, and coolness; (2) spatial acuity in the tactile sense varies with body location, in general being more acute on face, hands, and feet than on proximal body parts; and (3) more complex aspects of cutaneous sensibility, such as wetness, oiliness, and so forth are evoked by combinations of the basic qualities. Although subject to the vagaries of shifting and often quite different theories of cutaneous sensibility and the inevitable disagreements, these observations and the discoveries of Blix, Goldscheider, and Donaldson have withstood the tests of many experimental studies over the last century. They conform with the current concept of the stimulus selectivity of afferent fibers innervating the skin and subcutaneous structures.

Different Modalities of Somatic Sensibility Are Dissociated by the Selective Block of Afferent Axons of Different Sizes Gasser and Erlanger (1929), Heinbecker et al. (1933, 1934), and Zotterman (1933) discovered that block of conduction in afferent nerve fibers of different sizes produces a dissociation of the sensory experiences that can be evoked from the tissues innervated by the blocked nerve. The sequence of loss of different qualities of sensation as different fiber sets fail to conduct fits with the stimulus selectivity of different sets of cutaneous afferent fibers determined more recently by other means. For example, it has been shown by electrical stimulation on the distal side of an anesthetic nerve block, and recording on the proximal side, that C-fibers are blocked first, and then A-fibers in an ascending order of size, as anesthesia progresses (Collins et al., 1960; Torebjork and Hallin, 1973). The first sensations lost in this experiment are second pain and warmth, which are known to be served by different classes of C-fibers. As the block progresses, coolness and pricking pain are lost when the A-delta fibers block. Tactile sensibility remains intact so long as the A-beta fibers are conducting, but it is not possible to dissociate the different qualities of tactile sensibility in this way, for they are served by sets of fibers with overlapping sizes and electrical thresholds (Fig. 4–3). It is not known what mechanisms account for the selective sensitivity of fibers of different sizes to anesthetic agents; for review, see Raymond and Gissen (1987). Conversely, when block is produced by local pressure-asphyxia, the A-beta fibers fail first, followed by the A-delta fibers, and after

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Fig. 4–2 Three-dimensional reconstruction of part of the ending of an A-delta fiber innervating the articular tissue of the cat knee; its conduction velocity was 12.8 m/sec. A—sensory axon; SC—Schwann cell; T—small terminal branch. Left: Contour plots of ultrathin sections at 2-µm intervals along the fiber, arranged in true-to-scale three-dimensional projection. Right: Reconstruction of the same nerve fiber; bare areas of the axon not covered by Schwann cell are densely dotted. Bars for x, y, z directions = 2 µm. (From Messlinger et al., 1995.)

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Fig. 4–3 Form of the compound action potential in the human medial cutaneous nerve, calculated from the distributions of fiber diameters shown in the inset histogram. Data were recorded as fiber diameters, but converted to axon diameters for calculation of the reconstruction. Ordinate: relative amplitude of the expected compound action potential. Abscissa: time scale; latency is that expected after 4 cm of conduction; micron scale for fiber, not axon diameters. The conversion was made on the basis of conversion factor for velocity in meters per second equals 9.2 times axon diameter in microns. The largest afferent fibers (Group I) are not present in cutaneous nerves. (Data from Gasser, 1935.)

a delay of many minutes, the C-fibers. The major components of tactile sensibility disappear with the failure of the A-beta fibers, although a vague sense of contact, together with coolness and pricking pain, persists as long as the A-delta fibers conduct. After this, with the C-fibers alone conducting, only second pain and the

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noxious extremes of heat and cold can be perceived. This latter fits with recent descriptions of the varieties of C-fiber nociceptors (Perl, 1992). The sequential loss of different modalities of somatic sensibility, in step with the sequential loss of conduction in different sets of afferent fibers, gives added support to the principle of stimulus selectivity.

Modality Dissociation Is Produced by Differential Electrical Excitation of Afferent Fibers of Different Sizes In humans, surgical procedures with local anesthesia allow stimulation of bared cutaneous nerves in alert and reporting subjects. Electrical stimuli differentiate between nerve fiber classes of different sizes by their different thresholds. When stimulation is combined with recording of the afferent volleys evoked by the stimuli, it is routinely observed that when stimuli activate only the A-beta fibers, human subjects report only sensations of mechanical events referred to the peripheral distributions of the nerves stimulated. The mechanical sensations increase in intensity as stimulus frequency is increased, but they are never painful (Collins et al., 1960; Torebjork et al., 1987). Different mechanical experiences cannot be differentiated in this way, for there is nearly complete overlap of threshold for different classes of A-beta fibers. When the stimulus strength is increased to include the A-delta fibers, the sensation of pricking pain is added to the mechanoreceptive experience; and, when the stimulus strength is increased to include the C-fibers, long-latency burning pain is felt. Although coolness is known to be served by a set of A-delta fibers in primates, it is seldom reported in experiments of this type. These associations between fiber sizes and the varieties of somatic sensibility have been confirmed by recording directly from single afferent nerve fibers and nerve fascicles in humans during differential nerve block (Torebjork and Hallin, 1973; Mackenzie et al., 1975).

Somatic Sensory Modalities Are Dissociated by Disease Processes Many diseases and inherited disorders that affect peripheral nerve fibers do so in an indiscriminate manner, so that patients with them show a broad spectrum of sensory and motor defects. However, some of these conditions affect nerve fibers differentially as regards fiber

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size, and the resulting deficits in sensation provide evidence for the principle of stimulus selectivity. The most common of these is the group of diabetic neuropathies in which, at least in early stages, the abnormalities are confined largely to the small fibers of peripheral nerves serving pain and temperature sensibilities, with a preservation of mechanoreceptive sensibility (Dyck, 1984). The result is frequently a devastating loss of peripheral tissue, infection, and susceptibility to injury. A particularly clear dissociation occurs in amyloidosis, in which the loss of small myelinated and unmyelinated fibers is accompanied by defects in pain and temperature sensibilities with preservation of the mechanoreceptive aspects of somaesthesis (Dyck and Lambert, 1969). In contrast, in the large-fiber neuropathies, such as the early stages of Friedreich’s ataxia, the peripheral fiber damage may be confined to mechanoreceptive input in the sphere of proprioception, with little or no change in pain or temperature sensibilities. A few cases have been described of a widespread neuropathy confined to the large-fibered dorsal root afferents. It leads to a devastating and unremitting loss of position sense and motor control, and of the internal image of the body form (Cole, 1995).

Direct Evidence for Stimulus Selectivity Obtained by Recording from and Stimulating Single Somatic Afferents in Humans and Nonhuman Primates A major contribution to knowledge of the functional properties of sensory axons has come from the method developed by Hagbarth and Vallbo (1967) and Vallbo and Hagbarth (1968) for recording with transcutaneous microelectrodes from single axons in the peripheral nerves of waking humans. A large volume of observations has accumulated, and many of the classes of sensory fibers listed in Tables 4–1 and 4–2 have been studied. The results extend greatly the body of knowledge obtained in studies of single afferent fibers in nonhuman primates, limited by the extent to which it is possible to execute quantitative experiments in this experimental paradigm in human subjects (Ochoa and Torebjork, 1983; Vallbo and Johannson, 1984; Vallbo et al., 1984; Torebjork and Ochoa, 1987; Torebjork et al., 1987; Macefield et al., 1990). I shall describe these results where appropriate in the chapters that follow, but emphasize in the present context that the general principle of stimulus selectivity has been confirmed for each of the classes of afferent fibers. Modality

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specificity is emphasized by the results of the dual experiment of recording the functional properties of a fiber, and then stimulating that same fiber in isolation. The resulting perceptual experiences match the properties of the particular fiber determined in the electrophysiological phase of the experiment. A dramatic observation was made in the original studies of human cutaneous afferents by Hensel and Boman (1960), who microdissected their own cutaneous nerves, and those of volunteers. They observed that a single impulse in a single afferent fiber elicited a perceptual experience. This has been confirmed in a number of microneurongraphic experiments (Vallbo et al., 1984; Vallbo and Johannson, 1984; Torebjork et al., 1987; for reviews see Torebjork et al., 1984; Macefield, 1998). The general conclusion reached is that under normal circumstances the brain can identify a specific sensory quality, make a precise localization, and judge the magnitude of the sensation on the basis of afferent input confined to a single fiber innervating the glabrous skin of the hand. This is never the case in ordinary sensory experiences, in which the stimuli encountered will engage significantly sized populations of primary afferents and the neurons in the central projection pathways and cerebral cortical areas of the somatic afferent system. What is certain from these results, and from experimental observations described in later chapters, is that the primary afferents innervating the skin of primates including humans are selectively sensitive to different modes of stimulation.

Classifications of Somatic Sensory Afferent Fibers Mammalian primary afferent fibers may be classified on the basis of the peripheral tissue they innervate; the stimuli to which their peripheral endings are selectively sensitive; their axon diameters, and hence conduction velocities; and the special biochemical and structural properties of DRG neurons, and so forth. How sensory fibers vary in axonal diameter and conduction velocity is shown in Fig. 4–3 by the different components of the reconstituted compound action potential of the human medial cutaneous nerve (Erlanger and Gasser, 1937; Gasser and Erlanger, 1927). Figure 4–4 shows that cutaneous nerves contain large numbers of unmyelinated C-fibers, of which 85–95 percent are dorsal root or cranial ganglia afferents, and the remainder postganglionic, sympathetic efferent axons that innervate glands and vessels in peripheral tissues. The ratio of C-fibers

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Fig. 4–4 Above: Frequency histogram of axon diameters in sural nerve of a 15-yearold human; the shaded zone shows the distribution of diameters of unmyelinated fibers, the unshaded zone the bimodal distribution of myelinated fibers; all cutaneous afferents. (From Ochoa and Mair, 1969.) Below: A comparison of myelinated fiber diameters in a digital nerve of a macaque monkey with the distribution of the conduction velocities of the lowthreshold mechanoreceptive afferents in the same nerve. Peak distribution of conduction velocities matches that of the beta-sized mechanoreceptive afferents innervating the glabrous skin. (From Darian-Smith and Kenins, 1980.)

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to A-fibers varies from 3–5:1, in nerves innervating the hairy skin, to 1:1 in nerves innervating the face and the glabrous skin of the hand, where the mechanoreceptive aspects of somatic sensation are most acute. The results of many experiments establish that cutaneous afferent nerve fibers of different axonal diameters serve different somatic sensations. Further differentiation of sets of fibers within these classes has been made by combining conduction velocity with other defining characteristics. The listings in Tables 4–1 and 4–2 for the primate glabrous and mammalian hairy skin, for example, are based on the methods of classification by axonal diameters as well as upon their stimulus selectivities determined in physiological experiments. A wide overlap in fiber sizes exists between sets that differ in selective sensitivity, so that the particular sensitivity of any given afferent fiber cannot be determined unequivocally from its axon diameter. It is for this reason that Perl and others have used a scheme of classification based on these parameters and on the adequate natural stimuli required to excite particular sets of afferents at lowest intensity; for example, each one of the four classes of large myelinated mechanoreceptive afferents that innervate the glabrous skin of the human hand (SA-I SA-II, RA, PC of Table 4–1) responds to brief transient mechanical stimuli with quite similar brief bursts of nerve impulses. Undoubtedly each contributes to the perception of brief tactile contacts, even though these different sets respond quite differently to other patterns of mechanical stimuli. Convincing evidence now supports the generalization that large groups of A-delta and C-fibers signal the incipient or actual destruction of tissue in an unambiguous way. These nociceptive afferents have high thresholds to non-noxious mechanical and thermal stimuli, but are excited by destructive ones. Moreover, they discharge at increasing frequencies when the intensities of those destructive stimuli increase, and in this way provide graded signals of graded noxious stimuli. An important discovery is that the large majority of C-fiber nociceptive afferents are polymodal, for they respond indiscriminately to noxious stimuli whether those stimuli are mechanical, thermal, or chemical in nature (Bessou and Perl, 1969; Kumazawa and Perl, 1977; Perl, 1996). Perl has emphasized the evolutionary problem of producing a spectrum of afferent nerve fibers selectively sensitive to environmental stimuli that include those that destroy tissue, to changes in sur-

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rounding temperatures, and to light mechanical stimuli, and so forth (Perl, 1992). The requirements include low thresholds, adequate dynamic ranges, and signaling intensity differences over those ranges; population modes of signaling spatially extended stimuli; the position and movements of the body parts; and so on. Central nervous connections evolved to match appropriately the selective sensitivity of sets of afferent fibers, connections over which afferent activity could evoke appropriate reflex reactions and perceptual experiences of adaptive value. The problem was to package the large number of afferent fibers required into nerve trunks suitable in size for the body parts they innervate. The evolutionary solution was a wide range of fiber sizes, with the smallest predominating numerically, and with different sets selectively sensitive to the critical ranges of environmental stimuli, but only to those ranges. This appears to have been reached fully in the earliest mammals from 65 mya onward.

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Large-Fibered Peripheral Interface

Sensory transduction is a universal process in the lives of organisms, linking them in an adaptive way to the physical nature of the environments they occupy (Table 5–1). The electromagnetic and gravitational forces they transduce range from photoreception in plants, chemotaxis in bacteria, and electroreception in some fish to the familiar senses of mammals. Transducer mechanisms have evolved in individual cases to the levels of sensitivity, selectivity, and dynamic range adequate for the tasks confronted by the animal, and little more. Even though transducer mechanisms vary widely, study of them at the molecular level has revealed some features common to many—for example, the ubiquitous G-protein, second-messenger linkage from stimulus to membrane channel change in visual, smell, and some taste receptors. The mechanoreceptive senses have evolved more direct trajectories linking stimulus to afferent nerve discharge that do not include the second-messenger phase; even in these cases the mechanisms observed are the familiar ones that modulate the open–closed states of membrane ionic channels. In all known cases there is the general paradigm of a local receptor current flowing through opened membrane channels, the local receptor potential it produces, and the transition to conducted nerve impulses in afferent nerve fibers. A good deal is known of the overall transduction and encoding functions of somatic sensory afferents, especially as regards innervation patterns, sensory receptor organs, selectivity, coding schemes, dynamic range, adaptation, and the patterns of activity in populations

5

Table 5–1 A comparison of the sequence of operations in sensory transduction common in most sensory receptor cells, and the parallel operations in cell populations Transduction operations

Operations in single sensory cells

Operations in cell populations

Detection

Perireceptor mechanisms: filters, carriers, tuning, inactivation, sensitivity, rapidity Positive feedback, active processes, signal–noise enhancement Intensity coding, quality coding, temporal differentiation

Perireceptor mechanisms, filters, carriers, tuning, inactivation, different thresholds Positive feedback, signal–noise enhancement Different dynamic ranges, quality independent of intensity, center-surrounded antagonisms, opponent mechanisms, construction maps Temporal discrimination

Amplification Encoding, discrimination

Adaptation and termination

Sensory channel gating Electrical response Transmission to brain

Desensitization, negative feedback, temporal discrimination, repetitive responses Open- or closed-voltage gating? Depolarization or hyperpolarization Electronic spread, active properties, synaptic output or impulse discharges

Spatial patterns: maps and image formation temporal patterns: directional selectivity, etc.

(From Shephard, 1991.)

of afferents. Much less is known of the linkage between mechanical stimuli and the first response in the terminals of somatic afferent fibers, for it has not yet been possible to apply to those terminals the full panoply of molecular biological and cell physiological methods so productive in studies of receptor populations such as those of the retina or the olfactory mucosa. It is therefore necessary to infer those processes in somatic afferent terminals from knowledge obtained in studies of mechanoreceptive afferents in locations more accessible than the skin. Different properties of stimuli impinging on the hand or acquired by manipulation are transduced and signaled by several classes of afferent nerve fibers. Each class contains sets of axons with different transducer characteristics. A-alpha and A-beta afferents from muscle, and the A-beta afferents innervating the skin, differ in the particular properties of mechanical stimuli they transduce, but all are sensitive at low thresholds to one or another form of innocuous

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mechanical stimulation, all fall into overlapping ranges of conduction velocity, and each set is thought to serve a particular aspect of mechanoreceptive sensibility. It is shown in later chapters that the major classes of large mechanoreceptive afferents innervating the skin and subcutaneous tissues are parallel channels for distinct forms of tactile sensibility. The Pacinian afferents provide the afferent signals for the sense of vibration, sometimes sensed from a distance or via a hand-held tool; the Merkel afferents signal the spatial properties of cutaneous stimuli, particularly those of form and texture; and the Meissner afferents provide signals of low-frequency skin movement, the sense of flutter, and other types of movement over the skin. The Ruffini afferents, slowly adapting class II (SA-IIs), have been identified in the cutaneous nerves innervating the human hand, and by their response properties are thought to contribute to the sense of position of the hands and fingers. When stimulated in isolation in neuronographic experiments in humans, they evoke no conscious sensation. They are not present in the glabrous skin of the monkey hand, and have been identified only rarely in the palmar skin of humans (Pare et al., 2003). Sets of the small-fibered class differentially transduce stimuli that destroy, or tend to destroy, tissue and evoke pain, whether those stimuli are mechanical, chemical, or extremes of heat and cold. Other small-fibered sets innervating the glabrous skin are sensitive to changes in skin temperature in the innocuous range of 31°–41° C, between the thresholds for heat or cold pain. This separation between the stimulus parameters transduced by the large- and smallfibered classes of axons is especially clear in the innervation of the glabrous skin of the hands of humans and monkeys. An example taken from a study by Georgopoulos (1976) shows the contrast between the overlap in the conduction velocities of the A-beta and Adelta axons innervating the glabrous skin of the monkey’s hand (Fig. 5–1a and b). As the amplitude of a mechanical stimulus is increased it recruits to the discharge population fibers with successively higher thresholds, and at a critical point engages the mechanically sensitive nociceptors. Afferents sensitive to warmth and coolness may be activated at any point along the scale. When one considers the role of the hand in active life in the reception and acquisition of stimuli, it seems reasonable that the activity evoked in mechanoreceptive afferents, which we isolate so cleanly in the laboratory, is almost always accompanied by activity in small-fibered afferents. It is still

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Fig. 5–1 A: Cumulative frequency distributions of the conduction velocities of low threshold (A-beta) and high threshold (A-delta) myelinated afferents innervating the glabrous skin of the macaque hand. B: Similar frequency distributions for the two classes of afferents in terms of mechanical thresholds. Fibers were isolated for recording by microdissection of the median nerve. Overlap in the conduction range from 25 to 45 meters/sec means that in this range modality cannot be determined by conduction velocity alone. (From Georgopoulos, 1976.)

uncertain where and to what degree these two major components of the somatic afferent system converge. The large-fibered mechanoreceptive component of the dorsal column system operates through restricted and—in the dynamic state of sensory function—convergentfree transitions through the dorsal column and principal trigeminal

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prethalamic nuclei to the ventral posterior lateral and ventral posterior medial thalamic relay nuclei and into the somatic sensory areas of the postcentral gyrus (Chapters 6, 9, and 10). At the thalamic level, however, these throughput pathways are embedded within a surrounding matrix of thalamocortical neurons activated by the small-fibered afferent pathways of the spinothalamic and spinal trigeminal systems. The two systems converge at the level of the postcentral gyrus, but engage the cortex in quite different ways, the first via the intermediate layers, the second via the most superficial. The meaning of this difference for intracortical operations is still uncertain. Other projections of thalamic matrix cells reach the limbic areas of the cortex, which implies that the integration of the signals they carry for the full representation of somatic sensory experiences is a function of the distributed systems of the cerebral cortex. Each of the processes that link mechanical stimulation of the skin to the discharge of afferent impulses into the nervous system poses problems still only partially solved. The first is that of skin mechanics; that is, how the physical properties of the skin and immediately subcutaneous tissues determine which parameters of the mechanical stimuli are transmitted to the terminals of the large-fibered mechanoreceptive afferents. The second is how those different quantitative parameters of the transmitted mechanical events are transduced differentially at the terminals of different sets of those fibers. The third is how the properties transduced are encoded in trains of action potentials and transmitted to the central nervous system (CNS).

Skin Mechanics and Mechanoreception (This section contributed by KO Johnson) The specificity of a mechanoreceptor is determined by a serial chain of mechanical and electrical linkages between the external stimulus and the action potentials produced by the receptor. The first step in that chain is the mechanical linkage between the stimulus and the receptor structure surrounding the essential mechanoreceptor—the mechanosensitive ion channels in the axon terminal. To understand this linkage, we need to understand the mechanics at the point of contact between the stimulus and the skin and the continuum mechanics that link the surface deformation produced by the stimulus to the tissue deformation in the immediate vicinity of the receptor.

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The complex structure of skin suggests that no simple model of skin mechanics can account for the responses of mechanoreceptors. However, models with simple assumptions about the relevant skin mechanics provide detailed and accurate predictions of the responses of cutaneous mechanoreceptors to very complex tactile stimuli (Phillips and Johnson, 1981b; Dandekar et al., 2003).

Contact Mechanics When the skin contacts an object, the skin deformation depends on the shape and rigidity of the object. This discussion is restricted to rigid objects because the skin mechanics are much simpler when only one of the two contacting media is deformable, because large fractions of the objects that contact the skin are rigid, and because virtually all neurophysiological studies have been done using rigid stimuli. Some of the most important aspects of the contact mechanics between a rigid and a deformable object can be appreciated without any knowledge or assumptions about the internal (continuum) mechanics of the deformable medium. The effects of a complex stimulus are analyzed by breaking it into small units, analyzing the effects of the small units, and combining those effects. When the stimulus is rigid the skin displacement at all the points of contact is readily represented as an array of punctate skin displacements as though the displacement was produced by a very dense array of punctate probes. However, the effects of neighboring displacements are combined in a highly nonlinear way; the effects are not only not additive, but they are also in some ways subtractive. The nonlinear effects can be seen by considering briefly a thought experiment involving a very dense array of probes (at, e.g., 100-µm intervals). Advance one probe slowly to 1 mm indentation. That produces a tent-like displacement that extends for millimeters in all directions. The pressure beneath the probe (stress) is enormous because the small probe supports the entire tent-like displacement. Then, advance the adjacent probe slowly. If the effects were additive the displacements and forces would be the sum of the displacements and forces produced by the probes individually; but they are not, for the second probe fails to touch the skin until its displacement nears 1 mm. Then, at 1 mm the load and the responsibility for all the displacements shifts rapidly to the second probe and the first probe is left with no load and no effect on the skin.

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Now, consider, as an example of a more complex stimulus, indentation by the array in the form of a disk. The probes around the edge assume the load of the deformations directly beneath them plus the load of the entire surrounding tent-like displacement. The interior probes assume only the load of displacing the small region of skin directly beneath them. Consequently, the forces, stresses, and strains at the edge are much higher than those at interior segments of the face of the disk. It is for this reason that Merkel receptors (and Meissner receptors to a lesser extent) respond much more strongly when the receptor is beneath the edge than when it is beneath the center of the disk (Phillips and Johnson, 1981a). The result of these interactions is that indentation with a new probe in the skin surrounding a previous indentation reduces the stresses and strains beneath the first indentation. The effect on the neural responses of single mechanoreceptors is surround suppression, which is functionally equivalent to the effect of surround inhibition in the central nervous system (Vega-Bermudez and Johnson, 1999c). The stimulus can equally well be characterized as an array of forces. Every displacement profile has a paired, unique force profile and vice versa. Force profiles have all the desirable analytic properties that displacement profiles lack. If multiple probes (in any configuration) are applied with small forces, the total force is the sum of the individual forces and the overall displacement is (unless the resulting displacement seriously distorts the skin) a close approximation to the sums of the displacements produced by the individual forces. Furthermore, the subcutaneous stresses and strains are a close approximation to the sums of the stresses and strains produced by the individual forces. Unfortunately, the force profile is very difficult to measure. The force profile corresponding to a particular displacement profile can be computed, but that requires knowledge (or an educated assumption) of the underlying continuum mechanics.

Continuum Mechanics The importance of the subcutaneous continuum and its mechanics is that it is the medium through which the stimulus is transmitted to the receptor. The receptor has access only to the local stresses and strains, not to the stimulus itself; consequently, we need to understand how the local stresses and strains are related to the surface displacements and forces.

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Two extreme skin mechanics models and an intermediate model have been examined. The first is a “waterbed” model in which the finger is represented by an elastic membrane enclosing an incompressible fluid (i.e., an aqueous fluid) (Taylor, 1975). The strength of this model is that it predicts the tent-like skin displacement around a line load accurately (Srinivasan, 1989) but because the pressures (stresses) everywhere within a fluid are uniform (definition of a fluid) the model is unable to account even approximately for the responses of mechanoreceptors to cutaneous indentation. The second might be called a “rubber” model. It assumes that the skin is a homogeneous, isotropic, elastic, incompressible medium (qualities found in rubber) (Phillips and Johnson, 1981b). This model predicts the skin indentation profile produced by a line load less accurately than does the waterbed model, but it predicts the responses of mechanoreceptors to spatially complex stimuli so well that it is difficult to find a systematic lack of fit between the model predictions and the actual responses. The intermediate model assumes that the finger comprises three rubber-like layers corresponding to the epidermis, dermis, and subcutaneous tissues surrounding a rigid core (bone) (Dandekar et al., 2003). This model predicts the skin displacement produced by a line load and it predicts the mechanoreceptor responses almost as well as the uniform rubber model. To understand these models or, indeed, any mechanical model of skin, it is necessary to understand the basics of continuum mechanics. The stresses (pressures) and strains (deformations) at any point beneath the skin each require six parameters for their description, and a mechanoreceptor might, in theory, respond to any single component or combination of the components of stress or strain. Thus there are many possibilities. The evidence is that part of the difference between different mechanoreceptors is accounted for by the particular stress or strain components to which they respond (Phillips and Johnson, 1981b; Del Prete et al., 2003). A basic description of the six parameters of stress and strain and how they arise can be found in an appendix to Phillips and Johnson (1981b).

Mechanoreceptor Models Any mechanoreceptor model requires assumptions about the continuum mechanics, the locations of the receptors, and the specific component of stress and strain that is being transduced. A test of

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any specific model is the consistency between the stress or strain component that is putatively being transduced and the firing rate of the mechanoreceptor. If there is a consistent relationship, the hypothesis that the receptor’s firing rate depends on that stress or strain component cannot be rejected. Tests of that kind have shown that Merkel receptors are selectively sensitive to a component of strain that is either the local maximum compressive strain (Phillips and Johnson, 1981b) or the local strain energy density (Srinivasan and Dandekar, 1996). The two are closely related and both provide a close fit to Merkel afferent firing rates; no other component of stress or strain does so. Similar analyses suggest that Meissner receptors are sensitive to horizontal tensile strain, but the evidence is not nearly as strong as for the Merkel receptors. No comparable studies have examined the mechanics of Pacinian responses.

Molecular and Cellular Processes of Mechanical Transduction Sensitivity to mechanical stimulation serves such diverse functions as the avoidance movements of bacteria, volume regulation in cells, and the sensory transduction of mechanical stimuli, which, in multicellular animals, provides the sensory input for the somatic sensations of touch, kinesthesis, and so forth, and for hearing. A general paradigm is common to many receptors, including mechanoreceptors. The central player in mechanoreceptive afferent transduction is the unmyelinated peripheral nerve terminal, sometimes bare and exposed to the surrounding tissue, but often encased in multicellular, non-neural structures that filter or otherwise modify the transmission of stress to the nerve terminal. Mechanical sensitivity is mediated by stretch-activated channels (SACs) in nerve terminal membranes. These channels are gated by tension and the related deformation of the cell membrane. It is estimated that the SAC channels in the tactile sensory cells of Caenorhabditis elegans are opened by a few pico-Newtons of force, at delays of 100 µsec or less. Nothing intervenes: there is no intermediate biochemical step and no subsequent link to second messengers. The gating of such a channel allows a surge of inward current usually recorded as the decrease in membrane potential it produces. This generator potential is local, not conducted, and invades adjacent regions of the terminal and parent afferent axon by electrotonic extension; it can be summed both temporally and spatially, and graded by mechanical stimuli of

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different intensities, presumably by the spatial recruitment of additional channels. It has no refractory period. When the extended generator current depolarizes regenerative, spike-initiating membrane, action potentials are generated in the parent axon by a process determined by passive membrane properties as well as by the nature and densities of the voltage-gated ion channels in the nodal membrane. What role the proteins of the extracellular matrix and of the cytoskeleton may play in transduction is uncertain. Stretch activated channels were discovered in 1984 by Guharay and Sachs in tissue-cultured, embryonic, chick skeletal muscle, and in the same year by Brehm et al. in myotomal muscle of Xenopus laevis. The patch-clamp method of recording was used in both studies. These channels have since been identified in virtually every prokaryote and eukaryote examined. SAC densities are in the range of 1/µm2; thresholds in terms of membrane tension vary around 1 dyne/cm2. Mechanical stimuli induce an increase in the probability of channel opening with opening times in the microsecond range, with no qualitative change in ion selectivity. Gating is allosteric, as it is for other channels. The distribution of open times is exponential with a time constant of about 1 msec. Closed time distributions vary from 1 to > 30 msec. Of the receptor and voltage-gated channels from neural tissues that have been tested, only the N-methyl-D-aspartate (NMDA) channel in cultured cells from embryonic rat brains is mechanosensitive (Paoletti and Asher, 1994). Whether this property persists in adult neurons is unknown. The opening probability of SACs at a given membrane tension increases with depolarization over the range of membrane potentials from −40 mV to +40 mV, without change in ion selectivity, but SACs cannot be gated by changes in membrane potential alone. SACs are most commonly permeable to Na+, K+, and Ca2+, with conductances in the range of 25–80 pS. Channels thought to function in osmoregulation, particularly in bacteria, have much higher conductances. Stretch-inactivated channels (SICs) are much less common than are SACs; some SICs are K+ selective, for example, those in the growth cones of axons (Sigurdson and Morris, 1989). Discoveries of the molecular mechanisms in mechanical transduction have been made in studies of organisms in which structure and ontogenesis are well known, particularly bacteria, nematodes, and flies. The nematode C. elegans is perhaps the most completely known multicellular organism, for its 959 cells (302 neurons) and their

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connections have been mapped at the level of ultrastructure, and its genome sequenced (Chalfie and Jorgensen, 1998). Six of its cells are sensitive to gentle tactile stimulation; they control movements of avoidance and progression. More than a dozen genes have been identified whose products are important in mechanical transduction. In some C. elegans mutants, the touch-sensitive cells do not develop at all; in others the cells develop normally but are without touch sensitivity (Chalfie, 1993, 1995; Garcia-Anoveres and Corey, 1996, 1997; Tavernarakis and Driscoll, 1997) shown in some mutants to be due to loss of mechanosensitive channels (Walker et al., 2000). It has been suggested that proteins of the extracellular matrix and of the intracellular cytoskeleton play roles in mechanical transduction, perhaps by guiding selected stresses toward the channels, and/or tethering the channels in the membrane lipid bilayer (Du et al., 1996; Ghazi et al., 1998; Wang et al., 1993; Ingber, 1998). SACs can be activated when free of these accessory structures, for SACs isolated from nonspecialized cells and reconstituted in oocytes retain a normal range of mechanical sensitivity. The interdigitation of these terminals with surrounding non-neural cells, however, suggests that the latter are important for directing some selected strains and not others toward the channels, as is the case for the Pacinian corpuscle. Stretch activated channels are thought to be the critical links between mechanical stress produced by stimulation of the skin surface, described above, and the local currents that generate action potentials in the mechanoreceptive nerve fibers. These channels have not been demonstrated directly in the terminals of the A-beta afferents innervating the glabrous skin of the primate hand. The inference that they exist there, and that their properties may resemble those defined in studies of SACs in nonspecialized cells, is strengthened by their presence in the stretch receptor of the crayfish (Erxleben, 1989), and by the mechanical sensitivity of cultured, large-sized, dorsal root ganglion cells of rats. For reviews, see Sachs (1988), French (1992), Sachin (1995), and Sachs and Morris (1998).

Large-Fibered Mechanoreceptive Afferents Innervating the Primate Hand The terminals of different sets of large, myelinated, afferent fibers are interdigitated in the glabrous skin of the hand. They respond selectively at low thresholds to particular stimulus parameters. Each of

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these afferent sets projects a different representation of the physical form of the hand over the dorsal roots into parallel pathways of the ascending somatic systems to and through the somatic sensory areas of the postcentral gyrus. A degree of independence between these parallel channels within the large-fibered systems is preserved by the static microconnectivity and dynamic synaptic operations in each central transition zone. Convergence in transition zones occurs between the elements within any single channel in large-fibered systems, but convergence between sets appears first to any significant degree in the trans-postcentral somatic sensory areas of the cortex in the parietal lobe and parietal operculum. These merged representations are conjectured to be embedded in the activity of the distributed systems of the cerebral cortex beyond the entry funnel in the postcentral gyrus. The median and ulnar nerves carry the afferent innervation of the glabrous skin of the volar surfaces of the hand and fingers (Fig. 5–2). They share with the radial nerve the innervation of both the hairy skin of the dorsum of the hand and the transitional skin of the back of the fingers. Afferents from the skin of the hand enter the spinal cord over the 6th, 7th, and 8th cervical and the 1st thoracic dorsal roots. Branches of the cutaneous nerves contain all the classes of afferents that innervate the skin, together with the postganglionic autonomic C-fibers that innervate the sweat glands and vessels of the skin. These branches divide to form the distributed series of plexuses in the subcutaneous region, the dermis, and the subpapillary levels shown in Fig. 2–8. Small branches ascend from the subpapillary plexus to terminate in the various classes of receptors in each papillary region of the glabrous skin, bounded by the limiting ridges in one direction and cross-bridges in the other. Ascending bundles of axons, growing toward the epidermis early in development, are arranged in hexagonal, columnar arrays 30–40 µm apart. Different sets of A-beta myelinated afferents innervating the glabrous skin and the immediately subcutaneous tissues of the human hand end selectively in the multicellular Meissner, Merkel, and Pacinian nerve formations, some of which are enclosed in connective tissue capsules. I shall use alternatively the classical eponymic terminology as well as designations based on rates of adaptation to steadily maintained mechanical stimuli: RA—rapidly adapting, and SA—slowly adapting. They are the RA system (Meissners); the PC system (Pacinian); the SA-I system (Merkels); and, in humans but not in

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monkeys, the SA-II system (Ruffini). The word “system” refers to the first-order afferents and the central pathways over which they project through the transition nuclei of the brain stem and thalamus and into the somatic sensory cortex. The Krause “end-bulbs” described by classical neurohistologists are thought by some to be ventrally displaced and modified Meissners, and by others to be clusters of free nerve endings (Munger and Ide, 1988). No variety of somatic sensibility has been correlated with activity putatively derived from the Krause “end-bulbs.” Thinly myelinated A-delta nociceptive afferents and the set of A-delta low-threshold cooling afferents terminate in unencapsulated endings. Unmyelinated Cfiber nociceptive afferents and the C-fiber low-threshold warming afferents end peripherally in unencapsulated terminals only partially covered by Schwann cell membrane. There are two major differences between the mechanoreceptive afferent innervation of the glabrous and hairy skins. First, a set of low-threshold A-delta afferents innervates the hairy skin of the body and face in both monkeys and humans; it serves a poorly defined variety of mechanoreceptive sensibility. No such class of Adelta mechanoreceptive afferents has been identified in the innervation of the glabrous skin in primates. Second, a set of lowthreshold C-fiber mechanoreceptive afferents innervates the hairy skin of the human forearm and facial skin, but such a class has until now not been identified in the innervation of the glabrous skin of the hand (Vallbo et al., 1993). What function those particular C-fibers serve is unknown, for after pressure block of all A-beta and A-delta fibers innervating the human arm, with C-fibers shown to be conducting, the region of skin innervated by the blocked nerves is insensitive to mechanical stimulation.

Conduction Velocities, Innervation Densities, and Axon-Receptor Ratios The A-beta axons of the mechanoreceptive sets innervating the human hand are indistinguishable by axon diameters/conduction velocities. They vary in size from 5 to 12 µm, and in conduction velocities from 36 to 78 m/sec, with means of about 58 m/sec (Kakuda, 1992). The three sets innervating the monkey glabrous skin are similar in size and conduction velocities. Each palmar digital nerve of the monkey contains on average about 800 A-beta sized

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Fig. 5–2 Drawings to illustrate the pattern of neural innervation of the arm and hand by the median (left) and ulnar (right) nerves. Inset drawings show the areas of skin innervated by the two nerves. (From Netter, 1991.)

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mechanoreceptive afferents (Darian-Smith and Kenins, 1980). Table 5–2A shows the proportion of these fibers that end in the three established classes of mechanoreceptive organs in the dermis and epidermis of the glabrous skin of the monkey hand, and Table 5–2B gives the approximate innervation density for each receptor type. Similar observations in humans are summarized in the histogram shown in Fig. 5–3 for the four classes innervating the central part of the skin area served by the median nerve (Johannson, 1978; Johansson and Valbo, 1979). The proximal to distal increase in innervation density for the RA and SA-I afferents peaks at the finger tip, where the summed value for the large-fibered mechanoreceptive afferents, identified as innervating the glabrous skin, is 241 axons/cm2 for the glabrous skin of the human finger and 325 axons/cm2 for the monkey finger. On the order of 150–170 axons/cm2 terminate in Meissner corpuscles in the distal finger pads of monkeys and humans.

Table 5–2A Distribution of the receptive fields of different A-beta mechanoreceptive afferents innervating the glabrous skin of the monkey finger Receptive field locations Distal phalanx Middle phalanx Unidentified Total Percentage

Unidentified

Rapidly adapting fibers

Slowly adapting fibers

— — 36 36 9.0

136 65 — 201 50.5

103 38 — 141 35.4

Pacinian fibers

Totals

%

20*

249 113 36 398

62.3 28.4 9.0

20 5.0

*The receptive fields of each of the Pacinians extended over both distal and proximal phalanges; 10 fibers were allotted to each.

Table 5–2B Estimated innervation densities of A-beta mechanoreceptive afferent fibers innervating the glabrous skin of the monkey finger Receptive field locations Distal phalanx Middle phalanx

Rapidly adapting fibers/cm2 178 80

Slowly adapting fibers/cm2 134 46

Pacinian fibers/cm2 13* 13*

*Pacinians considered separately as all fibers innervated both phalanges. (From Darian-Smith and Kinnins, 1980.)

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Fig. 5–3 Diagrams illustrating the innervation densities of the four types of mechanoreceptive afferent fibers innervating the glabrous skin of the human hand. Fibers isolated by microelectrode recording from the median nerves of waking humans. a,b,c—Areas on the glabrous skin of the hand and fingers innervated by the populations of fibers studied. The filled, stippled, open, and hatched columns in the graph to the right refer to the RA, SAI, PC, and SAII fibers, respectively. Left ordinate indicates the number of fibers (u.) sampled per cm2; that to the right the estimate of the absolute number terminated in each cm2 of glabrous skin. SAII fibers innervating tissue around the nails were excluded. (From Johansson and Vallbo, 1979a.)

In young humans those RA axons terminate in 3000–4000 Meissners/cm2 (Bolton et al., 1966). The branches of each axon divides to innervate as many as 25 Meissners. Some Meissners are innervated by two or three axons, but the exact ratio is uncertain. Axonal innervation density of the Merkels is not known with certainty. Many Pacinian afferents terminate in a single corpuscle. The A-delta cooling afferents and the C-fiber warming afferents have innervation densities on the monkey finger pad of about 50 fibers/cm2.

Peripheral Sensory Nerve Formations: “Sensory Organs” The original discovery of what was later, and still is, called the Pacinian corpuscle was made by Lehman and Vater in 1741 (Vater, 1741) and “rediscovered” by Pacini in 1835. The independent discoveries of the sensory spots in the skin by Blix, Goldscheider, and Donaldson, together with the results of von Frey, supported the Muellerian doctrine of specificity of action of primary cutaneous afferents. Von Frey’s attempts (1897) to make direct correlations between different modalities of cutaneous sensibility and different multicellular receptor

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organs of the human skin were only partially successful. We now know that mammalian cutaneous afferents with multicellular receptor organs are mechanoreceptors, and that different sets are differentially sensitive to different physical properties of mechanical stimuli. Electron microscopic studies reveal that intracapsular terminals vary in their patterns of axonal division and terminal morphology; that some sensory organs have specializations of an inner core of nonneural cells; and that in some cases the sensory organ is enclosed in a capsule. Munger (1982) has provided a balanced view of the study of cutaneous receptors and their afferents from the time of Henry Head in 1905 until 1982.

Pacinian Corpuscle The Pacinian corpuscle (PC) is often the experimental choice among primary somatic sensory mechanoreceptors because its large size and ready accessibility allow biophysical methods to be used in analyzing its mechanisms of transduction and impulse initiation. PCs in the cat mesentery can be isolated for studies in situ with normal or perfused circulation, or removed for studies with biophysical methods. It is assumed that the transduction mechanisms of cat mesenteric corpuscles resemble those of PCs in the hand because of their identical structure. The ovoid-shaped PCs are gross anatomical structures. Those in the cat mesentery measure about 1000 × 670 µm along the two axes; very large ones are sometimes seen in aged humans, in whom they may range up to 4–5000 × 250 µm. In a single monkey hand studied completely they averaged from 470 × 229 µm in the finger to 703 × 377 µm in the palm (Kumamoto et al., 1993). PCs are common in the dermis and subcutaneous tissue beneath the glabrous skin of hands and feet, in the aponeuroses and tendon sheaths of skeletal muscle, around ligaments, in fascial planes, in the periosteum and interosseous membranes, and in muscle tissue itself; they occur rarely in hairy skin. Counts of PCs in hands in humans vary from a mean of 300 in the subcutaneous tissue of the human (Stark et al., 1998) to more than 1000 in a serial section study of a fetal human hand (Bushong, 1963) (Fig. 5–4). The density of subcutaneous PCs in the middle and distal phalanges of the monkey fingers is about 13/cm2 of skin surface. The ultrastructure of the PCs was first studied by Pease and Quilliam (1957); for later studies and reviews, see Ide et al. (1988),

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Fig. 5–4 Drawing showing the distribution of Pacinian corpuscles in the hand of a 7-month human fetus. The corpuscles are marked in black. They are concentrated in the thenar and hypothenar eminences, particularly along the tendon sheaths. (From Buschong, 1963.)

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Munger et al. (1988), and Zelena (1994, pp. 138–145), Bell et al. (1994). The central axon of the PC is long and nearly straight, and measures 5–10 µm in diameter and 500–600 µm in length. A node of Ranvier occurs after the axon enters the capsule, and a half node occurs farther in, after which the axon loses its myelin sheath (Fig. 5–5). The axon is elliptical in shape, with long Y-axis to short X-axis ratio of 2 to 1. Along the X-axis, the surface membrane is closely applied to the innermost lamella of the inner core, while that of the Yaxis faces two narrow radial clefts that divide the inner core into two hemiconcentric halves; many axonal spines project into the surrounding basal lamina-like matrix (Bolanowski et al., 1994). The mitochondria of the terminal are clustered along the inner surface of the cell membrane, and are differentially concentrated along the Yaxis. These structural specializations are interpreted to mean that the axonal spines are preferential sites of mechanical transduction (Ide and Hayashi, 1987), but there is no direct evidence that this is so. The elliptical form of the axon terminal and the axonal spines along the Y-axis are thought to determine the axial asymmetry of the axon’s sensitivity. Mechanical compression parallel to the X-axis evokes excitation at ON and suppression at OFF; stimuli parallel to the Y-axis evoke the reverse sequence (Ilyinski, 1965; Ozeki and Sato, 1965). The inner core of the PC is 20–30 µm in diameter, and contains 40–50 thin cellular lamellae whose cell bodies lie in the periphery of the inner core. Each lamella covers one half of the circumference of the capsule; the several on each side construct the two halves of the inner core. Inner core lamellae are linked by gap junctions that may form low-impedance ionic pathways between them. The outer core consists of up to 30 layers of connective tissue that surrounds the two halves of the inner core; these layers are separated by a few intermediate lamellae that resemble those of the inner core. The connective tissue of the capsule is continuous with the perineural sheath of the innervating nerve fiber. PCs are virtually incompressible by ordinary somatic stimuli, and are thought to change form by differential movement of fluid between the lamellae of the outer core.

Fig. 5–5 Electronmicrograph of a Pacinian corpuscle, showing the nerve terminal (N) in cross section of its longitudinal axis, and the inner core lamellae forming the extracellular cleft (C) by the near-contact of the two sides of the inner core. The terminal filopodium of the nerve fiber (arrows) is seen entering the cleft region. (From Bolanowski et al., 1994.)

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MECHANICAL TRANSDUCTION IN THE PACINIAN CORPUSCLE

The studies of Sato, Loewenstein, Hunt, and others, made more than 40 years ago, revealed the transducer mechanisms of Pacinians at the level of cellular mechanisms (Loewenstein, 1971; Hunt, 1974a). Some of Loewenstein’s results are shown in Fig. 5–6, and summarized

Fig. 5–6 Upper left: The method of stimulating a Pacinian corpuscle with a Rochelle salt crystal after isolation of corpuscle and its innervating axon from a cat’s mesentery. Recording of both the generator and action potentials made between one electrode on the axon and the second in the volume conductor. Right: Records a–d show increasing amplitudes of generator potentials evoked by increased amplitudes of brief mechanical stimuli; that for e reached action potential threshold. Sequence in 2 is unchanged after removal of the outer lamellae of the corpuscle, or, 3, after the inner core has been partially removed. In 4, pressure block at the node of Ranvier eliminates the action potential without changing the generator potentials; 5, both disappear after denervation. Lower left: Outline of the model of the local changes in membrane permeability and current flows of generator current reaching the first node of Ranvier. (From Loewenstein, 1971.)

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as follows. The PC is a high-pass mechanical filter, which accounts for the rapidly adapting property of the receptor and for its low threshold for sine-wave mechanical stimuli in the range of 250–300 Hz. The PC with intact capsule responds to brief or sustained mechanical compression with brief receptor currents, and a discharge of one to three action potentials generated at the first or second intracapsular node of Ranvier. After removal of much of the capsule, the terminal responds to sustained mechanical compression with a sustained generator current. The receptor or generator response has the general properties of such responses described above. A sustained generator current, or applied electric current, passing outward through the nodal membrane, evokes the same brief nerve impulse discharge as does mechanical stimulation of the intact capsule. Rapid adaptation in the PC depends on both the mechanical properties of the capsules and the intrinsic properties of the axonal membrane. RESPONSE PROPERTIES OF PACINIAN AFFERENTS

The Pacinian corpuscle is a high-pass filter, with best frequency at 250–300 Hz, nicely coupled to the natural frequency of the subcutaneous tissues of the hand. This accounts for the widespread spatial summation of the PCs, so that their receptive fields expand with increasing stimulus amplitudes. Those fields commonly include an entire digit, sometimes with parts of the palm and in the extreme the entire hand. Descriptions of the functional properties of the Pacinian afferents and their role in vibratory sensibility are given in Chapter 12. It is informative to compare the intrinsic, rapidly adapting nodal membrane of the Pacinian afferent fiber with that of the slowly adapting afferents that can be isolated for study, for example, the stretch afferents from muscle in crustacea and in submammalian vertebrates. It has been known since the experiments of Adrian and Zotterman (1926) that stretch of the frog muscle spindle evokes a repetitive discharge in the axon that declines slowly during maintained stimulation; and that the onset transient and the sustained discharge can be graded by differences in the rate of stretch and its final sustained value. Katz (1950) discovered that a local depolarization, a generator potential, linked the stretch of the muscle cell to nerve impulses in the stem axon. Figure 5–7 illustrates the sensitivity of the muscle spindle to rate and degree of stretch, the regular rate of

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Fig. 5–7 Left: Records made from an isolated frog muscle spindle stretched for 400 msec, before (A) and (B) after block of action potential initiation by local anesthetic. In both A and B, the upper trace is the neural response, the lower left the stimulus trace. Receptor potential shows the initial dynamic response, followed by a steadily maintained depolarization during the period of the muscle stretch. Time bar in B is 50 msec. Right: Upper records show dynamic phases of the receptor potential evoked by different stretches, shown below; impulse initiation blocked by anesthetic. Over a considerable range the amplitude of the dynamic phase of the receptor potential is a linear function of the degree of stretch; its slope is determined by stretch velocity. (From Ottoson and Shepard, 1971.)

discharge in the sustained state, and the onset transient and sustained level of the generator potential during sustained stretch (Ottoson and Shepherd, 1971). In this case, in contrast to that of the Pacinian nerve fiber, electrical current passed outwardly through the first Ranvier node produces an abrupt onset of a regular rate of discharge that can be graded by the intensity of the current applied. These two experiments, and many that followed on mammalian muscle afferents (Hunt, 1974b), indicate that axonal membranes of rapidly and slowly adapting afferents, while similar at the ultrastructural level, have contrasting mechanisms of adaptation to constant

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current stimuli, and differ in some fundamental way, most likely by the nature, densities, and distributions of ion channels. PCs provide the somatic afferent system with a set of distance receptors, for their high density in hands and feet and their low thresholds enable detection of transmitted vibrations produced by mechanical events at distances of many hundreds of meters.

Meissner Corpuscle (RA) Meissner corpuscles are located in the domes of the glabrous skin papillae on either side of the freely swinging intermediate ridges (Meissner, 1853) (Fig. 2–7). The corpuscles are 80–150 µm in length and 20–40 µm in diameter. Each is supplied by one, two, or occasionally by several A-beta afferent fibers, and each axon divides to innervate 15–25 Meissner corpuscles, distributed over 2–5 dermal ridges to form the oval shaped receptive fields of the parent axons. After penetrating the capsule, each axon divides several times to end in flattened expansions arranged parallel to the skin surface; the terminals range up to 30 µm in diameter (Castano et al., 1995). Nerve terminal discs are interleaved between disc-like extensions of the lamellar cells whose cell bodies are located in the periphery of the capsule (Yoshida et al., 1989); alternating discs of nerve terminal and lamellar membrane sheets are arranged in stacks (Fig. 5–8). Lamellar cells are modified Schwann cells of neural crest origin; capsular cells differentiate from local fibroblasts and form a continuation of the perineurium of mesenchymal origin. Capsules are frequently incomplete, and the stacked arrays are then exposed at their epidermal ends to the surrounding connective tissue matrix. Tonofibrils of the epidermis pass through the unencapsulated top of the Meissner to merge with collagen fibrils of the corpuscle. Two classes of unmyelinated, peptidecontaining, C-fibers enter the capsule (Pare et al., 2001). Meissner corpuscles appear late in skin development, after the dermal papillae are formed, after the Merkel cell–neurite complex is innervated, and after the Pacinians appear in the deep dermis. Meissners are generated by an interaction of the approaching growth cones of axons and their accompanying Schwann cells with local epidermal cells that produce the laminar cells (Zelena, 1994). The external capsule is derived from the perineurium of the innervating nerve fascicles. Pare et al. (2001) used antibodies against neurotransmitter-related molecules, receptor proteins, and ion channels to reveal that the

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Fig. 5–8 Schematic reconstruction of a Meissner corpuscle from a human finger tip. The tonofibrils of the epithelial cells are in continuity with the collagen fibers of the corium; some enter the upper part of the corpuscle; others are continuous with the endothelial sheath of the lower half of the corpuscle. The white arrow suggests how the corpuscle might move laterally in the tonofibrillar sling, and thus contribute to rapid adaptation. ax—myelinated axons; cp—capillary; pn—perineural sheath; ra— coiled receptor axon; sc—Schwann cells. (From Andres and von During, 1973.)

terminals of three types of afferent fibers terminating in Meissner corpuscles of the glabrous skin of the monkey express a wide variety of molecules, many identified in nociceptive afferents, as follows. 1. The A-beta myelinated axons—the classical, Meissner afferents—express immunoreactivity (IR)for substance P (SP) neurokinin-1 receptor (NK-1), the vanilloid-like-1 (VR-1)

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receptor, and the acid-sensing channel-3 (ASIC-3); and for adrenergic, opioid, and purinergic receptors usually associated with nociceptors. 2. One class of C-fibers in peptidergic, with IR for calcitonin gene–related peptide (CGRP) and substance P (SP), and for the adrenergic, opioid, purinergic receptors. 3. A second class of C-fibers is not peptidergic; it expresses the vanilloid receptor, and is IR for the purinergic receptor, P2X1. The second class of C-fibers is located between lamellar discs alternating with the mixed locations of the A-beta and the first class of C fibers. The meaning of these discoveries for Meissner function is unclear. It is perhaps too much to think that the terminals of the A-beta fibers and the two groups of nociceptive C-fiber afferents are located coincidentally, and function in an independent manner, although they do have different central targets. It remains to discover whether the response of the Meissner to adequate mechanical stimulation will be changed under conditions of skin pathology such as hyperalgesia with mechanical allodynia, when the C-fibers might also be activated by weak mechanical stimuli. Are we to conjecture, as Pare and his colleagues have done, that the Meissner is a “multi-afferented, polymodal, receptor”? RESPONSE PROPERTIES OF MEISSNER AFFERENTS

The Meissner (RA) afferents are quickly adapting, and are exquisitely sensitive to motion across or into the skin. They have a lower spatial acuity than do the slowly adapting afferents (SA-I), but their sensitivity to surface microgeometry enables the detection and representation of surface textures, described in Chapter 11. The sensitivity of the RAs to low-amplitude vibrations in the lower range of frequency accounts for their role in the sense of flutter described in Chapter 12. They signal slip between the fingers and objects held by the hand, and evoke necessary adjustments in manual grip force to maintain a steady hold (Macefield et al., 1996).

Merkel Cell–Neurite Complex (SA-I) The Merkel cell–neurite complex and its afferent innervation have been studied since the initial description by Merkel (1875). Merkels are present in fish, amphibians, reptiles, birds, and mammals, almost

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always in the ectodermis in association with sensory nerve terminals (Yamashita and Ogawa, 1991); they are ectodermal in origin (Saxod, 1996). In mammals, Merkel cells are concentrated in but not limited to three sensory nerve formations: the touch-domes and piloneural complexes in some regions of hairy skin and at the inner tips of the intermediate ridges of the glabrous skin, particularly in the glabrous skin of primates (Fig. 2–7). In each of these locations the Merkel complex has been identified with a slowly adapting, lowthreshold, mechanoreceptive afferent (Werner and Mountcastle, 1965; Iggo and Muir, 1969; Ogawa, 1996). The Merkel complex is not encapsulated. Merkel cells appear in the lower layers of the developing epidermis of the distal finger pads of humans in the eighth week of embryogenesis, before any nerve fibers reach the skin (Moore and Munger, 1989). No mitotic figure of this cell has ever been observed; they appear to be postmitotic cells derived from an unknown stem cell of the epidermis (Moll et al., 1996). It has often been suggested that the Merkel cells serve as trophic targets for ingrowing axons of dorsal root origin. However, these cells do not express a neurotrophic substance, nor the growth cones the appropriate receptors, until axon–Merkel cell contact is made. Merkel cells and the large dorsal root afferents that innervate them are supported from contact time until maturity by neurotrophin-3 and/or brain-derived neurotrophic factor; thereafter this dependence declines. At maturity Merkel cells are clustered in groups at the inner tips of the intermediate ridges of the glabrous skin of the primate hand. Such a group is usually innervated by one A-beta afferent that loses its myelin just below the epidermal basal layer, and then branches repeatedly to deliver expanded terminals, one to each of 25–75 Merkel cells in the group. Merkel cells differ from neighboring keratocytes by their clear cytoplasm, by the absence of intracellular fibrils, and by the presence in the cytoplasm of dense-core vesicles containing polypeptides. The close relation of the Merkel cell to the underlying nerve terminal suggests that it functions as a presynaptic, mechanical transducer (Ogawa, 1996). Merkel cell–neurite complexes have some of the structural details of chemically operated synapses. Figure 5–9 shows the ultrastructure in schematic form: a lobulated nucleus; dense-core vesicles poised on the terminal side of the Golgi apparatus; fixation by desmisomes to adjacent keratocytes; and a close membrane apposition to the underlying, expanded nerve terminal,

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which does not contain clear vesicles (Hartschuh et al., 1986). Evidence for and against the synaptic transmission hypothesis has accumulated, and the matter remains unsettled. Chemical agents that block Ca2+ channels reversibly reduce the responses of SA-Is to mechanical stimulation, preferentially the sustained component of the response. Local cutaneous anoxia blocks SA-I responses from the touch-domes of hairy skin, and reduces the dark-core vesicular content of the Merkel cells (Findlatter et al., 1987). Selective elimination of Merkel cells by light irradiation after loading them with lightsensitive dyes has produced conflicting results, and at best supports a role of the Merkel cells in eliciting the sustained component of the SA-I response (Ikeda et al., 1994; Senok et al., 1996). The Merkel ending in the piloneural complex is activated by glutamate-mediated synaptic transmission from the Merkel cell to the nerve ending, with aspartate as the likely transmitter. Blockade of transmitter action reduces dramatically the sustained component of the response, with little effect on the onset transient response to abrupt delivery of a mechanical stimulus (Fagan and Cahusac, 2001). Evidence that tells against the synaptic transmission hypothesis appears, at least for the moment, to be more convincing. Latencies to the onset response are 0.2–0.3 msec, which argues for direct mechanical transduction by the nerve terminal, for the onset response (Gottschalk and Vahle-Hinz, 1981). Merkel cells dissociated from rodent skin and studied with the patch-clamp method of recording are insensitive to direct mechanical stimulation and contain no mechanosensitive channels (Yamashita et al., 1992). Finally, the SA-I response is unchanged in mutant mice without Merkel cells (Kinkelin et al., 1999). Several alternative ideas have been proposed as candidate functions of Merkel cells: for example, that they may function in a paracrine mode to regulate the surrounding epidermal and dermal cellular elements, or that they function as components of the distributed neuroendocrine system, or that they play a role in the immune responses in the skin. RESPONSE PROPERTIES OF MERKEL AFFERENTS

The SA-I fibers are slowly adapting afferents sensitive to mechanical stimuli delivered to or acquired by the hand, and are especially sensitive to corners, edges, and curvatures. The distributed neural signals in populations of SA-I afferents and in their central targets are essential

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for the tactile perception of form and texture of objects palpated. SAIs may also contribute to the sensing of the three-dimensional form of objects grasped by the hand, perhaps in combination with afferents innervating the joints and muscles of the hand. Evidence from psychophysical and neurophysiological experiments relating to these hypotheses is given in Chapter 11.

Ruffini Corpuscles (SA-II) Ruffini (1905) discovered in the human dermis and deep connective tissue a multicellular receptor organ that resembles the Golgi tendon organ of muscle. It consists of tightly packed collagen fibers oriented between, parallel to, and sometimes encircled by the dividing terminal branches of the afferent myelinated fiber and its accompanying Schwann cells (Chambers et al., 1972). The capsule of the Ruffini ending is incomplete in many locations, and the details of Ruffini structure vary from place to place. Ruffini corpuscles are found in the subcutaneous connective tissue of the hairy skin of many mammals and in some skin regions within the hair follicles themselves (the “pilo-Ruffini complex,” Biemesderfer et al., 1978; Munger, 1982; Halata, 1988), and in the connective tissue surrounding joint capsules and tendon sheaths. Myelinated afferent fibers putatively linked to Ruffini receptors in the hairy skin of mammals and the glabrous skin of humans are classed as SA-IIs. They possess two defining properties: they are sensitive to stretch of the skin, sometimes with orientation preferences; and they discharge regular trains of impulses for long periods of time in response to sustained mechanical stimulation of the skin (Johansson and Vallbo, 1979;

Fig. 5–9 A schematic summary of the hypothetical functions of the Merkel cell. Descriptions are keyed to numerals on the drawing. 1. On mechanical stimulation messenger molecules released from Merkel cell granules act on the nerve terminal in either a nonsynaptic mode (small arrow to the left), or in a classical synaptic mode (small arrow to the right). 2. The hypothetical paracrine functions of the Merkel cell, acting on surrounding epithelial cells (2), on somatic nerve fibers (3), on autonomic nerve fibers (4), on blood vessels (5 and 8), influencing smooth muscle tone and permeability (7), or inducing the release of histamine from mast cells (7). Whether any or all of these candidate functions exist is uncertain. (From Hartschuh et al., 1986.)

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Torebjork et al., 1987). Published descriptions of more than 1300 large mechanoreceptive afferents innervating the glabrous skin of the human hand show that 18–20 percent were classified by these properties as SA-IIs. A similar survey of published descriptions of large mechanoreceptive afferents innervating the glabrous skin of the monkey hand revealed that only 5 of more than 1500 were classified as “SA-IIs.” My colleagues and I have studied several thousand slowly adapting afferents innervating the glabrous skin of the monkey hand, with controlled conditions of stimulation and quantitative analyses of the impulse discharge patterns in the responses evoked by steadily maintained mechanical stimuli. The fibers studied were beyond any reasonable doubt Merkel slowly adapting afferents, activated from small receptive fields on the dermal ridges of the glabrous skin: only a few were classified as sensitive to skin stretch. Skin stretch sensitivity does occur in some fibers of the SA-I population (Bisley et al., 2000), and a regularity of discharge is almost universal during the “early steady state,” the first half-second of the response (Mountcastle et al., 1966). This population cannot be divided on the basis of the SA-I/SA-II differences that separate so clearly the two populations innervating the glabrous skin of the human hand. It appears that Ruffini afferents are present in the hairy skin of the human hand and not in the glabrous skin of either human or monkey hands, but axons with SA-II properties have been identified in the innervation of the glabrous skin of the human hand. No other difference between the innervations of the human and monkey hands has been discovered. There is some uncertainty about the role of these afferents in signaling the shape of objects grasped by the hand, now attributed in humans to Ruffini afferents, for this manual skill is well developed in monkeys, and critical for survival in their lives in the trees. A serial section study of an entire monkey hand uncovered not a single clearly identifiable Ruffini corpuscle, and only one was found in human finger glabrous skin (Pare et al., 2003). Stimulation of single SA-II afferents innervating the glabrous skin of the human hand, recorded via microneuronography in waking humans, evokes “no distinct and constant quality of sensation” (Torebjork et al., 1987), an observation confirmed in several laboratories (Ochoa and Torebjork, 1983; Schady et al., 1983; Vallbo et al., 1984; Macefield et al., 1990).

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Innervation of the Hairy Skin Hairs of the skin differ in structure, distribution, and innervation. Down or vellus hairs are fine, small hairs present everywhere over the hairy surfaces of furred animals, forming the furry undercoat. Guard hairs are thicker and longer than the down hairs, and are less densely distributed but present everywhere. They form the furry overcoat. Tylotrich hairs are larger, stiffer, and less common than the down or guard hairs. Sinus or vibrissal hairs are present on the faces of almost all mammals except humans (Halata and Munger, 1980). Table 4–2 lists the sets of fibers that innervate the hairy skin of furred mammals including primates, and some of their structural and functional properties. There is general agreement on the categories listed, but details differ in different classifications. Hair follicles are innervated by a triad of receptor types: the lanceolate, Ruffini, and free nerve endings that compose the piloneural complex (Munger and Ide, 1988). Both guard and vellus hairs are innervated by A-beta mechanoreceptive afferents applied closely to or wrapped around the hair follicle just below the duct of the sebaceous gland, if one is present. Some vellus hairs receive only two or occasionally only one of the triad. The hairs of the skin are innervated by both slowly and rapidly adapting mechanoreceptive afferents. Lanceolates are flattened axonal terminations located between two similarly expanded and flattened expansions of Schwann cells. They are closely applied to the root of the hair follicle in a circular palisade of vertically directed nerve branches and terminals surrounding the hair follicle. The palisade consists of 40–60 terminals each 60–80 µm in length that arise from 10–15 axons that reach the base of the hair in a small bundle. It is generally assumed without direct evidence that these are quickly adapting mechanoreceptive afferents. The hair follicle and its vertically directed palisade of lanceolate terminals are encircled by a set of Ruffini endings wrapped around bundles of collagen fibers, and are separated from the surrounding connective tissue by a mesh of capillaries. These Ruffini endings are inferred from what is known of this class elsewhere to be slowly adapting mechanoreceptive afferents. Afferents with Ruffini-like properties also occur in the bare skin between the hair follicles. Merkel cell–neurite complexes (the touch-domes) are located in the epidermis between the hairs in primates and other furred mammals. This slowly adapting A-beta mechanoreceptor has

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properties resembling those of the Merkel receptors in glabrous skin: sustained responses to steady pressure, and an early regular pattern of discharge (Werner and Mountcastle, 1965). PCs are rarely if ever identified in cutaneous nerves of monkeys; they are common in mixed nerves. Some results from the many electrophysiological studies of the hairy skin in furred mammals have been confirmed and extended by microneuronographic studies in human cutaneous nerves innervating the hairy skin (Jarvilehto et al., 1976, 1981). Vallbo et al. (1995) provided a quantitative description of afferents from the hairy skin of humans. SA mechanoreceptors and some noncutaneous afferents in the radial nerve of humans are sensitive to static forces produced by different finger positions, and may contribute to the senses of position and kinesthesis of the hand. The hairy skin of the dorsum of the monkey’s hand is innervated by the A-beta classes of mechanoreceptive afferents listed in Table 5–3 (Merzenich, 1968; Merzenich and Harrington, 1969). The transitional skin of the dorsal surfaces of the distal phalanges is smooth and only thinly haired, a pseudo-glabrous skin without dermatoglyphics. Merzenich (1968) identified both quickly and rapidly adapting large-fibered afferents innervating small receptive fields here and in the folds of skin covering the proximal ends of the nails.

Table 5–3

Myelinated Mechanoreceptive Afferent Fibers Innervating Monkey Hairy Skin

Afferent type A-beta RA type G* Vibration-sensitive type G-2+* Vibration-insensitive type G-1+ A-delta RA type D* Type I SA* Type II SA* Classes unique to the dorsum of the hand Transition QA Transition SA Guard hair SA Nail SA

Number studied 119 27 118 47 28 20 30 28 14

Putative receptor ?Lanceolate, piloneural complex ?Lanceolate, piloneural complex FNE Merkel cell–neurite complex Touchdomes Ruffini of the piloneural complex ? ? Ruffini of the piloneural complex ?

FNE, free nerve endings, unencapsulated; RA, quickly adapting; SA, slowly adapting *+, Analogous to fibers innervating the hairy skin, according to classifications of Brown and Iggo (1967) and Burgess et al. (1968).

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The properties of these sets of afferents resemble those of the RAs and SA-Is innervating the glabrous skin on the volar sides of those same digits. The transitional skin contains modified Meissner and Merkel cell receptor organs. Little is known about the innervation of the nail bed, save for the general experience of its exquisite sensitivity to noxious stimuli. Cutaneous afferents from the backs of hands and fingers, and those from the interphalangeal joints, have been studied in waking humans. They are activated during intentional and passively imposed movements of hands and fingers, as are the mechanoreceptive afferents innervating the glabrous skin of the hand. What role these may play in the position sense of the fingers is a subject of active study and speculation (Hulliger et al., 1979; Burke et al., 1988). The hairy skin of the monkey’s face differs from the general bodily hairy skin by the presence of sinus hairs, the vibrissae, in addition to the ubiquitous down and guard hairs. Each of these classes of hairs is innervated by two or more of the five types of peripheral nerve formations identified by Munger and Halata (1983): free nerve endings, Merkel cell–neurite complexes, Ruffini receptors, lanceolate endings, and simple coiled corpuscles. The skin of the face changes abruptly from hairy to glabrous at the vermilion border, and then more gradually to the mucosa of the oral cavity. The dense innervation of these regions sustains thresholds for tactile and thermal detections and discriminations lower than those at the finger tips. Afferent activity from these tissues plays an important role in speech, mastication, swallowing, and so on, but the details of the exquisite afferent control of these delicate movement patterns are not known. Meissner corpuscles, simple core receptors, free nerve endings, and Merkel cell–neurite complexes are densely distributed in the lip and vermilion skin. Halata and Munger (1983) found neither Ruffini nor lanceolate endings in these nonhairy regions. The method of microneuronography has been used in waking humans to study the trigeminal afferents that innervate the facial skin and oral mucosa (Johansson et al., 1988; Nordin and Hagbarth, 1989; Nordin, 1990). Several A-beta classes previously found in other locations were identified in the facial innervation: slowly adapting afferents, but with less clear separation into those with SA-I and SA-II properties than in other locations; quickly adapting afferents from skin and mucosa, but no PCs; C-fiber nociceptive afferents, and in addition, a class of C-fiber low-threshold mechanoreceptive afferents

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similar to those that innervate the hairy skin of primates and other furred mammals. The A-beta mechanoreceptive afferents are actively driven by the movements of the face and mouth in speaking and chewing, and are essential for oral stereognosis (Jacobs et al., 1998). The proposition that these afferents are important in the reflex regulation of the muscles of the face is supported by three observations: (1) activity in them is driven by the facial movements; (2) the movements are severely disordered by anesthetic block of the sensory input; and (3) the facial muscles do not contain the classical stretch receptors seen in the general musculature, and that the facial muscles insert directly into the skin with no intervening tendinous linkages. There are significant differences between the putative sensory functions of the large-fibered mechanoreceptive innervations of the glabrous and hairy skins of primates. For example, stimulation of the SA-I afferents innervating the glabrous skin in waking humans evokes the sense of light pressure predictable from the known functional properties of this set of afferents. By contrast, it is a widely confirmed observation that local mechanical stimulation of the touch-dome receptors in hairy skin, stimuli known to evoke robust trains of impulses from touch-dome receptors in humans and monkeys, evokes no conscious sensation in waking humans.

Innervation of the Deep Tissues of the Primate Hand A vexing question in somatic sensory physiology is what roles different sets of afferents play in providing the peripheral input for the senses of position and movement. For the distal joints of the hand and fingers, the evidence suggests that skin, joint, and muscle afferents all contribute to the sense of the position and movement of the fingers at their joints. However, any one of these by itself is not sufficient to sustain maximal perceptual performance. Many studies of the innervation of joints show a rather uniform pattern of innervation by A-delta and C-fiber nociceptive innervation, and two multicellular peripheral nerve formations with A-beta-sized myelinated afferent fibers, Ruffini and Pacinian organs located in joint capsules, synovial membranes, and ligaments about joints. Microneuronographic studies in humans have confirmed the sensitivity of mechanoreceptive afferents from the distal finger joints to the direction of joint movement, but indicate that they provide inconstant

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signals of joint movement or direction (Burke et al., 1988; Macefield et al., 1990). The deep tissues of the human hand are densely innervated, as shown by the distribution of PCs along the deep tendons and surrounding connective tissue matrix. The architecture of the intrinsic muscles of the hand is characterized by a large-fiber length/muscle length ratio that is compatible with their rapid actions. They are packed with spindle and tendon organ afferents. It is conjectured that these various sets of afferents contribute to the senses of kinesthesis and stereognosis in the hand.

Denervation and Reinnervation of the Glabrous Skin of the Primate Hand A major objective in reconstructive surgery is to achieve reinnervation of tissue denervated by transection or crushing injury of peripheral nerves, and to promote the recovery of sensory and motor function after reinnervation. The use of the hand in many dangerous tasks makes it and the lower forearm common sites of peripheral nerve injury. Some days after nerve injury the dorsal root ganglion cell bodies enlarge, their nuclei move to eccentric positions, and the rough endoplasmic reticulum clumps in the cell periphery. These are classical signs of chromatolysis, described originally in motoneurons after section of their axons. The distal segment of a peripheral axon degenerates rapidly after a crushing injury in continuity; PC terminals begin to degenerate within hours. The distal axon and the surrounding myelin are phagocytized by the adjacent Schwann cells and by invading macrophages, leaving a tissue tube of Schwann cell columns bounded by the basal lamina which later may serve as a conduit for reinnervating axons growing from the proximal segment. After neural crush injury this pathway guides the regenerating axons into the correct fascicular targets in the distal segment. This fascicular matching contributes to the recovery of function that follows crushing nerve injuries in continuity, which is usually better than the degree of recovery that follows nerve transection and sutured approximation of the severed nerve parts. After nerve injury by crush or transection the processes of regrowth are initiated by a poorly defined retrograde signal to the cell body from the distal segment via, or alternatively directly from the cut end of the proximal segment. The axons in the proximal segment

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emit sprouts, either at the next or the next but one proximal node of Ranvier. These sprouts develop growth cones that project into the distal segment. The basal lamina of the distal segment of a transected nerve is adequate for guiding regenerating axons into and along the distal segment peripheral to the transection. Ide and her colleagues killed the Schwann cells in the distal segment by several methods. In each case the growth cones of the regenerating axons from the proximal segment entered and moved through the Schwann-free distal segments, closely adhering to the scaffolding provided by the surviving basal lamina. The tips of the regenerating axons were usually naked, but were followed closely by proliferating Schwann cells derived from the proximal segment. Schwann cells of the distal segment are not essential for regeneration (Ide, 1996). The growing axons are supported by NGF synthesized by the proliferating Schwann cells of proximal segment origin, perhaps stimulated by interleukin-1 released from macrophages that converge on the lesion site. A question much debated is whether regenerating sensory axons approaching the skin can induce the formation of new multicellular mechanoreceptors by transformations imposed upon the cells of the dermal–epidermal matrix. Although such transformations occur in some submammalian forms and in the hairy skin of some mammals, direct study by serial skin biopsies after denervation and reinnervation show that this is not the case for the glabrous skin of the primate hand (Dellon, 1976). The degree of recovery after reinnervation depends upon the nature and density of the mechanoreceptive organs that survive in the glabrous skin through the period of denervation, and the proportion of them successfully reinnervated. The time scale of this sequence of events differs for different sets of afferent fibers innervating the glabrous skin. The first to reach their normal dermal and epidermal targets are the thinly myelinated and unmyelinated fibers with unencapsulated terminals, and pain and temperature sensibilities are the first to reappear in the reinnervated skin area, sometimes in distorted forms. There follow in sequence the reinnervation of the surviving Meissner and Merkel receptor organs. Reinnervation of PCs in the hand has not been demonstrated in microneronographic experiments on human nerves, even months or years after the initial transection and resuturing. Functional recovery after reinnervation rarely reaches the pre-injury functional level. In the early months after reinnervation the partial recovery of sensation is frequently accompanied by dysesthesias and

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by the spatial mislocation of stimuli. These defects become less marked over the following months with further progress of reinnervation toward an asymptote. Many such patients, especially those with nerve section and suturing, reach a final state with substantial sensory defects (Mackel et al., 1985). Sensory recovery may be absent altogether if neuromas form at the site of nerve transection. Some further improvement in the sensory capacity of the hand can be achieved by sensory training, even after reinnervation has reached an asymptotic level (Mackinnon and Dellon, 1988, Chapter 11; Dellon, 1987, Chapter 18). This further improvement is attributed to synaptic plasticity in the central somatic system (Chapter 15). In experimental studies in animals partially atrophic PCs are reinnervated by several axon branches; whether they are branches of one or several stem axons is uncertain (Zelena, 1994). Each of these branches induces its own small inner core; all are surrounded by the single, surviving outer core and the capsule. Denervated Meissner corpuscles of the glabrous skins of monkeys and baboons are reinnervated within a few weeks or months after experimental nerve crush injury; reinnervation reverses the slow, ongoing trophic process, with no evidence for the inducement of new Meissner corpuscles (Dellon, 1976, 1987; Dykes and Terzis, 1979). The quasi-atrophic Meissner is reinnervated by several axons, followed by the formation of the typical stacked arrays of expanded nerve tips and the lobular lamellae of the receptor cells. Afferent axons with the functional properties characteristic of Meissner afferents (the RA population) have been identified in microneronographic recording in regenerated nerves innervating the human hand (Hallin et al., 1981; Mackel et al., 1985). Less is known of the details of the reinnervation of touch spots in primate glabrous skin, or of the capture of Merkel cells by nerve terminals. Afferent fibers with properties characteristic of the Merkel set (SA-I properties) have been identified in recordings from human nerves after reinnervation of the glabrous skin.

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6

Dorsal Systems and the Dorsal Column Nuclear Complex

The dorsal column system is a major ascending conduit of the spinal cord linking several sets of dorsal root afferents to the forebrain. The system has been identified in fish (Ebbeson and Hodde, 1981; Dubuc et al., 1993), amphibia (Munoz et al., 1995, 1997), reptiles (Joseph and Whitlock, 1968; Siemen and Kunzle, 1994), birds (Wild, 1997), and in every mammal examined. Dorsal columns enlarge in the mammalian series to become major ascending systems characterized by large numbers of myelinated axons and by the precision of synaptic operations in their supraspinal target, the dorsal column nuclear complex (DCNC). This medullary transition complex of the system contains several nuclei that differ in the ascending spinal pathways that project to them. The dorsal column system occupies about 40 percent of the cross-sectional area of the human spinal cord in the high cervical region. In carnivores, the dorsal columns contain 10- to 100-fold more fibers than either the spinothalamic or spinocervicothalamic tract (Hwang et al., 1975); for monkeys and humans these ratios are undoubtedly larger. A dorsal column is an anatomically defined conduit bounded medially by the medial septum, laterally by Lissauer’s tract and the mediolateral septum, ventrally by the spinal gray, and dorsally by the pia; it contains a number of ascending sets of axons with different peripheral inputs, supraspinal targets, and functional properties. The most prominent of these in terms of axonal size and number is the lemniscal system, and it is this component that is usually meant by the traditional

term “dorsal column system.” A major task in study of the dorsal column somatic system is the identification of sources, ascending courses, supraspinal targets, functional properties, and degrees of convergent interaction among several different components. At least five have been identified: (1) the lemniscal system whose myelinated axons arise from dorsal root ganglion cells; (2) the intrinsic, postsynaptic dorsal column system whose axons arise from neurons in the dorsal horn, mainly in lamina IV, at all segmental levels but most densely in the lumbar and cervical enlargements; (3) a set of unmyelinated axons of dorsal root origin that project directly into the dorsal columns, but whose supraspinal targets, if any, are unknown; (4) a set of ascending fibers clustered along the central fissure of the dorsal columns activated by visceral nociceptive afferents; and (5) a small number (2–3 percent) of axons that descend from the dorsal column nuclear complex to terminate in the dorsal horns. A conspicuous feature of the lemniscal component of the dorsal column system is that information concerning the location, form, quality, and temporal patterns of mechanical stimuli reaching the body surface, or generated by body movements, is encoded in trains of impulses in afferent nerve fibers, and transmitted with fidelity through the transition nuclear complexes of the system at medullary and thalamic levels and into the somatic sensory areas of the cerebral cortex. Under normal circumstances the system maintains this precision despite nuclear convergence upon it, at each level, by smallfibered afferent systems with quite different properties (Chapter 8). The functional meaning of these convergences is presently a matter of much speculation, particularly whether the convergence is nuclear but not cellular. The characteristics of the system are determined by several general properties. 1. The quantitative precision of the peripheral transducer mechanisms of the primary afferents feeding the system. 2. The representation of those afferents in detailed topographic patterns, resorted from dermatotopic to somatotopic modes within the central pathways of the system. 3. A modular segregation for modality within the system; crossmodality convergence appears only after progression into the trans-postcentral areas of the cerebral cortex.

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4.

Synaptic operations within the lemniscal component sustain a high level of dynamic neural activity, influenced in certain states by ascending and descending converging systems.

The sources, fiber spectra, and targets of the sets of afferents in the conduits of the spinal cord described here are based on information from primates, where available; if not, on the assumption that pathways and structures identified in carnivores have homologies in primate nervous systems. How many ascending pathways can be identified varies between classifications depending upon the criteria used to label a group of ascending fibers a “tract”; those described here are generally accepted. Several afferent pathways of the dorsal half of the spinal cord converge upon the DCNC: the direct gracile and cuneate tracts, the dorsal column postsynaptic system, and the spinomedullothalamic tract of the dorsolateral column. The last two contain postsynaptic ascending axons of intrinsic neurons of the spinal gray. The gracile, cuneate, and spinomedullothalamic tracts receive and transmit through the DCNC and the medial lemniscus to the forebrain afferent signals in the large-fibered dorsal root afferents that innervate the skin and deep tissues. These three are labeled lemniscal because of their common output from the DCNC through the medial lemniscus that projects mainly to the ventral posterolateral nucleus (VPL).1 I use the term lemniscal to designate some features of a system conveying veridical signals used in the discriminative aspects of mechanoreceptive sensibility in primates: contact–touch–pressure, form, texture, flutter–vibration, kinesthesis, and stereognosis. The system also signals the general attributes of quality, intensity, movement, duration, extension, and temporal pattern common to many somesthetic experiences. These neural patterns are open to modification at every level: in the presynaptic afferent pathways of the spinal cord by axonal resorting; in each transition nuclear complex by the synaptic actions in local microstructures; and by the actions of descending systems, which may impose the effects of central state on afferent sensory transmission. The direct gracile and cuneate tracts and the two ascending systems of intrinsic origin that converge upon the DCNC are described here. The spinocerebellar systems are components of the central

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systems controlling movement, but are not known to play a direct role in somatic sensibility. The spinocervicothalamic tract reaches its largest size both relatively and absolutely in carnivores, declines in primates, and is vestigial in humans. The spinomedullothalamic system consists of axons of cells located mainly in laminae IV of the dorsal horns that receive input from muscle and other deep afferents, as well as from slowly adapting cutaneous afferents from the arm and leg, and project through the dorsolateral columns to the DCNC. Several other tracts that project in the cephalad direction through the lateral and ventral funiculi are activated largely, but not exclusively, by thin-fibered dorsal root afferents. Other possible functions of this multireceptive, thin-fibered systems are considered in Chapter 8: that they evoke some of the cognitive and affective overtones accompanying all somesthetic experiences and that they influence the general excitability of the forebrain.

Dorsal Columns Myelinated dorsal root afferents in the size range of 4–20 µm project through the medial division of the dorsal root into the adjacent dorsal column. A local lesion of this medial division produces defects in all somesthetic qualities served by these afferents in the dermatomal distribution, obscured by the degree of overlap in the distributions of adjacent dorsal roots. This medial division of each dorsal root includes A-alpha and A-beta afferents from muscle, A-beta afferents from the skin and from the joints and other deep tissues. All are specifically mechanoreceptive, and respond to appropriate mechanical stimuli at low thresholds. Many of these project for only short distances in the rostral direction, emitting collaterals to the spinal gray that form the pathways for the mechanically evoked reflex actions of the spinal cord, before terminating upon cells of origin of secondary ascending systems. In the cat, about 25 percent of the large mechanoreceptive afferents entering the dorsal columns at segmental levels project directly to the DCNC. Near their terminations, they dwindle in size to half their diameters at entry level. The fraction projecting directly to the DCNC in primates is unknown, but it seems likely that more

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A

CERVICAL

SUBMODALITY

LUMBAR

RECEPTIVE FIELD LOCATION

B

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than 25 percent of the large mechanoreceptive afferents that innervate the glabrous skin of the hand project directly to the DCNC. Substantial numbers of dorsal root C-fibers project directly into the dorsal columns through the medial division (Briner et al., 1988; Garrett et al., 1992). Different C-fiber axons project rostrally for different distances, but none have been shown to reach the DCNC directly. The inference is that they are nociceptive and thermoreceptive afferents; if so, they form another access for nociceptive afferents to the reflex and projection systems of the spinal gray.

Initial Mapping Rules in the Lemniscal System Are Set by Transformations in the Dorsal Ascending Systems Axon degeneration studies in primates indicate that within the dorsal columns there is a successive lateral application of laminae from successively more rostral dorsal roots, each containing a full complement of large-fibered mechanoreceptive afferents. Laminae shift medially in their upward courses, arranged one after another from caudal to rostral in the medial to lateral dimension of the dorsal column (Walker and Weaver, 1942; Chang and Ruch, 1947). Werner, Whitsel, and their colleagues examined the representation of the body form at several levels of the lemniscal system. They used neuroanatomical methods to trace fiber projections, and electrophysiological recording from large numbers of axons, seriatim one by one, to determine modality types and to plot receptive fields (Werner and Whitsel, 1967, 1968; Whitsel et al., 1969a, 1970, 1971; for reviews, see Whitsel et al., 1972a,b; Werner and Whitsel, 1973). They established two mapping rules that determine the initial input pattern of representation of the body in the lemniscal system: (1) a

Fig. 6–1 Illustration of fiber sorting for topography and modality in the dorsal column system in the squirrel monkey. Gracile fibers are sorted for modality type and receptive field location. Compare the results obtained in microelectrode penetrations of right gracilis tract shown on the left and right sides of row A, and the receptive field locations lumbar and cervical levels in row B. (Data largely from Whitsel et al., 1972a,b. Figure courtesy Professor B. Whitsel.)

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transformation from the dermatomal representation at dorsal root entry to a somatotopic one at the cervical level of entry to the DCNC, with emphasis on the adjacency of the peripheral receptive fields of adjacent axons, but with breaks and discontinuities determined by body form; and (2) modularization for modality, which persists from the rods of the DCNC through those of the ventral posterolateral nucleus of the thalamus, to the columns of the postcentral somatic sensory cortex (Fig. 6–1). These mapping functions and the maps they generate are described below and in Chapters 9 and 10.

Re-Sorting for Modality and Topography Lumbosacral dorsal roots and the immediately adjacent gracile tract into which they project contain full spectra of large-fibered mechanoreceptive afferents from skin, muscle, and other deep tissues of the leg and foot. A resorting for modality occurs in the gracile system at the thoracic level, where the slowly adapting cutaneous afferents and large afferents from muscle and joints project into the dorsal horn to terminate upon the cells of origin of the spinomedullothalamic and spinocerebellar tracts that project through the dorsolateral columns to terminate respectively in the DCNC and the cerebellum (Whitsel et al., 1969b). Above this level, the gracile tract contains only quickly adapting cutaneous afferents (Table 6–1). It is a system specialized to signal the dynamic, time-dependent aspects of cutaneous sensibility; at that level it contains no proprioceptive afferents. This modality shuffle at the midthoracic region explains why transection of the dorsal columns at a high cervical level in primates produces more severe defects for proprioceptive sensibility and motor control in the arm than in the leg. Re-sorting for modality in the gracile tract is accompanied by a change in place representation in the system, from a dermatotopic one at the level of dorsal root entry to a somatotopic one at entry to the DCNC. The receptive fields of contiguous, cutaneous axons of a single dorsal lumbosacral dorsal root innervate cutaneous peripheral receptive fields that trace a continuous path on the surface of the leg (Fig. 6–1; Werner and Whitsel, 1967). This linear order is retained at lower lumbar levels, but the overlap between dermatomal laminae increases with further upward progression, so that abrupt recursive jumps in the progression of receptive fields occur at each laminar transition, with the result that adjacent axons often innervate widely

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separated receptive fields. This somatotopic pattern retains adjacency between neighboring axons and their peripheral receptive fields to the degree possible in the representation of a three-dimensional body form with recursions and discontinuities, and with differences in peripheral innervation densities, both between different body parts and between the innervation patterns of different sets of afferents. The central projections of afferents entering the spinal cord through dorsal roots rostral to T6 are less well known. A major component, including samples of all classes of large-fibered, mechanoreceptive afferents from skin and deep tissues, projects directly into and through the cuneate tract to the DCNC, a projection documented in many anatomical experiments in cats (Bakker et al., 1985; Jasmin et al., 1985; Abrahams and Swett, 1986) monkeys (Albright and Friedenbach, 1982; Culbertson and Brushart, 1989), and in humans. Secondorder axons from the upper thoracic and cervical levels originate from a broad band of neurons in lamina IV of the dorsal horn and, like similar elements from post-thoracic levels, project into the dorsolateral fasciculus and the spinomedullothalamic “tract,” to terminate in the DCNC (Nijensohn and Kerr, 1975; Rustioni and Molenaar, 1975; Rustioni et al., 1979; Gordon and Grant, 1982). Electrophysiological studies of the DCNC in cats (Dykes et al., 1982), and in macaque (Florence et al., 1988, 1989), squirrel (Florence et al., 1991; Xu and Wall, 1999a,b) and marmoset (Xu and Wall, 1996) monkeys show that at the postsynaptic level a resorting for place and modality has occurred, imposed by resorting in sets of ascending axons. How much of this

Table 6–1 Contrasting Modality Representations in Gracile Tract at Lumbar and Cervical Levels Lumbar Skin No. Tail Hip-knee Knee-ankle Ankle-foot Sums

87 37 59 173 356

Cervical Deep

Skin

Deep

%

No.

%

No.

%

83 18 27 70 46

18 171 161 74 424

17 82 73 30 54

81 60 41 55 257

100 92 95 98 97

No.

%

0 5 2 1 8

0 8 5 2 3

(From Whitsel et al., 1972.)

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occurs directly in the asynaptic projection of the cuneate tract (Culbertson and Albright, 1984), and how much trans-synaptically via the dorsolateral column loop, is uncertain. The conclusion is that re-sorting within the ascending pathways of the dorsal and dorsolateral columns transforms the dermatotopic patterns at the level of dorsal root entry to somatotopic ones at entry to the DCNC. Similarly, a segregation for modality is achieved by afferent re-sorting and redirection, sharpened by operations within the DCNC, and is projected in mode specific channels characteristic of the ventral posterior thalamic nucleus and the somatic sensory cortical areas. Following chapters will detail how this system maintains these specificities under normal operating conditions, in spite of the convergence upon it at each level of multireceptive afferents and their central projections.

Dorsal Column Nuclear Complex (DCNC) This heterogeneous group of nuclei in the lower medulla consists of three major elements: the gracile, cuneate, and lateral (external) cuneate nuclei; and two smaller cell clusters, nuclei Z and X. The DCNC receives direct projections of dorsal root axons through the dorsal columns, and convergent systems of intrinsic origin projecting through the dorsal and dorsolateral columns: the postsynaptic dorsal column and the spinomedullothalamic systems, as well as descending projections from the forebrain, mainly from the parietal somatic sensory areas (Table 6–2). Eighty-ninety percent of the DCNC

Table 6–2

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Input–output DCNC

Nucleus

Input source

Output targets

Gracile

Gracile tract, dorsolateral funiculus, pons, PSDC, SS cortex

Dorsal thalamus, mesencephalon, olive

Cuneate

Same

Same

External Cuneate

DR C2-C7 via DC

Dorsal thalamus, cerebellum

Nucleus Z

Dorsolateral funiculus

Dorsal thalamus

Nucleus X

Dorsolateral funiculus

Dorsal thalamus

Dorsal Systems and the Dorsal Column Nuclear Complex

neurons project their axons out of the complex into the medial lemniscus; the large majority terminate in the ventral posterolateral nucleus of the thalamus. Smaller numbers project to the cerebellum, mesencephalon, pons, and inferior olive and some project downward through the dorsal columns to spinal targets (Berkley et al., 1986), apparently in decreasing numbers from rat to cat to monkey (Burton and Lowry, 1978). The remaining 10–20 percent are local, GABAergic inhibitory interneurons whose axons do not exit the DCNC.

Functional Organization A three-dimensional reconstruction of the cat DCNC of cat is shown in Fig. 6–2; numerical values for the three major nuclei in the monkey DCNC are given in Table 6–3 (Heino and Westman, 1991; Heino, 1995). The cuneate nucleus contains a rostrocaudally oriented central core, the pars rotunda, in which round neurons are grouped into elongated rods or columns, separated by cell-poor

Fig. 6–2 Schematic reconstruction of dorsal column and spinal trigeminal nuclei of cat, made from serial sections. CUN—cuneate nucleus; exCUN—external cuneate nucleus; G—gracile nucleus; TRIG—spinal trigeminal nucleus. Nuclei X and Y not shown. (Figure courtesy of R. W. Dykes.)

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Table 6–3 Some Numerical Values for the Dorsal Column Nuclear Complex in Monkeys

Volume Lengths Above obex Below obex Number neurons (means) Neuronal density Percent GABA-positive

Gracile

Cuneate

External cuneate

5.4 mm3

7.0 mm3

4.7 mm3

3.3 mm 4.8 mm 61,500

3.7 mm 5.2 mm 70,300

3.7 mm p. 3 mm 22,000

11,000/mm3 34%

10,200/mm3 31%

4700/mm3 ?1%

(From Heino, 1995.)

regions filled with incoming myelinated fibers (Fig. 6–3). Lateral to the central core is a region of more uniformly distributed fusiform cells, the pars triangularis. A similar duality is evident in the gracile nucleus, but in each nucleus these separations are less obvious at the caudal and rostral poles than in this central region. The distribution of the place- and mode-specific modules in the central cores of the gracile and cuneate nuclei has been studied with the microelectrode mapping method (Fig. 6–4) (Dykes et al., 1982). The central core regions are “composed of spatially segregated nuclear volumes that serve different classes of afferent fibers.” Those volumes coincide with the neuronal clusters of the core regions. Segregation for place and modality is imposed on the DCNC by the re-sorting operations in the dorsal ascending systems, and by dynamic actions in converging intrinsic ascending systems (Dykes and Craig, 1998). The place- and mode-specific clustered modules are arranged in separate, mutually overlaid maps of the body form. This principle of organization obtains also in primates. Florence et al. (1989, 1991) combined histological staining for cytochrome oxidase, which defines the core regions, with horseradish peroxidase tracing of the projections to the DCNC from the glabrous skin of the hand, in squirrel and macaque monkeys. Figure 6–5 shows the results obtained after small injections of the tracer into the glabrous skin of the digit 2 and digit 3 finger pads of a macaque. Figure 6–6 shows similar results in schematic form, and the proposed relation-

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Fig. 6–3 Histological sections of the pars rotunda (Ro) and pars triangularis (Tri) of the cuneate nucleus in a monkey. A: Section stained for cytochrome oxidase. B: Adjacent section stained for myelin. The CO dense patches are in the myelin-light zones, surrounded by networks of myelinated fibers. Marking arrows serve as guides. D—dorsal; L—lateral. Scale bars = 0.25 mm. (From Florence et al., 1989.)

ship in the human pars rotunda of the cuneate nucleus. Xu and Wall (1999b) used the method of single-neuron analysis to study the patterns of representation in the cuneate nucleus of the squirrel monkey. Receptive fields were normalized for different hand sizes as percentages of the total hand surface. Transverse maps in the middle

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Fig. 6–4 Results of a microelectrode mapping experiment in which penetrations were made in the horizontal plane passing from medial to lateral through the dorsal column nuclear complex of a cat. Receptive fields and modality properties of single neurons and small clusters of neurons were determined at 50-µm intervals. Symbols: black, activation from deep tissues; diagonals, cutaneous; cross-hatching, Pacinian. C—cuneate nucleus; EC—external cuneate nucleus, G—gracile nucleus; L—low velocity; P—Pacinian; R—rapidly adapting; RC—rostral cuneate nucleus; S—slowly adapting; ST—spinal trigeminal nucleus. T—“tap.” The results illustrate the modular organization of the complex. (From Dykes et al., 1982.)

region of pars rotunda show a precise parcellation for modality that fits neatly to the cytochrome oxidase-stained horizontal columns. Single receptive fields on the glabrous skin of the fingers averaged 5–7 percent of total hand surface; the glabrous skin representation occupied 75 percent of the total hand representation. Xu and Wall found that the receptive fields of cortical area 3b glabrous skin neurons are slightly smaller than are those in the pars rotunda of the

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Fig. 6–5 Matching of the projections of the skin of the ipsilateral hand and fingers to the cytochrome oxidase–stained columns of cells in the pars rotunda of cuneate nucleus of macaque monkey. Left: Drawing of the pattern of the cytochrome oxidasedense patches in the cuneate superimposed on the pattern of terminal labeling after local injections of tracer into the glabrous skin of the third finger tip. Right: Overlap after injection of transport into the glabrous skin of the distal pads of digits 1, 3, and 5. The first, third, and fifth dense patches are labeled in a lateromedial sequence. Bar = 0.5 mm. (From Florence et al., 1989.)

Fig. 6–6 Schematic diagrams that summarize the relationship of the cutaneous inputs from different regions of arm and hand to the cytochrome oxidase densely stained patches in the pars rotunda of the macaque monkey cuneate nucleus. Experimental observations in the monkey are summarized at left, and a similar relation proposed for the human at right. D—dorsal; M—medial. (From Florence et al., 1989.)

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cuneate nucleus, and that the number of multifingered receptive fields changed from 23 percent in the DCNC to 12 percent in area 3b of the postcentral gyrus. This emphasizes the dynamic sharpening function of synaptic operations within the lemniscal system.

Synaptic Operations in the DCNC Excitatory and inhibitory synaptic actions within the DCNC limit the spatial spread of the activity evoked by afferent input over the dorsal column system. These mechanisms sustain the throughput from those primary afferents to the lemniscal projection neurons at frequencies scarcely equaled at synapses elsewhere in the nervous system. Converging inputs from the dorsal horns tend to support the spatial sharpening operation, while dense projections from the somatic sensory areas of the parietal lobe may modify DCNC transmission, depending on behavioral context, particularly that of ongoing motor activity. Terminals of the primary dorsal column fibers project upon both the glutaminergic lemniscal relay neurons and the GABAergic interneurons of DCNC (Lue et al., 1997). The large terminals upon the dendrites and somata of the relay cells exert a powerful transsynaptic excitation. The GABAergic neurons account for about 30 percent of the neurons in the gracile and cuneate nuclei; they are rare in the external cuneate nucleus, which does contain GABAergic terminals. Inhibitory interneurons are found throughout the gracile and cuneate nuclei, and in their central core regions are concentrated at the rims of the clusters (Rustioni et al., 1984). GABAergic interneurons make classical inhibitory synapses with the dendrites and cell bodies of the lemniscal relay neurons, and axon–axonic synapses upon the terminals of the primary afferent dorsal column fibers, but not upon the terminals of the converging postsynaptic dorsal column fibers. Postsynaptic inhibition is effected at the cell body by the linkages of GABA with GABAa receptors, leading to opening of Clchannels and inward Cl- current, with hyperpolarization or stabilization of the cell membrane and decreased responsiveness to all presynaptic excitatory inputs. Presynaptic inhibition operates quite differently, for at this axon–axonic synapse GABA links with GABAa receptors to produce a paradoxical outward Cl- current and depolarization, because in these terminals Cl- is not distributed passively across the membrane. The intracellular activity level of Cl- is maintained at two to three times the passive value in the dorsal root

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ganglion (DRG) cells and their terminals, explained by the presence of a cation transporter. I assume that the observations made on the DRG cells and their intraspinal terminals are true also for the terminals of those same axons in the DCNC (Alvarez-Leefmans et al., 1988; for reviews see Wu and Saggau, 1997; Rudomin, 1999a; Rudomin and Schmidt, 1999). This depolarization extends electrotonically, and in the dorsal roots can be recorded as a primary afferent depolarization, which decreases the amplitude of the incoming axonal impulses, and presumably for that reason decreases transmitter release. GABA linkage with GABAb receptors leads, via a G-protein link, to closure of Ca2 + channels and decrease in transmitter release (Fig. 6–7). Presynaptic inhibition from either segmental or supraspinal sources can be selective, and can control differentially the flow of afferent activity to and through spinal reflex circuits (Rudomin, 1999b). The axon terminals of those same dorsal root afferents within the DCNC are presynaptically inhibited by both afferent and descending inputs, which may explain in part the dynamic maintenance of place specificity in the transition of large-fibered mechanoreceptive activity through the DCNC. Is it possible that such a mechanism could allow a switching between afferents of the different modality types that

Fig. 6–7 A model illustrating presynaptic inhibition of elicited synaptic transmission. A modulator (MOD) binds to its presynaptic receptor (PreR) causing inhibition of its neurotransmitter (NT) release, mainly by inhibiting voltage-dependent calcium channels (VCC), and by inhibiting release mechanisms downstream from calcium influx. AP—action potential; NtR— neurotransmitter receptor; Ves—vesicle;— inhibition; +—excitation; ?—unknown. (From Wu and Saggau, 1997.)

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Fig. 6–8 A schematic diagram illustrating the connections and directions of synaptic actions between the primary afferent collaterals of dorsal column axons, the axons of the pyramidal tract, and the cuneate neurons. (From Andersen et al., 1964a.)

converge upon some DCNC neurons, particularly those of the matrix but not those of the core? This proposition appears unlikely because lemniscal neurons at thalamic and cortical levels evoke modality specific perceptions, regardless of how they are activated. The descending projections from the somatic sensory cortex to the DCNC elicit both post- and presynaptic inhibition, but it is unknown whether they do so via a separate set of GABAergic interneurons, or converge with the dorsal column afferents upon a common set. Serotonin projections from the raphe nuclei to the dorsal column nuclear complex have been described, but their function there is not known (Blomqvist and Broman, 1993). The classical model of the synaptic circuits of the DCNC shown in Fig. 6–8 derives from the studies of Andersen et al. (1964a,b), made nearly 40 years ago, and has scarcely required amending since.

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Dynamic Channeling Operation in the DCNC-Thalamic Transition Rowe and his colleagues measured in anesthetized and decerebrated cats the capacity of the modality-parcellated cuneo- and gracilothalamic channels for high-frequency transmission of primary afferent activity into the lemniscal system. Single afferent fibers were isolated in continuity for recording afferent signals evoked by electrical stimulation, or by modality-appropriate natural stimuli. DCNC neurons activated by these inputs were recorded with extracellular microelectrodes, and the capacities for synaptic transfer measured over a wide range of input frequencies for Pacinians (Ferrington et al., 1987a,b; Greenstein et al., 1987), for slowly adapting afferents from hairy skin with Ruffini-like receptors (Vickery et al., 1994; Gynther et al., 1995), for muscle spindles (Mackie et al., 1998, 1999), and for quickly adapting cutaneous afferents from the cat’s forefoot (Douglas et al., 1978). Somewhat similar experiments have been made for the muscle afferents from the monkey arm by Hummelsheim and Wiesendanger (1985). The general results illustrate properties of the lemniscal system: specificity for place and mode, sequestered channels for different modalities, and synaptic security that supports high-frequency, dynamic transmission. For example, when convergent Pacinian inputs were driven with different phase-locking relations to the sine-wave mechanical stimulus delivered to the skin, the second-order DCNC Pacinian remained phase-locked to the wave-form of the mechanical stimuli, at frequencies up to 400/sec. The high-frequency, 1–1 coupling with phase-linking was observed for each of the four sets of afferents tested, including the cutaneous quickly adapting afferents and Pacinian sets that serve the senses of flutter and vibration (Chapter 12). Similar experiments have not been made in the DCNC receiving large mechanoreceptive afferents from the monkey hand.

Postsynaptic System of the Dorsal Columns (PSDC) The dorsal column postsynaptic system is composed of axons of intrinsic neurons of the spinal dorsal horn that project through the dorsal columns to terminate convergently with the gracile and cuneate tracts within the DCNC. Although it has been known for a century that the dorsal columns contain nonprimary afferents, the first single fiber recordings of the system were made only much

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later, by Uddenberg (1968). Since then the system has been studied in anatomical and physiological experiments in rats, cats, and monkeys (for reviews, see Brown 1981, chapter 8; Chung and Coggeshall 1985; Willis and Coggeshall 1991, pp. 256–264). Axons of the system in the cat are small to medium-sized myelinated fibers, with conduction velocities ranging from 20 to 60 m/sec, mean = about 40 m/sec (Brown et al., 1983). The neurons of origin receive afferent input from both large and small myelinated dorsal root fibers; many are multireceptive, responding both to gentle mechanical stimulation of the skin or deep tissues, and also to noxious mechanical stimuli transduced by thin myelinated fibers. In some cat experiments they responded to noxious heat, after sensitization of the skin (Kamogawa and Bennett, 1986). The number of axons in the system in any species is not known, but in the primate the PSDC system is a large-numbered afferent pathway projecting from the spinal cord to the DCNC (Rustioni et al., 1979). One difficulty in experiments on this system is to prove that an axon of a dorsal horn neuron that projects directly into the adjacent dorsal column projects all the way to the DCNC, and is not a short or long intersegmental fiber, or does not project upon some other supraspinal target; for discussion see Enevoldson and Gordon (1989). The cells of origin of the PSDC system form a broad band centered upon, but not restricted to, lamina IV at all segmental levels, more densely in the lumbar and cervical enlargements than in the thoracic segments (Rustioni, 1977; Rustioni et al., 1979). Double degeneration and autoradiographic tracing experiments revealed that in the monkey, as in the cat, axons from the lumbar region terminate throughout the gracile nucleus, densely in the matrix surround, less so in the modular core (Cliffer and Willis, 1994). Axons from the lower cervical segments, where the hand of the primate is represented in an expanded version, terminate densely in the matrix of the cuneate pars triangularis, and thinly in the modular core, the pars rotunda. Some afferents terminate in the lateral cervical nucleus. The function of the PSDC system in somatic sensibility is uncertain. One hypothesis—that the system serves as an alternate pathway for pain sensibility—is based partly on the observation that some of its elements respond to input in nociceptive visceral afferents (Willis et al., 1999). Plastic changes in the system may enhance its nociceptive function after anterolateral cordotomy, and account for the reappearance of pain sensitivity in some cordotomy patients

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after months or years of postoperative freedom from pain, but there is no direct evidence for this supposition. The receptive fields (RFs) of cortical lemniscal neurons are dynamically restricted in size by converging activity generated in smallfibered afferents innervating the lemniscal cutaneous receptive field, as well as a large area of surrounding skin. Capsaicin block of C-fibers with overlapping receptive fields, produces a large and immediate expansion of the RFs of postcentral neurons (Calford and Tweedle, 1991). Dykes and Craig (1998) obtained evidence in anesthetized cats that this control is imposed, at least in part, by the convergence of the PSDC system upon the lemniscal transition in the DCNC. They first isolated for recording a single neuron of the DCNC, defined its receptive field, and then anesthetized or destroyed chemically the topographically related segmental dorsal horn. This produced enlargements of the lemniscal RF by 1.5–5.0 times, in 14 of 16 experiments. Normally, the RFs of DCNC neurons are spatially restricted by this convergent projection. The general conclusion is that one function of the small-fibered PSDC system is to regulate the static and dynamic properties in lemniscal transition zones. This may be only one of the many regulating functions suggested for the small-fibered systems of intrinsic origin (Craig, 1996). In summary, the several interdigitated and intermittently recursive mappings of the body form to the DCNC and the parcellation of modality channels in the lemniscal system are set by the re-sorting of primary afferents, and preserved through the first transition zone of the system, the DCNC. Specificity for place and mode depends in the first instance upon a limited suprathreshold convergence in the projection of first-order afferents into the DCNC. On one hypothesis, this restriction is reinforced by activity in the postsynaptic dorsal column system that suppresses the action of converging afferent input from the cutaneous areas surrounding the receptive fields of mechanoreceptive DCNC neurons. The tight, phase-linked, synaptic transmission capacities in the core regions of the cuneate and gracile nuclei allow transmission into the forebrain of faithful replicates of high-frequency activity in peripheral afferent fibers.

Visceral Afferent Projections in the Dorsal System It has been known since the single fiber studies of the dorsal columns made in anesthetized cats by Yamamoto et al. (1956) that “from a

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localized superficial portion of Gall’s funiculus closely adjacent to the septum, slowly adapting impulse discharges were obtained subsequent to filling the bladder.” The presence of a visceral mechanoreceptive/nociceptive afferent pathway in this restricted area of the dorsal columns has been confirmed, and studied in rats (Berkley et al., 1993; Wang et al., 1999) and monkeys (Al-Chaer et al., 1996, 1997; for reviews see Willis and Westlund, 1997; Willis et al., 1999). Visceral afferents from the abdominal organs run through the splanchnic nerves and communicating rami, enter the spinal cord over dorsal roots T-6 to T-11, and terminate upon the group of neurons just dorsal to the central canal, Rexed lamina X. Ninety percent of these afferents are unmyelinated, and virtually all appear to be multireceptive (Cervero and Tattersall, 1986; Cervero, 1994). Axons of some of these neurons project in the contralateral spinothalamic tract, while others ascend through the dorsal columns to terminate in the outer shell of the gracile nucleus upon neurons whose axons pass through the medial lemniscus to the contralateral thalamus. The second-order visceral afferent fibers are tightly clustered in a vertical line along the median septum and the intermediate septum of the gracile tract in rats; they are not distributed through the gracile tract (Yamamoto et al., 1956; Wang et al., 1999). If this is true in humans, it may account for the effectiveness of midline myelotomy in relieving the severe pain of invasive carcinomata of the abdominal cavity. A dramatic effect on pain in widely distributed areas of the body is produced by a midline myelotomy at a high cervical level (Hitchcock, 1970; Cook et al., 1984; Hirshberg et al., 1996; Nauta et al., 1997). The anatomical basis for this result is still uncertain, but it may be effective because a large number of spinothalamic neurons are concentrated in upper cervical dorsal horns; they project through the contralateral spinothalamic tract to the dorsal thalamus (Apkarian and Hodge, 1989a,b). It remains to be determined whether these spinothalamic neurons have RF locations over wide areas of the body. These new discoveries suggests that the postsynaptic dorsal column system contains a major visceral nociceptive pathway important for the sense of visceral pain. This raises a more general question that deserves further study: How is it possible for a group of lemniscal neurons under one condition of afferent input, for example, from mechanoreceptors of the skin, to evoke somatic sensory mechanoreceptive sensations, and under another to evoke

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visceral pain? Each of these convergent inputs evokes, by variations in intensity of peripheral stimulation, a wide range of frequency of discharge of the DCNC neuron, and so far as is known neither evokes any unique pattern of the temporal order of discharge or distributions of activity within the lemniscal pathway. It is unlikely that the same sets of DCNC neurons signal different modalities by differences in these temporal properties. Until now, no pathway in the dorsal columns or in any other quadrant of the spinal cord has been identified as one uniquely and specifically activated by visceral afferent input; and virtually all of neurons identified as activated by visceral afferent input are reported to be multireceptive, that is, to be activated also by somatic sensory input in addition to the visceral afferents. No testable solutions to this enigma have been proposed.

Spinocervicothalamic System The spinocervicothalamic system discovered by Morin (1955) originates from intrinsic neurons of the dorsal horn, and links hairfollicle mechanoreceptive afferents to the forebrain. This system reaches its apogee in furred quadrupeds, and dwindles in comparative size in nonhuman primates. It was not found in the human spinal cords studied by Brodal and Rexed (1953), and was identified in vestigial form in about one half of those examined by Truex et al. (1968). In carnivores, the spinocervical tract arises from neurons distributed in a sheet across the dorsal horn, largely in lamina IV through the length of the cord, and projects through the ipsilateral dorsolateral funiculus to the lateral cervical nucleus, a collection of cells ventrolateral to the dorsal horn within the lateral funiculus in cervical segments C1–C3 (Brodal and Rexed, 1953; Nijensohn and Kerr, 1975). There are about 2200 neurons in this nucleus on each side in the spinal gray of the cat, compared with about 61,500 cells in the gracile nucleus on each side (Heino, 1995). Axons of the lateral cervical tract vary in conduction velocity over a range from 7–60 m/sec; mean = 28m/sec (Bryan et al., 1974). Ascending axons of the cells of the lateral cervical nucleus cross in the anterior commissure of the spinal cord and join the medial lemniscus to project, in the cat, in a common topographic pattern to the ventral posterolateral nucleus of the thalamus. The spinocervicothalamic system appears to be specialized in cats to signal the movement of hairs on furred skin (Brown, 1981).

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Nearly 100 percent of spinocervical cells in the dorsal horn receive afferent input from one or another of the sets of hair follicle afferents, and are related to small contralateral receptive fields. Brown discovered that this selectivity for modality and place depends in part on activity in systems descending to the spinal cord from the brain stem (Brown, 1971). Selective qualities were observed in decerebrated animals without anesthesia, but after the descending systems were blocked at a high cervical level by local cold, spinocervical tract cells changed to subtend larger excitatory and inhibitory fields than those seen in the decerebrate state; they were activated by hair follicle afferents as before, but also by other A-beta afferents, and by Cfiber nociceptive afferents. The spinocervicothalamic system is much attenuated in monkeys, and may not exist at all in humans. I conclude that it contributes little to the mechanoreceptive capacities of the primate hand.

Loss and Retention of Somesthetic Capacities in Primates After Lesions of the Dorsal Ascending Pathways of the Spinal Cord It is a formidable task to identify from study of the results of clinical and experimental lesions in primates the functional roles of afferent systems within the anatomically defined funiculi of the spinal cord. Sets of primary afferent fibers of the dorsal roots with different peripheral innervation patterns and transduction properties project into the same anatomically defined, ascending conduit of the spinal cord (in cats, Yamamoto et al., 1956; Uddenberg, 1968; Rustioni, 1973; Anguat-Petit, 1974; in monkeys, Rustioni, 1977; Rustioni et al., 1979). An analytic approach to this problem is possible based on knowledge of the functional properties of afferents innervating peripheral tissues, particularly of the hands of humans and monkeys (Chapter 5), and of the response properties of neurons in central targets of the somatic system (Chapters 11–15). Much of this knowledge has been obtained in experiments in waking monkeys as they worked in somesthetic tasks, or in waking humans producing verbal reports of somesthetic experiences evoked by stimulation of single afferent fibers. This correlative, analytic approach is used in this and in several following chapters. The traditional concept of dorsal column function, held in some form by many, came from studies by clinical neurologists of humans

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with disease or injuries of the spinal cord, as well as from experimental studies in monkeys with surgical transections of pathways; for historical review, see Finger (1994, pp. 134–164). Lesions of the dorsal ascending systems produce two general classes of defects. The first is proprioceptive in nature: a loss of the sense of the position and movements of the limbs; a reluctance to make and clumsiness when making projected movements of the limbs into surrounding space; and deficiencies in active grasping. There are defects in the control of fine movements of the fingers, and loss of the long-latency, servo-response evoked by afferents from the muscles of the forearm in humans (Marsden et al., 1977); and from the finger muscles in monkeys (Cooper et al., 1993; Glendenning et al., 1993). All these defects are severe in the arm and hand, but scarcely discernible in the leg and foot. A second class of defects produced by dorsal column lesions includes an incapacity to detect or to discriminate between moving cutaneous stimuli, which require for their perception differentiation between distributed, moving patterns of afferent input, as when we sample the texture and pattern of objects or surfaces by a moving hand, or identify numerals or letters written on the skin; all are components of dynamic cutaneous sensitivity. Defects in vibratory sensibility are considered by many to be signs of dorsal column lesions; I consider this much debated problem in Chapter 12. Abnormalities in humans after dorsal column lesion are paralleled by the results of the classical studies of Ferraro and Barrera in monkeys with dorsal column lesions (Ferraro and Barrera, 1934, 1935a–c). These monkeys showed impairments in positioning and movement of the limbs, in spontaneous grasping and in controlling fine movements of the hands and fingers, and a reluctance to move the limbs and clumsiness when doing so. These deficiencies were more severe in the arm and hand than in the leg and foot, after high cervical sections, like those in humans, and were attributed to a loss of proprioceptive input from the limbs, not to direct injury to elements of the motor system. Ferraro and Berrera’s observations were confirmed and extended 30 years later by Gilman and Denny-Brown (1966), who observed a similar set of defects in motor control, particularly in projected movements of the limbs into space, again much more severe in the monkey arm than in the leg after high cervical transection. Dynamic cutaneous sensibility could not be examined in either of

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these studies, which relied on clinical examination of monkey subjects over long periods of time, and anatomical demonstration of the lesions and the resulting fiber tract degenerations. Nevertheless, it remains uncertain whether the full dorsal column syndrome can be produced in humans or in monkeys without accompanying damage to the adjacent dorsolateral column. An alternative view held by some is that the dorsal columns are not sensory in the usual sense, but play a role in the control of movement and should be regarded as part of the motor system. No one doubts the importance of the dorsal column system in movement control, but its essential role in the discriminative aspects of cutaneous sensibility is well established. Moreover, signaling of limb position by proprioceptive afferents commonly evokes conscious kinesthetic perceptions, a role these afferents play in addition to the preconscious guidance of limb movement. These disagreements should now be ignored, and correlations sought between the sensory defects produced by lesion of a particular spinal cord afferent conduit and the functional properties of the sets of afferent fibers and their second-order axons that transit through it. Spinal cord conduits are not functional entities; they are defined by spatial anatomical landmarks. Each contains the direct or relayed ascending projections of several sets of afferents, with different functional properties. Lesion of any such structurally defined afferent conduit, for example, the dorsal columns, produces a mixed set of functional defects reflecting the properties of the sets of afferents transected. There are several reasons for the persisting uncertainty in an area of neurology studied so long and as intensively as have the dorsal columns. 1. Dorsal columns are defined in mammals by external landmarks that invite direct surgical transection, but it has proved difficult to produce complete transections of these tracks without damage to adjacent structures. No histological proof of a complete, but restricted, dorsal column lesion produced in monkeys by surgical means has appeared. 2. Similarly, there is no disease of the spinal cord in humans that affects the dorsal columns completely and exclusively.

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The conditions most often studied in clinical neurology are tabes dorsalis, combined system disease, disseminated sclerosis, and Friedreich’s ataxia. Each of these produces lesions of the dorsal roots and/or the dorsolateral columns, or both, as well as of the dorsal columns. Injuries to the spinal cord in humans are rarely confined to a single pathway. 3. Even if perfect lesions of the dorsal columns could be produced experimentally, or occurred naturally in humans, analysis would be confounded by the heterogeneous nature of these pathways. 4. A confounding factor in attempting to assign function to structure on the basis of defects that appear after lesions of the nervous system is the rapid onset of adaptive changes is central synaptic connectivity. Adaptive changes may begin immediately after lesion and continue for months or even years before a steady plateau of reduced function is reached, which may be much less severe than that present immediately after lesion or injury (Xu and Wall, 1997, 1999a,b). Plastic adaptation has been studied intensively over the last two decades in both humans and monkeys with lesions of the central or peripheral nervous systems (Kaas, 1991; Frackowiak et al., 1997, chapter 12; Buonomano and Merzenich, 1998). Adaptive changes occur at each level of the somatic afferent system (Florence and Kaas, 1995; Jones, 2000a,b), and may involve changes in synaptic efficiency and synaptic ultrastructure, the growth of new axonal connections, and even gross changes in connectivity patterns. What is usually called the period of “recovery from surgery” in experimental work is mixed with the rapid onset of the adaptive processes. If lesion work is to continue to contribute to knowledge of brain function, as it has so productively in the past, recourse might be taken in experimental work to further use of reversible lesions so that the immediate loss of function can be observed, and its recovery traced over a short time scale. What is certain is that the remaining deficit after the period of adaptation is not the mirror image of the functions previously served by the transected pathway(s) or lesioned nuclear structure(s).

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Defects in Motor Control and Dynamic Somatic Sensibility After Lesions of the Gracile and Cuneate Tracts Differences in the defects produced in the arm and leg by high cervical transections of the dorsal columns have been further documented in studies with quantitative measures of the deficiencies. High cuneate transection produces the full dorsal column syndrome, with particular defects in controlling fine movements of the hands and fingers (Glendenning et al., 1992) and in grip formation (Leonard et al., 1992), accompanied by severe defects in dynamic cutaneous sensibility. Nevertheless, it has not been demonstrated that the full dorsal column syndrome can be produced by lesions confined to the cuneate tract. Transection of the gracile tract, above the upper thoracic level, produces in monkeys and humans minimal defects in proprioception and motor control, which are limited to the distal leg and foot. Defects in dynamic cutaneous sensibility match those of arm and hand after lesions of the cuneate tract; for example, defects in discrimination between stimuli of different textures delivered to the glabrous skin of the foot (Vierck and Cooper, 1998). The proprioceptive and motor deficiencies of the full dorsal column syndrome appear immediately if a lesion of the dorsolateral column is added to a high thoracic gracile lesion. The differences in the effects of high cervical transections of the cuneate and gracile tracts, on the arm and leg respectively, are readily understood in terms of: (1) the projection pathways of different sets of dorsal root afferents and (2) the re-assortment for place and modality that occurs in the primate gracile tract in the high thoracic level, as described above. The result is that, from the high thoracic to the high cervical region, the primate gracile tract contains almost exclusively quickly adapting cutaneous afferents from the leg and foot that are critical for dynamic cutaneous sensibility. Second-order proprioceptive afferents from the lower limb project through the spinomedullothalamic tract of the dorsolateral column to the DCNC. The assumption is made, without direct proof, that a similar rearrangement occurs in the human spinal cord. Vierck and his colleagues have exploited this re-direction of the proprioceptive and slowly adapting cutaneous afferents out of the gracile tract at the upper thoracic level, by using quantitative methods to measure the loss and the retention of proprioceptive and cutaneous sensibilities in the legs and feet of monkeys after gracile

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transection in the high thoracic level. They found—so far as the surgical transection method allowed—that lesions at the high thoracic level of the gracile tract produced sensory defects that mirror the functional properties of the quickly adapting cutaneous afferents described in Chapter 5. Vierck et al. concentrated on the study of the deficiencies produced in their monkey subjects in the chronic, fully adapted state of the somatic afferent system, and followed their condition for months or years. Their monkeys showed the following long-term changes: 1. Loss of the capacity to discriminate between mechanical stimuli of different frequencies delivered to the skin of the foot (Vierck et al., 1985; Vierck, 1998). 2. Inability to recognize the spatiotemporal sequence of tactile stimuli delivered to the skin (Vierck et al., 1983). 3. Inability to discriminate between the directions of moving tactile stimuli (Vierck, 1974). 4. Impairment of the grasp reflex in the foot (Vierck, 1978). 5. Loss and delayed recovery of absolute size discrimination (Vierck, 1973). 6. Loss of texture discrimination (Vierck and Cooper, 1998). Their animals retained: 1. Absolute tactile localization (Vierck et al., 1988). 2. The ability to project leg and foot into surrounding space. 3. Detection of joint angle at the knee (Vierck, 1966). Nathan’s review of 65 patients after anterolateral cordotomy, with histological examination of the lesioned spinal cords in 38, has confirmed many well-known facts concerning the functions of the dorsal columns (Nathan, 1990). No form of static or dynamic tactile sensibility was affected in any single one of the 65 subjects. The senses of position and movement of the joints and vibratory sensibility were normal in 62 of the 65. It is clear that the uninjured dorsal ascending systems can sustain, in undiminished form, the discriminative

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aspects of mechanoreceptive somatic sensibility, after transections of afferent systems of the ventral cord. Nathan’s studies also showed that after total dorsal column lesions humans retain the rudimentary aspects of mechanoreceptive sensibility, including static localization and two-point discrimination, presumably signaled by mechanoreceptive elements of afferent pathways in the anterolateral quadrant (Nathan et al., 1986).

Concluding Remarks The descriptions of structure and function of the lemniscal component of the dorsal ascending systems of the spinal cord emphasize their importance for the discriminative aspects of mechanoreceptive sensibility. These capacities depend on the properties of these systems: a precise somatotopy, modality segregation into local sets of afferent fibers and central neurons, strong synaptic security subtending dynamic operations, and a susceptibility to plastic changes in synaptic microstructure produced by changes in experience or by lesions removing afferent input. A number of new discoveries support an added formulation—that at each level the system consists of a central core of modules of neurons with lemniscal properties, embedded within and surrounded by a matrix of elements with different properties. The matrix surround receives convergent projections of neural elements of the intrinsic ascending systems that originate in the spinal gray at segmental levels of the spinal cord. These latter are composed of medium to thin fibers with functional properties quite different from those of the discriminative systems; they are commonly nociceptive. It seems likely that stimuli that reach or are actively captured by the hand activate elements of both classes of systems, to degrees that vary greatly from one time to another. An important experimental objective is to discover how those systems interact at forebrain levels of thalamus and cortex, and to identify the dynamic mechanisms that maintain the discriminative levels of the large-fibered, mechanoreceptive systems, as well a those which evoke the affective overtones of sensory experiences evoked by all stimuli, whether noxious or pleasant. N OTE 1. No pathway in the nervous system contains a pure sample of axons originating from a single source and projecting to a single target. All contain in varying degrees axonal elements with different

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connections, for example, the optic and pyramidal tracts. It seems unnecessarily pedantic to repeat in every use of these terms their heterogeneous nature. Assuming that all neuroscientists know these facts, some efficiency attends use of the classical terms of, for example, optic tract, pyramidal tract, medial lemniscus, and so forth. See “On Naming” in Chapter 3.

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7

Small-Fibered Peripheral Interface

The controlled mechanical stimuli used in psychophysical and neurophysiological laboratory studies of somatic sensibility are restricted abstractions of the somesthetic experiences of everyday life. Although it is the activity of the large-fibered mechanoreceptive afferents from the hand that provide neural signals of the quantitative and dynamic aspects of mechanical stimuli, in ordinary sensory experiences these may be accompanied by afferent activity in simultaneously activated small fibers, including those serving pain and temperature sensibilities, and those active in the innocuous ranges of warming and cooling. The small-fibered afferents project into the intrinsic ascending systems of the spinal cord, the majority by transition through the dorsal horn, and converge upon the transition zones of the large-fibered lemniscal system. The functional meaning of these convergences is still unknown, and whether both nuclear and cellular uncertain. I shall pursue as far as reasonable the proposition that it is the small-fibered afferents and their central projection systems that provide the cognitive and affective overtones of naturally encountered mechanoreceptive experiences, as they do for pain and temperature sensibilities. The classes of thinly myelinated A-delta and unmyelinated Cfibers innervating the glabrous skin of primate hands contain sets that serve the varieties of pain and temperature sensibilities (Table 4–1). All are relatively insensitive to the innocuous mechanical stimuli transduced at low thresholds by the A-beta mechanoreceptive afferents that evoke the somatic sensory mechanical perceptions

of pattern, contour, movement, vibration, and so forth. These lowthreshold mechanoreceptive afferents grade frequency of discharge systematically with increases in stimulus intensity, but reach their maximum rates of activity just at the mechanical thresholds of nociceptive afferents. The several sets of nociceptive afferents differ in the qualitative range of stimuli they transduce, but they have in common two attributes: they all respond to stimuli that tend to destroy tissue, and when active they evoke pain. Direct proof of the specificity of nociceptive afferents and their role in evoking painful sensations in waking, normal humans has been obtained by intraneural microstimulation of single afferent fibers, using the method of microneuronography introduced by Vallbo and Hagbarth (1968). Microstimulation of single, identified A-delta nociceptive afferent fibers evokes sharp, pricking pain at short latency. The sensation evoked by single fiber stimulation is projected by subjects close to or directly upon the peripheral receptive field of the fiber on the glabrous skin of the hand, determined in a recording phase of the experiment. This pain disappears after block of A-delta fibers in the innervating peripheral nerve. Similarly, intraneural microstimulation of single C-fiber nociceptive afferents evokes a slow burning pain at a long latency, and accurate spatial projection of the sensory experience to the receptive field of the fiber onto the glabrous skin. This pain survives A-delta block and is eliminated by anesthetic block of C-fibers in the peripheral nerve. These observations have confirmed in a direct and convincing way the specificity for fast and slow pain of the A-delta and C-fiber nociceptive afferents, respectively (Konietzny et al., 1981; Torebjork et al., 1984a,b, 1987, 1996; Torebjork, 1993). Although many earlier experiments suggested that specific nociceptive afferents existed in the peripheral nerves of mammals, the results of the initial electrophysiological experiments produced somewhat equivocal results (Iggo, 1959a,b). This uncertainty was resolved by Perl and his colleagues, who discovered the specific nociceptive sensitivity of A-delta and C-fibers innervating the hairy skin of cats and monkeys, and the glabrous skin of monkeys (Burgess and Perl, 1967; Perl, 1968, 1984, 1996a,b; Bessou and Perl, 1969; Perl et al., 1976; Kumazawa and Perl, 1977). These investigators also discovered sets of C-fiber afferents they termed polymodal because they are sensitive to noxious mechanical (M), heat (H), and chemical (C)stimuli. Their sensitivity is to the destructive nature of

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the stimuli, not to the form of destructive energy. Polymodal afferents of both the A-delta and C-fiber sets have since been identified in the innervation of the glabrous skin of the hand in monkeys and humans, where the large majority of C-fiber nociceptive afferents are polymodal. Sets of C-fiber afferents with different thresholds to these stimuli are sometimes labeled C-fiber mechanical (CM), C-fiber mechanical-heat (CMH), or C-fiber mechanical-heatchemical (CMHC) to indicate their preferential sensitivities. Many nociceptive C-fibers innervating the skin are insensitive to natural stimuli used in neurophysiological experiments, and are revealed by an electrical search technique (Meyer et al., 1991). They are labeled CiMi to indicate their insensitivity to intense mechanical stimuli. Some of these afferents can be activated by chemical stimulation, a few by itch-producing molecules; almost all respond to both mechanical and heat stimuli after sensitization. Many of the polymodal C-fibers innervating the glabrous skin of the primate hand are specific for one or another form of noxious stimulation, and one could, on these differences, define a large number of different classes of nociceptive afferents innervating the glabrous skin. Whether this further subdivision is useful depends on showing that each set evokes, when active, a particular and different aspect of the pain experience. Moreover, the pattern of sensitivity of nociceptive afferents changes with sensitization and tissue damage or inflammation. For example, the A-delta nociceptive afferents innervating the hairy skin are normally sensitive only to destructive mechanical stimuli, but after sensitization respond to noxious heat stimuli, as well (Campbell et al., 1979). Two sets of heat-sensitive A-delta afferents have been defined. AMH-Is (A-fiber mechanical-heat) are sensitive to destructive mechanical stimuli and to heat, with thresholds at about 52°C. They innervate both the hairy and glabrous skin. The AMH-IIs respond to destructive mechanical stimuli and to heat, with thresholds for the latter in the range of 42°C. They are present only in the innervation of the hairy skin. The slow onset of the discharge of the AMH-Is innervating glabrous skin accounts for the absence of first pain to noxious heating stimuli delivered to the glabrous skin. The functional properties of nociceptive afferents are given in Table 7–1; for reviews, see Torebjork et al. (1996), Raja et al. (1999), and McKleskey and Gold (1999).

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Table 7–1

Properties of Thin-Fibered Nociceptive Afferents C-Polymodal-I

C-Polymodal-II

A-Delta

Axon properties

Unmyelinated CV = 0.6–2.0 m/sec

Unmyelinated CV = 0.6–2.0 m/sec

Thinly myelinated CV = 5–30 m/sec

Dorsal root ganglion cell

Small-dark

Small-dark

Medium-light

Dorsal horn target

Lamina I, lamina II-outer

Lamina II—inner

Laminae I and V

Central small molecule Transmitter agent

Glutamate

Glutamate

Glutamate

Heat channel

VLI Cation nonselective Ca2+ > Mg2+ > Na+> Cs+ > K+

VLI cation nonselective Ca2+> Mg2+> Na+> Cs+> K+

VRLI cation nonselective

Proton channel

Yes

Yes

No

Polypeptides

SP, CGRP, VIP, NK1

Binds with IB-4 lectin, P2X3

CGRP, IB-4 lectin binding

Stimulus sensitivities

Noxious mechanical, chemical, heat Th = 42°C, range 42–52°C

Noxious mechanical, chemical, heat Threshold = 42°C, Range 42°C–52°C

Noxious mechanical, heat Thresholds: AMH-class II–42°C AMH-class I–52°C

Capsaicin sensitivity

Yes

Yes

AMH-I—No AMH-II—Yes

Neurotrophin support

NGF

GBNF

—

Sensitization

Yes

Yes

AMH-I—yes; AMH-II—no

Role in pathological pain

Inflammation

Nerve injury

Neurofilament

No

No

Yes

Note: Many of the facts tabulated were obtained—necessarily—in rodents, or in excised tissues, cultured cells, and so forth. Whether and if so which can be transferred to the nociceptive afferents innervating the glabrous skin of the hand is unknown.

Transducer Mechanisms at Small-Fibered Nociceptive Endings The discovery that many receptor ionic channels are expressed in the dorsal and trigeminal root ganglion neurons, and by inference, in their peripheral terminals, is a major event in the rapidly evolving field of pain research (Kress and Zeihofer, 1999; Treede, 1999). Knowledge of the molecular structure of those receptor channels opens the possibility that therapeutic agents will be developed that may block pain at its inception, with minimal effect on the central nervous system. The majority of these new discoveries

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have—necessarily—been made in intact rodents, in culture systems of rodent dorsal root ganglion cells, or in transfected Xenopus oocytes. The dorsal root ganglion cell is taken to represent its peripheral terminal, and the question explored whether channel proteins expressed in the cell body are transported to the peripheral terminal, inserted into its membrane, and function there in the nociceptive transduction process. There is evidence that this is true for some channel proteins: they accumulate proximal to a nerve ligature; immunohistochemical staining shows their location in the terminal membranes; blocking agents render the animal immune to the appropriate nociceptive stimulus; and mutants absent that particular channel are insensitive to that stimulus. For any given protein identified at the ganglion cell level, it then remains to show whether it is transported to the peripheral or to the central terminals of the dorsal root ganglion neuron, to both or neither, or is inserted into the axonal membrane closer to the cell body. Study of the molecular mechanisms of transduction at the terminals of nociceptive afferent fibers was accelerated by Jansco’s discovery in rodents that capsaicin, the pungent agent of red peppers, first stimulates and then kills the terminals of nociceptive afferent fibers, including all C-fibers and some A-delta sets (Jansco, 1968; for reviews, see Holzer, 1991; Szallasi, 1994; Wood and Docherty, 1997; McKleskey and Gold, 1999). Injection of capsaicin into the skin first excites, and then kills, the small afferents in the nerve, their smalldark cells of origin in the dorsal root ganglia, and their terminals in laminae I and II of the dorsal horn. Capsaicin acts as a ligand for a heat-sensitive channel protein identified by Cesare and McNaughton (1996), and then cloned as a vanilloid-type, VR-1 (Caterina et al., 1997). Heat is the natural ligand for the VR-1 channel, with threshold at about 42°C. VR-1 is a nonselective cation channel with permeabilities in decreasing order of Ca > Na > K > Cs > Mg. Single-channel conductance is 30–40 pS. Heat affects the probability of channel opening, not its conductance. The response of the “heat” channel is incremented after phosphorylation by protein kinase (Cesare et al., 1999), while protons modulate the VR-1 channel so that at pH levels in the range of 6.8–7.0, the heat threshold is lowered to about 37°C (Tominaga et al., 1998). Capsaicin has proved a useful tool for the study of nociceptive afferents, particularly since an agonist, resinferatoxin, and a specific antagonist, capsazepine, for the VR-1 channel were discovered (Szallasi, 1994; Kirchstein et al., 1999); see Fig. 7–1.

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Fig. 7–1 A scheme illustrating some of the molecular systems that determine the excitability of peripheral nociceptive afferents. AA—arachidonic acid; AC—adenylate cyclase; BK—bradykinin; cAMP—cyclic adenosine monophosphate; DAG—diacylglycerol; IP3—inositol-1,4,5—triphosphate; PG—prostaglandin; PKA—cAMP-dependent protein kinase; PKC—protein kinase C; PLA2—phospholipase A2; PLC—phospholipase C. (From Bevan, 1999.)

Na+ Channels and Nociception Several Na+ channels with different electrophysiological properties are expressed in the small, dark nociceptive dorsal root ganglion neurons, and transported to their peripheral terminals. These include the ubiquitous tetrodotoxin-sensitive channels essential for excitation and conduction in all neurons, and, in addition, several tetrodotoxininsensitive Na+channels (Na+i ). One of the later is found almost exclusively in nociceptive afferents, and plays a role in producing the sometimes intense hyperalgesia of inflamed tissues. Inflammatory mediators, for example, substance P (SP), prostaglandin E2, somatostatin, serotonin, adenosine, and especially nerve growth factor (NGF), are transported to DRG cells and induce increased expression

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of the Na+i channels, which are then found in increased density in the nociceptive terminals innervating inflamed tissues. The Na+i channel has a high threshold, sustained activation, and rapid recovery from inactivation, properties that contribute to the sustained, high-frequency discharges of nociceptive afferents innervating inflamed tissue. Modulators released in inflamed tissues and linked to terminal membranes also increase the ion transport capacity of the Na+ channels by the ubiquitous G-protein-mediated phosphorylation. What role the Na+i currents play in pain transduction in normal tissue is still uncertain; preliminary evidence shows that knockdown of the gene for the neuron specific (SNS) TTX resistant sodium channel alpha subunit in mice produces a mild general analgesia (Akopian et al., 1999; Waxman et al., 1999).

Proton Channels and Nociception Acid-sensing ion channels (ASIC) gated by protons have been cloned and shown to exist in the brain and in DRG cells of origin of thin-fibered nociceptive afferents (Waldman and Lazdunski, 1998; Waldman et al., 1999). They are nonselective cation channels (Na+ > Ca2+ > K+). An H-gated channel in the small, dark dorsal root ganglion cells is independent of the capsaicin sensitive heat channels in the same neurons. This channel is closed at pH values of 7.0 and above, but generates both fast and slow currents with gating thresholds below pH 7.0, values reached in anoxic, exercising muscle and in inflamed tissues, where these channels are thought to contribute to the heightened excitability of nociceptive afferents (Waldman et al., 1999).

Correlations: Psychophysical Measures and First-Order Afferents The perception of heat stimuli in the moderately noxious range of 42–53°C delivered to the glabrous skin of the hand is served by polymodal C-fibers (Table 7–1). These nociceptive afferent C-fibers have vanilloid receptors sensitive to capsaicin and heat that are modulated by protons with opening thresholds at about 42°C and ranges up to about 50–55°C. Thresholds of these fibers to heat coincides with the heat threshold in humans, and their discharge frequencies increase monotonicly with increasing stimulus intensities, paralleling

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Fig. 7–2 Responses of a nociceptive afferent innervating the palm of a macaque monkey to stimuli of 41–49°C, presented at 25-sec intervals. Base temperature, 38°C. A: Replicas of impulse trains on each trial; trials are grouped by stimulus temperatures. B: Intensity functions constructed from data in A. Solid line represents the mean cumulative impulse count during each stimulus, averaged for all stimuli of that intensity. The dotted lines show the stimulus response functions obtained when the preceding stimulus was low (41–43°C) or high (47–49°C) intensity. (From LaMotte and Campbell, 1978.)

the human subjective estimation functions for identical stimuli (Fig. 7–2) (LaMotte and Campbell, 1978; Meyer et al., 1994). Torebjork and his colleagues observed sensory and neural events in humans who made threshold detections and subjective magnitude estimations of pain produced by electrical stimulation of single nociceptive C-fibers in their peripheral nerves, at different frequencies (Torebjork et al., 1984a; Torebjork, 1985) The results obtained in a number of human subjects showed a reasonably close correspondence. Sensitivity to heat is extended into the intensely noxious range above 53°C by a set of A-delta afferents that innervate the glabrous and hairy skin in primates, the AMH-Is of Table 7–1. They have thresholds of about 52°C, but their upper range has not been tested into the zone of tissue destruction by heat. The medium-sized, clear dorsal root ganglion cells of origin of the A-delta fibers express a nonvanilloid channel receptor protein, with an opening heat threshold of about 52°C that is insensitive to capsaicin or protons (Caterina et al., 1999). This channel is a nonspecific, cation-selective

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channel with permeabilities of Ca2+ > Mg2+ > Na+ = Cs+ = Na+. Although the A-delta class contributes to the overall sense of pain, the perception of heat pain survives block of all A fibers, with C-fiber conduction unchanged. Systematic decreases in cold stimuli stepped down from adapting temperatures of 10°, 5°, and 0°C evoke pain when delivered to the facial or the palmar skin in humans. At threshold, the pain is pricking in nature, then changes to burning pain with further decreases in stimulus temperatures. Detection times are longer, thresholds for detection higher, and discriminations less exact for stimuli in the noxious cold than in the innocuous cooling range, in both monkeys and humans (Morin and Bushnell, 1998; Harrison and Davis, 1999; Rainville et al., 1999). A subclass of polymodal C-fibers innervating the human hairy skin is selectively sensitive to noxious cold stimuli between 19° and 0° C (Campera et al., 1996), and some polymodal afferents in both the A-delta and C-fiber sets innervating the hairy skin of monkeys are sensitive to noxious cold stimuli (LaMotte and Thalheimer, 1982). Nociceptive afferents innervating the cutaneous veins in humans are differentially activated by cold, induced by immersing the hand in ice water, with intravenous thresholds between 23° and 28°C. Maximum pain is produced at 9°C and is blocked by local intravenous anesthesia (Klement and Arndt, 1992). If cold stimuli are carried down to −20°C, virtually all nociceptive afferents innervating the hairy skin of the rat respond, with thresholds distributed between +2°C and −20°C. Systematic decreases in cold stimuli below thresholds evoke, in these rat afferent fibers, monotonic increases in the low discharge frequencies evoked at stimulus onset and during steadily maintained noxious cold stimuli (Simone and Kajander, 1997). Test stimuli were not carried down to the extreme of −20°C in any of the electrophysiological experiments in monkeys or humans, and it remains uncertain whether noxious cold in humans is mediated by quasi-specific sets of afferents, or whether some or all classes of nociceptive afferents respond at some level of noxious cold. However, nerve blocking experiments in humans indicate that somewhat different qualities of noxious cold pain may be evoked by A-delta and C-fiber nociceptive afferents. When both are conducting, noxious cold elicits an initial experience of pricking pain, coldfreezing, and aching pain. After A-fibers are blocked, with C-fibers still conducting, noxious cold stimuli evoke a severe, burning pain (Wahren et al., 1989; Yarnitsky and Ochoa, 1990; Davis, 1998).

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Fig. 7–3 Responses of a warm-sensitive C-fiber innervating the glabrous skin of the hand of a macaque monkey. Stimulus profile at upper left. Controlled base stimulus, 34°C. Vertical strokes replicate action potentials on two trials for each stimulus at temperatures above base, shown to the left, and post-stimulus time histograms for five trials at each stimulus to the right. Stimulus intervals, 60 sec. (From I Darian-Smith et al., 1979.)

Innocuous Warming and Cooling How we perceive warming and cooling of the skin in the innocuous range of temperatures between the thresholds for noxious heat and noxious cold has been studied intensively for more than a century, following the discovery of the warm and cool spots in the skin by Blix, Goldscheider, and Donaldson; and Sherrington’s review of 1900. Psychophysical studies of the human perception of warmth and coolness were made by Hardy and Opel (1937, 1938) and Stevens and Stevens (1960). It was Zotterman who, with Iggo and Hensel, first made direct studies of the first-order thermoreceptive afferents, in the hairy skin of cats and monkeys (Zotterman, 1959; Hensel, 1981). Darian-Smith and his colleagues carried out definitive studies of the thermoreceptive afferents innervating the glabrous skin of the monkey hand (DarianSmith et al., 1973, 1979; Darian-Smith, 1984). Examples of the response patterns of these afferents are shown in Figs. 7–3 and 7–4.

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Fig. 7–4 Responses of a delta-sized, thinly myelinated cold fiber innervating the glabrous skin of the macaque hand. Base temperature 34°C; steps were delivered below that from none to 10° of cooling. Evoked responses shown for two trials at each stimulus level. Upstrokes on each line are replicas of action potentials. Stimulus pattern shown at top. (From I Darian-Smith et al., 1973.)

A-delta cooling and C-fiber warming afferents are both active at rates of 2–6 impulses/sec in the neutral zone of temperature of the glabrous skin of the hand, 31–36°C. Contact with an object cooler than about 31°C evokes in the cooling afferents brief discharges graded in frequency by the degree of cooling, and suppression of the ongoing discharge in the C-fiber warming afferents. Reciprocal events occur in the two sets on hand contact with an object warmer than the glabrous skin. These investigators also specified the correlation between psychophysical measures of warming and cooling in human subjects, and response properties of these sets of afferents.

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Fig. 7–5 Results of a study relating the population signal in warm fibers innervating the glabrous skin of the macaque hand to the human discriminable increment (DSI), over the same range of intensities. Each curve shows relation for a population of fibers (n = 1, 2, 5, 10, 25, 50, 100). Increments above and below steps of 4°C discriminated by both human observers and fiber populations. In the reconstruction of the responses of the warming fibers equal weighting was given to the contributions of each fiber; the fiber responses were assumed to be independent. Shaded areas show discrimination of a trained human observer with warming pulses similar to those used in the fiber studies. The shaded zone is bounded by the human discrimnination level, and stimulus duration. Only when the function for a fiber overlaps the shaded zone does that population provide enough information to account for the human capacity. (From Johnson et al., 1979.)

The warming afferents are marked by an extreme degree of spatial summation, even for the whole body, as Hardy obseerved long ago. Johnson et al. (1979) showed in a population reconstruction the number of fibers required for spatial summation to threshold (Fig. 7–5). The A-delta cooling afferents are activated paradoxically by heating stimuli when the body temperature is elevated (Long, 1977). This may contribute to the sensation of coldness sometimes

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Fig. 7–6 Stimulus–response functions for a slowly adapting mechanoreceptive afferent (Merkel) innervating the glabrous skin of finger pad of a macaque monkey. Stimulus durations, 0.5 sec; stimuli of different amplitudes delivered in random order. Four functions at the different skin temperatures indicated are virtually identical. Body temperature constant at 38°C. S-R function for this particular fiber slightly above the population average of 1.0. (From Mountcastle, unpublished experiments.)

experienced with sudden heating of the skin, or in diseased states with elevations of body temperature. Activity in the warming or cooling afferents accompanies that in mechanoreceptive afferents during manipulations, and influences our perception of objects, as evidenced by the classical observation of Weber that objects of equal weight are judged heavier when cool than when warm. The stimulus–response function of the slowly adapting mechanoreceptive afferents innervating the glabrous skin of the hand is invariant over the innocuous range of cool and warm skin temperatures (Fig. 7–6), although these same mechanoreceptive afferents may under some

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circumstances respond with brief onset discharges to change in skin temperature. The inference is that phenomena such as the Weber illusion are produced by the central integration of the simultaneous input in the small-fibered temperature-sensitive afferents. I have found no psychophysical studies that go beyond this to measure the effect of temperature of objects on the human capacity to identify, discriminate between, and rate mechanical stimuli. Moreover, it is common experience that the temperature of objects influences the affective and cognitive components of our perceptions of them. Although some uncertainties remain about the afferents serving the extreme of noxious cold, it is likely that the human perceptual range of the temperature of the skin of the hand is served by several sets of temperature afferents with discrete, but overlapping, ranges of sensitivity (Table 7–2). R LaMotte and Campbell (1978) compared the magnitude estimations of humans receiving warming and heating stimuli (over the range from gentle warming to noxious heat delivered to the glabrous skin of their hands) with the C-fiber warming and the cold-mechanical-heat (CMH) nociceptive afferents innervating the glabrous skin of monkey’s hands. The transition zone between the perception of gentle warming and first heat pain, at about 45°C, is just the zone in which the warm fiber function turns down, and the CMH nociceptor curve turns up (Fig. 7–7). A similar overlap occurs between the functions for the innocuous warming and cooling Table 7–2

Sets of Afferents Sensitive to Temperature Threshold (°C)

Range (°C)

C-fibers, 0.5–2.0 m/sec, rare

26–27

Down to tissue destruction

Cooling

A-delta, 13–15 m/sec, density 50–70 fibers/cm2

34

34–26

Warming

C-fibers, 0.5–2.0 m/sec, density 50–70 fibers/cm2

36

36–42

Noxious heat

(1) C-fibers, 0.2–2.0 m/sec

42

42–52

(2) A-delta-I

42

42–52

A-delta-II, rare

52

Up to tissue destruction

Group

Axon

Noxious cold

Extreme heat

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afferents in the neutral zone of skin temperature, but it is uncertain whether such a pattern obtains in the transition between cooling and noxious cold, for the sets of afferents serving the latter have not been clearly defined.

Sensitization, Hyperalgesia, and Allodynia It has been known for a century that antidromic impulses in thinfibered afferents produce vasodilatation in the tissues they innervate (Bayliss, 1901). Foerster (1936b) discovered that antidromic impulses in small sensory afferents in waking humans produce pain, vasodilatation, and edema in the skin. Local injury to the skin produces an intense vasodilatation and edema at the site of injury, surrounded by a larger zone of less intense vasodilatation, the triple response of Lewis (1937, 1942). Within this zone, noxious stimuli elicit pain at lowered thresholds, and suprathreshold stimuli provoke more intense pain experiences than they do when delivered to normal skin. Triple responses can still be produced after acute section of innervating nerves, but after axons degenerate local injury to the skin produces local edema and vasodilatation but no surrounding flare. The flare and change in pain sensitivity produced by injury to innervated skin are attributed to an axon reflex, and to the release of pain producing and vasodilatory substances from the antidromicly activated terminals of nociceptive afferents, notably substance P (SP) and calcitonin gene–related peptide (CGRP) (Baluk, 1997). This phenomenon of primary hyperalgesia is defined by a leftward shift in the stimulus response function that relates the magnitude of pain sensations to the intensities of the stimuli that evoke them.

Fig. 7–7 Scale of subjective estimates of thermal intensity, over the range from gentle warming to intense thermal pain. Pooled data from study of four trained subjects. Stimuli delivered to the glabrous skin of the hand with a CO2 laser, to test spots 7.5 mm in diameter, and rotated randomly between nine separate locations; stimulus interval in that series, 225 sec (closed circles). Open circles show scale values obtained in another series with stimuli delivered to the thenar eminence, at 25-sec intervals. Dotted lines mark the scale values bounding each category. Each stimulus scale value represents the mean of the normal distribution of category responses obtained for a given stimulus temperature and interval. The distribution of responses to 45°C stimuli delivered at longer stimulus intervals is illustrated, and represents all distributions, which were similar. (From LaMotte and Campbell, 1978.)

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Primary hyperalgesia is equated with the phenomenon of sensitization discovered by Perl and his colleagues in their studies of nociceptive afferents. Repeated heat stimuli at 49°C or higher, delivered to the peripheral receptive fields of both C-fiber and A-delta nociceptive afferents, are followed by the appearance of spontaneous activity in previously silent nociceptors, by a lowered threshold to noxious stimuli, and by increasingly robust responses to suprathreshold stimuli. Sensitization may last for hours in many fibers, but for others repeated noxious stimulation makes them unresponsive. Sensitization of both classes of nociceptive afferents has been described for the innervation of the hairy skin of rodents, carnivores, and primates, including humans. Normally insensitive CMiHi afferents may contribute to primary hyperalgesia after sensitization by mechanical or heat stimuli. An expansion of the receptive fields of the nociceptive afferents innervating the damaged skin may also contribute to sensitization by allowing increased spatial summation. The A-delta, but not the C-fiber, nociceptive afferents innervating the glabrous skin of monkey and human hands are sensitized by heating; the A-delta fibers alone provide the afferent input responsible for sensitization and primary hyperalgesia on the glabrous skin. Differential block of A-fibers with C-fibers still conducting eliminates primary hyperalgesia on the glabrous skin, but not that on the hairy skin, where it depends on C-fibers. Similar hyperalgesias are produced by other forms of injury, including mechanical, heat, ultraviolet light, electrical stimulation, and local irritating substances such as mustard oil or capsaicin. For reviews, see, Treede et al. (1992), Lynn and Perl (1996) and Perl (1996a,b). The local region of primary hyperalgesia is quickly surrounded by a much larger area of normal skin in which noxious mechanical, but not heat stimuli, evoke increased intensities of pain sensations at lower thresholds, a phenomenon called secondary hyperalgesia. This change begins within seconds after injury, reaches its peak within a few minutes, and may last for hours. Under circumstances of sensitization and hyperalgesia, a gentle tactile stimulus elicits pain, a phenomenon called allodynia. A dynamic form of allodynia is evoked by light brushing of the skin, which evokes afferent impulses in large-fibered mechanoreceptive fibers. A second form called punctate allodynia is evoked by unmoving local skin stimulation, and depends on afferent input in C-fibers. Both forms of allodynia are produced by central sensitization of the dorsal horn neurons, not by peripheral changes.

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Primary hyperalgesia is induced and sustained by increased afferent inflow from the site of skin injury, for it is reduced by local cooling and eliminated by peripheral anesthesia or denervation. This form of hyperalgesia depends directly on pain-producing molecules released from damaged nerve terminals and tissue cells. Secondary hyperalgesia and allodynia, by contrast, depend critically on central changes and much less on peripheral ones, just as Hardy et al. (1950) concluded from their early psychophysical studies of pain produced by local skin injury. The sensitization of neurons in the spinal nociceptive circuits during secondary hyperalgesia has been observed directly in the monkey spinal cord (Simone et al. 1991). The increased excitability of neurons of the dorsal horn is produced by the increased release of glutamate from the primary nociceptive afferent terminals, and linkage to N-methyl-D-aspartate (NMDA) receptors. Secondary hyperalgesia is sustained by activity in superimposed loops linking local spinal circuits with nuclei of the central core of the brain stem, for it is eliminated by local lesion or anesthesia of those nuclei, or by transection of the pathways linking them reciprocally with the spinal dorsal horn circuits (Urban and Gebhart, 1999). These changes in excitability occur within seconds, and depend on dynamic changes in preexisting synaptic circuits. Sustained central sensitizations may account for some central pain syndromes in humans that persist after removal of the precipitating afferent input. For review, see Raja et al. (1984). Allodynia may also depend on dynamic changes in excitability of connections between the collaterals of A-beta mechanoreceptive afferents and the nociceptive networks of the spinal gray that exist before skin injury, so that activity in low-threshold mechanical afferents gains access to spinal synaptic nociceptive circuits, and elicits pain. There is some evidence that a phenotypic change may occur in lowthreshold A-beta mechanoreceptive afferents innervating regions of inflamed tissue, for they acquire the capacity to express SP, as well as some other characteristics of nociceptive afferents, and in this way may contribute to the heightened excitability in the nociceptive circuits of the dorsal horn and to the appearance of allodynia (Cervero, 1996; Neumann et al., 1996). It is possible that a low-intensity grade of primary hyperalgesia is common in the glabrous skin under many circumstances of use of the hands in ordinary life, in which the glabrous skin of the hand is subjected to many hours of traumatic mechanical stimulation.

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Under these circumstances, sensitization may lower the thresholds of the mechanical nociceptors so that they are activated simultaneously with the large-fibered mechanoreceptive afferents. I know of no direct tests of this speculation.

Chemical Activation of Nociceptive Afferents Innervating Injured or Inflamed Skin The changes in inflamed tissue are vasodilatation, infiltration by immunocompetent cells, and the release of a number of activating molecules from damaged nerve terminals and from adjacent tissue cells, including bradykinin, histamine, prostaglandin E2, serotonin, nerve growth factor, adenosine, and so forth. Receptor channels not previously active appear quickly in nerve terminal membranes; these provide binding sites for the released activating molecules. Modulator molecules released from damaged cells increase the excitability of peripheral nerve terminals by inducing the phosphorylation of membrane channel proteins via G-protein links to tyrosine phosphate A and C, which produces an increased conductance in the Na+ channels, and contributes to increased terminal excitability. After i anterograde axonal transport to the dorsal root ganglion cells, they induce changes in gene expression, particularly an increase in production of Na+ channels, which then appear in increased densities in the terminals of nociceptive afferents. These changes also contribute to central sensitization in the spinal cord dorsal horn nociceptive circuits. The results are a lowering of thresholds, the appearance of spontaneous activity in nociceptive afferents thought to be responsible for the spontaneous pain that arises in inflamed tissues, and increases in the frequency and duration of the trains of impulses evoked in nociceptive afferents by previously innocuous stimuli and in the excitability of the spinal cord circuits to which they project. Nerve growth factor is a key modulator driving the transcriptional changes that sustain both peripheral and central sensitization after injury or inflammation of the skin. About 70 percent of dorsal root ganglion neurons, including virtually all of the small, dark neurons with thin-fibered afferent axons, are sustained in development by NGF; one class of these, the class I C-fiber nociceptive afferents of Table 7–1, depends on NGF throughout life. Injection of NGF locally or systemically produces hyperalgesia within minutes, and

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neutralization of NGF prevents the hypersensitivity that normally develops in inflamed skin. The spontaneous activity, lowered thresholds, and increased responses to stimuli commonly present in afferents innervating inflamed skin do not appear after NGF blockade (Koltzenburg et al., 1999; Shu and Mendell, 1999). For more general reviews, see Wood and Docherty (1997), Basbaum (1999), McKleskey and Gold, (1999, 2001), Millan (1999), and Woolf and Costigan (1999).

The Neurosecretory Function of C-Fiber Nociceptive Afferents The vasodilating action of antidromic impulses in a subset of dorsal root C-fiber nociceptive afferents and the triple response of Lewis are both produced by the release from the fiber terminals of vasodilating and plasma-leaking peptides; among them, substance P, calcitonin gene related peptide, and neurokinin I (Hokfelt et al., 1992; Lawson, 1996a,b). It has been proposed that some C-fibers function in an efferent, neurosecretory mode, and release peptides from their vesicular stores into the extracellular space, where they exert excitatory and regulatory influences on several cell types, including skin, mast, and immune cells. Messlinger’s (1996) reconstructions show that large areas of the terminal membranes of C-fibers are not covered by Schwann cell membrane. One hypothesis is that this release depends on antidromic impulses, yet there is no evidence that the central terminals of these fibers in the dorsal horn or their cells of origin in the dorsal root ganglion are normally activated by the central nervous system. A second hypothesis is that these particular C-fibers are neither sensory nor motor, play no role in nociception, and do not depend on nerve impulses to initiate secretion (Holzer and Maggi, 1998). Under these circumstances, the secretory actions are driven by ligands released by tissue cells and their linkage with terminal membrane receptors. Whether this group of “non-sensing” dorsal root afferents functions in this way is still uncertain. The question remains how such a secretory function might be initiated and controlled (LaMotte, 1992; Maggi, 1995; Kruger, 1996; Lynn, 1996).

“Sleeping” or “Silent” Nociceptive Afferents Schaible and Schmidt (1985, 1988) discovered that sets of A-delta and C-fiber nociceptive afferents innervating the cat’s knee joint

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were not activated by any normal joint movement, but only by intense local pressure, or by the injection of concentrated KCl solution into the joint capsule. These “sleeping” nociceptive afferents became spontaneously active and exquisitely sensitive to stimulation, even to gentle joint movement, when the joint was inflamed in an induced arthritis. They were then activated by molecules known to be present in inflamed and damaged tissues, including bradykinin, the prostaglandins, and serotonin. How these molecules act on the terminals of nociceptive afferents is uncertain, but it is surmised to be via receptors in the terminal membranes and activation of second-messenger systems (Schmidt, 1996). Normally unresponsive nociceptors have been identified in the innervation of the hairy skin of monkeys (Meyer et al., 1991) and humans (Schmidt et al., 1995). They have also been identified in the innervation of several viscera, for example, the bladder (Habler et al., 1990), and are thought to be responsible for the intense and chronic pain that may accompany the inflammation of viscera such as bladder, gut, or gall bladder. For review of visceral innervation, see Cervero (1994). Other instances of afferents silent under normal circumstances are well known; for example, the special classes of C-fibers sensitive only to the extremes of heat and cold are silent over the usual range of skin temperatures.

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Ascending Spinal Cord Systems of Intrinsic Origin

Several components of the somatic afferent system arise from intrinsic neurons of the spinal cord and spinal trigeminal nucleus and project to supraspinal structures; second-order systems are located in each quadrant of the spinal cord. The terms large-fibered/smallfibered indicate the size range of the majority of the dorsal root afferents that project either directly into the first-order system of the dorsal columns, or indirectly by synaptic relay to intrinsic neurons, whose axons compose the second-order ascending systems. There is overlap in sizes and properties between the axons of these two systems, and while the afferent systems of intrinsic origin receive input largely from small-fibered dorsal root afferents, they also receive some larger fibers. Perl and his colleagues discovered that large neurons of the marginal zone of the dorsal horn receive specific and restricted sets of primary afferent fibers of the dorsal roots, without convergence from other sets (Christensen and Perl, 1970; Kumazawa and Perl, 1978). This was followed by the discoveries of Craig and his colleagues that there are three stimulus-selective ascending sets of these neurons of lamina I that project through contralateral spinothalamic (ST) system of the spinal cord and serve the senses of pain and temperature—the traditional function of the ST system; for summarizing reviews, see Craig and Dostrovsky (2001); Craig et al. (2001), and Craig (2003). These three sets of ST axons arise from three morphologically identifiable and afferent input-selective sets of neurons in lamina I of the dorsal horn, and from lamina I of the spinal

8

trigeminal nucleus. Their ascending axons project as labeled lines to the thalamus of monkeys and human (Blomqvist et al., 2000). Axons of neurons of lamina I account for about 50 percent of spinothalamic axons, in monkeys. Some uncertainty exists concerning the ascending course of the axons of the lamina I axons through the spinal cord and their terminations in the dorsal thalamus (Willis et al., 2002; Graziano and Jones, 2004). I discuss this problem in Chapter 9. Other major components of the ST system arise from neurons in laminae IV–VII of the dorsal horn, the majority from lamina V. Many of these neurons receive convergent inputs from several sets of dorsal root afferents, including those activated by thermal, noxious, and non-noxious mechanical stimuli, and are classed as polymodal neurons, a name meant to indicate that they respond to both gentle mechanical and to noxious stimulation of peripheral tissue, produced by the convergence upon them of dorsal root afferents with different, specific properties, or by dorsal root afferents that are themselves polymodals. The axons of these neurons pass through the anterolateral columns to terminate in several thalamic nuclei, including those in the matrix region of the posterior thalamus, in nuclei of the medial and intralaminar groups, as well as in the thalamic target of the spinal lemniscal systems, the ventral posterior lateral nucleus (VPL); see Table 8–1. Similar convergent sets of neurons of lamina V of the spinal trigeminothalamic (STT) nucleus project to the matrix regions of the posterior thalamus, and to the thalamic target of the trigeminal lemniscal system, the ventral posterior medial nucleus (VPM). Other ascending systems of intrinsic origin project through the dorsal columns to the dorsal column nuclear complex (DCNC); for example, the postsynaptic dorsal column pathway described in Chapter 6. An inference frequently drawn is that the convergent interactions of activity in the direct lemniscal and indirect ascending systems of intrinsic origin account for the affective overtones that accompany the full range of somesthetic experiences. Anatomical convergences between these systems pose the question of how the precise capacity for processing mechanoreceptive inputs is retained in the discriminative lemniscal systems in spite of converging smallfibered systems that, if active at adequate levels, would compromise the specificity for place and mode so clear in that system at the level of cortical operations, and in sensory experience. One suggestion is that dynamic processes within transition nuclei, contributed by

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Table 8–1 Thalamic Targets of the Spinothalamic and Spinotrigeminothalamic Systems Spinal source

Thalamic target

Forebrain projection

Lamina I Lamina I Lamina I

VPI VMpo Ventral, caudal mediodorsal nucleus Pf (weak) VPL,VPM to the matrix cells VL CL

SII areas, not better defined Dorsal posterior insula Area 24, anterior cingulate

Laminae I and V Laminae III–V Laminae V–VII Laminae V–VII

Basal ganglia, motor cortex Superficial laminae postcentral cortex Precentral motor cortex Basal ganglia, motor cortex

Information from many sources. CL—central lateral nucleus; Pf—parafascicular nucleus; VL—ventrolateral nucleus; VPI—ventral posterior inferior nucleus; VPL—ventral posterior lateral nucleus; VPM—ventral posterior medial nucleus.

descending systems, under normal conditions suppress the effects of activity in small-fibered convergent inputs. A second proposition is that although the direct and intrinsic ascending systems converge upon thalamic transition nuclei considered as nuclear structures, they project selectively upon different groups of cells within those nuclei (Rustioni et al., 1979; Rausell and Jones, 1991a,b; Rausell et al., 1992; Jones, 1998a,b; Apkarian et al., 2000). I shall refer to the two classes of spinothalamic and spinotrigeminothalamic afferents as the input-selective set, originating from lamina I in the dorsal horn and in the principal trigeminal nucleus, and the convergent set from deeper layers of the dorsal horn and spinal trigeminal nucleus.

Dorsal Root Segregation and Lissauer’s Tract At the point of entry of a dorsal root into the spinal cord, large myelinated fibers form a medial division that merges into the adjacent dorsal column, emitting collaterals into the spinal gray below. Small, thinly myelinated and unmyelinated fibers form a lateral division that projects as Lissauer’s tract through the marginal plexus to reach the dorsal horn, without a synapse en route. Lissauer’s tract is a shortrange distribution channel located between the dorsal pial surface and the gray matter of the cord; it is present through the length of

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the spinal cord. The discovery of Lissauer (1886) that the tract contains small-calibered axons from the dorsal roots, which we now know include nociceptive afferents, was confirmed by Ranson in cats (Ranson, 1914) and by Snyder (1977) and C. LaMotte (1977) in monkeys. Thinly myelinated and unmyelinated nociceptive dorsal root fibers travel for short distances in Lissauer’s tract before leaving it to project to dorsal horn targets. They account for 80 percent of the tract fibers in the monkey (Coggeshall et al., 1981); the remainder are intersegmentally projecting axons of the neurons of laminae I and II, which may extend for up to five segments before leaving the tract. In humans and other mammals many dorsal root C-fiber afferents pass directly into the dorsal column, not into Lissauer’s tract, and project upward for variable distances before terminating in the spinal gray (Chung and Coggeshall, 1988). Whether they constitute a nociceptive afferent pathway to more central structures is uncertain. The sequestration of nociceptive afferents in Lissauer’s tract suggested that transection of this short-range distribution channel might be effective in the treatment of patients with chronic pain (Mullan et al., 1963). Electrolytic lesions of the tract in the cervical cords of cats and monkeys produce analgesia of their forelimbs. Similar results were obtained in humans by Hyndman (1942) and Rand (1960). Lissauer tractolysis has since been used for treatment of chronic pain of central origin, for example, the severe pain that follows traumatic dorsal root avulsions (Sindau et al., 1974; Nashold and Ostdahl, 1979; Jeanmonod and Sindau, 1991). Lasting analgesias are produced in two thirds of these patients (Sindau, 1995). The few postmortem descriptions available indicate that the effective lesions also destroyed the upper layers of the dorsal horn.

The Dorsal Horn as an Integrating Center The cytoarchitectural and laminar organization (Rexed, 1964) of the spinal gray are shown in Fig. 8–1. They traverse 8 of the 10 Rexed layers in the human spinal cord (Schoenen, 1982; Schoenen and Faull, 1990). The projections of different classes of dorsal root afferent fibers to the Rexed layers are shown in Fig. 8–2. The laminae vary in volume at different levels of the spinal cord, but all extend continuously throughout its length (Fig. 8–3). The dorsal horn is a center in which afferent input is complexed with activity in the propriospinal and descending systems projecting

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Fig. 8–1 Cytoarchitecture and lamination of the spinal gray matter. The classical cell groupings are shown and labeled to the left. The systematic subdivisions of the spinal gray into 10 laminae are shown to the right. The lamination pattern was originally described by Rexed for the cat, and has since been applied to the spinal gray of primates. (From Netter, 1991.)

to it. Spinal laminae emit local and intersegegmental projections into spinal reflex circuits, and into several postsynaptic ascending systems. Some of these are affective–cognitive systems driven by small-fibered afferent inputs that flood in an untessalated way the matrix components of the transition nuclei of the large-fibered, discriminative, sensory systems. Other ascending systems originating in the spinal gray serve discriminative functions; for example, the spinomedullothalamic system described in Chapter 6, as well as the

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Fig. 8–2 Representation of the projections of different classes of dorsal root afferent fibers to the Rexed layers of the cervical spinal cord in humans. (From Hendry and Hsiao, 2003.)

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Fig. 8–3 The variations in the sizes of the cytoarchitectural laminae, shown in surface projections, from the level of the cervical to the sacral spinal cord in a 45-year-old human. D—dorsal nucleus of Clarke; IML—intermedio-lateral cell column. (From Schoenen and Faull, 1990.)

stimulus-selective components of the spinothalamic system serving the discriminative aspects of pain and temperature. Craig and his colleagues discovered that the three sets of morphologically identifiable sets of neurons in lamina I receive specific sets of primary dorsal root afferents of the cooling, nociceptive specific, and polymodal classes, without convergence, in both cats and monkeys. The axons of each of these sets of input-selective neurons of lamina I project into the contralateral ST system, clustered in the most dorsal wedge of the anterolateral quadrant, just below the dentate ligament (Apkarian and Hodge, 1989a,b). They terminate both directly and by axonal collaterals in several structures of the spinal

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cord and brain stem that regulate the efferent autonomic system, in others that project downward into the cord and regulate dorsal horn transmission, and in still others that project upward to the thalamus and influence forebrain excitability. They finally project to a region of the posterior dorsal thalamus in monkeys and in humans, called VMpo, which has some properties of a specific thalamic relay nucleus for pain and temperature (Blomquist et al., 2000; Craig et al., 2001; Craig, 2003). Many spinothalamic neurons in deeper layers of the dorsal horn (IV–VI), and of the spinal trigeminal nucleus, receive convergent input from several classes of primary dorsal root afferents, including those activated by noxious thermal and mechanical stimuli. The axons of these convergent neurons project into the ST and STT systems, and terminate in several dorsal thalamic nuclei, including the lemniscal relay nuclei VPL/VPM, and nuclei of the medial, intralaminar, and posterior groups. It is conjectured that the input-selective and the convergent components of the ST and STT systems contribute differently to the overall perceptual experiences of pain and temperature, and to the affective overtones that accompany innocuous somesthetic perceptions. For reviews in this field, Cervero and Iggo (1980), see Iggo et al. (1985a,b), Schoenen and Faull (1990), Willis and Coggleshall (1991, chapters 4, 5, and 6), Craig et al. (1999, 2001), Willis et al. (2001), and Craig (2003).

Sustaining and Guidance Mechanisms in the Development of Afferent Projections to the Dorsal Horn The role of neurotrophic factors in sustaining dorsal root ganglion neurons and their peripheral and central axons is described in Chapter 4. During embryonic life different sets of dorsal root afferent fibers are guided through the developing neuropil of the spinal gray to reach their laminar targets. The guides are sets of protein molecules intrinsic to the spinal cord, for the central branches of dorsal root fibers reach their targets in the spinal gray just as, or in some cases before, the peripheral branches of those same axons reach their destinations in peripheral tissues (Minics and Koerber, 1995). Moreover, in explant experiments dorsal root afferents project to their spinal destinations after the removal of all peripheral tissue (Redmond et al., 1997). Some guiding protein molecules diffuse freely while others are membrane linked, and may be either attractive (permissive) or repellant in interaction with their receptors in

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growth cones. This distinction is not absolute, for in any particular case the growth cone response may depend on the levels of secondmessenger systems that, when activated, lead to cytoskeletal changes and growth or retraction of growth cones (Goodman, 1996; Mueller, 1999). A remarkable precision results, for each dorsal root afferent class projects directly to its targets without collateral terminations in inappropriate laminae (Konstantinidou et al., 1995). These pathways to dorsal horn targets appear to be preset, and if activity plays a role in the axonal targeting of postsynaptic cells, as it does elsewhere in the nervous system, it must influence the maturation of the synaptic microstructure, not large-scale target selection. Several families of molecular guide proteins have been identified as fixed or diffusing, or both. They are the semiphorins, netrins, and ephrins, all found in many locations in many nervous systems, where they function in axonal guidance, and contribute to the formation of topographic maps and neuronal commissures. Semiphorin proteins serve as repellant guides by linking with their receptors, the neuropilins, in axonal growth cones in many locations, including the spinal gray (Messersmith et al., 1995; Puschel et al., 1996) and in comparable regions in the trigeminal system (Ulupinar et al., 1991). How these and other repellant molecules together with attractive or permissive ones form precise pathways for axonal projections remains a difficult problem at the level of molecular and cellular anatomy.

Differential Projection of Sets of Dorsal Root Afferents to the Dorsal Horn Table 8–2 lists the laminar terminations of the major sets of dorsal root afferent fibers and/or their collaterals into the dorsal horn. A dense projection of a set of afferents to one lamina is usually bordered by much less dense projections of the same set to adjacent laminae. There is a rough gradient of modality, from the projections of stimulus selective nociceptive and thermoreceptive afferents into laminae I and II to the successive projections of large-fibered afferents to deeper layers. The projection of nociceptive and thermoreceptive afferents to the two outer layers of the dorsal horn accord with the traditional view that the substantia gelatinosa of Rolando is a transition zone and integrative center in the afferent pathways for pain and temperature (Cervero and Iggo, 1980). The large marginal cells of Waldeyer

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Table 8–2

Properties of Dorsal Root Afferents

Cell type

Axon size

Peripheral target

Central target

Neurotrophin/receptor

Intermediate light

Myelinated A–beta

Low-threshold cutaneous mechanoreceptors

III/IV/V

NT3/BDNF-Trk?

p75

Large-light

A-alpha A-beta

Muscle spindles

V and below

NT3/Trk-C

P75

Large-light

A-alpha

Muscle tendon organ

V and below

NT3/Trk-C

P75

Medium-dark

A-delta

D-hair cutaneous

III

NGF/Trk-A

P75

Medium-dark

A-delta

Mech nociceptors skin, muscle, and viscera

I

NGF/Trk-A

P75

Small-dark

C-fiber

Polymodal nociceptors, skin and muscle

II

NGF/Trk-A

P75

Small-dark

C-fiber

Low-threshold mechanical

II

NGF/Trk-A

P75

Small-dark

C-fiber

Nociceptors, chemical and mechanical, viscera

V

NGF/Trk-A

P75

were conjectured to be a source of an ascending pain pathway because they degenerate after anterolateral cordotomies that produce contralateral analgesia in humans (Kuru, 1949; Smith, 1976). Christensen and Perl (1970) provided direct evidence for this in electrophysiological experiments in cats by combining extracellular recording in the dorsal horn with definition by natural stimulation of the functional properties of lamina I neurons, and by measuring the conduction velocity of the dorsal root afferents that activated the lamina I marginal cells. Perl and his colleagues found that the A-delta, high-threshold, mechanical nociceptors project to lamina I, and also to laminae V and X, and that the nociceptive, some thermoreceptive, and low-threshold mechanoreceptive unmyelinated C-fibers from the hairy skin project mainly to lamina II, with some divergence to lower lamina I (Kumazawa and Perl, 1978; Light and Perl, 1979a,b; Light et al., 1979). The three classes of Waldeyer cells of lamina I project directly to the thalamus in both cat (Craig, 1996; Zhang et al., 1996; Han et al., 1998) and monkey (Zhang and Craig, 1997). Each class receives a preferential input from a functionally defined class of dorsal root afferents, without convergence (Table 8–3). Pyramidal cells

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Table 8–3

Properties of Stimulus-Selective Spinothalamic Neurons of Lamina I of the Cat Spinal Cord

Name*

Cell morphology

Number studied

Afferent input

Axon output CV

Thalamic target

Functional properties

Nociceptive specific

Fusiform

100

A-delta

2.5 m/sec

VMpo

Respond to noxious heat and mechanical stimuli; linear response functions

Innocuous cooling (rarely warming)

Pyramidal

135

A delta + C-fibers Cold specific

5–6 m/sec

VMpo**

Mean population function nearly linear over range 35–15°C

Polymodal

Multipolar

128

Polymodal C-fibers

4–6 m/sec

VMpo

Respond to noxious cold, or noxious mechanical stimuli; linear response functions

(From Craig et al., 2001.) *Several other types have been identified; e.g., lamina I cells activated by iontophoresis of histamine, and proposed to serve as a labeled line for itching (Andrew and Craig, 2001). The projection of the lamina I classes to the human analogue of VMpo has been observed in many microelectrode explorations of the thalamus in waking humans. **Pyramidal cell axons terminate in a slightly different area of VMpo, separately from the target zones of the fusiform and multipolar cell axons.

respond preferentially to mild cooling of the skin; a few to mild warming (Dostrovsky and Craig, 1996; Craig et al., 1999). Fusiform cells are selective for specific nociceptive afferents; they respond to both destructive mechanical stimuli and to excessive heat. Multipolar cells are selective for polymodal dorsal root afferents; they respond to extremes of heat and cold, and to destructive mechanical stimuli. The proportion of cells in each class varies between cats and monkeys, as well as between different levels of the spinal cord, but each is robustly represented at every level. Most fusiform and multipolar cells of lamina I express the protein neurokinin-1, the receptor for substance P, a diagnostic label for nociceptive neurons (Yu et al., 1999). Lamina II contains small, closely packed neurons of several classes. Ramon y Cajal (1909; translated, 1952, pp. 411–412) described “marginal” neurons located close to the border between what we now designate as laminae I and II, and a large number of somewhat smaller

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Fig. 8–4 Three-dimensional reconstructions of the spinal terminations of the collaterals of primary afferent fibers, determined by intra-axonal injection of tracer horse radish perioxidase, in the cat. From above downward, for a rapidly adapting afferent, for a Pacinian afferent, and for a slowly adapting afferent, type 1. (From AG Brown, 1981.)

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cells as “central,” although they are distributed throughout lamina II. Schoenen defined four neuronal classes in the dorsal horn of the human spinal cord (Schoenen, 1982; Schoenen and Faull, 1990). Two of these four make up the majority of lamina II cells. Stalked cells are concentrated along the outer rim of lamina II, and make up lamina II-o. Their dendrites are distributed in a ventrally directed fan and may sample lower layers; axons of some stalked cells project upward into lamina I, those of others downward into laminae III, IV, and V, but none are known to exit the spinal gray. The smaller islet cells are found throughout lamina II, but are heavily concentrated along its inner rim, thus composing lamina II-i. Islet cell dendrites and axons are distributed in the immediately surrounding space, in the manner of Golgi-II cells elsewhere in the nervous system. Dorsal root nociceptive and multireceptive C-fiber afferents project to the stalked cells. Low-threshold, C-fiber, mechanoreceptive afferents from hairy skin and deep tissues, but not from viscera, project to the islet cells (Kumazawa and Perl, 1978; Sugiura et al., 1986). These inputs determine the functional properties of lamina II cells (Light et al., 1979; Bennett et al., 1980; Iggo et al., 1985a,b). It is conjectured that the stalked and islet cells of lamina II are excitatory and inhibitory interneurons, respectively. Afferent C-fibers projecting into the dorsal horn differ in their neurotrophic support. One nociceptive set is nerve growth factor (NGF) dependent, contains substance P, and projects to laminae I and outer II. A second set is changed from NGF to glial cell line-derived neurotrophic factor (GDNF) support early in embryogenesis, contains no neuropeptides, and projects to inner lamina II (Molliver et al., 1995, 1997). These latter may be the low-threshold mechanoreceptive afferents that innervate hairy but not glabrous skin. Low-threshold myelinated mechanoreceptive afferents project through the medial division of the dorsal root into the adjacent dorsal column, emitting collaterals at and just above the segment of entry (Chapter 6). Collaterals of the A-beta afferents from the skin course down though the dorsal horn without emitting synaptic terminals in laminae I or II to reach their targets in III, IV, V, and VI, which in the cat contain cells of origin of the postsynaptic dorsal column and spinocervical systems. In primates, a larger proportion of these are spinothalamic neurons. Each afferent projects onto a sagittal sheet of neurons distributed over two or more segments of the spinal cord (Fig. 8–4). Axons of the hair follicle class enter lamina

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IV and curve upward just to the laminae I–II border to end in the bushy, flame-shaped terminals described by Ramon y Cajal (1909); see also Scheibel and Scheibel (1969). These local, segmental projections of the collaterals of the large myelinated afferents pack laminae III, IV, and V with myelinated axons. Some neurons of lamina III are thought to be cells of origin of the postsynaptic dorsal column axons; their dendritic expansions into lamina II may account for the nociceptive–mechanoreceptive convergence in lamina III. The spinal reflex pathways from muscle receptors to motoneurons were the experimental objects for exploration and discovery that led to an important part of present-day neurophysiology. They were the centerpiece for Sherrington’s expositions of central nervous action, with the stretch reflex as the chosen object of study; for Eccles’ studies of excitation and inhibition in motoneurons with the method of intracellular recording; and for Granit’s explorations of the action of receptors and the central reflexes they evoke (Creed et al., 1932; Eccles, 1952, 1957; Granit, 1955). Spindle axons project into the medial division of the dorsal root, enter the adjacent dorsal column, and divide into ascending and descending branches that extend for several segments, emitting collaterals as they go. The stem axons project farther cranially to targets that differ at different segmental levels (Chapter 6). Ia afferent collaterals pass down the medial side of the dorsal horn without emitting collaterals to layers I–V, to reach the motoneurons directly. They emit branches to the interneurons of VI and VII, where they engage cells with a wide variety of connections in spinal segments T1–L4, and give collateral innervation to the cells of origin of the spinocerebellar tracts. The Ib afferents from tendon organs make no direct monosynaptic projection to motoneurons, but terminate in the interneuron pools of laminae VI and VII, and on cells of Clarke’s column that compose the spinocerebellar tract of the dorsolateral column (Mann, 1973). The secondary spindle afferents, group II, terminate upon interneurons of laminae IV–V and VI–VII, and also contribute to the spinocerebellar systems. Nociceptive afferents from muscle and other somatic deep structures project into the dorsal horn via the lateral division of the dorsal root, Lissauer’s tract, and the marginal plexus. Their A-delta afferents project to laminae I and V; the C-fiber nociceptive afferents project to lamina II. Lamina X is not truly a lamina, but a cylindrical group of cells that runs the length of the spinal cord. It receives small-fibered projections of visceral afferents (Wall, 1999).

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A number of large-fibered afferent pathways originate in the spinal cord and project to the cerebellum, including the dorsal and ventral spinocerebellar, cuneocerebellar, and rostral spinocerebellar tracts (Bloebel and Courville, 1981). Activity in these afferent pathways contributes to the central control of movement, and is involved in somatic sensibility only indirectly in that skilled movements of the hand are essential for the acquisition of three-dimensional haptic stimuli. Large-fibered mechanoreceptive afferents from joints project into the dorsal column, and those from the post-thoracic segments transit synaptically to the spinomedullothalamic tract. Smaller myelinated and unmyelinated, largely nociceptive, afferents from joints project to laminae I and V–VII, and lower VIII. There is a wide convergence of joint, muscle, and cutaneous afferents upon neurons of these deeper layers, as observed in deeply anesthetized cats (Schaible et al., 1986; Craig et al., 1988).

Representation of the Body Form in the Spinal Gray

Fig. 8–5 Somatotopic organization of the termination of afferents from the forelimb into the dorsal horn in macaque monkeys. (From Florence et al., 1991.)

The hand of the macaque monkey is represented in the spinal gray in a mediolateral gradient with the finger tips most medial and the proximal parts in successively more lateral locations (Brown et al., 1989; Florence et al., 1989). Afferents from digits 1–5 terminate in a rostrocaudal sequence in the lower cervical and upper thoracic segments in separate, elongated column-like groups of cells that generate a somatotopic map of the hand in the horizontal plane of the spinal cord (Fig. 8–5). Successively more caudal body parts are represented in successively more caudal spinal cord segments. Map scaling is determined by peripheral innervation density. PB Brown proposed that the dorsal horn map in the cat is formed in development and maintained thereafter by dynamic processes that match the terminal brushes of the collaterals of dorsal root fibers with the distribution of the dendritic trees of dorsal horn neurons (Brown et al., 1997).

Neuronal Operations in the Dorsal Horn Dorsal horn neurons have a variety of soma morphologies and dendritic aborizations, but until now intracellular recording has not revealed any biophysical properties of these cells unknown in other

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central neurons. The number and complexity of the local segmental, propriospinal, and descending inputs, coupled with an equally complex interneuronal network, make the dorsal horn perhaps the most difficult location in the nervous system for neurophysiological study. The many sets of axonal inputs have different terminal structures and distributions, and they express many synaptic transmitter and modulator molecules. A general principle has emerged that transmission through the dorsal horn may change rapidly over a range from the normal signaling of transient noxious stimuli to complete suppression of that transmission, or, by contrast, to a state of greatly increased circuit excitability and severe pain, a central sensitization (Doubell et al., 1999). This state of heightened excitability is characterized by the expression of a number of transmitters and modulators after acute injury to peripheral nerves or the tissues they innervate, or chronically in pathological pain states. Such a state of heightened excitability can also be produced by descending excitatory input from the forebrain, even when there is no increased nociceptive input. Many of the transmitter and modulator molecules active during central sensitization are not expressed during “normal” signaling of transient noxious stimuli, when the prevalent transmitters are glutamate and substance P. Glutamate is stored in small, translucent vesicles and when released may evoke postsynaptic responses that differ with different postsynaptic receptors. When linked to AMPA (alpha-amino-3 hydroxy-5 methyl-4 isoxazole proprionic acid) receptors on neurons of laminae I, II, or V, glutamate evokes a transient excitatory postsynaptic potential (EPSP); when linked to N-methyl-D-aspartate (NMDA) receptors in any of those laminae, it evokes a prolonged EPSP, and for neurons of lamina V stimulus repetition leads to a facilitation of response. Metabotropic receptors are present on the somatic and dendritic membranes of dorsal horn cells; when activated by glutamate, they evoke mixed and long duration excitatory and inhibitory responses via G-protein-linked second-messenger systems. Glutamate is quickly removed from the synaptic zone by an uptake mechanism. Substance P is stored in large, dense vesicles, and when released evokes prolonged EPSPs. No reuptake mechanism has been discovered for substance P so that, absent enzymatic hydrolysis, it may diffuse to and activate NK-1 receptors on adjacent neurons.

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Suppressive Interaction Between Large- and Small-Fibered Afferents It is a common experience that innocuous mechanical stimulation of the skin near a source of pain may relieve the pain, if only transiently; vibratory stimuli are frequently effective (Bini et al., 1984). This covering function is thought to be due in part to the convergence, through inhibitory interneurons, of the collaterals of low-threshold mechanoreceptive and nociceptive dorsal root afferents upon nociceptive projection neurons of the dorsal horn. Electrical stimulation of the large-fibered afferents in peripheral nerves, or their axonal extensions in the dorsal column, produces dramatic relief for some but not all patients with severe pain of peripheral origin (Simpson, 1999), and this method for the control of intractable pain has now been supplanted by others. The convergent interaction between the largefibered and small-fibered afferents in the spinal gray, and the control of this convergence by descending elements, was included by Melzack and Wall (1965) in the “gate control theory” of pain, which for a time exerted considerable influence in the field of pain research.

Supraspinal Loops Control Nociceptive Transmission Through the Dorsal Horn Each major sensory system of the brain contains descending elements that project from cephalad structures to transition zones of the system and regulate the flow of afferent activity into ascending pathways. This bulbospinal reciprocal circuit links brain stem nuclei and the dorsal gray at all segmental levels, and with the spinal nucleus of the trigeminal. Reynolds (1969) discovered that electrical stimulation in the periacqueductal gray (PAG) of the mesencephalon produces an analgesia sufficiently deep to allow general surgical procedures, with no behavioral signs of pain and with retained awareness of other environmental stimuli. This was confirmed in rats (Mayer et al., 1971), monkeys (Hayes et al., 1979), and humans (Boivie and Myerson, 1982), and further supported by the observation made in anesthetized monkeys that brain stem stimulation inhibits identified nociceptive projection neurons of the dorsal horn (Haber et al., 1980; Gerhart et al., 1981). Electrophysiological and anatomical studies have since revealed

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that neurons of the PAG project indirectly to the spinal cord via links in the rostroventral medulla, including the raphe nuclei and adjacent regions of the reticular formation; and to the dorsolateral pontine tegmentum, including the locus coeruleus and adjacent groups of cells. For reviews, see Fields et al. (1991) and Fields (1999, 2000). These two groups of nuclei project descending axons through the dorsolateral funiculus to terminate in laminae I, II, and V, as well as less densely in deeper laminae of the spinal gray, at all segmental levels, and in the spinal nucleus of the trigeminal. They receive reciprocal projections from nociceptive neurons of the dorsal horn, which by their convergence produce the large and sometimes allbody nociceptive receptive fields of brain stem neurons. The descending systems contain some axons that inhibit and others that facilitate transmission through the dorsal horn; excitability in those circuits is controlled by a balance between the two. Descending inhibition could be imposed by direct synaptic inhibition of dorsal horn neurons; by excitation of inhibitory interneurons that synapse upon dorsal horn neurons; or by presynaptic inhibition of the terminals of primary afferents, and in this way decrease the transmitter released from afferent dorsal root fibers. The mode of operation of the opioid inhibitor interneurons is not clear but it must be pivotal, for the suppressive effect of brain stem stimulation, or the injections of opioids, is blocked by the opiate antagonist naloxone. It is assumed that the descending excitatory inputs operate in a somewhat reciprocal manner.

Descending Systems Have Integrative Functions Blockade of the descending projections from the brain stem to the spinal cord changes the functional properties of dorsal horn neurons. Hillman and Wall (1969) compared the properties of lumber dorsal horn cells in decerebrate cats before and after cold blockade at a higher spinal level. Collins devised a method of recording from neurons of the lumbosacral dorsal horn in waking, gently restrained cats, and compared the properties of dorsal horn cells in this waking state with those observed during brief periods of general anesthesia (Collins, 1985, 1987; Collins and Ren, 1987); see also Sorkin et al. (1988). The general conclusions reached in these experiments are as follows. (1) The spontaneous activity of dorsal horn cells of the con-

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vergent set is much reduced in the waking state as compared to that after descending blockade produced in any way; (2) the receptive fields of dorsal horn cells are generally enlarged after descending blockade; (3) many dorsal horn neurons that are specifically mechanoreceptive or nociceptive in the waking state, or in one with intact descending systems, gain convergent inputs that convert them to multireceptive or polymodals neurons after descending blockade. In Collins’ experiment the percentage of multireceptive neurons rose from 9 percent in the waking state to 34 percent in the anesthetized state, which indicates that the descending system is selective in its action, and can block differentially some and not other inputs to dorsal horn neurons. Similar results have been described for the cells of origin of the dorsal column postsynaptic system (Noble and Riddell, 1989). Electrical simulation of the human brain at sites clustered around the third ventricle and the PAG elicits analgesia without loss of consciousness. Similar effects are produced by stimulation of many structures of the forebrain, including the amygdala, hypothalamus, medial prefrontal and insular cortices, and the ventral posterolateral nucleus of the thalamus. These observations led to the use of chronically implanted stimulating electrodes in the brains of humans, in attempts to control the intense suffering in chronic pain states (Richardson, 1995; Simpson, 1999). Clinical control of pain can be achieved in some but not all of these patients; the decrease in the effectiveness of stimulation with time, and some complication of the method, have led to its decreased use.

The Brain’s Own Opiate System Two independent but closely related discoveries were major events in the recent history of neuroscience. The first is that the brain expresses molecules with opiate-like action, the enkephalins and endorphins, which function as synaptic transmitters in a pain control system within the brain (Hughes, 1975; Kosterlitz and Hughes, 1978). The second is that the opioid transmitters act by binding to opioid receptor molecules in postsynaptic membranes, a discovery made independently by Pert and Snyder (1973), Simon et al. (1973), and Terenius (1973). The receptors are members of the seven-transmembrane class, which contains many other peptide receptors. Binding of opioid ligands to receptors in presynaptic terminals leads via G-protein-linked second-messenger systems to a decrease in Ca2+

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conductance and in the amplitude of action potentials, and thus to a decrease in excitatory transmitter release and to an increase in K+ conductance, which hyperpolarizes the postsynaptic membrane and depresses synaptic transmission. The distributions of the three receptor classes, mu, delta, and kappa, coincide with loci in which stimulation-induced analgesia is readily evoked, and into which microinjections of morphine-like molecules produce a general analgesia (Kuhar et al., 1973; Mansour et al., 1995).

Ascending Systems of Intrinsic Origin Results obtained with tracing methods have led to the generalization that many structures of the subcortical forebrain receive projections over the intrinsic ascending systems of the spinal cord. These systems influence forebrain functions that include specific pain and temperature sensibilities, the affective–cognitive aspects of all somesthesis, and the regulation of autonomic and endocrine functions. A difficult problem in hodology follows from the custom of labeling as a separate tract each projection to a forebrain target by the source and target labels (e.g., spinoreticular, spinotectal, spinomesencephalic, etc.). Even these “tracts” are to varying degrees intermingled with each other and with more clearly defined afferent pathways in several columns of the spinal cord. Nevertheless, this naming custom is so entrenched that no change seems possible.

General Properties of Spinothalamic Systems in Primates It has long been known from studies in humans that the lateral spinothalamic tract is essential for the human senses of pain and temperature and, with less certainty, that a ventral spinothalamic tract serves some never clearly defined form of mechanoreceptive sensibility. The path of discovery leads from the clinical investigations of the nineteenth century by Schiff (1858), Brown-Sequard (1868), and Gowers (1878), to the report by Schuller (1910) that transection of the anterolateral columns in monkeys blunted their reactions to painful stimuli; he coined the word “chordotomie.” Spiller and Martin (1912) described a case in which bilateral transection of the anterolateral funiculi modified the pain produced by a spinal cord tumor located at a lower spinal level. Neurosurgical experience since that time supports the notion that a pain pathway

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exists in the anterolateral funiculus of the human spinal cord (Sweet and Poletti, 1984) (Fig. 8–6). Although there are case reports of a dissociation of pain and temperature sensibilities after cordotomy, no clear correlation has been established between those dissociations and the locations or sizes of the lesions that produced them (Friehs et al., 1995). It remains unexplained why in some patients the pain reappears after months or even years of pain relief produced by cordotomy. This may be due to the projection of nociceptive afferent input into the ipsilateral anterolateral funiculus. Moreover, there is evidence in monkeys that other ascending systems originating in the spinal gray contain neurons sensitive to noxious stimuli, and it may be that in time afferent input in these systems suffices to elicit the experience of pain (Vierck and Luck, 1979). Electrical stimulation in the anterior quadrant of the spinal cord in waking humans elicits sensations of pain and temperature, but few reports of tactile experiences, despite the fact that anterolateral cordotomy produces a mild elevation of tactile sensibility on the contralateral side of the body below the transection. Moreover, some of the static properties of mechanoreceptive sensibility are retained in both humans and monkeys after transection of the dorsal

Fig. 8–6 Diagram of a cross section of the human spinal cord at the level of C3, to illustrate the classical anterolateral cordotomy operation. (From Taren and Kahn, 1966.)

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systems, while more complex and dynamic aspects are lost (see Chapter 6, and Noordenbos and Wall, 1976; Wall and Noordenbos, 1977; Vierck, 1998). Sweet et al. (1950) found in a series of 200 local stimulations in the anterolateral quadrants of humans that pain was evoked at 54 percent of the locations stimulated, heat at 37 percent, coolness at the remaining 9 percent, and touch at none. The sensations were referred to the contralateral side of the body in 82 percent, to the ipsilateral side in 12 percent, and to both sides in 6 percent. The open surgical procedure has been replaced by transcutaneous cordotomy, in which an electrode for stimulation or lesion-making is passed into the cord through the skin (Mullan et al., 1963). This allows mapping of the spinothalamic tract in its course upward through the anterolateral quadrant and into the brain stem, between the medial lemniscus ventrolaterally and the auditory lateral lemniscus dorsally, and into the ventral and posterior nuclear groups of the dorsal thalamus. There is an imprecise topographic representation of the body form in the ST, independently of that in the adjacent medial lemniscus (Tasker et al., 1976). Tracer experiments show that in the lumbosacral region of the monkey spinal cord 90 percent of the labeled ST axons are located contralateral to their thalamic targets. In the cervical enlargement a larger proportion project to the ipsilateral thalamus. Contralateral ST axons cross in the median white commissure. They are predominantly thinly myelinated fibers, 2–7 µm in diameter. Dense concentrations of ST neurons occur in laminae I and V, with less dense distributions in the IV and VI; for reviews, see Hodge and Apkarian (1990) and Willis and Westlund (1997). Apkarian and Hodge (1989a) counted 18,235 labeled ST neurons in one monkey spinal cord; of these cells more than one half were in the cervical enlargement, one quarter in the lumbosacral region. It is likely that the human spinal cord contains several times that number.

Input-Selective Channels of the Spinothalamic System Craig and his colleagues described the functional properties of three classes of input-selective neurons of lamina I of the dorsal horn, and of the spinal trigeminothalamic nucleus, that project to a nucleus in the posterior thalamus of monkeys and humans proposed to be specific for pain and temperature (Table 8–3) (Craig et al., 1994, 1999, 2001; Blomqvist et al., 1996, 2000; Craig, 1996, 2003; Dostrovsky

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Fig. 8–7 Mean response population response functions for the three classes of stimulus selective lamina I neurons, in cats. For each, there is a range of temperature over which the response is quasi-linear. Classes of neurons: COOL—thermoreceptive specific; HPC—polymodal nociceptive; NS— nociceptive specific. (From Craig et al., 2001.)

and Craig, 1996; Han et al., 1998; Craig and Dostrovsky, 2001). Neurons were identified as spinothalamic by antidromic excitation from thalamic loci, and their functional properties studied using quantitatively controlled physiological stimuli for cool, noxious cold and heat, and noxious mechanical stimulation delivered to the skin surface, usually the glabrous skin of the cat’s paw. The stimulus– response functions shown in Fig. 8–7 are linear over a considerable range of stimulus amplitudes and correspond with measurements made in human psychophysical experiments.

Convergent Channels of the Spinothalamic System The functional properties of the convergent components of the primate spinothalamic system have been identified in electrophysiological experiments made in the lumbosacral spinal cord of anesthetized monkeys (Willis and Coggleshall, 1991, pp. 341–398; Willis and Westlund, 1997). Spinothalamic (ST) neurons located in laminae IV, V, VI, VII, and X were identified antidromicly by stimulation of the thalamic terminations of the spinothalamic system. The majority of convergent ST neurons (85 percent) respond over a range of stimulus intensities, from gentle innocuous to damaging mechanical stimuli,

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and to injurious heat or cold as well, produced by the convergence upon the ST neurons of several classes of peripheral nerve fibers. The remaining 15 percent are classed as tactile selective, and are unresponsive to stimulation of nociceptive afferents. This leaves the mystery of why in humans local stimulations of the anterolateral spinothalamic systems do not evoke tactile sensations. Can the same set of multireceptive ST neurons contribute to such different sensations as pain, touch, or temperature change when activated by one or another of the different inputs that converge upon them? This appears unlikely in view of the frequently confirmed results of microneuronographic experiments in waking humans in which stimulation of single identified A-delta or C-fibers in peripheral nerves invariably evokes the appropriate type of pain, fast or slow, and never touch. Increasing frequency of stimulation of each class of the large mechanoreceptive afferents elicits increasing intensity of the relevant mechanoreceptive experience, with never a transition to pain. These observations were made in normal humans without peripheral inflammation or central pain states. In monkeys and humans, the ST neurons of lamina V project to the ventral posterior lateral nucleus of the thalamus (VPL) and to the intralaminar complex; those from IV and V project also to VPL and centralis lateralis; those from laminae VII and X project to nucleus centralis. Tactile stimulation of unsensitized skin does not evoke the sense of pain. Yet both the first-order polymodals nociceptive afferents and the convergent spinothalamic neurons of the spinal gray (lamina V neurons) upon which they project over polysynaptic pathways may under some conditions be activated by gentle tactile stimuli. The peripheral terminals of polymodals afferents have several transducer channels in their terminal membranes, among them low-intensity heat (VL-1), high-intensity heat (VRL-1), proton sensing, and ATP-gated channels, but no mechanosensitive channels. Impulses in the multireceptive, convergent spinothalamic tract neurons generated by any form of stimulation activate the medial thalamic–limbic circuits of the forebrain, and it is conjectured that some major components of the convergent channels evoke the affective overtones for several forms of somatic sensibility, particularly pain and temperature, but also for the several varieties of tactile experience (Price, 2000).

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Price et al. (1978) discovered that one class of polymodals ST neurons of lamina V of the monkey cord responds to the usual range of noxious stimuli, but also to gentle tactile stimuli, particularly to those moving lightly across the glabrous skin, in this case that of the monkey’s foot. Such stimuli evoke in humans an exquisite tactile sensation with some overtones of tingling, followed by an after-image of tingling with some painful component that lasts for seconds. These stimuli evoke a prolonged after discharge in this particular set of lamina V neurons. Morisset and Nagy (1999) observed a comparable phenomenon in slice preparations of the spinal cord, that a brief input stimulus to some neurons of lamina V evoked a sustained, highfrequency, discharge lasting for seconds, driven by an equally longlasting depolarization initiated by an L-type calcium current, and sustained by a calcium-activated, nonspecific, cation current.

Does a Separate Ventral Spinothalamic Tract for Tactile Sensibility Exist in Primates? A ventral spinothalamic tract serving tactile sensibility has long been thought to be present in the ventral funiculus in humans, distinct from the lateral spinothalamic tract serving pain and temperature, and to account for whatever mechanoreceptive sensibility remains in some humans and monkeys after section of the dorsal and dorsolateral columns. Yet no evidence for such a segregated pathway comes from the many electrical stimulations of afferent pathways in the spinal cord in waking humans. Low-threshold, mechanoreceptive spinothalamic neurons without convergent nociceptive input have been identified only rarely in the anterolateral quadrant of the monkey. Axons of these putatively tactile-specific neurons are distributed with the much larger number of multireceptive STT axons in a common topographic pattern in the anterolateral quadrant. It is unknown whether the low-frequency discharge evoked in the polymodals afferents by mechanical stimuli evokes tactile experiences, but this seems unlikely in view of the evidence from microstimulation of peripheral axons in humans. Perhaps the low-frequency discharge in polymodals nociceptive afferents produced by weak mechanical stimuli evokes a prodromal sense of pain, or no perceptual experience at all. This latter is suggested by observations made in microstimulation experiments in humans, that single impulses in identified nociceptive afferents seldom evoke sensations of pain,

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or any sensation at all, and that stimulation in the range of 2–3 impulses/sec is required to elicit a perception, which is always of pain.

Convergence of Somatic and Visceral Afferents in the Dorsal Horn: Referred Pain Visceral afferents run toward the spinal cord in the pelvic, splanchnic, and cardiac nerves. About 10 percent of those in the splanchnic nerve are A-beta fibers; in the cat these are Pacinian afferents, which project through the medial division of the dorsal root into the adjacent dorsal columns. Of the remaining 90 percent, one tenth are thinly myelinated nociceptive afferents; the rest are C-fiber nociceptive afferents. Many of these respond to chemical stimuli and to such noxious mechanical stimuli as excessive distension of a hollow viscus (Cervero, 1994). These afferents project through the lateral division of the dorsal roots and Lissauer’s tract to the dorsal horn, most densely in the upper thoracic and upper cervical segments. The small contingent of visceral A-delta fibers terminates in lamina I; the more numerous C-fibers, unlike C-fibers from other tissues, bypass laminae II, III, and IV to terminate in lamina V, and in more ventral laminae including lamina X (Cervero and Connell, 1984). C-fiber visceral nociceptive afferents enter the cord and divide into long ascending and descending branches, emitting thinly distributed collaterals to many segments. This wide divergence may account for the recruitment power of visceral nociceptive afferents in evoking both reflex actions and painful experiences. The convergence of somatic and visceral nociceptive afferents upon the same sets of ST neurons has often been proposed as a mechanism of referred pain. It is conjectured that the reference is due to the more frequent activation of the somatic input in ordinary life, and a “learned” place reference. The somatic–visceral convergence is mainly upon ST neurons of lamina V, and below, that project their axons into the ascending systems of the contralateral anterolateral quadrant. Pain of visceral origin is commonly referred to somatic structures innervated from the same or nearby spinal segments, and preferentially to deep tissues and/or the skin of proximal limbs and the body. For example, pain of cardiac or pulmonary origin is referred to deep tissues of the arm, chest, and shoulder, and/or to the skin of the proximal arm and shoulder (Hobbs et al., 1992;

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Foreman, 1999). Cardiac pain is rarely referred to the glabrous skin of the hand, and somatic–visceral convergences are rare in segments C-7 and C-8, the segmental levels of entry of afferents from the hand. The details of convergence and reference are well known from clinical observations, and have been documented in many studies of the spinal cord in monkeys, including those for pain from the ureter, kidney pelvis, gall bladder, etc. (Ammons, 1992). There is evidence that some elements of the postsynaptic dorsal column system described in Chapter 6 are activated by visceral nociceptive afferents. The details of referred pain direct the physician’s attention to the locus of disease. Referred pain by itself has no biological meaning; e.g., pain in the right shoulder referred from a diseased gall bladder led to no adaptively useful behavior before the advent of clinical medicine.

The Spinotectal and Spinomesencephalic Tracts These two collections of ascending axons arise from neurons in laminae I, V–VII, and X of the spinal gray, more heavily from cervical than from lumbosacral segments, and project through the anterolateral funiculus, largely on the contralateral side. Their cells of origin subtend large and sometimes bilateral receptive fields in the skin and deep tissues, driven by both innocuous and noxious stimuli. The spinotectal tract divides into lateral and medial components on entry to the reticular formation; its lateral branch projects to the lateral reticular nucleus, a precerebellar transition zone, and provides afferent input used in motor control. The medial division projects into the brain stem nuclei of origin of the descending limb of the supraspinal pain control loop, described above, providing wholebody nociceptive afferent input. It may also provide a subsidiary pathway for pain, for some of the cells upon which it projects send their axons to the dorsal thalamus. Axons of the spinomesencephalic system project to the PAG and adjacent nuclei, and thus also provide afferent input to the brain stem nodes of the pain control system. It may also function as a subsidiary pathway for pain, for some of its axons project directly to the thalamus.

Propriospinal Systems Propriospinal neurons are those whose axons arise and terminate within the spinal cord; however, some long intraspinal projection

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systems such as the spinocervical are not usually termed propriospinal. True propriospinal neurons are located most densely in laminae V–VIII. Their axons enter the adjacent white matter in all quadrants and turn upward or downward; many project for only one or two segments before re-entering the spinal gray, but others project for long distances; some of the latter link the cervical and lumbosacral enlargements. Projections are made upon motoneurons and interneurons of the intermediate and ventral portions of the spinal gray, both contralaterally and ipsilaterally to the side of origin. The number of propriospinal fibers is estimated at 30–50 percent of all fibers in the spinal cord, but this number varies with species and spinal cord segmental level. The traditional view has been that propriospinal systems function in local and long reflex spinal arcs, a generalization confirmed in experiments in nonhuman primates and clinical observations in human subjects (Nathan and Smith, 1959). Some propriospinal systems control complex motor operations; for example, Alstermark and Lundberg (1992) discovered that a propriospinal network at the C1–C4 level of the spinal cord of cats links descending signals from the forebrain to the motoneurons in the lower cervical segments controlling projection of the foreleg and food-grasping with the paw. This system is present in macaque monkeys, where it functions in parallel with direct monosynaptic linkages of forebrain systems to the motoneurons (Maier et al., 1998), and is also important in humans (Burke et al., 1994; Pierrot-Deseilliguy, 1996). It is this function of regulating the movements of the arm and hand in reaching to and grasping objects that makes the cervical propriospinal system important for somesthesis, for example, in stereognosis (Chapter 13).

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9

Dual Functions of the Dorsal Thalamus

Discoveries of the last two decades have established that the thalamus functions in two different modes. The first is the relay function, the projection of neural activity in afferent systems to the cerebral cortex, and of neural signals from the cerebellum and basal ganglia to the motor and premotor cortical areas. The second deals with the states of excitability of the forebrain, the initiation and control of patterns of forebrain activity correlated with states of vigilance, and the transitions between them. These dynamic states occur in many of the same neuronal populations and the same systems of thalamus and cortex; transitions between those states are paralleled by changes in behavioral state. How these sequential alternations between states are initiated and controlled has been revealed by discoveries made at systems, cellular, and molecular levels. Advances in knowledge of thalamic function in this period have been summarized in a series of monographs written by several major contributors to the field, in temporal order: The Thalamus (EG Jones, 1985); Thalamic Oscillations and Signaling (Steriade, Jones, and Linas, 1990); The Thalamus, Vol. 1 (Steriade, Jones, and McCormick, 1997); Exploring the Thalamus (Sherman and Guillery, 2001); and The Intact and Sliced Brain (Steriade, 2001a). See also the collection of papers in Adams et al. (2002).

The Two Modes of Thalamic Function The relay function is the transmission of activity in prethalamic systems to forebrain structures, largely to the cerebral cortex: from the

peripheral visual and auditory systems via the geniculates to visual and auditory cortices; from the sensory lemnisci via the ventral posterior lateral and ventral posteromedial nuclei (VPL/VPM) to the somatic sensory cortex; from the deep cerebellar nuclei via the ventral lateral nucleus, posterior part (VLp) to the motor cortex, and from the globus pallidus through the ventral lateral nucleus, anterior part (VLa) to the premotor cortex. The major relays through the ventral tier of VPL/VPM, VLp, and VLa occur without overlap: they are restricted throughput systems. In the relay mode thalamocortical neurons discharge trains of nerve impulses at rates and with adaptive properties determined by their inputs from prethalamic afferent systems. Other thalamic nuclei receive their major inputs from the cerebral cortex, transmit signals from cortex to cortex, and also receive afferents from subcortical structures. These are the lateral dorsal, lateral posterior, mediodorsal, and pulvinar nuclear groups that function as nodes in thalamocortical circuits executing higher order cerebral operations through their reciprocal connections with the homotypical cortex of the occipital, parietal, temporal, and frontal lobes. The thalamus functions also to initiate control of the patterns of forebrain electrical activity correlated with states of vigilance, including the shift from quiet wakefulness to alertness, or through the several stages of sleep. The intermittently bursting pattern of discharge of relay neurons in this mode is produced by the interplay of several voltage-gated membrane currents, by a precipitous decline in excitatory drive in the cholinergic system of brain stem origin, and by a strong inhibition from the thalamic reticular nucleus. In this mode of operation the dorsal thalamus is an essential locus in the reciprocally connected thalamocorticothalamic systems that generate the patterns of forebrain electrical activity characteristic of the several stages of sleep: sleep spindles, delta waves, and slow waves. The security of transmissions in lemniscal systems so clear in a waking monkey working in a somesthetic task depends on the sharply restricted divergence for space and modality at each level of the system and on dynamic mechanisms, especially afferent inhibition.

Development of Ideas of Thalamic Function Ideas concerning thalamic function began in the era of prescientific speculation, continued through the period of gross neuroanatomy, to

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the demonstration in the nineteenth century that lesions of the human dorsal thalamus produce disturbances in sensation. There followed a period in which the thalamus was described at the level of light microscopy in many mammals. The recent transition has been to study of the thalamic sensory operations in waking primates, and the use of physiological and anatomical methods for study of the topographic representation of the body form in the somatic relay nuclei, combined with those of molecular neurobiology for the identification of transmitters, receptors, channel proteins, and conductances. Concepts of how the thalamus initiates and maintains levels of vigilance and awareness, and the transitions between them have evolved along different paths. Although older ideas of diffuse systems influenced subsequent developments, recent research programs are aimed at understanding the origin and nature of the varieties of electrical activity recorded from the surface of the head or brain. The relationship of electroencephalographic (EEG) activity to accompanying behavioral states was the original research program of Berger, from 1929 onward (see Gloor, 1969). Bremer (1935, 1975) studied cats after brain stem transections made either in the caudal medulla or in the midbrain. He discovered that after lower bulbar transections animals fluctuate between states of sleep and arousal, measured by ocular and EEG signs, but that after midbrain transections they are continuously somnolent. This discovery set the problem of how ascending systems control the excitability of the forebrain. This role of the thalamus was specified more exactly by the discovery of Morrison and Dempsey that electrical stimulation in the intralaminar thalamic nuclei, in anesthetized cats, evoked EEG signs of cortical arousal (Dempsey and Morrison, 1942; Morrison and Dempsey, 1942). More than a decade elapsed between Bremer’s discovery and that of Moruzzi and Magoun (1949), that electrical stimulation of the brain stem reticular formation—between Bremer’s two levels—evoked EEG signs of arousal in anesthetized cats. These studies, and the many that followed on the reticular formation, pointed to an ascending system of brain stem origin and thalamic target controlling the levels of forebrain excitability. Herbert Jasper concentrated attention on thalamocortical systems, and searched for a generalized thalamocortical system projecting to the cortex “diffusely” to account for the general and widespread effects produced by local thalamic

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stimulation, at lowest threshold in the intralaminar nuclei (Jasper, 1960). Compelling evidence now defines the role of the dorsal thalamus and associated thalamocorticothalamic re-entrant systems as neuronal oscillators controlling transitions between states of vigilance.

Fig. 9–1 A series of frontal sections in anterior to posterior order through the thalamus of a macaque, showing the sectors of the reticular nucleus (R) that are related to each of the nuclei or groups of nuclei of the underlying dorsal thalamus. A symbol appears only once on a dorsal thalamic nucleus but appears throughout the related sector of the reticular nucleus. (From Jones, 1998c.)

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Thalamic Organization The thalamus is a small, multinucleated, diencephalic structure that occupies 18 cm3 of tissue in the human brain, 1.4 percent of total brain volume. It develops in ontogeny within the wall of the primordial diencephalon, separated by a sulcus from the hypothalamus below (Le Gros Clark, 1932). Three areas develop within the thalamic plate: a dorsal area termed the epithalamus; a middle and largest, the dorsal thalamus; and, below, the ventral thalamus. The dorsal thalamus is reciprocally linked to the cerebral cortex and other forebrain structures; the ventral thalamus receives projections from the cortex but does not project to it; and the epithalamus is not connected to the cortex either way. The divisions and nuclei of the dorsal thalamus in monkeys and humans are shown in camera lucida drawings of Fig. 9–1, and listed in Table 9–1. The thalamus receives direct inflows from the major afferent systems: the visual and auditory systems project to the lateral and medial geniculate complexes, respectively; the several ascending systems of spinal and trigeminal origin serving the modalities of somatic sensibility project to the ventral posterolateral and ventral posteromedial nuclei (VPL/VPM), to adjacent nuclei, and to some components of the posterior and intralaminar groups. Large-scale projections from subcortical structures controlling movement project through the dorsal thalamus to the cerebral cortex: from the cerebellum via the ventrolateral group to the motor cortex, and from the basal ganglia via the ventral anterior nuclear complex to the premotor cortex. There are strong similarities between the thalami of monkeys and humans, even though they have followed separate lines of evolution for more than 25 million years. The human thalamus is twice as large as that of the macaque, and several nuclei of the human thalamus, particularly of the pulvinar group, have enlarged differentially in parallel with the expansion of the homotypical cortex in hominids (Hirai and Jones, 1989). Several authoritative descriptions of thalamic anatomy are available (Macchi et al., 1996; Jones, 1997, 1998b). Anatomical studies using histochemical and immunocytochemical methods have produced a chemical neuroanatomy in which cell types are defined by transmitter agents and their receptors, by cell surface molecules, and by intracellular proteins; for review, see Jones

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Table 9–1

Major Groups and Nuclei of the Dorsal Thalamus in Macaque

Division

Group

Major nuclei

Epithalamus

Paraventricular nuclei (para) Habenular nuclei

Anterior paraventricular n. Posterior paraventricular n. Hm/Hl–medial and lateral habenular n R–Reticular n. ZI–zona incerta FF–fields and n. of Forel Prg–ventral lateral geniculate n AD–Anteriordorsal n. AV–Anteroventral n. AM–Anteromedial n. LD–Lateral dorsal n. Pt–Paratenial n. MV–Medioventral n. (Reuniens n.) MD–Mediodorsal n. Rh–Rhomboid n CeM–Central medial n. Pc–Paracentral n. Central and midline extensions of CL and CeM Pf–Paradascular n. CM–Center median n. VA–Ventral anterior n. Vla–Ventral lateral anterior n. Vlp–Ventral lateral posterior n. VPL–Ventral posterior lateral n. VPM–Ventral posterior medial n. VPI–Ventral posterior inferior VMb–Basal ventral medial n. LP–Lateral posterior n. Pla–Anterior pulvinar n. Pll–Lateral pulvinar n. Pli–Inferior pulvinar n. Plm–Medial pulvinar n. Po–Posterior n. L/SG–limitans/suprageniculate n. MGv–ventral nucleus MGad–anterodorsal n. MGpd–posterodorsal n. MGmc–magnocellular n. LG–dorsal lateral geniculate body

Ventral thalamus

Dorsal thalamus

Anterior group

Medial group

Anterior intralaminar group

Posterior intralaminar group Ventral group

Lateral posterior pulvinar group

Posterior group Medial geniculate complex

Lateral geniculate

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(1998b). The results confirm and make more precise the nuclear definitions of Fig. 9–1. Identification of cell types by molecular markers indicates that thalamic relay cells fall into two classes with contrasting sets of properties. Tracing studies suggest that there is minimal convergence between the major afferent inflows to the dorsal thalamus, and that a segregation into parallel subchannels exists within those systems. The lemniscal systems engage preferentially type I thalamic cells, defined below, that project upon the cortex in precisely defined patterns characterized by topographical order and areal specificity. They terminate in layers III and IV of the cortex. A contrasting set of properties characterizes the thalamic projections of ascending systems arising from intrinsic spinal cord neurons, those driven largely by small-fibered somatic sensory afferents (Chapter 8). Although in some cases these afferent systems diverge to terminate in several thalamic nuclei, in all they project preferentially to the type II thalamic relay cells, the “matrix” cells defined below (Jones and Hendry, 1989; Rausell and Jones, 1991a,b). Many neurons of this class project in a “diffuse” way upon the cortex, without regard either to cytoarchitectural boundaries or to functionally defined cortical areas. They terminate in layers I, II, and thinly in III.

Thalamic Cell Types and Their Connections There are four classes of thalamic neurons.

Relay Neurons Type I relay cells are bushy thalamic neurons that vary in crosssectional area over the range of 200–400 µm2. They emit stout dendrites to form large, symmetrical, dendritic fields (Fig. 9–2A,B), and are identified by immunoreactivity to the calcium-binding protein parvalbumin, by the expression of the cell surface proteoglycan, Cat301, by intense cytochrome oxidase activity, and by an identifying set of physiological properties. Type I relay cells are distributed widely in thalamic nuclei (Fig. 9–3), and predominate numerically in first-order relay nuclei. Within VPL/VPM, they are arranged in horizontal rods oriented in the anterior–posterior dimension, immersed in a matrix of type II relay cells and interneurons. Type I relay neurons

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Fig. 9–2 Above—A: Reconstructed dendritic fields of neurons of ventral posterior lateral nucleus of macaque monkeys labeled by retrograde transport of the dye diamidino yellow, injected into areas 3b/1 of the postcentral gyrus. B: Similar reconstructions of cells of the medial pulvinar by retrograde transport of the dye fast blue injected into area 7. Below: The Sholl method of analysis applied to the “average” dendritic field of thalamocortical projection neurons. The intersection profile of this average neuron is plotted (filled squares) to the right, compared with averaged data obtained from 19 VPLc neurons (closed circles) and 12 pulvinar neurons (open circles). The dendritic intersection profiles of all appear to be identical. (From C Darian-Smith et al., 1999.)

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Fig. 9–3 Drawing to contrast the origins and terminations of the core thalamocortical projections from the “specific” thalamic relay nuclei neurons to the middle layers of the cerebral cortex with that of the diffusely distributed matrix cells to the superficial layers. (From EG Jones, 1998.)

in VPL/VPM receive the ascending, parvalbumin-labeled, axons of the medial and trigeminal lemnisci that terminate in excitatory, glutamate-operated synapses, and are themselves glutaminergic. Their axons emit no intranuclear collaterals, do not project to other thalamic nuclei, project through the thalamic reticular nucleus making collateral projections to reticular neurons, and terminate in a focused manner in layers III and IV of the cerebral cortex; in the somatic case, from VPL/VPM to the postcentral gyrus. The specific properties for place and modality characteristic of the lemniscal and trigeminal afferent systems are preserved in the synaptic transfer to type I thalamic relay neurons. Type II relay cells are bushy, glutamatergic neurons a bit smaller than type I neurons; they emit thinner dendrites into symmetrically extended dendritic fields, and are identified by immunoreactivity to the calcium-binding protein, calbindin (some are immunoreactive, instead, to calretinin); by the absence of staining for Cat 301; by

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weak cytochrome oxidase staining; and by a set of functional properties and connectivities quite different from those of type I cells. Axons of type II relay neurons emit no intranuclear collaterals; do not project to other thalamic nuclei; pass through the reticular nucleus making collateral connections with cells of the reticular thalamic nucleus; project to the cerebral cortex in an unfocused “diffuse” way, unconstrained by cytoarchitectural or functional boundaries; and terminate in layers I, II, and thinly to III. Type II neurons are colocalized with the terminal tufts of spinothalamic axons (Gingold et al., 1991; Shi and Apkarian, 1995), which extend into the two sets of thalamic nuclei described below (Rausell et al., 1992). The functional properties of type II relay cells are determined by those of the intrinsic spinal and spinal trigeminal afferent systems projecting to them, including both the input-selective sets from lamina I (Chapter 8) and the convergent sets from deeper laminae of the dorsal horn. The ratio of type I to type II cells is about 60:40 in the monkey ventral posterior medial nucleus, but the two are differentially distributed within that nucleus, where type II cells are clustered about, but only thinly within, the mode-specific rods of type I cells. The latter are most densely concentrated within but not confined to the firstorder sensory and motor relay nuclei. Type II cells are distributed throughout the dorsal thalamus, and nuclei such as those of the posterior nuclear complex contain predominantly type II cells. This system satisfies the objective of earlier investigators who sought a diffusely projecting system to account for the wide distribution of changes in cortical electrical activity produced by local thalamic stimulation, at lowest stimulus intensities in the intralaminar nuclei. Although the calcium-binding proteins serve as markers for the two types of relay cells, it is uncertain whether they determine any difference in functional properties. Ca2+ binding proteins buffer and regulate internal Ca2+ concentrations, and in this way control the activity levels of several intracellular enzyme systems, and thus the activation state of Ca2+-dependent ion channels and in part the dynamic aspects of the responses of relay cells (Heizmann, 1992, 1993; Huguenard, 1996).

Reticular Neurons The reticular nucleus (RTN) is a double layer of neurons partially surrounding the lateral and dorsolateral contours of the dorsal

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thalamus. It lies between the external medullary lamina and the internal capsule, across the trajectories of axons running to and from dorsal thalamic nuclei. The large neurons of RTN extend smooth, widely distributed dendrites that bear appendages presynaptic to the dendrites of other RTN neurons, in some species. The small myelinated axons (1.5mm) of RTN project to dorsal thalamic nuclei. Sectors of RTN project preferentially to one or two thalamic nuclei, where they end as -aminobutyric acid-ergic (GABAergic) inhibitory synapses upon both relay and interneurons, activating both GABAA and GABAB receptors (Steriade et al., 1984). Synaptic inputs to RTN cells are projected over the excitatory collaterals of thalamocortical, thalamostriatal, and corticothalamic axons; those projecting to and from a particular thalamic nucleus and its forebrain targets pass through the same sector of RTN, and create well-defined areas for different systems within RTN, in organized topographic maps (Crabtree, 1999). The RTN projects to all dorsal thalamic nuclei, including in the monkey the anterior nuclear group (Ilinsky et al., 1989; Velayos et al., 1989; Kultas-Ilinsky et al., 1995). There is a difference in the synaptic strength of corticothalamic axons upon their two targets. The GluR4-receptors are about 4 times more plentiful at RTN synapses than they are at relay cell synapses, and the synaptic responses of RTN neurons to corticothalamic volleys are about 3 times larger than are those of thalamic relay neurons (Golshoni et al., 2001). Reticular nucleus neurons are immunoreactive for the calciumbinding protein parvalbumin, stain for Cat 301, and express several synaptically active peptides. The reticular nucleus also receives afferent projections of systems from the brain stem and forebrain that are specified by their transmitters: acetylcholine, serotonin, or noradrenaline. The reticular nucleus is a pattern generator in the recurrent thalamocorticoreticulothalamic loop controlling activity in thalamocortical systems, and the related levels of awareness and vigilance along the continuum from focused alertness to deep sleep (Steriade, 2001b).

Interneurons Interneurons are small cells with cross-sectional areas of about 65–100 µm2. They have been identified in all thalamic nuclei of all species examined except rodents, where they occur only in the lateral geniculate nucleus. They increase in proportion from about

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15 percent of thalamic neurons in rabbit and guinea pig to 25–35 percent in primates, including humans (Arcelli et al., 1997). Interneurons emit short axons that terminate upon relay neurons within the boundaries of the nucleus of origin. Their long dendrites bear synaptic specializations, with synaptic vesicles and symmetrically opposed membranes with relay cells (Ralston and Herman, 1969; Ralston, 1991). Thalamic interneurons are GABAergic and inhibitory (Hunt et al., 1991); they receive direct synaptic input from the axons of ascending systems projecting to the thalamus, from the reticular nucleus, and from corticothalamic axons.

Common Properties of Thalamic Nuclei 1. All thalamic nuclei contain relay cells of types I and II; both project to extrathalamic targets, including the neo-, archi-, and paleocortex; the basal ganglia, amygdala, and other basal forebrain structures. Virtually all thalamic cells project to only one of these targets. There are no intrathalamic, nucleus to nucleus projections. So far as is presently known, all relay cells are glutamatergic and excitatory. 2. Afferent pathways to thalamic nuclei, and the extrathalamic projections from them, are arranged in segregated and parallel pathways. Parallel subchannels characterize the projections of the major sensory and motor thalamocortical projections. 3. All primate dorsal thalamic nuclei contain 25–30 percent of interneurons, whose axons project locally within the nucleus containing them; all are GABAergic and inhibitory. 4. All dorsal thalamic nuclei receive dense corticothalamic projections; the ratio to thalamocortical projecting axons is of the order of 5 to 1. There is a close topographical relation between the sources and targets of these reciprocal projections, but with some spatial shift—a small lateral mismatch between cortical areas of source and target may account for the rapid spread of activity in linked thalamocortical and corticothalamic circuits. 5. Axons that link reciprocally local cortical areas with local regions of thalamic nuclei pass through the same locus in the reticular nucleus, creating zones in that nucleus related to a

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particular cortical areas and thalamic nuclei, and to particular functions. All of the axons of layer VI pyramidal cells, in primates, emit collaterals to innervate reticular nucleus cells. Corticothalamic axons from neurons in cortical layer V also project through the reticular nucleus, but do not emit collaterals to reticular cells. They terminate in an unfocused way in the target and in several adjacent thalamic nuclei; some of these axons project to the spinal cord. 6. Neurons of RTN project to all dorsal thalamic nuclei in primates in a focused manner; RTN cells are GABAergic and inhibitory. 7. All dorsal thalamic nuclei receive ascending projections from the cholinergic, noradrenergic, and serotonergic ascending systems projecting from the brain stem.

Synaptic Mechanisms at Thalamic Neurons Synaptic Structure The thalamic synaptic neuropil has been defined in electron microscopic serial reconstructions, combined with tracer identification of particular sets of terminals, and immunohistochemical identification of transmitter molecules. Type I and type II relay cells differ slightly in size, but display no other differentiating morphological features at the level of synaptic neuropil; their different roles in forebrain function depend upon their different afferent inputs and output targets. The descriptions that follow apply, so far as is known, to both types of relay cells. The relay cell synaptic complex consists of a relay neuron and synaptic terminals from several sources, loosely surrounded by glial cells in a structure sometimes called a glomerulus. A number of afferent inflows to the relay cells of VPL/VPM have been identified; they differ in numbers and density, cellular targets, and terminal structure. Four terminal types have been described in the VPL/VPM of the macaque monkey (Ralston, 1991). They are: •

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Round-small (RS) terminals of the corticothalamic fibers from layer VI of the cerebral cortex; in some studies they account for about 70 percent of the synaptic terminals in VPL/VPM.

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•

Round-large (RL) terminals of lemniscal afferents projecting to VPL/VPM; they account for 6 percent of all terminals. Corticothalamic axons from pyramidal cells of layer V also end in RL terminals.

•

Flat (F) inhibitory, GABAergic, terminals of reticulo-thalamic axons and of intrinsic interneurons; about 10 percent of terminals in the monkey VPL/VPM.

•

Presynaptic dendrites (PSD), inhibitory and GABAergic, about 14 percent of all terminals.

Figure 9–4 shows the relations of several elements in the relay cell complex; it emphasizes the central position of the large-round synaptic terminal. An electron micrographic serial reconstruction of the synaptic terminals of separately labeled lemniscal and spinothalamic axons upon a relay cell in monkey VPL revealed that single dendrites receive terminals from either one but not the other of these two terminal sets (Ralston and Ralston, 1994). Whether dendrites with different sets of terminals are parts of the same relay cell was not determined, nor whether the reconstructed relay cell was of type I or type II.

Transmitters and Receptors The transmitter molecules and the postsynaptic receptors to which they bind have been identified for at least eleven presynaptic pathways converging upon the thalamocortical relay cells of VPL/VPM (Table 9–2). There are two major classes of postsynaptic receptors in the thalamus. Transmitter binding to ionotropic receptors induces a conformational opening (but never closing) of an embedded ion channel leading to rapid transmembrane flow of ionic current. Transmitter binding to metabotropic receptors produces a transmembrane activation of G-proteins, and through intervening biochemical steps frequently involving cAMP to either opening or closing of membrane channels. Ionotropic receptor activation produces postsynaptic membrane changes of rapid onset and short duration, metabotropic activation to low-amplitude, postsynaptic responses of longer duration. Lemniscal, spinothalamic (ST), and spinotrigeminothalamic (STT) systems transmit signals concerning peripheral somatic sensory events.

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Fig. 9–4 Schematic drawing synthesizing the structural relationships typical in thalamic nuclei. Protrusions of dendrites (D) of thalamocortical relay cells (R) receive terminals (T1) of ascending fibers (A) and presynaptic dendrites (T2) of interneurons (I). Axons of interneurons also terminate (F) on the T1 terminal and on the presynaptic dendrite (not shown). The entire synaptic complex is frequently sheathed by astrocytic processes (G). Outside the complex, the terminals of corticothalamic fibers (C) terminate on the dendritic shaft, or on the presynaptic dendrites of interneurons. The thalamic terminals of reticular nucleus axons (R) also terminate on or close to the somata of relay neurons. (From EG Jones, 1985.)

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Table 9–2

Afferent Inputs to Ventral Posterior Nuclei Relay Cells Transmitter and Receptor Types Terminal type

Transmitter

Targets

Synaptic action

Receptor type

Medial and trigeminal lemniscal axons

RL

Glu

Somata and proximal dendrites of relay cells. PSDs of interneurons

Ex

Ionotropic

Spinothalamic and spinal trigeminal axons

RL

Glu

Dendrites of relay cells/ not to interneurons

Ex

Ionotropic and metabotropic

Corticothalamic—VI

RS

Glu

Distal dendrites of relay cells. Collaterals to RTN

Ex

Ionotropic and metabotropic

Corticothalamic—V

RL

Glu

Proximal dendrites of relay cells. No collaterals to RTN

Ex

Ionotropic for most nuclei

Reticular nucleus

F

GABA

Somata + proximal dendrites of relay cells in all nuclei

In

Ionotropic and metabotrpic

From pedunculopontine and laterodorsal

RS

ACh

Proximal dendrites of relay cells

Ex

Ionotropic and metabotropic

Tegmental nuclei

F

ACh

To RTN cells

In

Locus coeruleus

?

NA

Dendrites of relay and interneurons. Nonsynaptic release sites

Ex

Metabotropic

Dorsal raphe n.

?

5-HT

Weak innervation, pericellular nests varicosities

Ex

Metabotropic

Tuberomammillary n.

?

HA

?

Ex

Metabotropic

Axons of intrinsic interneurons

F

GABA

Relay cell dendrites

In

Ionotropic and metabotropic

Presynaptic dendrites of intrinsic interneurons

F

GABA

Relay cell dendrites

In

Ionotropic and metabotropic

Source

Ach—acetylcholine; F—flat, inhibitory terminals; GABA—γ-aminobutyric acid; Glu—glutamate; NA—noradrenergic; PSD—presynaptic dendrites; RL—round large excitatory terminals; RS—round small excitatory terminals.

Other thalamic input systems function in one or another mode of modulation. Two of these, 3 and 4 of Table 9–2, signal the state of the cerebral cortex, may modulate transmission through thalamic nuclei, and may under other circumstances entrain thalamocortical relay cells into the dynamic activity of distributed thalamocortical systems. The ascending sensory systems and the descending corticothalamic systems projecting to VPL/VPM operate with the

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transmitter glutamate, via a number of different glutamate receptors. These include the classical N-methyl-D-aspartate (NMDA) and amino3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptors, each of which when activated by glutamate leads to rapid, shortlasting, postsynaptic depolarizations—that via the NMDA channel a bit slower than that produced via the AMPA channel. NMDA is the most densely distributed glutamate receptor in the ventral posterior nuclei. It requires first a partial depolarization to dislodge a blocking Mg2+ ion in the pore entry zone, then opens after binding with glutamate, allowing inflow of Ca2+ as well as Na+ and K+ ions. The inhibitory pathways, numbers 5, 10, and 11 of Table 9–2, operate via GABA receptors (GABAA and GABAB) receptors, and produce postsynaptic inhibition, an essential component in the integrative action at thalamic synapses; for example, in limiting spatial divergence and restricting the enlargement of peripheral receptive fields. The remaining input systems projecting to VPL/VPM, #s 6, 7, 8, and 9 of Table 9–2 are modulatory in function. When active they produce small, prolonged depolarizations of thalamic relay cells. The cholinergic system controls by its active–inactive sequences the transitions of thalamic relay nuclei from the relay to the controlling mode of function, and the reverse, described below. This description of the afferent excitatory and inhibitory pathways converging upon thalamic relay neurons has been changed by a series of discoveries made with both anatomical and physiological methods. In situ, hybridization histochemistry and immunocytochemical labeling of in vitro slices of the thalamic nuclei show that they possess a large number of variants of the glutamate and GABA families, and it is likely that each of these has different functional properties in controlling trans-membrane ionic flows; for reviews, see Jones (1998a) and Sherman and Guillery (2001). Electrophysiological studies have shown that the relay cells possess many voltageand ligand-gated channels, and that the interaction of these with ongoing synaptic input determines the functional states of the relay neurons at any given moment. Some of these are described below.

Multiple Conductances of Thalamic Neurons The ionic theory of excitation and conduction in nerve axons by Hodgkin and Huxley (Hodgkin, 1964; Hille, 1992; Armstrong and Hille, 1998) provided a knowledge base for the discovery that central

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neurons are equipped with many voltage- and ligand-controlled channels. The temporal interplay between the voltage-regulated conductances of these channels determines in part the dynamic functional states of central neurons. This includes the transitions of relay cells of VPL/VPM between the tonic and the bursting patterns of impulse discharge, respectively, characteristic of the relay and control mode of operation. In the early 1970s, intracellular studies of invertebrate neurons revealed that they possess a number of voltagedependent ionic conductances, in addition to those that generate action potentials in their axons. The temporal interplay of the transmembrane currents produced by these conductance changes determines the functional states of these cells and of the small-numbered circuits they compose (Getting, 1989; Selverston, 1993). The rapidly accumulating knowledge of membrane channels and their conductances in mammalian thalamocortical and cortical neurons provides understanding of the function of these neurons in the thalamocortical circuits that initiate and control the patterns of activity in the electroencephalogram, and the correlated behavioral states.

Voltage-Gated Channels Control the Transitions Between the Tonic and Bursting Modes of Thalamic Relay Cell Discharge Llinas and Yarom (1981a,b) discovered that several voltage-dependent conductances exist in the neurons of the inferior olive of the mammalian brain, and that the interplay of these currents determines the functional state of the neurons. Llinas and Jahnsen, recording in slice preparations of the guinea pig thalamus (Llinas and Jahnsen, 1982; Jahnsen and Llinas, 1984a,b), and Steriade and his colleagues, recording in anesthetized cats (Deschenes et al., 1982; Steriade and Deschenes, 1984), discovered independently that the relay neurons of the dorsal thalamus can be shifted between the tonic and bursting modes by imposed changes of membrane potential, produced in these experiments by passing transmembrane currents through intracellular micropipettes. The sequence of transitions between the oscillatory and tonic modes of discharge produced by sequential changes in membrane potential are shown in Fig. 9–5A, in recordings made in a slice preparation of the cat lateral geniculate nucleus. Figure 9–5B shows an expanded record of the oscillatory pattern of discharge. The bursting mode recurs at frequencies of 0.5–4.0/sec in various states

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Fig. 9–5 Electrophysiological evidence for the dual function of thalamocortical neurons. A: Cat LGNd neuron generated rhythmic burst discharges at about 2/sec. Depolarization of this cell to −58 mV by intracellular injection of depolarizing current switched the discharge pattern to the single spike mode, produced by inactivation of IT; removal of the depolarizing current restored the low-frequency oscillatory activity. C: Expanded record of the activity of the cell. B: Expanded record of the oscillatory activity, showing the currents proposed to produce it. Activation of the low-threshold calcium current, IT, depolarizes the cell towards the threshold for a burst of sodium/potassium dependent fast action potentials. This depolarization deactivates the portion of IT remaining after the calcium spike. Repolarization of the membrane is followed by a hyperpolarizing overshoot due to the depolarizing effect of IH. The hyperpolarization in turn leads to a repetition of the cycle. (From McCormick and Bal, 1997, after McCormick and Papes, 1990.)

of unconsciousness such as deep sleep. These synaptic events are ubiquitous in thalamic relay neurons, and have been observed in several different species and different experimental circumstances. They are produced by the temporal sequence of activation of a number of conductance channels in relay neurons.

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The Channels Ion-specific channels in cell membranes are pores regulated to open or close at certain membrane potential levels, or by molecular ligands, or both. In the open state channels pass 108 ions/sec, three orders of magnitude faster than do carrier mechanisms. Gating is achieved in voltage-gated channels by helix rotation of charge within the channel, which produces a gating current. The low-threshold calcium spikes are produced by the interplay of a Ca2+ current, IT, and a cation depolarizing current, IH, and are conditioned by a number of K+ currents, a high-threshold Ca2+ current, and a persistent Na+ current. The transient IT is inactive at resting membrane potential levels, is slowly de-inactivated by hyperpolarizations to −80/−90 mV, is activated into the calcium spike bursting mode by depolarizations from those levels, and is again inactivated by depolarizations positive to about −65 mV, at which the tonic mode of discharge is dominant (Jahnsen and Llinas, 1984a,b; Coulter et al., 1989; Hernandez-Cruz and Pape, 1989). In the intact brain of a dozing or sleeping mammal, this bursting pattern is influenced also by the postsynaptic membrane responses evoked by presynaptic inputs. The amplitude of the low-threshold calcium spike is determined by the level of hyperpolarization and by the degree of de-inactivation from which it is evoked, and may display an all-or-none property when these variables are constant (Sherman and Guillery, 2001). Low-threshold calcium channels are densely packed in the dendrites of relay cells, where the Ca2+ current is 4–5 times higher than in somata (Destexhe et al., 1999). The Na+/K+ cation current IH is activated by hyperpolarization, and the net, slow, depolarization it produces activates IT and the low-threshold calcium spike follows (McCormick and Pape, 1990). The slow kinetics of IH delay the post-calcium spike repolarization; and, together with the slow rate of de-inactivation of IT after hyperpolarization, limits the frequency of bursting discharges. The several K+ currents activated at different membrane potential levels exert a repolarizing pressure, opposed by the depolarizing action of the persistent, noninactivating, Na+ current; the effect of the high-threshold calcium current is uncertain. The different ascending inputs to type I and type II relay cells suggests that the interaction in them of voltage- and ligand-gated channels may differ. It is unknown whether the two types of relay cells have different or identical patterns of input from other sources, such

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as RTN, the cerebral cortex, or the ascending modulatory systems of brain stem origin. For reviews, see Llinas (1988); Steriade and Llinas (1988); Huguenard (1996); McCormick and Bal (1997); Sherman and Guillery (2001, Chapters IV and V); and Steriade (2001a).

Core and Matrix Model of Thalamic Organization The discoveries of two classes of thalamic relay cells with different chemical identities, input and output connections, and different thalamic distributions, in primates, form the basis for E. G. Jones’ hypothesis of core and matrix (Jones, 1998a–c, 2002). This replaces older ideas of “specific” and “diffuse” but retains the essence of that dichotomy. Thalamic matrix cells (relay type II) of VPL/VPM receive ascending input over ST and STT systems (Chapter 8). The moderately divergent projections of the matrix cells of a single thalamic locus to the cerebral cortex, and the reciprocal divergence of the corticothalamic efferents evoked by it, can lead to a rapid spread of synchronous activity throughout the cortex and thalamus. This accounts for the observations, made in earlier studies, that repetitive local stimulation of the intralaminar nuclei evokes the recruiting response, a long-latency, slow, surface-negative, potential that appears nearly simultaneously in many cortical areas (Purpura, 1970). Core neurons are concentrated in the sensory and motor relay nuclei. In the somatic sensory nuclei they are arranged in long, narrow rods oriented anteroposteriorly in the horizontal plane (Rausell and Jones, 1991a,b; Kalil, 1981). The parvalbumin-labeled type I relay neurons of each rod are mode- and place specific. They are embedded in a thin envelopment of matrix cells, receive afferent input from parvalbumin-labeled, prethalamic, axons of the medial and trigeminal lemnisci, and project to layers IV and III of the postcentral somatic sensory cortex in a focused rod to column manner. The core system serves the specific sensory and motor system transitions from the dorsal thalamus to the sensory and motor areas of the cerebral cortex, with preservation of mode and place specificity, and in somatotopic regularity. The matrix system serves the nociceptive and thermoreceptive senses, and is also thought to control variations in affective and conscious states, but much uncertainty attends this latter inference. The differentiation of two classes of relay cells by their different afferent inputs and cortical projection targets appears to be general

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for primate thalamic nuclei (Hashikawa et al., 1991; Yan et al., 1996; Sherman and Guillery, 2001). A differential distribution of matrix and core relay neurons has been observed in the auditory (Molinari et al., 1995) and visual (Hendry and Reid, 2000) thalamic complexes in the macaque monkey, and in a number of other primates, including humans (Munkle et al., 2000). A question awaiting experimental test by intracellular recording and natural stimulation of peripheral tissues is whether the convergences between the two major somatic afferent systems, described at the nuclear level in a number of studies, are or are not cellular selective in their projections to VPL/VPM. The differential cortical layer terminations of the core and matrix neurons poses a second difficult problem. When the lemniscal and spinothalamic/trigeminothalamic systems are active simultaneously, as they are in the sensory experiences of ordinary life, the cortex of the postcentral somatic sensory area is simultaneously activated through both its layer I, and its middle layers, III and IV. How are the highly specific responses of the latter conditioned by the simultaneous input from the matrix system via layers I and II?

Relay Functions of Somatic Sensory Thalamic Nuclei It has been known for nearly a century that the ventral posterior complex of the dorsal thalamus in primates contains the relay nuclei for the somatic afferent pathways, and that these nuclei project upon the postcentral somatic sensory cortex, a fund of knowledge generated by studies of humans with local thalamic lesions. Experimental work in nonhuman primates with the methods of anterograde and retrograde degeneration yielded more precise definitions of the thalamic zones of termination of the lemniscal and spinothalamic systems within the ventral posterior complex, and of the somatotopic patterns of projection of the ventral posterior nuclei upon the postcentral gyrus. See, for example, Le Gros Clark et al. (1932, 1936), Walker (1934, 1938), and Le Gros Clark and Boggon (1935). For later historical summaries see Welker (1974) and Jones (1985, chapter 1).

The Relay Mode The capacity of a thalamic nucleus to function in the relay mode depends on a maintained excitatory input that depolarizes thalamo-

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cortical (TC) relay cells to levels positive to about −65/−70 mV, at which the low-threshold Ca2+ spike generating mechanism is inactive. This depolarizing pressure is produced by sustained activity in cholinergic afferents to the thalamus from the pedunculopontine and lateral tegmental nuclei, whose cells are in turn driven by afferent input originating in the periphery and relayed via spinoreticular systems. When that falls, TC neurons in relay nuclei revert to the control, bursting state. When in the partially depolarized, relay mode, TC neurons respond to afferent input with trains of action potentials, sometimes called the “tonic” mode of response; mistakenly, I believe, for the response patterns of TC neurons in the relay mode are determined mainly by the patterns of activity in the particular sets of first-order afferents projecting to them over lemniscal systems.

General Properties of Thalamic Relay Nuclei A number of features characterize the lemniscal thalamocortical relay nuclei: 1. They have a distinctive cytoarchitecture, with interneurons, two classes of thalamocortical relay cells with different afferent inputs, intranuclear distributions, biochemical characteristics, and cortical targets, described above. 2. The lemniscal, spinothalamic, and spinotrigeminothalamic systems (ST/STT)converge within the ventral posterior lateral and medial nuclei (VPL/VPM). There is substantial evidence that this nuclear convergence is cellularly selective: lemniscal axons terminate on type I thalamocortical relay neurons of the thalamic rods; ST/STT axons terminate selectively on type II thalamocortical relay neurons in and between the thalamic rods, and in several nuclei in the matrix regions of the thalamus. 3. A somatotopic representation of the body form is apparent at successively more detailed levels of study and analysis. 4. There is a modular organization with restricted-throughput channels for sets of relayed cutaneous inputs with similar modality and spatial properties and restricted overlap, and.

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segregation of cutaneous inputs to the cores of VPL/VPM, of deep modalities to their anterior and dorsal shells. 5. Powerful synaptic actions support transfer of temporal and spatial details of lemniscal inputs to thalamocortical neurons. 6. Intranuclear GABAergic interneurons modulate synaptic transfer, and there is a powerful inhibition from the surrounding reticular nucleus. 7. Corticothalamic axons outnumber thalamocortical axons by ratios up to 5 to 1, enabling cortical modulation of relay actions.

Modularity, Divergence, and Convergence in the Lemniscal Afferent System Modular organization is a consistent feature of the lemniscal afferent systems that link body and face to the central nervous system. Parallel sets of large-fibered, first-order, mechanoreceptive afferent axons of the three cutaneous classes, which innervate the glabrous skin of the primate hand, are ordered into modality specific fascicles in their projections through the dorsal ascending pathways of the spinal cord. Fasciculation is a prelude to cortical columnar organization and map formation (Chapter 10). Each fascicle of axons at the upper cervical level of the dorsal columns, composed of primary afferent and secondarily relayed axons, terminates in a horizontal, anteriorly–posteriorly oriented rod-like group of neurons in the dorsal column nuclear complex (DCNC), preserving in that transition their specific properties of place and mode. The rods of the DCNC are 200–400 µm in cross-sectional diameter, and 3–4 mm in length (Chapter 6). They have been defined in cats (Dykes et al., 1982), raccoons (Rasmussen, 1988), and in several monkey species (Dykes et al., 1981; Florence et al., 1988, 1989; Culbertson and Brushart, 1989; Garraghty and Sur, 1990; Noriega and Wall, 1991; Rausell and Jones, 1995; Rausell et al., 1998). Any single dorsal column axon distributes its terminals in a smaller part of such a rod, in a volume of about 0.5 mm in length and 0.4 mm2 in cross-sectional area (Jones, 1983). In the cat, each rod contains up to 1700 postsynaptic neurons (Heino and Westman, 1991); comparable measurements have not been made in monkeys. This divergence is comple-

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mented by a convergence of several axons to single loci within the rod-space. A number of anatomical studies have shown a comparable degree of modularity in the thalamic ventral posterior nuclei. The several presynaptic inputs to the ventral posterior nuclei are among those listed in Table 9–2. Axons of the medial and trigeminal lemnisci terminate almost exclusively upon type I relay neurons of VPL/VPM. Single lemniscal axons terminate in clusters of type I relay cells in the thalamic rods, where their elongated terminals and the thalamic cells they innervate are distributed in narrow zones, 200–800 µm wide, which extend for one third to one half the anteroposterior extent of VPL (Jones, 1983). Full innervation of a rod requires that each receive a fascicle of lemniscal axons of the same class whose axons engage different elongated sets of relay cells within a rod. Separate sets of type I neurons project to each cytoarchitectural area of the postcentral gyrus, and separate sets project to somatic sensory areas I and II; the separate projection sets are intermingled in the somatotopic patterns of VPL/VPM (Nelson and Kaas, 1981; Darian-Smith and Darian-Smith, 1993). A divergence at both the dorsal column nuclear complex and thalamic levels occurs within but not between modality specific sets. The excitatory receptive field sizes at each stage of the system are much smaller than might be predicted from the cascaded anatomical divergence and convergence at each synaptic transfer level. For example, the peripheral receptive fields of cutaneous neurons of area 3b of the postcentral gyrus, measured in alert monkeys, are no more than 2–3 times larger than the fields of the relevant sets of first-order afferents which project to them (DiCarlo and Johnson, 2000). I discuss in later chapters what these facts imply, that there exist dynamic mechanisms maintaining spatial selectivity at every stage of the system, in spite of considerable convergence–divergence revealed by anatomical methods. The group of neurons at any level driven to action potential discharge, the discharge zone, is surrounded by a zone of neurons with subthreshold synaptic responses. That subthreshold fringe is thought to provide the connectivity base for the early phase of plasticity in the somatic afferent system (Chapter 15). Explicit, suprathreshold divergence begins in area 2, where cutaneous neurons are activated from multifingered receptive fields, a pattern unusual at any previous level of the lemniscal component of the somatic afferent system (Darian-Smith et al., 1984). Spatial and modality divergences increase further in the transpostcentral regions of the cortical somatic sensory systems.

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The dynamic characteristics of the lemniscal somatic afferent systems are determined by a strong synaptic security up to and through the initial stages of intracortical processing, a throughput function that belies the anatomical divergence and convergence within them. The spatial and modality specificity of these systems persists unchanged over a wide range of brain states. The parallel sets of afferent fibers and their central projections compose at each level of the lemniscal system detailed somatotopic images of the body form that reflect the innervation densities of body parts, described below.

The Ventral Posterior Relay Nuclei The VPL/VPM nuclei contain clusters of heavily stained neurons embedded in a lightly stained matrix. The clusters contain predominantly type I and fewer type II relay neurons, local interneurons, and the terminals of converging thalamopetal axonal systems. The matrix contains largely type II relay neurons, interneurons, and the terminals of the ST/STT systems. Crossing sets of myelinated axons of the lemniscal and spinothalamic systems ascending from below, and the thalamocortical and corticothalamic systems running to and from the internal capsule produce the reticulated appearance of the nuclei. The cellular clusters are cross sections of the horizontally oriented thalamic rods running through the nuclei. Posteriorly, the rods diminish in size, and the matrix fuses imperceptibly with region “s” and with adjacent matrix regions to form a cap covering the dorsal and posterior aspects of VPL/VPM; the cap consists almost exclusively of type II relay neurons and interneurons. Cytochrome oxidase staining shows that the rod regions are metabolically active, the matrix regions less so. The rod regions are selectively labeled by the calcium-binding protein parvalbumin, the matrix regions by calbindin.

Somatotopic Pattern: The Lamellar Model Following on the clinicopathological and anatomical studies described, the detailed representation of the body form in the ventral posterior nuclei was mapped with the evoked potential method. The results obtained in study of the dorsal thalamus of the macaque monkey are shown by the figurine map for one transverse plane of VPL/VPM (Fig. 9–6) (Mountcastle and Henneman, 1952). The

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Fig. 9–6 Representation of cutaneous tactile sensibility in one frontal plane of thalamus of an anesthetized monkey, determined by the evoked potential method using gross recording electrodes. Inset drawing of frontal section of brain in the plane of the electrode penetrations; dots indicate positive points, and figurine drawings are arranged accordingly. Gradations of intensity of response from most to least indicated by solid shading and cross-hatching on the figurines. With exceptions of intra- and perioral regions, all responses were evoked from the contralateral body surface. CM—Center median; LD—lateralis dorsalis; LG—lateral geniculate; LP—lateralis posterior; MD—medialis dorsalis; P—parafacicularis; VPL, VPM, and VPI—divisions of the ventral posterior nuclear complex. (From Mountcastle and Henneman, 1952.)

representation is somatotopic, not dermatomic, and of peripheral innervation density, not body form. Each particular body segment, for example, a finger, is represented in a thin, curving lamella of thalamic neurons extending through the anteroposterior and dorsoventral

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Fig. 9–7 Representation in the ventral posterior nucleus of monkeys, in the lamellar pattern, derived from single and multiunit recording, mapped onto a horizontal and a frontal section. Deep, representation of muscles and joints; all else is cutaneous representation. (From Jones and Friedmann, 1982.)

extent of the nuclei, concave medially. In each lamella, there is a dorsal to ventral representation of the proximal to distal dimension of the body part. The somatotopic pattern of representation in the ventral posterior nuclei has been mapped in similar gross electrode recording experiments in rodents, carnivores, and other nonhuman primates, and in microelectrode recording experiments in cats (Poggio and Mountcastle, 1960), monkeys (Poggio and Mountcastle, 1963), and humans (Lenz et al., 1998a; Hua et al., 2000). Each type I thalamocortical neuron of the cutaneous class is related to a small, constant, continuous, peripheral receptive field on the contralateral body surface. Together they form the somatotopic pattern of representation of the body form. The patterns of representation vary in different animals in terms of the sensory function of body parts; for example, there is disproportionately large and detailed representation of the tail in both the VPL and the postcentral somatic sensory cortex in the spider monkey, in whom the tail is an efficient tactile organ (Pubols, 1968). The drawings of Fig. 9–7 illustrate the lamellar model of representations in the cutaneous cores of VPL/VPM in macaque monkey. Many VPL neurons are activated selectively by joint rotation, others by stretch of muscle.

Somatopic Pattern: The Core and Matrix Model A general proposition is that in primates the cytochrome oxidase (CO)-weak, calbindin-labeled, smaller type II relay cells, distributed mainly to the inter-rod zones of VPL/VPM, increase in proportional

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numbers in more posterior regions of these nuclei, fuse with a matrix region that caps the posterior contours of these relay nuclei, and are continuous with the widespread distribution of matrix cells in surrounding nuclei of the posterior nuclear group. A portion of this matrix is co-extensive with terminations of the ST and STT systems. On this model, the type I dominated rods of VPL/VPM, the regions of termination of the medial and trigeminal lemniscal systems, are embedded within the matrix, and contain within them small numbers of matrix cells, as well as the GABAergic interneurons (Jones, 1998a,c). Combination of the methods of single neuron analysis with immunocytochemical staining of histological sections of the experimental brains for cytochrome oxidase has revealed more detailed images of the representations of the body and face in the VPL/VPM of the macaque thalamus (Jones et al., 1979, 1982; Rausell and Jones, 1991a,b; Rausell et al., 1992; for review, see Jones, 1998b). The drawings of Fig. 9–8 were constructed from microelectrode recordings in the VPM of anesthetized macaque monkeys, superimposed upon drawings of thalamic histological sections stained for cytochrome oxidase, that outlines the rods. The matrix regions of VPI, VMb, region “s,” and of other adjacent nuclei not shown in the drawings were unresponsive to gentle mechanical stimulation of the face. The serial images show that the region of the face, mouth, or teeth, represented in a given rod remains virtually the same over the anterior to posterior rod dimension. Separate sets of neurons within a single rod project from VPM to areas 3b and 1, fewer to area 2, and some sets project only to SII, the majority only to SI; virtually no neurons of VPM project by axonal branches to both. Although the rods of VPL are outlined less clearly by cytochrome oxidase staining than are those of VPM, single-neuron studies show that the core and matrix model fits both.

Modality Segregation Each of the several classes of thalamic neurons selectively activated by one class of large mechanoreceptive afferents innervating the glabrous skin of the monkey’s hand is segregated into modalityspecific rods of VPL; they project to similarly modality-segregated columns in areas 3b and 1 of the postcentral gyrus. Thalamic neurons

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Fig. 9–8 Camera lucida drawings of frontal sections through the thalamic ventral posteromedial nucleus of a macaque, in Horsley–Clarke planes A7–A4.5. Thalamic rods stained for cytochrome oxidase are shown by interrupted lines, containing the representation of body determined by microelectrode mapping. Contralateral representation shown by normal type; ipsilateral by italic type. (From EG Jones, 1998, after Rausell and Jones, 1991a,b.)

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activated by stimulation of afferents innervating the deep tissues of the body are clustered in a dorsal shell that surrounds the cutaneous core in front, above, and behind, but contained within the nuclear confines of VPL. The majority of neurons in the anterior part of the shell are activated by stimulation of muscle afferents, and project to area 3a (Maendley et al., 1981). Those in the more posterior part of the shell are activated by joint rotation, and project preferentially but not exclusively to area 2. In the human thalamus, the shell is identified as a separate nucleus, VPLa (Hirai and Jones, 1989). The shell-core relation shown in Figs. 9–9 and 9–10 for anesthetized macaques (Jones and Friedman, 1982) was also clear in a microelectrode mapping experiment in unanesthetized macaques (Poggio and Mountcastle, 1963). The modular organization of the lemniscal system is set first by the resorting and fasciculation operations in primary afferent fibers and their central projections in the spinal cord. The system is organized in an optimal way for the parallel processing of inputs generated in separate sets of primary afferent channels into separate channels in the central projections of the lemniscal system. The development of stereotactic neurosurgery and the use of microelectrodes for thalamic stimulation, and for recording the activity of single neurons, has produced valuable new information concerning the function of dorsal thalamic nuclei in the central neural processing of somatic sensory signals, and for the control of movement. These interventions are made to locate the optimal regions for thalamic lesions, or for implanting electrodes for chronic thalamic stimulation. Paradoxically, the two may have similar effects in the same thalamic locus; for example, by making lesions in or stimulating in the ventral tier of nuclei (Vim) in patients with Parkinson’s disease. Disruption of the abnormal temporal patterns by high-frequency electrical stimulation has an effect resembling that following a lesion in the same place, which provides some evidence of the importance of abnormal rhythms in generating the tremor of Parkinsonism. Lenz et al. (1998a) made an extensive study (531 single neurons) of the somatic sensory responses of neurons in the human equivalent of the monkey VPL/VPM, called Vc. The results fit the lamellar model of representation, as did the differential distribution of neurons of different somatic sensory modality types observed in both the human and monkey thalamic sensory relay nuclei.

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Fig. 9–9 Results of a micro-mapping experiment in which penetrations were made in a single parasagital plane. Clear or stippled regions indicate regions activated by tactile stimulation of the body parts indicated; locations of single neurons studied shown by horizontal bars. Vertical hatching shows dorsal region in which neurons were activated by stimulation of deep tissues. Inset, lower right shows summary of a series of vertical microelectrode penetrations made in a single frontal plane. (From Jones and Friedman, 1982.)

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Fig. 9–10 A schematic drawing, shown as if in a sagittal section, of the input–output connections of the ventral posterolateral and adjacent ventral thalamic nuclei. (From Jones and Friedman, 1982.)

Dynamic Relay Functions I describe in Chapter 11 the relay functions of the lemniscal components of the somatic afferent system, treated as system functions extending from primary afferent input to cerebral cortex, and their correspondence with psychophysical measures of the somesthetic functions of the primate hand for the varieties of tactile experience, and for flutter-vibration in Chapter 12.

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Trans-thalamic Relay of the Spinothalamic and Spinal Trigeminothalamic Systems The ST/STT systems project to several sets of dorsal thalamic nuclei, to nuclei in the posterior matrix, to the lemniscal relay nuclei VPL/VPM, to a medial group including centralis lateralis, the ventral portion of the mediodorsal nucleus, and thinly to the parafascicular nucleus, Pf. The axons of these systems terminate selectively but perhaps not exclusively upon the type II, calbindin-labeled, thalamocortical neurons of the thalamic matrix, and also upon interneurons. A widely distributed central neural network operates in the processing of nociceptive input, and generates the sensory and affective dimensions of the pain experience. Among cortical areas, it includes SI, SII, the insular cortex, and the cingular gyrus, described in Chapter 13. Which components of this system serve the discriminative and which the affective aspects of pain is a subject of intense study at the present time; see Schnitzler and Ploner (2000) and Craig (2003).

Thalamic Projections of the Stimulus-Selective, Lamina I Axons About 50 percent of all ST/STT axons derive from lamina I neurons. They are grouped by cellular morphology and different input selections into the nociceptive (NS), thermoreceptive (cool–cold cells—C), and the polymodal set (HTC). A selective set responding only to intracutaneous histamine has been identified as a central pathway for itch (Andrew and Craig, 2001). About 95 percent of those of lamina I origin cross in the anterior commissure of the spinal cord, and project toward the brain in the lateral spinothalamic tract (Chapter 8) to terminate in three thalamic targets: a nucleus of the posterior complex, named VMpo, in VPI, and in the magnocellular nucleus (MG vc). The nucleus labeled VMpo by Craig and Blomqvist (Blomqvist et al., 2000) is located just posteriorly to VPM and VMb. It contains almost exclusively type II thalamocortical relay neurons distributed continuously with the type II matrix of VPL/VPM. This posterior region receives an afferent projection from lamina I neurons of the dorsal horn and the spinal trigeminal nuclei. The dense axonal plexus terminating in or passing through VMpo stains heavily for calbindin. Its cells stain lightly for cytochrome oxidase, but positively for calbindin. VMpo has been identified and described in both

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the monkey and the human brain, where it is greatly enlarged (Blomqvist et al., 2000). In waking humans, stimulation in this region evokes sensations of pain or thermal change, commonly cooling, rarely warming. Occasionally, pain and thermal change are evoked from separate locations within VMpo (Lenz et al., 1993a,b; Davis et al., 1999; Dostrovsky, 2000). The pain evoked in waking humans by VMpo stimulation is extremely unpleasant, which indicates that the affective component of pain can be evoked by isolated stimulation of the lateral system, as well as via the medial pain system, to which it is sometimes exclusively assigned. In both monkeys and humans VMpo neurons are activated by thermal and/or noxious stimuli delivered to relatively small receptive fields on the contralateral body surface (Craig et al., 1994; Dostrovsky and Craig, 1996). The lamina I ST neurons deliver to this thalamic target graded neural signals in correspondence with both the graded intensities of the peripheral stimuli that drive them, and with psychophysical measures in humans. Vascular infarcts in this region, in humans, frequently result in analgesia, sometimes accompanied by the paradoxical thalamic syndrome of severe, spontaneous pain of central origin, described originally by Dejerine and Roussy (1906). These observations support the idea that VMpo is a relay nucleus for pain and temperature (Craig, 1996, 2003; Craig et al., 1999, 2001; Blomqvist et al., 2000); but not exclusively so, for elements of the input selective set of the spinothalamic system and those of the convergent set project to VPL/VPM, terminate in tufts closely aligned with groups of type II neurons in VPL/VPM, and in other thalamic nuclei, including the ventral part of the mediodorsal nucleus, and nuclei of the posterior intralaminar group. Uncertainty remains concerning the anatomical position and relations of the posterior thalamic target of the input-selective set of axons of ST/STT arising from lamina I, defined by Craig et al. as VMpo. This region stains for both calbindin and parvalbumin, an unusual double staining pattern for somatic sensory nuclei. Anteriorly, the calbindin cells are immersed in a dense, calbindin-labeled set of axons, and more anteriorly both are interdigitated between the parvalbumin-stained rods of VPM. Jones regards the region defined as VMpo by Craig and his colleagues as a part of VPM, and to be contained within the limits of that nucleus (Jones, 1998c; Jones et al., 2001; Graziano & Jones, 2004). Blomqvist, Craig, and their colleagues locate VMpo behind VPM and VMb, separated from

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them by a thin posterior nucleus, and thus within the posterior nuclear complex (Blomqvist et al., 2000). There is general agreement that this posterior region of the thalamus receives afferent projections from the pain and temperature systems, and projects to the cerebral cortex, but its specific cortical target is uncertain. There is now anatomical evidence that the stimulus-selective sets of neurons of lamina I in the dorsal horn and the spinal trigeminal nucleus project to the nucleus VMpo, as defined by Craig (Craig, 2003). And, there is preliminary evidence from imaging experiments in humans that nociceptive afferents project in a somatotopic pattern to the medial and posterior insula.

Thalamic Projections of the Convergent Sets of ST/STT Axons from Deeper Layers of the Dorsal Horns Eighty-five percent of the ST/STT neurons in laminae IV, V, and VI, usually called lamina V neurons, of the dorsal horn and of the spinal trigeminal nucleus are activated convergently by specific dorsal root afferents responding to innocuous or noxious mechanical, noxious heat or cold, and/or by polymodal dorsal root afferents of the A-delta and C-fiber classes. The axons of these convergent, polymodal dorsal horn neurons, together with those of a smaller group of nociceptive specific neurons, pass through the anterior commissure of the spinal cord and project cephalad in the spinothalamic tract. A body of experimental evidence supports the classical notion (Mehler et al., 1960) that the ST/STT systems project to the sensory relay nuclei VPL/VPM, in nuclear convergence with the projections medial and trigeminal lemnisci. The projection of ST/STT to the somatic sensory cortex through VPL/VPM may contribute to the discriminative aspects of pain and temperature sensibilities (see Chapter 14). For reviews, see Jones (1997, 1998a,b, 2001) and Willis et al. (2002). The evidence is summarized briefly as follows: 1. Anatomical studies using either antegrade or retrograde tracing methods show a substantial projection of ST/STT neurons to VPL/VPM (Apkarian and Hodge, 1989a,b; Willis et al., 2001). 2. Neurons of origin of ST and STT axons in the deeper laminae are activated antidromically by weak electrical stimuli

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delivered to VPL/VPL, stimuli thought to be confined to the region of those axonal terminations. 3. Single-neuron recordings in monkeys show that both polymodal and nociceptive specific neurons are found in VPL/VPM. However, the number observed is usually small, varying from 0 to 10 percent of the neurons studied in different experiments. This is surprising, for the type II thalamocortical neurons account for about 30 percent of all neurons in these nuclei, and if they receive mainly ST/STT inputs, then the percentage of cells driven by ST/STT input should be much larger. Given sampling and design-ofexperiment problems the percentage figures are tentative. 4. The thresholds for VPL/VPM heat-sensitive polymodal neurons match the waking monkey’s detection thresholds, and they provide graded responses to graded stimuli that parallel human rating functions. 5. The receptive fields of the nociceptive specific neurons of VPL/VPM are small and located on the contralateral side of the body, comparable to those of adjacent neurons activated via the lemnisci. The two are interspersed within the same topographical pattern but are separated into the lemniscal rods and the inter-rod matrix, which is described by Apkarian et al. (2000) as being also rod-like in form and distribution. 6. The nociceptive neurons of the somatic sensory thalamus project to the postcentral somatic sensory cortical area, which is thought to provide analyses for place, intensity, quality, and duration of noxious stimuli. Microelectrode stimulation and recording in the dorsal thalamus of waking humans has been used by neurosurgeons in the search for the critical thalamic nuclei transmitting to the forebrain afferent signals evoked by noxious peripheral stimuli, with the aim to define the location at which lesions or high-frequency stimulation might alleviate the severe and sometimes life-threatening chronic pain syndromes of central or peripheral origin. A vast amount of information has accumulated (Dostrovsky, 2000; Gybels, 2001; Lenz and Dougherty, 1997; Ohye, 1997; Magnin et al., 2001). Dostrovsky

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summarized the experience of the Neurosurgical Department in the University of Toronto. They stimulated at more than 5800 locations during more than 500 microelectrode penetrations into the thalami of 86 patients, 49 with movement disorders, 37 with chronic pain syndromes. Painful and thermal sensations were evoked at 7 percent of the stimulated sites, and 85 percent of the 7 percent were located posterior and inferior to the posterior extremities of VPL/VPM—called Vc in the neurosurgical literature. That is, only about 1 percent of the positive points were located in the classical sensory relay nuclei. Similar results are described by others (Lenz et al., 1993a). These observations raise the numerical mismatch problem described above. Anatomical studies show that the ST/STT tracts terminate in VPL/VPM in clusters of terminals distributed through the full anterior–posterior dimensions of those nuclei. The thalamic neurons receiving the ST/STT terminals project to the sensory cortical areas I, and much less densely, to SII; they are thought to provide the quantitative processing necessary for identification of location, modality, temporal pattern, and so forth, of noxious stimuli. The apparent mismatch between the predictions of anatomical connectivity and the results of extensive studies of the human thalamus remain unexplained. Consideration of the somatic sensory relay functions of dorsal thalamic nuclei reveals a difficult problem: how to account for transmission, in close correspondence with peripheral afferent input, of activity in ascending lemniscal systems through those thalamic relay nuclei to the somatic sensory areas of the postcentral gyrus, in spite of the convergence of lemniscal and spinothalamic systems. If this nuclear convergence includes terminations on the same relay cells, the question to be answered is how the specificity of lemniscal transfer for place, modality, and dynamic temporal pattern of input is maintained in spite of what would be a disorganizing convergence. If, on the other hand, the convergence is nuclear but not cellular, or if cellular but subthreshold, or if cellular but restricted to type II relay neurons, an explanation is readily at hand; that is, the lemniscal afferents selectively engage the type I relay neurons of VPL/VPM; and, that small-fibered spinothalamic and spinal trigeminal systems engage selectively type II relay neurons.

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Thalamocortical Control of Vigilant States and Sleep–Wakefulness Transitions In humans, the waves of the electroencephalogram (EEG) recorded from the surface of the head vary from 1 to 100 Hz in frequency, and from 1 to about 100 µv in amplitude. EEG potentials are generated by the flow of ionic current through the low resistance of the extracellular space, the sum of currents produced by inhibitory and excitatory postsynaptic potentials (IPSPs and EPSPs) in cortical neurons. The quasi-regularity of brain waves reflects the synchronization of local events in large populations of neurons. The most consistent correlations between EEG patterns and simultaneously behavioral states are those between different levels of vigilance, over the range from intense cerebral activity with focused attention, through inattentiveness and the several stages of sleep, to deep unconsciousness. These are: 1. The alpha rhythm of relaxed wakefulness, at 8–12/sec. 2. Faster waves at 20–40/sec, previously called beta or gamma waves, during active brain operations such as focused attention, or calculation. Paradoxically, similar fast patterns occur in the rapid eye movement (REM) phase of sleep. 3. Spindle waves at 7–15/sec that often appear in the early period of going to sleep. 4. Delta waves at 1–4/sec, that are characteristic of deep or “slow-wave” sleep. 5. Slow oscillations at 0.3–0.4/sec, generated in deep sleep by prolonged depolarization of cortical pyramidal neurons in layers II through VI, accompanied by repetitive impulse discharges followed by a prolonged hyperpolarization (Steriade et al., 1993b–d; Contreras and Steriade, 1995; Amzica and Steriade, 1998; Steriade, 2001a, Chapter 4). The slow waves of pyramidal cell membrane potentials are synchronous with grouped EEG waves recurring at the same frequencies. Slow oscillations are generated in cortical networks, are powerfully transferred to all the projection targets of cortical pyramidal cells, and through synchronization of neurons in the corticothalamocortical

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reentrant circuits tend to group together the thalamically generated spindle and delta rhythms (Steriade et al., 1993b,c; Destexhe et al., 1999; Amzica and Steriade, 2000). These sleep oscillations are combined in the complex and polymorphic patterns of the EEG in resting sleep, occur rarely in the waking state, and are common in both anesthetized and normally sleeping cats and humans. Studies of the transitions between states have been particularly informative, for they can be marked in time and defined precisely. The general proposition is that the patterns of electrocortical activity and their correlated behavioral states are generated both by the intrinsic properties of thalamic and cortical neurons and the network operations in the linked, thalamocorticothalamic systems.

Brain Stem and Thalamic Mechanisms Maintain the Waking State It has been known since the discoveries of Bremer (1935, 1975), Moruzzi and Magoun (1949), and Jasper (1960) that systems originating in the reticular core of the brain stem exert an activation on the forebrain, and that they do so through the dorsal thalamus. Activation in this case is defined as a steady depolarizing pressure upon forebrain neurons that raises their excitability to levels at which they readily respond to afferent sensory input, or initiate motor actions. This steady activation is accompanied by fast rhythms in the surface recorded cortical electroencephalogram, at frequencies in the range of 20–40/sec, which replace the alpha rhythm of relaxed inattentiveness. This EEG pattern was previously termed “desynchronized,” but it is now clear that fast rhythms are synchronized in local, not global, areas of the cortex. The tonic mode of discharge of regular trains of single action potentials in thalamocortical relay neurons is maintained in waking by the continuous synaptic input from cholinergic neurons in the pedunculopontine tegmental nucleus (PPT) in the peribrachial region, and in the lateral tegmental nucleus (LDT), within the periacqueductal gray (Steriade et al., 1982, 1988, 1990; Mesulam et al., 1989; Woolf et al., 1990; Lavoie and Parent, 1994). In humans, 90 percent of LDT neurons are cholinergic; the proportion of cholinergic and glutaminergic neurons varies between species (McCormick and Bal, 1997; Steriade et al., 1997, chapters 5 and 7). These nuclei receive af-

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ferent inputs over spinoreticular pathways, from cranial nerve and deep cerebellar nuclei, and from the cerebral cortex. They project to virtually all dorsal thalamic nuclei, including sensory, motor, intralaminar, and ventromedial groups, to the reticular nucleus, and to other forebrain structures, but not to the cerebral cortex. In waking, they maintain a strong depolarization of thalamic relay neurons, holding the membrane potentials of relay cells in the partially depolarized zone where the low-threshold Ca2+ spike-generating channel is inactive (Curro Dossi et al., 1991). These same cholinergic afferents inhibit neurons of the reticular nucleus, and by removing the inhibitory action of reticular thalamic nuclear neurons on thalamocortical relay neurons increase the excitability of the latter. The depolarizing action of cholinergic axons upon thalamic relay cells is imposed thorough nicotinic and muscarinic receptors.

Transitions Between Waking and Sleeping: Thalamic Origin of Spindles and Delta Waves The onset of sleep is defined by the loss of perceptual awareness, is initiated by the decrease in afferent sensory signals that accompany drowsiness, and follows, with a few seconds lead before sleep onset, a decrease in the discharge frequency of the cholinergic and glutamatergic neurons projecting from the mesopontine nuclei PPT/LDT to dorsal thalamic nuclei. Presumably this results from a decrease in afferent inflow to those nuclei, but perhaps also from direct inhibition by axons projecting from the 5-hydroxytryptamine (5-HT, serotonin) neurons of the dorsal raphe nucleus. The decrease in excitatory input, and the released inhibitory input from RTN neurons, drives the membrane potentials of thalamic neurons in the hyperpolarizing direction, into the zone of activation of the low-threshold Ca2+ spike generating channel (Destexhe et al., 1998). The bursting mode of thalamic neuron activity follows, soon accompanied by intermittent spindle waves, the classical EEG sign of light sleep (Fig. 9–11). Spindles are synchronized in large populations of thalamic and cortical neurons, and are readily recorded from the surface of the scalp. They were first observed by Berger in his original description of the human EEG, then in cats by Bremer (1935, 1975), and again in humans by Loomis and colleagues (Davis et al., 1938; Loomis et al., 1938), and in early intracellular studies of thalamic neurons (Andersen and Anderson, 1968).

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Fig. 9–11 EEG recording from the head of a normal human subject during natural sleep. Spindle sequences occur simultaneously at all recording sites, indicated in the inset, diagram, upper right. Crosscorrelations calculated between recording location C3A2 and each one of the other channels. Averaged correlations show rhythmicity at 14 Hz. (From Contreras et al., 1997.)

A spindle is a series of waxing and waning waves in the EEG, at frequencies of 7–15/sec; each wave is seen in the dorsal thalamic relay neurons as a strong IPSP synaptically evoked by volleys in reticulothalamic axons. Knowledge of the cellular mechanisms is based almost completely on experiments in cats. Spindle frequency is determined by the intrinsic oscillation within reticular nuclear networks; the sequences last 0.5–1.0 sec, and recur at intervals of 3–10 sec. They spread rapidly through the thalamus, and may appear almost simultaneously in widely separated areas of the cerebral cortex, a distribution attributed to the partially shifted, divergent–convergent relationships of the reciprocal thalamocorticothalamic connections (Contreras et al., 1997). The irreciprocal projections of layer V corticothalamic neurons, together with layer VI corticothalamic neurons and thalamocortical cells, form reverberating circuits with the power to spread activity quickly over wide areas of the cortex (Jones, 2001). Spindles disappear in TC neurons and in the cortex if RTN is disconnected from the underlying dorsal thalamus; and, they persist in de-afferented preparations of RTN (Steriade et al., 1987; Destexhe et al., 1994, 1996); for reviews, see McCormick and Bal (1997) and Steriade (2001a,b). The hyperpolarization of the spindle waves leads to rebound Ca2+ spikes and trains of action potentials in thalamic relay neurons, which are projected back to the locus of origin in RTN, and to the cerebral cortex. The cycle repeat frequency of 7–15/sec is limited by the slow repolarization after the Ca2+ spike, and the slow conduction velocity of the connecting axons. Spindle oscillations in dorsal thalamic and reticular nuclei, and cerebral cortex rapidly become synchronized, with phase shift. Although they are generated

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by local intrinsic properties, first in RTN cells, they depend also on network operations in thalamocorticothalamic systems; for example, impulses in corticothalamic axons facilitate spindle generation (Contreras and Steriade, 1996; Bazhenov et al., 2000). The waxing phase of the spindle sequence is attributed to recruitment of adjacent neurons. The waning phase may be due to a prolonged after-depolarization of thalamic relay cells that limits the generation of rebounding, lowthreshold Ca2+ spikes in response to IPSPs generated by the burst of impulses in RTN-thalamic axons. This reduction of the Ca2+ spike amplitudes is attributed to the inactivation of IT by the prolonged depolarization (McCormick and Bal, 1997). As sleep deepens thalamocortical relay neurons are further hyperpolarized by the decrease in activity in the activating brain stem systems that project to dorsal thalamic nuclei. Spindle waves, which occur in the membrane potential range of −55/−65 mV, decrease in frequency. With hyperpolarization into the range of −70/−90 mV spindles are first mixed with and then largely replaced by delta waves, which recur at 1–4/sec. Delta waves are the classical EEG signs of deep, slow-wave, sleep. They are produced by intrinsic cellular mechanisms in thalamocortical relay cells, by the interplay between the IH and IT currents described in an earlier section. Thalamic neurons generate this clock-like rhythmicity in the frequency range of delta after removal of the cerebral cortex, and they have been observed in TC neurons studied in vitro (McCormick and Pape, 1990). Delta oscillations survive tetrodotoxin block of all action potentials incoming to relay cells, further evidence that they are internally generated cellular events. Each delta wave is composed of a lowthreshold Ca2+ spike with a variable number of Na+/K+ action potentials riding on its crest. Delta oscillations in TC cells are synchronized with similar oscillations at delta frequency in RTN and the cerebral cortex; stimulation of the cortex elicits a powerful synchronizing influence on the linked thalamocortical circuits. Spindles and delta waves are not mutually exclusive, and are grouped together by the slow sleep wave of cortical origin into the polymorphic EEG of mammals in normal sleep. The transition from sleep to waking is preceded by a few seconds of increasing rates of discharge in the cholinergic neurons of the brain stem that project to dorsal thalamic nuclei. This produces a depolarization of the TC neurons, a shift in the thalamic pattern of activity from the bursting to the tonic mode, and the disappearance

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of bursts, spindles, or delta waves, if previously present. The slow sleep oscillations of the cortex are abruptly replaced by fast rhythms at 20–40/sec (Steriade et al., 1993b,c, 1994, 1996a,b; Steriade and Contreras, 1995). The afferent modulatory systems also contribute a depolarizing pressure on dorsal thalamic nuclei and the cerebral cortex. The abrupt change from any stage of sleep to the waking state may occur with or without re-tracing the staged decline into sleep.

Rapid Eye Movement Sleep Rapid eye movement sleep is a second and distinctive phase of sleep characterized by rapid eye movements (REMs), a profound and widespread muscular atonia, aside from the REMs, and a high-frequency, low-amplitude synchronization of the EEG resembling that in waking. Humans awakened from REM sleep have much higher probability of reporting they were dreaming than when awakened from slow-wave sleep. In animals, REM sleep is also characterized by large-amplitude pontogeniculooccipital electrical waves (PGOs) in the EEG, which usually just precede the onset of eye movements. During a night’s sleep, slow-wave and rapid eye movement episodes of sleep alternate, slow-wave periods always preceding. REMs occupy a much greater percentage of sleep time in human infants than in adults, but whether this indicates some role of REM sleep in the maturation of the brain is uncertain. Speculations abound concerning the role of REM sleep in cerebral function.

Where Is the Sensory Blockade in Various Stages of Sleep? In the slow-wave stages of sleep mammals do not respond to tactile, visual, or auditory stimuli of moderate intensity, but are aroused by strong stimuli, and readily by noxious ones. Blockade of nonnoxious stimuli has been observed in many sleep experiments, in which it was shown to be imposed at the level of synaptic transmission in thalamic sensory relay nuclei. However, some exceptions suggest that the blockade may not be complete at that level in all cases, and is imposed through the reciprocally connected thalamocortical systems; it may be completed only after several further stages of intracortical processing. Livingstone and Hubel (1981), for example, observed in cats that the decreases in the responses of cells of the visual cortex to visual stimuli during slow-wave sleep were

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seldom complete; block was most common for efferent pyramidal cells of layers V and VI. Experiments in the cyclically sleeping and waking macaque monkey, with single-neuron recording of the responses of postcentral neurons driven by low-frequency mechanical sinusoids delivered to the glabrous skin of their contralateral hands, revealed that in deep sleep about two thirds of the postcentral neurons responded to those stimuli, at thresholds undiminished from those observed in the alert state. By contrast, only 9 percent of those neurons could be driven in the REM stage of sleep, when monkeys can be aroused only by more intense stimuli (Fig. 9–12). Sherman

Fig. 9–12 Results of study of a single neuron of area 3b of the postcentral gyrus of a monkey before, during, and after an episode of REM sleep, monitored with EEG recording, not shown. Neuron activated by sine-wave mechanical stimuli of different amplitudes (mm peak-to-peak, shown to the right). Expectation density histograms, left and right, show the cyclic entrainment of the neuron’s responses to the mechanical stimuli, which were irrelevant behaviorally. During the period of REM sleep there is a complete disconnection between the lemniscal system inflow via the thalamocortical projection to the cerebral cortex. (From unpublished experiments of VB Mountcastle, 1969.)

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and his colleagues found that the bursty mode of discharge of neurons of the lateral geniculate, in anesthetized cats, could be driven by drifting visual sinusoids (Lu et al., 1992, 1993). The responses were invariantly of a few spikes, matching those riding on the crowns of the low-threshold Ca2+ spike, and presented a markedly nonlinear representation of stimulus parameters. The results show that the neuronal blockade is not absolute at the thalamic level. In sum, the three sleep oscillations, spindles, delta waves, and slow waves, originate in different nodes of the linked thalamocortical systems: slow waves in the cortex, spindles in the reticular nucleus, and delta waves in the thalamocortical cells of dorsal thalamic nuclei. The thalamus is critical for all these mechanisms controlling forebrain excitability. In the intact brain all are synchronized and together make up the complex electrical patterns recorded from the scalp of sleeping humans. The function of sleep in humans remains unknown, in spite of the intensive studies of a large number of investigators using a variety of methods. An hypothesis now under intensive study is that the central neural mechanisms involved in the consolidation of recent memory and in learning occur during sleep. For a review of the supporting evidence, see Peigneux et al. (2001) and Rock (2004); for summaries of the contrary evidence, see Vertes and Eastman (2000) and Siegel (2001).

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Postcentral Somatic Sensory Cortical Areas in Primates

The terms somatic sensibility and somesthesis describe the several varieties of touch, pressure, flutter, vibration, kinesthesis, position sensibility, pain, warmth, and coolness, as well as the more complex sensations such as the appreciation of the size and form of threedimensional objects examined by the hand. The four somatic sensory areas of the primate postcentral gyrus are major cortical targets of the somatic system, which includes the dorsal column–medial lemniscal system and the ascending systems of intrinsic origin, the spinothalamic and spinotrigeminothalamic pathways. I describe here the functional organization of the postcentral somatic sensory cortex in terms of static properties of the component neurons, representational maps, cytoarchitecture, connectivity, and columnar organization. The postcentral somatic sensory areas function both as neuronal processing centers and as gateways to the distributed cortical processing system (Fig. 10–1; see also Fig. 3–1). A major problem is whether and if so where the major sets of afferent systems converge and interact in the distributed cortical somatic system, and if so with what functional result. Over the period from about 1850 to the turn of the twentieth century, it became clear that the concept of a conjoint and overlapping sensory–motor cortex straddling the Rolandic fissure was incorrect. Small lesions of the postcentral gyrus produce defects in somesthesis with retained motor control; small pre-Rolandic lesions the reverse. More posteriorly, postcentral lesions produce defects in the recognition of objects with the hand in the presence of intact tactile

Fig. 10–1 Cytoarchitectural map of the lateral surface of the human brain, a rendering by Fuster (2001) of the original map of Brodmann of 1909.

cutaneous senses—the closer the lesion to the central sulcus the more likely it is to produce defects in the primary aspects of touch. Studies of men with gunshot wounds of the head during World War I, by Head and Holmes in Great Britain and by Kleist and Goldstein in Germany, established that (1) the body is represented in the postcentral gyrus in a regular pattern with the foot most medial and face most lateral and (2) tactile sensibility appears to be “localized” closer to the central sulcus than are those other aspects of cutaneous sensibility upon which stereognosis depends. It was from these observations that Holmes generalized the idea of a body schema localized in the parietal lobe. The differential effect upon different components of somatic sensibility by lesions at different anteroposterior positions in the postcentral gyrus has been confirmed in recent studies in monkeys and humans.

Definitions of Somatic Sensory Cortical Areas A somatic sensory cortical area is one that receives a direct thalamocortical projection from a somatic sensory nucleus of the dorsal thalamus, and whose removal produces defects in primary components

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of somatic sensibility. On these criteria the somatic sensory areas of the postcentral gyrus of primates, traditionally called the “first somatic, SI,” composed from before backwards by cytoarchitectural areas 3a, 3b, 1, and 2, are somatic sensory areas (Fig. 10–1). In monkeys, each of the four receives a distinct thalamocortical inflow that generates a separate somatotopic representation of the body form, and each contains defining sets of modality-specific modules. Areas 3b and 1 receive independent thalamocortical inputs generated by different classes of cutaneous afferents. Areas 3a and 2 receive independent thalamocortical inputs generated mainly but not exclusively from peripheral muscle and joint afferents, respectively. There is a sharp gradient from dominance by thalamocortical input in 3b to one of mixed thalamocortical and corticocortical projections from area 3b in 1 and 2. In the monkey, the representation of the glabrous skin of the hand in area 1 is denervated by removal of areas 3a and 3b (Garraghty et al., 1990). The similarity of the four postcentral cytoarchitectural areas in monkeys to those in humans implies that the human postcentral areas have separate somatotopic representations of the contralateral body surface, and partial modality segregations, as they do in monkeys. The somatic sensory areas of the parietal operculum, the region traditionally termed the “second somatic—SII,” receive thalamocortical projections from thalamic somatic sensory nuclei, and also dense cortico–cortical projections from the postcentral somatic sensory areas (Burton, 1986). Areas of the posterior parietal, temporal, and frontal lobes are in a sense somatic sensory also, for they receive relayed cortico–cortical projections from primary somatic sensory areas, but no direct thalamocortical projections from thalamic somatic sensory nuclei. Lesions in these areas produce complex disorders of somatic sensibility, frequently associated with defects not strictly somatic sensory in nature. They are essential nodes in the central mechanisms executing complex somatic sensory operations such as stimulus recognition and discrimination, short-term sensory memory and learning, and in the somatic sensory engagement of the motor system at the cortical level. The somatotopic mapping of the body surface is less precise in these areas than in primary somatic cortical areas, and in some a detailed pattern of representation is scarcely discernible. The functional properties of neurons in trans-postcentral somatic areas are less exactly defined by the properties of first-order somatic sensory afferent fibers, and new properties generated by

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intracortical operations appear (Chapter 14). On these same criteria the precentral motor cortex is not a primary somatic sensory area, even though it receives somatic afferent signals, for lesions restricted to the precentral gyrus produce no clear defects in somatic sensation. Some somatic sensory cortical areas function as initial processing and distribution channels to the distributed and interconnected nodes of the somatic sensory cortical system. They may function as the lowest level in what some regard as a distributed, hierarchical arrangement, as Van Essen and his colleagues proposed for the visual areas of the macaque cerebral cortex (Fellerman and Van Essen, 1991; Lewis and Van Essen, 2000a,b). However, significant processing of thalamocortical afferent input occurs within the postcentral cortical areas, with further elaboration of the complex aspects of peripheral stimuli. Connections between the nodes of the system are so dense and widespread that level identification is difficult, and neuronal processing within them is likely to be a concatenation of direct thalamocortical input with that from the coupled areas. This suggests that processing in the cortical somatic sensory system may vary from time to time in a dynamic way, operating in either a hierarchical or distributed style, or some mixture of the two.

Location Determined by Studies of Humans with Brain Lesions Lesions of the postcentral gyrus in primates produce defects in somatic sensation on the contralateral side of the body. Local lesions produce sensory defects of limited peripheral extent that vary systematically in body location with the postcentral location of the lesion. Lesions elsewhere in the cortex may produce complex disorders of somesthesia, but the primary attributes remain intact if the postcentral gyrus and its afferent inflow are undamaged. These results establish that the body surface is represented in an orderly somatotopic sequence in the postcentral gyrus, with caudal segments most medial and face most lateral. Small postcentral lesions in humans produce a differential loss of some but not all modalities of somatic sensation. This evidence for a differential representation of modalities in different zones of the postcentral gyrus has been confirmed in electrophysiological studies in monkeys and imaging studies in humans (Burton, 2002). In monkeys, area 1 lesions produce defects in texture discrimination, and area 2 lesions produce defects in the

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recognition of spatial contours. Local lesions of area 3b produce more global deficiencies in somatic sensibility because it is the major funnel to areas 1 and 2 (Randolph and Semmes, 1974; Carlson, 1981). Selective lesions of 3a and 2 together denervate the somatic sensory areas of the parietal operculum of neurons activated by stimulation of deep tissues, and lesions of areas 3b and 1 together remove a major cutaneous input to the parietal operculum (Pons et al. 1992). Discharging postcentral epileptic foci in humans may produce a sensory progression of paresthesias that traces a sequence of representation of the body in the medial to lateral pattern of tail to head on the postcentral gyrus (Jackson, 1863). For more detailed descriptions of the effect of cortical lesions upon somatic sensibility see Head (1918, 1920), Head and Holmes (1911–1912), Holmes (1927), Critchley (1953), Corkin et al. (1970), Roland (1987), and the historical review by Finger (1993, Chapter 10).

Electrical Stimulation of the Postcentral Gyrus in Waking Humans Confirmed the Location of the Somatic Sensory Cortex It was shown by Cushing (1909) and elaborated by Foerster (1936) and Penfield (Penfield and Jasper, 1954) that electrical stimulation of the postcentral gyrus in locally anesthetized humans elicits somatic sensory experiences referred to the contralateral side of the body, and that stimulation from place to place along the gyrus reveals a map of the body surface there (Fig. 10–2). It is possible under some circumstances to elicit somatic sensory experiences by stimulation of other cortical areas, but it is in the postcentral gyrus that such experiences can be provoked most consistently and at lowest thresholds, are referred regularly to local contralateral body parts, and when composed together in spatial order reveal a detailed pattern of the body form. Normal somesthetic experiences are not evoked. Penfield wrote: “When the somatic cortex is stimulated, he (the patient) reports a sensation of tingling or numbness, or of movement in some particular part. But he is never under the impression that he has touched an external object. He considers it an artifact, not an ordinary sensation” (Penfield and Roberts, 1959, p. 36). It seems likely that in most of these observations the just suprathreshold electrical stimuli activated area 1, which covers the exposed surface of the postcentral gyrus in humans.

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Fig. 10–2 Map of the representation of cutaneous sensibility on the postcentral gyrus of humans, determined by electrical stimulation of the exposed postcentral gyrus in waking humans, under local anesthesia; the patients reported verbally the body locations of the paresthesias evoked by the stimulation. It is likely that all the responses were obtained from area 1 which occupies the large majority of the surface of the postcentral gyrus. (From Penfield and Jasper, 1954.)

The Detailed Pattern of the Body Representation in the Postcentral Gyrus of Monkeys Mapped with the Evoked Potential Method A new era was opened in the mid-1930s for study of the geography of cortical sensory areas by the development of the evoked potential method. A brief mechanical stimulus to the glabrous skin of the

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hand evokes a synchronous volley of impulses in primary afferents that, after transmission over the ascending pathways, invades the postcentral gyrus and produces there a local slow-wave electrical response that serves as the mapping tool. The early publications of Gerard et al. (1933), Bartley and Bishop (1933), and Marshall et al. (1937, 1941) were followed by those of Adrian (1941) and others. Development of the field of evoked potential mapping of the sensory areas of the neocortex in experimental animals since then is largely attributable to the efforts of Clinton Woolsey and his colleagues (Woolsey et al., 1942; Woolsey, 1958, 1981). Among the results obtained were: (1) the general sequence of representation from tail to face (Fig. 10–3) in the medial to lateral dimension of the postcentral gyrus resembled that obtained by electrical stimulation in humans; (2) the tactile representation was thought to occupy all of areas 3, 1, and 2—area 3a was not recognized at that time; (3) a reciprocal relationship exists between peripheral innervation density, tactile acuity, and the area of cortical representation of a body part, and may vary by two orders of magnitude between the most and least densely innervated body parts. The smearing effect of the slow-wave potential method obscured the presence of four separate maps, one in each of the four cytoarchitectural areas of the postcentral gyrus, revealed in later studies made with the microelectrode mapping method. Nor did the evoked potential method reveal the differential projection of different somesthetic modalities to different postcentral areas. The somatic sensory evoked potential has proven to be a useful method for the study of normal brains and those with lesions, with recordings made from the surface of the head, or through implanted sub-dural electrodes.

Symmetry in the Postcentral Areas A general principle is that the size of a cortical area corresponds to the functional importance of the part or faculty represented within it. This was thought to be true for the sensory and motor areas of the left hemisphere opposite the preferred hand of right-handed humans. A study of both hemispheres of 20 normal human brains by White et al. (1997b) confirms the variability in the external morphology of the pre- and postcentral gyri between different individuals and between the two hemispheres of the same brain. However, measurements of the lengths and areas of areas 4 and 3 (3a +3b) by White et al. (1997a), and volume measurements by Rademacher et al. (2001) indicate that

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Fig. 10–3 Map of the projection of the body and head on the postcentral gyrus of anesthetized macaque monkeys, determined with the evoked potential method. On each figurine the solid and hatched areas indicate different amplitudes of responses evoked by light mechanical stimulation of body parts. The evoked potential obscured what later methods revealed, that there is a separate map in each of the four postcentral areas, 3a, 3b, 1, and 2. (Original data from Woolsey et al., 1942; modified for this figure by Woolsey, 1958.)

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these areas in the two hemispheres of the same human brain are virtually identical. The inference is that if right-handedness is associated with asymmetries in brain structure, those differences are not present at the level of areas 4 and 3 in the pre- and postcentral gyri.

A Morphological Landmark of the Hand Representation Anatomical studies by White et al. (1997b) of 42 normal human brains, and of 17 normal brains by Sastre-Janer et al. (1998) confirm the original observation of Cunningham (1892) and others since (Yousry et al., 1997) of a morphological landmark of the hand representation within the fundus of the central sulcus. This consists of interdigitating gyri, a protrusion backward from the precentral gyrus, and an adjacent protrusion forward from the postcentral gyrus. The central sulcus is shallow in this region, and in some brains an annectent gyrus links the pre- and postcentral gyri. A different morphological landmark is found in the postcentral gyri of owls, squirrels, and macaque monkeys, where microscopically visible lines of decreased neuronal density and increased glial accumulations form isomorphs of the finger and face representations (Jain et al., 1998, 2001).

Cytoarchitecture of Postcentral Somatic Sensory Areas Cytoarchitecture is a cortical descriptor based on the variation in neuron types and their differential distributions along the vertical dimension in different cortical areas. Laminar differences occur within a relatively constant total number of neurons in that vertical array (Rockel et al., 1980; Hendry et al., 1987). In his monograph of 1909, Brodmann described the general principles, methods, and criteria used for nearly a century as defining rules in cytoarchitectural studies. Brodmann recognized a transitional area in the fundus of the central sulcus now defined as a distinct area, 3a. The cytoarchitecture of the human postcentral gyrus was described by the classical neuroanatomists (Brodmann, 1909; von Economo, 1929) and more recently with new methods by Geyer et al. (1997, 1999, 2001) and Grefkes et al. (2001); for reviews see Zilles et al. (1991). Similar studies have been made in many other primates, including macaques (Brodmann, 1909; Powell and Mountcastle, 1959a). It is illustrated for the human brain by the micrographs of Fig. 10–4. The transition from the agranular motor cortex of the precentral bank

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Fig. 10–4 Micrographs of the cortex of the human postcentral somatic sensory areas 3a, 3b, 1, and 2; Nissl stains; long bar = 1 mm. Insets for 3a, 1, and 2 show at higher magnification (short bar = 100 µm) the large pyramidal cells in layer V of area 3a (2); large and elongated pyramidal cells in layer III of area 1 (4), and small pyramidal cells in layer III of area 2 (5). (From Geyer et al., 1997.)

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of the central sulcus to the weakly granular cortex of area 3a, with an attenuated layer IV, commonly occurs just at or anterior to the bottom of the central fissure, marked by the border between the cortical projection of VPLo and VLc to area 4 and VPL/M to area 3a. Area 3a is an integral part of the somatic sensory cortex; it is not a transitional area, and is not part of the motor system (Friedman and Jones, 1981). The transition from area 3a to 3b is marked by the appearance of a conspicuous layer IV packed with small granular neurons (“koniocortex”), by a fusion of layers III and IV, and by a decreased number of pyramidal cells in layer V of 3b. At the 3b–1 junction, layers II, III, and IV are once again distinct; area 1 is distinguished by the presence of large, long pyramidal cells in lower layer III, and by a clear columnarization. Layer III and V pyramidal cells in area 2 are somewhat smaller than are those in area 1, and the cortex is thinner in 2 than in 1. The vague architectural transition from area 2 to area 5 is marked exactly in electrophysiological experiments by the appearance of functional properties unknown in area 2: bilateral receptive fields for neurons driven by light cutaneous stimulation, and the presence of reach and grasp neurons whose activity reflects the behavioral intentions and actions of the animal (Mountcastle et al., 1975). It is also defined by the posterior margin of the cortical projection field of thalamic nuclei VPL/M to area 2, and by the anterior margin of the projection field of the lateral posterior nucleus to area 5. The four architectural areas of the postcentral gyrus are correlated with the different physiological properties of their constituent neurons (Powell and Mountcastle, 1959a,b).

Observer-Independent Method of Cytoarchitectonics Cytoarchitectural studies based on visual inspection of sections are compromised by the observer-dependent nature of the evidence, and the variability in the size and location of cortical areas between individual brains of the same species (Haug, 1987; Rajkowski & Goldman-Rakic, 1995a,b). Zilles and his colleagues devised an observer-independent method of microstructural parcellation of the cortex based on a gray-scale index, a measure of the density of darkly staining cell bodies. They used statistical analyses to establish change or no-change status between successive small increments (100– 200 µm) of cortex in the direction parallel to the pial surface (Fig. 10–5) (Schleicher et al., 1999). Studies of the human postcentral gyrus with this method confirmed the presence of areas 3a, 3b, 1, and

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Fig. 10–5 A: Dorsal view of brain after fixation in formalin for 5 months; the postcentral sulcus (pos) is connected with the intraparietal sulcus (ips) in both hemispheres. B: A sagittal section of the brain through the dashed line lin in A; region of interest boxed. Gray level image of the region of interest; equidistant profiles 200 µm apart from number 1 on the crown of pos to number 97 close to the fundus of the pos. D: Distance functions plotted against the index numbers; two significant maxima marked by drop lines correspond to the cytoarchitectural transitions from area 1 to 2, and from 2 to the posterior parietal cortex. (From Grefkes et al., 2001.)

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2 in anterior to posterior sequence in the postcentral gyrus, and showed that the transitions between them are independent of sulcal or gyral landmarks (Geyer et al., 1999, 2000, 2001; Grefkes et al., 2001). Zilles et al. also used a method based on in vitro receptor autoradiography to map the differential distribution of postsynaptic receptor proteins. Tests were made for the receptors for acetylcholine (muscarinic), noradrenaline, serotonin, glutamate, and γ-aminobutyric acid (GABA) (Zilles et al., 1991; Geyer et al., 1997; Kotter et al., 2001; Zilles and Palmero-Gallagher, 2001). Some but not all of these receptors are distributed heterogeneously between cortical areas, and change congruently with cytoarchitectural changes across the postcentral gyrus as measured in the gray-scale maps; that for serotonin made the best fit. Variations occur between different cortical layers, and differ between the architectonic fields of both the postcentral sensory and the precentral motor cortex (Munoz et al., 1999). They also occur in the homotypical cortex of the posterior parietal cortex where cytoarchitectural differences are uncertain. It remains to determine whether these receptor density maps match the several different zones of the posterior parietal cortex that differ in the functional properties of their constituent neurons. For reviews, see Roland and Zilles (1998) and Zilles and Palomero-Gallagher (2001).

Functional Organization of the Postcentral Somatic Sensory Areas The functional organization of the postcentral gyrus in primates is characterized by columnar organization, by a separate and complete representation of the body form in each of the four areas, by a direct scaling between peripheral innervation density of a body part and the area of cortex in which it is represented (the scale may be different for different representations of the same body part), by a specificity for place and mode in postcentral neurons, and by a partial segregation of neurons with different somatic sensory modalities in each of the four areas.

Columnar Organization of Postcentral Somatic Sensory Areas The columnar organization of the postcentral cortex is an example of modular design documented at many levels of vertebrate and

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invertebrate nervous systems (Szentagothai and Arbib, 1974; Liese, 1990). The basic unit in the mammalian neocortex is the minicolumn, a vertically oriented, re-entrantly linked chain of neurons extending from layer II through layer VI. Minicolumns are grouped into larger functional units, columns, discovered in electrophysiological experiments in the somatic sensory and visual areas of cats and monkeys (Mountcastle, 1957; Hubel and Wiesel, 1959, 1968, 1977; Powell and Mountcastle, 1959b). Grouping of minicolumns into columns is determined in postcentral somatic sensory areas by the focused input of sets of mode- and place-specific thalamocortical projections from the ventral posterior lateral and medial nuclei (VPL/VPM), that is, by their static properties (Chapter 9). A column in the somatic sensory cortex of primates is a place- and mode-specific set of neurons interconnected in the vertical direction, normal to the pial surface. Lorente de No (1949) recognized what we define as the cortical minicolumn, and he envisaged how variations in the vertical distributions of cells of different morphology and connectivity could contribute to the cytoarchitectural differences described above. The present state of knowledge concerning columnar organization is as follows. The minicolumn contains on the order of 80–100 neurons (doubled in primate striate cortex) and measures 40–60 µm in transverse diameter. The cell-rich minicolumns are separated by vertical, cell-poor regions of concentrated neuropil, which vary in width in different cortical areas in different species. Each minicolumn contains all cortical cell phenotypes, and each has several output channels. The minicolumn is produced by the iterative division of a small set of progenitor cells in the neuroepithelium (Rakic 1988, 1995). By the 26th gestational week, just before lamination begins, the human embryonic cortex is composed of a large number of minicolumns in parallel vertical arrays; the density and width of the intercolumnar cell-sparse regions change with age (Fig. 10–6). Optical density measurements reveal oscillating changes in cell density in the horizontal dimension, with periods at the minicolumnar distance of about 50 µm (Schlaug et al., 1995). Cortical columns are formed by the linking of many minicolumns by common, focused input, and short-range horizontal connections. The number of minicolumns per column varies between 50 and 80. Long-range, intracortical projections link columns with similar functional properties. Columns vary between 300 and 500 µm in transverse measure, and do not differ significantly in size between

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26-week foetus

9-year-old human

67-year-old human

Fig. 10–6 Micrographs of minicolumns in the neocortices of a 26-week human fetus, and of humans at ages 9 and 67 years. Thick sections stained with Nissl, 100µ magnification. (From Buxhoeveden and Casanova, 2002.)

brains that vary in volume over three orders of magnitude (Bugbee and Goldman-Rakic, 1983; Manger et al., 1998). Cortical expansion in evolution is marked by increases in surface area with little change in thickness. Columnar organization allows for intermittently recursive mapping, so that two or more variables can be represented in a single X–Y map on the cortical surface. For reviews, see Mountcastle (1978, 1997, 1998), Jones (1981), Powell (1981), Buxhoeveden and Casanova (2002), Hutsler and Galuske (2003). Figures 10–7 and 10–8 illustrate the defining properties of columnar organization, observed in single-neuron experiments in anesthetized macaque monkeys (Powell and Mountcastle, 1959b; Mountcastle and Powell, 1959a,b). The electrode penetrations illustrated in Fig. 10–7 entered the postcentral gyrus parallel to one another and to the vertical axes of areas 1 and 2. The neurons studied and the multiunit records observed in each were of the same modality type and related to closely superimposed receptive fields (Fig. 10–8). Those penetrations that passed across white matter to enter area 3 crossed its vertical axis at angles. In these deeper traverses the modality properties of neurons observed occurred in alternating blocks of cortical tissues; neurons of different modality types were not randomly intermingled. The similarities between the vertical processing chains in different cortical areas suggested that the intrinsic functions of different cortical areas might be due in large part to differences in the sources

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Fig. 10–7 Reconstructions of nine tracks of microelectrode penetrations into the postcentral gyrus of an anesthetized macaque monkey, all made within 1 mm mediolateral distance of the level marked A in the inset. Outline drawing is the mean contour of the sections containing these tracks. Tracks in area 2 are nearly normal to the cortical surface, and parallel with each other. Multi- and single-neuron recording indicated by cross-hatching and short lines. Each of the neurons encountered was driven either from the skin or deep tissues, but not both. Upper sections of the penetrations in area 1 were also “modality pure,” but as they entered area 3b they encountered successive blocks of neuron belonging to one or the other, without mixing. No recordings were made in these experiments from area 3a. (From Powell and Mountcastle, 1959b.)

and patterns of afferent inputs. Some differences exist between the processing chains in different cortical areas, however. For example, new cell phenotypes appear in the frontal and limbic cortices of humans and chimpanzees and not in other primates (Nimchinsky et al., 1999). Pyramidal cells in frontal areas 10, 11, and 12 in macaque monkeys are more spinous than are those in the striate area (16 times), in area 7a (4 times), or in area TE (1.5 times) (Elston 2000; Elston and Rosa, 2000); pyramidal cells in the prefrontal areas in humans have more branched dendrites with more spines than do those in the homologous areas in the macaque monkey (Elston et al., 2001). Differences in the microstructure of minicolumns in different areas and in different species may produce differences in dynamic intracolumnar processes. These differences are convolved with different patterns of extrinsic connectivity to produce what we call different functions. Selden (1985) studied the most columnated areas in the human brain, the auditory and speech areas of the temporal lobe. He

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Fig. 10–8 Drawings of the receptive fields of neurons activated by light mechanical stimulation of the skin, encountered in five microelectrode penetrations into the postcentral gyrus of anesthetized monkeys. The nearly superimposed receptive fields in a penetration vary around a common “hot center” for each penetration. No neurons activated by simulation of deep tissues encountered in these penetrations. (From Powell and Mountcastle, 1959b.)

established an average minicolumn width of about 40 µm, including both cell-rich and cell-poor regions, and that columns were slightly wider in the left than in the right hemisphere, an asymmetry also observed by Galuske et al. (2000). Schlaug et al. (1995) devised a parameter-free verticality index and used it to characterize five cingulate and pericingulate areas in the human neocortex (areas 24b, 23b, 31, 7, and 19). The verticality index varied only slightly between these areas, or between the layers within them. Buxhoevenden et al. (1996, 2000) used a quantitative method to characterize neocortical minicolumns. In their method, Nissl-stained images magnified × 100 are first transferred to a computer-based imaging system, and the contrast between the stained neurons and background is enhanced in a series of steps. A vertical central line is then set to a

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putative minicolumn, and the horizontal distance from it of every neuron measured. These data yield minicolumn widths, the distance between minicolumns, and the width of the cell-poor intervals. Buxhoevenden et al. (2001a,b) used this method to establish differences between minicolumn parameters in human, chimpanzee, and monkey cortex, and showed that the asymmetry in minicolumnar parameters in the planum temporali is present only in the human brain.

Extrinsic Connectivity of Postcentral Somatic Sensory Cortical Areas Thalamocortical Projections The functional organization of thalamic somatic sensory nuclei VPL/M, and their dynamic action when functioning in the relay mode, are described in Chapter 9 in the context of the core and matrix model of EG Jones (1998a,b). Briefly stated, VPL/M contain longitudinal rods of parvalbumin-labeled, thalamocortical neurons embedded in a surrounding matrix of calbindin-labeled, somewhat smaller, thalamocortical neurons, distributed thinly within but thickly surrounding the rods. Rod neurons receive place- and modespecific input generated by peripheral stimuli in large-fibered, firstorder mechanoreceptive afferents, for example, those innervating the glabrous skin of the hand, relayed through the lemniscal system to the dorsal thalamus. Different sets of place- and mode-specific neurons send bundles of axons to each of the four postcentral areas, most densely to 3b (Jones and Friedmann, 1982), creating by those projections the columns described above, and the topographic patterns of body representation within the four postcentral areas. The terminals of the axons of rod cells are concentrated in layers IV and IIIb (and thinly in layer VI), where they synapse upon excitatory and inhibitory interneurons. It is likely that all cortical neurons whose cell bodies are within or whose dendrites pass through the zones of termination of the thalamocortical axons receive synaptic inputs from them. The afferent terminals, all excitatory, form parvalbumin-immunoreactive microzones coincident with the cortical columns (DeFlipe and Jones, 1991). Separate sets of rod neurons project to the somatic sensory areas of the parietal operculum (Chapter 14). Matrix neurons compose an interdigitated but different system; they receive input from the small-fibered ascending

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systems of intrinsic spinal cord origin (Chapter 8), and project to layers I and II of the postcentral cortex, irrespective of columnar and areal boundaries.

Ipsilateral and Commissural Connectivity The postcentral somatic sensory areas are heavily interconnected, as are those of the parietal operculum, and the two sets with each other. The more distant linkages of these areas to the posterior parietal, frontal, and limbic lobes are indicated in the block diagram of Fig. 3–1. The postcentral and parietal opercular areas are homologously linked to loci matched for place in the opposite hemisphere, hand excepted; in addition, those of the postcentral group project upon the contralateral opercular group. There are two different sets of connections. Feed-forward connections originate largely in layer III of the source area and terminate in layers III/IV, and less densely to layer VI, of the target cortex. The second set is termed feedback because its axons project from what are labeled higher areas to those labeled lower. The feedback connections are axons of pyramidal cells of layer III of the source cortex, and in some cases from the infragranular layers as well, and terminate diffusely in layers I and II of the target cortex, irrespective of columnar and areal boundaries; they converge to the laminae of termination of thalamic matrix cell afferents. It is conjectured that feed-forward projections carry precise signals of the output of the processing mechanisms in the source cortex, while feedback projections may control excitability levels in some more general way (Zarzeki, 1986). Cells of origin and the terminals of ipsilateral and commissural connecting axons are arranged in coincident columns of about 0.5 mm dimension, separated in the dimension parallel to the pia by zones of about equal size in which terminal density is much lower. These columnar zones of termination are coincident with a similar distribution of the cells of origin of interhemispheric axons; in the connections between areas 3b of the two hemispheres the linkage is precisely point to point. The hand and foot regions of area 3b are virtually free of trans-callosal connections. The disjunctive pattern was discovered by Goldman and Nauta (1977) in the frontal cortex, where the columnar sources and sinks for different connections of a single area are interdigitated (Goldman-Rakic and Schwartz, 1982).

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The arrangement of the sets of ipsilateral, contralateral, and thalamic columns in the somatic sensory areas is still uncertain, but whether congruent or interdigitated the inference is that two adjacent postcentral columns may have somewhat different extrinsic connectivities.

Properties of Postcentral Neurons Determined with Methods of Single-Neuron Analysis Single-neuron analyses revealed the functional organization of these cortical areas and the dynamic actions of postcentral neurons in several varieties of somatic sensibility. Several general principles have evolved. (1) In the postcentral gyrus, as everywhere in the brain, operations are executed through the action of populations of neurons. (2) Postcentral neurons are specific for place and mode of peripheral stimuli that activate them, reflecting the properties of sets of primary afferents that project with minimal cross-modality convergence through the lemniscal system to sets of postcentral neurons. The activity patterns of neurons in the trans-granular layers are transformations of that projected input, created by intracortical processing. (3) Afferent inhibition plays a role in maintaining specificity in the system. (4) There are separate representations of the body in each of the four postcentral areas. (5) Postcentral neurons of the different modal types are distributed differentially across the four postcentral areas. (6) The postcentral cortex is organized in the columnar manner.

On Populations A major objective in use of single-neuron analysis in studies of the cerebral cortex has been to reconstruct population events. So long as recordings were made through single intracortical microelectrodes, the post hoc reconstructions preserved only the static properties of neuronal populations, and not what may be an essential component of the population signal, the timing relationships between the activity of the single neurons composing the populations. These dynamic properties of population actions are now studied by the simultaneous recording of the action of many neurons in waking monkeys working in behavioral tasks (deCharms et al., 1999; Kralik

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et al., 2001; Romo et al., 2003; Goodwin and Wheat, 2004). The half-century of study of postcentral somatic sensory areas with single microelectrodes, in anesthetized and in waking, behaving monkeys, yielded descriptions of the static properties of postcentral neurons, and of the functional organization of postcentral somatic sensory areas, the subject of much that follows.

Postcentral Neurons Are Specific for Place and Mode Neurons of areas 3b and 1 are classified in terms of their response properties which replicate those of large mechanoreceptive afferents innervating the hand. Cortical rapidly adapting (RA) cutaneous neurons are related to the rapidly adapting Meissner afferents; cortical slowly adapting (SA-I) neurons to the slowly adapting Merkel afferents, and cortical Pacinian (PC) neurons to first-order Pacinian afferents. The proportions of Pacinians in the total populations studied, including both area 3b and area 1, are 5–9 percent, and roughly equal at peripheral and central levels. SA-I afferents innervating the glabrous skin of the hand, and the postcentral neurons to which they project, provide neural representations for form and texture perception; RA-I neurons and their postcentral targets signal the varieties of stimulus motion across the skin, including the sense of flutter. PC afferents and the postcentral neurons to which they project account for the sense of high-frequency vibration. Sets of postcentral neurons with properties matching those of the Ruffini SA afferents innervating the human hand have never been identified in studies of postcentral cells in monkeys, nor have Ruffini afferents been identified in the glabrous skin of the monkey hand. Serial section studies of the distal pads of monkey fingers have not revealed a single Ruffini receptor (Pare et al. 2003). The static properties of place and mode of cutaneous cortical neurons remain relatively constant in behavioral conditions that vary from that of the waking animal working in a somesthetic task, or resting in a quiet waking state, or in the deepening stages of slowwave sleep, up to the point of somesthetic denervation of the forebrain at some levels of rapid eye movement sleep (Chapter 9). Stability obtains absent any experimental or behavioral manipulation of the input, and contrasts with the subtle changes in the dynamic functional properties of these same neurons when behavioral states do change, for example, in the level of attention.

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The sets of mechanoreceptive afferent fibers innervating the glabrous skin of the primate hand project through the parallel channels of the lemniscal system to the postcentral gyrus with preservation of their properties of place and mode; they serve selective aspects of mechanoreceptive sensibility. Yet considerable evidence indicates that the small-fibered ascending systems of intrinsic spinal origin converge upon the lemniscal relay nuclei in the dorsal column nuclei and the ventral posterior thalamic nucleus (DCNC and VPL), and in the distributed cortical system serving somatic sensibility, including the postcentral gryus itself. It remains to be determined whether these convergences are nuclear only, or both nuclear and cellular. Whether these systems remain segregated through the postcentral gyrus to its output targets is uncertain.

Peripheral Receptive Fields of Postcentral Cutaneous Neurons The receptive fields of the cutaneous neurons of areas 3b and 1 are local, single, continuous, and contralateral, except for those in a partial ipsilateral representation of the face. They vary from the smallest on the finger pads (means = 14–17 mm2), shown in Figs. 10–9 and 10–10, to those on the proximal limbs and body, shown in Fig. 10–8. The receptive fields of postcentral neurons are not isomorphic replicates of

Fig. 10–9 Receptive fields of neurons in areas 3b, 1, and 2, determined with light mechanical stimulation of the skin areas marked in black on the figurine drawings. The microelectrode penetrations were made in a line sagittal to the central sulcus in the finger/hand area, in daily recording sessions over a period of several weeks in an alert monkey trained to scan textured surfaces manually. The changes in location sequence marks the transition from area 3b to 1. The change from single to multi-fingered fields marks the transition from area 1 to area 2. (From I Darian-Smith et al., 1984.)

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Fig. 10–10 Distribution of neurons in areas 3b, 1, and 2 in the postcentral gyrus activated when a macaque monkey scanned a grating with the contralateral index finger, D2. Dot density illustrates distribution of activated neurons. The zone of thinning indicates transition to proximal regions of the finger in the transition from 3b to 1, and the broadening of the distribution at the transition from area 1 to 2 marks the appearance of multifingered fields in area 2. (From I Darian-Smith et al., 1984.)

those of the relevant first-order fibers, but representations in which afferent input, local inhibitory circuits, and central processes combine to create transforms leading to those abstracted ones thought essential in perceptual operations in form, texture, and movement sensibilities. The receptive fields of neurons are defined in terms of neuronal action potentials evoked by peripheral stimuli. Their spatial restriction is maintained over the dorsal column and trigeminal nuclear complexes and thalamic VPL/VPM nuclei, in spite of a spatial divergence evidenced by the distribution of the terminals of thalamocortical fibers, and by the subthreshold postsynaptic potentials evoked by impulses in them. The receptive field of a neuron of area 3b, defined in terms of action potentials, is surrounded by a larger field in which stimuli evoke local postsynaptic responses. This accounts for the fact that a lesion of at least 15 percent of the volume of VPL/VPM is required to produce an unresponsive area in the postcentral fields (Jones et al., 2002), and this subliminal surround allows for the rapid plastic changes in the cortical representations produced by acute lesions in the periphery (Chapter 15). Afferent inhibition is a dynamic synaptic operation in the local circuits of each of the subcortical nuclei of the lemniscal system, and in the postcentral sensory areas. It functions to limit the spatial extent of their peripheral receptive fields; and, by the inverse interpretation, the size and form of the population of postcentral cells activated by a local

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cutaneous stimulus. At the cortical level inhibition is predominantly feed-forward and postsynaptic, although recurrent intracortical pathways and descending inputs from higher level cortical areas may engage the local inhibitory circuits in the postcentral areas. There are no long-axon inhibitory neurons projecting to or between areas of the cerebral cortex. Inhibition is more susceptible to the depressing effects of general anesthetics than is excitation, and under general surgical levels of anesthesia may not be observed at all. The receptive fields of Figs. 10–8, 10–9, and 10–10 were determined with local punctate stimuli. The dynamic properties of the receptive fields of 3b neurons activated from the finger pads by moving stimuli are described in Chapter 11.

There Is a Somatotopic Representation of the Body Form in Each of the Four Postcentral Areas Merzenich and his colleagues discovered two complete and separate representations of the hand in the postcentral somatic cortex where only one had previously been thought to exist (Paul et al., 1972a,b, 1975). This led to the discoveries that there are separate representations of the entire body in each postcentral area, 3a, 3b, 1, and 2 in simian primates. They differ in the modality properties of constituent neurons, and in their roles in the central neural mechanisms in somatic sensibility. Wall and colleagues discovered a plasticity of the central synaptic connections of subcortical components of the somatic system in rodents and cats (Wall and Egger, 1971; for review, see Wall, 1976). This phenomenon has since been studied intensively by Merzenich, Kaas, and others; for review see Buonomano and Merzenich (1998). Somatic sensory cortical maps are now known to be dynamic constructs, and are changed during development and learning, and by training or by change in afferent input (Chapter 15). Maps of the representation of the skin in areas 3b and 1 of the postcentral gyrus of the Old World cynomologus monkey (Macaca fascicularis) are shown in Fig. 10–11. The maps have the following characteristics: 1. They are somatotopic; that is, a given zone of peripheral tissue is represented in a given zone in the cortical area, and the several cortical zones are fitted together to form the

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Fig. 10–11 Representation of the body surface in areas 3b and 1 of the cynomolgus monkey, shown on the surface of the left hemisphere, unfolded from the central sulcus and the medial wall. Cortex activated from the designated body surfaces outlined, and those for the digits are numbered (D1–D5). The shaded areas indicate representation of the hairy skin on the dorsal surfaces of the digits. Dotted line—central sulcus; dashed line—region on the medial wall containing portions of areas 3b and 1; heavy line—order between areas 3b and 1. The map was constructed from those obtained in detailed micromapping experiments in several animals, and combined based on overlap. (From Nelson et al., 1980.)

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precisely ordered, tail-to-tongue sequence of representation known from studies of both monkeys and humans. 2. Two adjacent skin areas may be represented in separated cortical zones, and vice versa. Yet when a peripheral stimulus extends or moves across the boundary of two skin zones distantly represented in the cortex, there is no spatial discontinuity in the perceptual experience. This suggests that the somesthetic perception of a continuous extension or movement of the stimulus is integrated at some higher level where the two spatially separate representations may converge; but there is no direct evidence for this conjecture. 3. The patterns of representation in areas 3b and 1 are mirror images for some but not all body locations. The hand is represented in 3b with fingers pointing anteriorly, and in area 1 with the fingers pointing posteriorly, as shown by the results obtained in rows of penetrations made along a forward to backward line across 3b and 1 (Fig. 10–12), and by the mapping experiments of Darian-Smith et al. (1984), made in waking macaques (Figs. 10–9 and 10–10). Cutaneous neurons of areas 3b and 1 of glabrous skin hand area subtend single-fingered receptive fields. The mirror image representation of the hand and fingers in areas 3b and 1 has been observed also in imaging studies in the human postcentral cortex (Blankenburg et al., 2003). The transition from area 1 to 2 is marked by the appearance of multifingered receptive fields, and that from area 2 to area 5 by the appearance of cutaneous neurons with bilateral receptive fields, and projection and grasping neurons active only during willed movements (Mountcastle et al., 1975). 4.

In both brains the representations in 3b are 30–40 percent larger than are those in area 1; the difference may approach 3 to 1 in the representations of the hand/fingers and foot/toes. No single scaling factor relates peripheral innervation density to the area of cortex within which a part is represented, although a general inverse relationship exists. An increased area of representation is interpreted to mean a finer representation with greater

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Fig. 10–12 Receptive fields of neurons studied in two rows of penetrations made in anteroposterior lines across the separate hand/finger representations in areas 3b and 1 of an owl monkey. Each of the two rows show similar progressions of receptive fields from digit tip to palm and back again. The reversal point is at the 3b-1 border. The digits are symmetrically represented in mirror image in the two areas. Shaded areas, representation of hairy skin of dorsal surfaces. (Data from the experiments of Merzenich et al., 1978, published by Kaas, 1987.)

stimulus resolution, and more elaborate local circuits for intracortical processing, but there is little direct evidence for these assumptions. 5. Further experiments have shown that there is a complete representation of the body form in areas 3a and 2; the four maps are shown for the macaque in Fig. 10–13. 6. Area 3b is considered to be the homologue of somatic area I (SI) described in many nonprimates. 7. The sizes of the maps and of the proportional areas of the zones within them vary between individuals of the same species, sex, and age, in owl and squirrel monkeys (Merzenich et al., 1987).

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Fig. 10–13 A summary of the separate representations of the body in the four areas of the postcentral gyrus of the macaque monkey. Data from several microelectrode mapping experiments in anesthetized animals: for 3a and 3b from Nelson et al., (1980) and Pons et al. (1985); details on the cutaneous intrusion into areas 2 and 5 from Pons et al. (1985). Drawing at upper left indicates postcentral gyrus opened up and displayed to the right. D1–D5—digits of hand or foot; FA—forearm; LL—lower lip; occ.—occiput; should.—shoulder; UL— upper lib; wr—wrist. This synthesized map is from Pons et al. (1987).

Neurons of Different Modalities Are Differentially Distributed in the Four Postcentral Areas Neurons of different modalities are differentially distributed between the four cortical areas. The differences are not absolute, and when modal types are mixed in an area they are arranged in separate, mode-specific columns. The distribution of joint and cutaneous neurons between areas 3b, 1, and 2 in the arm area of the postcentral gyrus is given by Mountcastle and Powell (1959b) and Gardner (1987). It was later discovered that Group I muscle afferents project to area 3a (Phillips et al., 1971; Lucier et al., 1975; Hore et al., 1976; Wise

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and Tanji, 1981; Wiesendanger and Miles, 1982). These distributions differ between different mediolateral locations in the postcentral gyrus; for example, in the hand zone there is a posterior extension of cutaneous neurons into area 2. The slowly and quickly adapting neurons are preferentially but not wholly restricted to area 3b and 1, respectively, at least not in the macaque monkey. The two sets are mapped in an intermittently recursive manner in the finger representation zones in area 3b (Fig. 10–14), where the cell types are arranged in separate columns (Sur et al., 1984).

Fig. 10–14 Evidence for the modular organization of postcentral neurons adapting slowly and quickly to sustained mechanical stimulation of the glabrous skin of the fingers: the strong inference is that they are activated selectively by the slowly and quickly (Merkel and Meissner) first-order afferents innervating the glabrous skin. Upper right: Outline drawing of the macaque brain; the four dots indicate loci of entry of the four microelectrode penetrations detailed below. Upper left: Outline drawing of the portion of area 3b explored in the four penetrations; numbers on the lines correlated with numbers of the receptive fields shown lower left. Synthetic drawing lower left shows the separate bands of representation of the two classes of neurons, with some overlap. (From Sur et al., 1984.)

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The projection of type I muscle afferents to area 3a is interpreted by many as evidence that stretch afferents from muscle play a role in conscious somatic perceptions, for example, in position sensibility. Others conjecture that this is the input stage for cortical loop reflexes operative in the control of movement without conscious perception. In this regard, it has been shown in several neuronographic experiments in waking humans that electrical stimulation of isolated type I muscle afferents evokes no conscious sensation at all, in contrast to the clear cutaneous sensations evoked by stimulation of single cutaneous afferents innervating the glabrous skin of the hand (Torebjork et al., 1987; Macefield et al., 1990). Stimulation of most isolated joint afferents innervating the fingers elicited sensations referred to the joints (8/11), and in half of the 8 in this series stimulation evoked a sense of joint displacement. It has been suggested that simultaneous activity in several stretch afferents may be required to evoke a conscious perception, but there is no direct evidence for this conjecture. However, there is evidence that stretch afferents from the short muscles of the hand play a cooperative role with joint and cutaneous afferents in signaling the position of the fingers at their joints (McCloskey, 1978), described in Chapter 11.

Imaging Studies of Postcentral Somatic Sensory Areas in Normal Humans The use of imaging and direct recording techniques in study of the waking human brain have changed the clinical neurological disciplines in a radical way, and their use is pervasive in neuropsychological studies of language, perception, memory, cognition, and so forth, in normal humans, including the distributed cortical system for somatic sensibility. The methods used are positron emission tomography (PET); functional magnetic resonance imaging (fMRI); magnetic and electrical recording from the surface of the head (MEG, EEG); recording of the intrinsically generated or reflected changes in light emission associated with changes in activity; and, where therapeutic measures allow, recording from and stimulation through electrodes implanted within the brain. Results obtained with imaging reveal a dynamic geography of the cerebral cortex previously unknown. These geographic discoveries have been made with methods that record second-order events that veil the details of the neural activity that produces them. Further development of these

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methods promises to solve this problem by improving their spatial and temporal resolving powers (Ogawa et al., 2000; Kim and Ogawa, 2002; Urgurbil et al., 2003). Logothetis et al. (2001), for example, have studied the relationship between the neural activity evoked in the monkey visual cortex by a visual stimulus, recorded with an intracortical microelectrode, and the changes in blood flow evoked by the same stimulus, recorded with MRI. Changes in blood flow are better correlated with local field potentials than with the multiunit record of neuronal impulse activity. The inference is that the blood oxygen level is determined in parallel with active presynaptic and postsynaptic local responses, regarded as the input signals to the local region of cortex, and much less by neuronal impulse activity, regarded as the output signals of the local cortical region. Grinvald and his colleagues have developed methods for the direct measurement of intrinsic cortical activity, and its relationship to the associated changes in blood flow, based on imaging spectroscopy of intrinsically generated light emissions (Malonek and Grinvald, 1996), and more recently have used long-term voltage sensitive dye imaging to study cortical dynamics in waking monkeys over periods of time up to 1 year (Slovin et al., 2002). The results obtained in studies of the somatic sensory cortical system with these methods are summarized as follows (Paulesu et al., 1997). 1. The pattern of representation of the hand in the human postcentral gyrus has been documented, as well as the representations of the fingers in areas 3b and 1, with partially shifted overlap (Maldjian et al., 1999a,b; Francis et al., 2000; Burton, 2002; McGlone et al., 2002), and in humans and monkeys with high-resolution imaging (Shoham and Grinvald, 2001). 2. The variability between human subjects in the affective and cognitive overtones of some somatic sensory experiences, including painful ones, is paralleled by variation in the number, amplitudes, and patterns of activity in cortical areas activated by those stimuli. 3. Moore et al. (2000) have demonstrated with fMRI the differential projection of somesthetic modalities to the several postcentral fields in the human brain (Fig. 10–15).

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Fig. 10–15 Average tactile and kinesthetic/motor maps in the pre- and postcentral gyri in humans determined with fMRI. and averaged for five subjects. A: Left, a gray matter–white matter reconstruction; middle, an inflated reconstruction where dark areas are sulci, light areas are gyri; right, a flattened reconstruction oriented over the hand area of the central sulcus. The box outlines the region expanded in the flattened reconstruction; white arrows mark the central sulcus. B: Activation patterns from five subjects outlined for each by gray lines and white fill. These were projected onto the flattened reconstruction for a single subject after transformation into the representational space. Tactile activation is on the left, kinesthetic–motor on the right. Solid black lines indicate areal borders, derived from sulcal/gyral anatomy and extending the mediolateral length of the hand area. C: The average tactile (left) and kinesthetic-motor (right) activation patterns projected onto the same brain as in B. (From Moore et al., 2000.)

4. Modality specificity declines and convergence increases with progression into the networks beyond the first cortical representations in the somatic system, which raises the question of how modality specificity is preserved from its initial exquisite representation in the postcentral areas to its equally precise component of perceptual experience. Convergence occurs in such far-field targets as the cingular gyrus and the premotor cortical fields. At these levels it is likely that each contributes to the neural activity evoked by any one of the sets of afferents reaching it, combined with attributes generated by its own internal operations, and with signals in its extrinsic connections. A very large literature has accumulated; for general reviews see Raichle (1998), Casey (2000), Treede et al. (2000), and Burton (2002). For reviews of methods, see Toga and Mazziotta (1996) and Frakowiak et al. (1997).

Complexity of the Somatic Afferent System The somatic afferent system is a complex of several superimposed systems. The skin, muscles, and joints of the primate hand are innervated by as many as 14 sets of primary afferent fibers; the number depends on classification criteria (Table 4–1). Under normal circumstances each of these transduces and encodes particular and different properties or sets of properties of stimuli reaching or obtained by the hand. The specificity of these sets of afferent fibers, long known from studies in nonhuman primates, has been confirmed and extended in human neuronography: stimulation of single fibers in the peripheral nerves innervating the glabrous skin of the hands of waking humans evokes a single mode of somesthetic experience, no matter what the stimulation frequency. The problem is how these several superimposed peripheral sets project into the somatic sensory afferent pathways of the spinal cord, thalamus, and cortex in such a way as to provide both the isolated signals necessary for perceptual identifications of the specific and different varieties of somatic sensations, and at some stage of the system the convergence thought necessary for more complex sensory experiences. There are at least four ways. The first is by channeling and parallel processing. The large mechanoreceptive afferent fibers project in fascicles via successive relays through restricted channels in the dorsal column, medial lemniscal system, without supraliminal

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cross-modality convergence (Chapter 9). Second, in the evolutionary transition from prosimians to simians the areas of the postcentral somatic sensory cortex become more clearly differentiated, each with a representational map of the body surface, and each with a differential segregation of different somatic modalities. Third, within any cell of an X–Y map of a postcentral area two or more modes are mapped in an intermittently recursive way, so that two or more can be represented in a single X–Y map (Fig. 10–15). Fourth, the dynamic mechanisms of afferent and feedback inhibition tend to constrain convergence between adjacent channels with different modespecific neuronal elements. Suprathreshold convergence occurs in trans-postcentral cortical areas “more central” than the primary receiving areas.

Evolutionary Development of Somatic Sensory Areas Absent living forms that may have been in the direct line of descent, comparative neurobiologists study extant species regarded as living products of several evolutionary lines. Knowledge of the somatic sensory areas has rapidly increased since the application of the micromapping method in studies of a large number of mammals. The general result is that all four of the anterior parietal fields, clearly defined in the postcentral gyrus of simians, are present in monotremes, marsupials, rodents, carnivores, and prosimians. The areas of the parietal operculum (SII plus others) described in Chapter 14 are equally ubiquitous. Mapping findings in many species have been correlated with cortical architecture and connectivity; see Carlson and Welt (1980); Carlson and Fitzpatrick (1982), Carlson et al. (1986), Kaas (1989, 1995, 2002), Krubitzer and Calford (1992), Sur (1993, 1995), Krubitzer (1995), and Slutsky et al. (2000). No claim is made that the four anterior parietal areas are fully differentiated and serve different aspects of somatic sensibility in all mammals as they do in simian primates. Prosimians have relatively primitive capacities for detection and discrimination with their hands in some spheres of somatic sensation, as compared to simians, although they possess in poorly differentiated form the several anterior parietal fields. The marmoset, one of the most primitive simians, possesses all four anterior parietal fields but has inferior capacities for complex somesthetic tasks such as texture discrimination, compared with the simian macaque (Carlson, 1990; Carlson and Nystrom,

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1994). The evolution of somatic sensory fields is a gradual process over the range from prosimians through simians, with an increasing differentiation in terms of properties of sensory stimuli represented in cortical areas, and the roles of those areas in somesthesis. The surface of the human cortex at 2600 cm2 is three orders of magnitude larger than that of the most primitive prosimian or that of the mouse; thickness increases only two to four times. The cortex of these small mammals is almost completely occupied by what were earlier regarded as “primary” motor and sensory areas, while in the human these areas occupy no more than 5–7 percent of the total. A large proportion of the remaining neocortex in humans and other simian primates is occupied by what are termed “higher order” motor and sensory maps. Initial cortical somatic sensory representations, such as that of the hand in area 3b, are specified by primary afferent mapping parameters of place and modality, but these are followed in higher level somatic sensory areas by maps defined by the movement, direction, texture, and form of somatic stimuli. The number of identified cortical fields ranges from about 15 in the most primitive prosimian to perhaps 100 in humans, of which 12–15 are involved in the cortical mechanisms of somatic sensibility. Central to these problems is a more general one: upon what source of variability did evolution operate selectively to yield the enlargement of neocortex, and the multiplicity of cortical areas? For example, how did Old and New World simian primates, separated by 40–50 my of evolutionary history, both evolve four postcentral somatic sensory areas, with similar differential distributions of modalities across them? Such an evolutionary convergence might be due the fact that both New and Old World simian primates adapted to life in the trees, where the rapid perception of the size, shape, slipperability, and so forth of tree limbs had value for survival, as did rapidly evolving binocular vision. Discoveries of the last three decades have clarified many details of the generation of the cerebral cortex, and its genetic control (Rakic, 1988, 1995, 2000, 2002; Donoghue and Rakic, 1999; Rubenstein and Rakic, 1999). Early in gestation the incipient cerebral ventricles are lined with a sheet of generative epithelium, the ventricular zone (VZ), which is distributed in two dimensions and from which the cerebral cortex is formed, together with a contingent of GABAergic interneurons arising from the ganglionic eminence. The size and areal specificities of the adult cortex are largely determined by the mode

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and tempo of cell divisions within the VZ. In the monkey, cell division occurs in the 60-day period from E-40 to E-100 of the 165-day gestational period; in that time about 25 cell cycles occur in the VZ. During about the first half of the cell cycles all divisions are symmetrical, so that the VZ enlarges exponentially. At about midpoint asymmetrical division begins to produce neurons that migrate over glial guide fibers to the cortical plate, terminating in layers from the inside out. Neuronogenesis begins slowly, so that the departure rate of new neurons is less than 0.5 of all divisions, and the VZ continues to enlarge. With further time and cell cycles the departure rate increases dramatically, and a final surge produces the hypercellularity of the late forming layers II–IV, as compared with layers V–VI. Cell division then ceases, and the VZ is replaced by nongenerative columnar epithelium (Kornack and Rakic, 1998; Takahashi et al., 1999; Caviness et al., 2000). The cell type, whether pyramidal or interneuron, is determined for each new neuron one or two divisions before final migration (Desai and McConnell, 2000). All these events are controlled by regulatory genes, and are thus open to change by mutational events that could affect one or more of the steps outlined. The inherent variability of the series of time-dependent events allows some of the variability required for natural selection (Rakic, 1988, 1995, 2000; Kornack & Rakic, 1995; Kornack, 2000). These observations support an hypothesis concerning the evolution of the neocortex; that is, that a small modification (a mutation) of the genes controlling one or more of the processes of cortical generation could account for the enlargement of the cortex and the appearance of new areas in phylogenesis. Kaas and Krubitzer and their colleagues propose a different hypothesis to explain neocortical expansion and the formation of new areas (Kaas, 1989, 1995, 2002; Krubitzer, 1995; Northcutt and Kaas, 1995). That is, new cortical areas evolve when the cortex is “invaded” by new sets of correlated inputs, presumably generated in new sets of primary afferent fibers, and produce new sets of cortical modules that over many generations coalesce into new areas. They cite as an example the evolution of the four areas of the postcentral somatic sensory cortex. The development of several somatic sensory areas each with a complete representational map appears to have progressed in step with the development of specific, differentiated, sets of primary afferents innervating peripheral tissues. Multiple maps occur in species with hand-like structures. This is not confined

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to simians, for multiple maps have been described in raccoons and gray squirrels, both of which use hand-like appendages with dexterity. This lends support to the hypothesis that new cortical areas form through the segregation of sets of modules activated selectively by the same set of primary afferents. It seems likely that both of these mechanisms function in the evolutionary expansion of the neocortex, and the formation of new areas, and that one or another may dominate in one species or another.

On Mapping Central neural representations of the body form are topographic in the sense that there is an orderly relation between the spatial distribution of primary afferent fibers and their central projection targets, and that these relations are maintained through several transitions from periphery to cortex. They are not topological transforms of the natural disposition of the body parts, for there are interruptions and transpositions in the cortical maps so that some adjacent body parts are represented in cortical areas that are not contiguous; the result is a composite, or somatotopic, representation of the body form. No case has yet been described in which any two of the multiple maps of the body form in any given neocortex are exactly identical. Each somatic sensory map replicates some particular subset of the anatomical and physiological properties of the system. At each stage in the development of neuroscience the experimental methods available have been adaptable to the mapping experiment. When executed with care, this technically demanding experiment has often yielded new discoveries; for example, early mapping studies elaborated the general idea of an orderly projection of afferents to the postcentral gyrus, and led to continuing studies of these relationships, initially with the evoked potential method and then to that of single-neuron analysis applied first in anesthetized primates and later in waking primates as they executed somesthetic tasks. Preoccupation with mapping derives, in part, from the cerebral organ concept of nineteenth century neurology, a legacy from Franz Joseph Gall (Temkin, 1947; Critchley, 1965; Young, 1970). That is the idea that the cerebral cortex is “divided” up into separate organs that, at some level of independence, execute certain brain functions more

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or less in isolation. This concept of the cerebral cortex is now being gradually replaced by others, but we are still haunted by the question: Why cortical maps at all? The question of what selection pressure led to the development of multiple cortical maps in sensory systems, and what advantages they provide for cortical neuronal processing of sensory input, has been the subject of much study and speculation (Phillips et al., 1984; Barlow, 1986; Kaas, 1995). The several cortical maps in each of the primate sensory systems are activated both in parallel and in series, and are heavily interconnected. Different stimulus parameters are mapped to the X–Y dimensions of different cortical maps. With further steps into the cortical processing systems, more abstract stimulus features are mapped, the topographic property of maps becomes less prominent, and finally maps for abstracted features appear that are independent of input topography. It is surmised, without direct proof, that the final association of outputs of these several processing locations projects into distributed systems to produce the neural image of a perceptual whole in the dynamic activity of the neocortex and its linked appendages. Such a system presents several advantages for neuronal processing: 1. Parallel processing in several chains of maps is a time saver, compensating to some degree for the processing operations of single neurons. 2. Parallel processing and population coding compensate for the limited dynamic range of single neurons or small groups of neurons. 3. Parallel processing in several spatially separate chains of maps may allow the survival of some (reduced) capacity for perceptual operations after lesions of a part of the cortical somatic sensory system. 4. In somatotopic maps such as those in the postcentral gyrus sets of neurons that commonly interact are placed close together; that is, neurons with different modality or dynamic functional properties are frequently found in adjacent or nearby columns in the postcentral gyrus. Adjacency decreases interaction time and the distance requirement for the axons of interacting cells.

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The development of many maps in the somatic system parallels that of several sets of large-fibered mechanoreceptive afferents innervating peripheral tissues (Chapter 5), as well as their projection to the cerebral cortex in quasi-isolation from each other and from other components of the somatic afferent systems. The selection pressure met by this massive parallelism may have been the need to make rapid and accurate discriminations between different properties of stimuli encountered by the hand: between smoothness/roughness, hardness/softness, movement and direction, curvature and orientation, texture, form, and vibration. Each of these might evoke different motor patterns of response necessary for successful life in the trees.

Functional Implications of Cortical Maps The partially shifted, smoothly progressive, intermittently recursive, and overlapping representation of the sensory surface in the X–Y dimension of the maps in the somatic sensory cortex has important functional meaning. In the simplest case, it allows the correlation of two spatial variables in specifying the spatial location of a peripheral stimulus. In combination with short-range axonal projections, it allows for rapid integration of activities in neighboring modular elements. The combination of columnar organization with intermittently recursive mapping of different modalities within each of the X–Y specified cells of a spatial map permits the mapping of several modalities in the two dimensions of the cortical surface. It appears likely that when in primate evolution the pressure grew for cortical representation of the many different modalities, the emerging solution was the appearance of several separate maps in the cytoarchitectural divisions of the postcentral gyrus, with the resulting capacity to represent a number of modalities within those cortical sensory areas. This representation style allows for continued functional integrity in the face of randomly distributed cell death, for a continuous representation of the form of spatially extended peripheral stimuli and of their movement and direction of movement. The occasional interruptions and intermittencies in the cortical maps do not interrupt the perception of stimuli whose spatial representations overlap them. The precise locus-to-locus registration of sensory and motor maps enables the spatial direction of cortically dependent sensory–motor transitions, such as the elegantly directed placing reactions of the hands of primates (Bard, 1937). Finally, the registered

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coupling of feature maps in the distributed systems of the cortex beyond primary sensory areas allows the correlative interaction of many variables in the ongoing dynamic activity conjectured to be the neuronal embodiment of perception. If the definition by Knudsen et al. (1987) of computation as “any transformation in the representation of information” is correct, then all maps are computational, for I know of no map in the somatic afferent system—or indeed in the brain—in which there is not a transformation. What is true is that with further projection into and through the somatic areas of the postcentral gyrus and the parietal operculum, the balance between computation and topographic representation shifts toward the former, and I conjecture that at even higher levels computation may be the dominant theme of operation, even in the absence of signals of place.

Summary: General Principles Predicted from Structure and Connectivity Several general principles of the organization of the somatic afferent system and the somatic sensory areas of the cerebral cortex have emerged from studies of structure and connectivity, and to a degree are predictive of dynamic activity of the system. 1.

Somatic afferent systems are modular in nature; they consist of parallel processing channels specific for modality and place.

2. Central neural images are not isomorphic to body form; they are somatotopic, and are determined in part by peripheral innervation density. The “maps” for different somatic sensory modalities may differ substantially. 3. Central neural images are abstracted constructions, and result from the combination of the afferent signals evoked by peripheral stimuli, the memorial residua of previous perceptual experiences, and central affective–cognitive set. 4. Specificities for place and mode within the lemniscal components of the system are maintained by limited divergence at synaptic junctions, and by dynamic mechanisms, including afferent inhibition.

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5. Afferent activities evoked by peripheral stimuli in both the lemniscal system and those of intrinsic spinal origin frequently converge to evoke the final somatic sensations. 6. Cortical somatic systems are composed of local cortical processing nodes linked together in distributed systems. The relevant signals for somatic perceptions are embedded in the dynamic activity in those systems. 7. The large-scale spatial dispositions in the major afferent pathways and central targets of the somatic afferent system are determined by genetic factors, and can be described at the first level of analysis by anatomical criteria. A major discovery of recent decades is that the detailed representational maps within these gross anatomical structures are dynamic and plastic. They can readily be modified by changes in peripheral afferent input reaching them. I treat this general subject in Chapter 15.

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Dynamic Neural Operations in Somatic Sensibility

A general aim of perceptual neuroscience is to discover the peripheral and central neural events evoked by sensory stimuli, and the correlations between them and the perceptual performances they evoke in humans. This endeavor is part of the more general aim of present-day Neuroscience, to provide an objective account of the dynamic neural operations of our mental life, as Parker and Newsome emphasized in their review of 1998. This chapter is the first of three in which I describe dynamic operations in the somatic system. Wherever available I shall emphasize the results of experiments in which psychophysical and neurophysiological measures were made simultaneously in primates working in somatic sensory tasks. The general result is that the primary afferents innervating the primate hand, and the central neurons of the lemniscal system upon which they project, produce neural signals of cutaneous stimuli in correspondence with the perception of those stimuli by primates. The term dynamic refers to the changing patterns of activity in peripheral and central neural populations on time scales from 0.1. to 1.0 sec. It includes how evoked neural activity is modified in central targets, influenced at all levels by local processing mechanisms and by convergent central control systems, as well as how neural ensembles are further “processed” and projected into the distributed cortical somatic system, leading to perception and, at will, to motor response. The present state of knowledge of dynamic operations is more complete for the first-order levels of the system than for any other.

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Each of the four sets of large-axoned mechanoreceptive afferents innervating the glabrous skin of the human hand (three in monkeys) transduces a particular profile of stimulus properties, and transmits signals of them over restricted-throughput pathways to the cerebral cortex, and to perception. In ordinary life two, three, or even all four of these sets of tactile afferents may be activated simultaneously, for the surfaces of objects scanned or grasped by the hand have a panorama of stimulus properties, not restricted to those used in laboratory experiments. They are commonly either warmer or cooler than the glabrous skin, temperature differences signaled simultaneously by specific warm and cool fibers that innervate the glabrous skin in a continuous overlay with the innervation by the large mechanoreceptive afferents. How signals in these six sets of afferents, leaving aside those sensitive to noxious stimuli and the proprioceptive afferents from deep tissues, are integrated in the brain to form a complete perception remains a subject of intensive study and speculation. These neural images are conjectured to be stored in short-term memory and, when compared with those previously stored, lead to perception. This program of research exposes many general questions. What are the perceptual thresholds and ranges of operation of primates using their hands in detecting and discriminating between the locations and intensities of tactile stimuli, the features of surfaces scanned by the hand, or the three-dimensional geometry of objects grasped by the hand? How are the properties of peripheral stimuli transduced and encoded by first-order afferents that innervate the hand, and how are these codes transformed by central processing? What are the central neural mechanisms for detecting, rating, and discriminating between peripheral stimuli, and so on. Success in somatic sensory research in the last decades has been enabled by discoveries made with a variety of methods applied at several levels of the somatic afferent system (Fig. 11–1). In particular, the anatomy of the somatic system has been enriched by accumulating knowledge of the structure, microstructure, and connectivity of the system, and of the cellular and molecular properties of synaptic transmission within it. Representations of the body form within the system have been described in preceding chapters. Each class of mechanoreceptive afferent fibers innervating the glabrous skin differentially transduces and encodes in trains of action potentials a particular property of mechanical stimuli. The thresholds and ranges of somesthetic experiences are set by the

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Fig. 11–1 A schematic outline of the order of neuronal operations thought to lead from stimulus to perception. Below: the classes of experiments used in study of these processes. S = stimulus.

initial transduction and encoding of sensory stimuli at peripheral axon terminals. This first-order representation of stimulus qualities is transmitted through the lemniscal afferent system and into the early trans-synaptic stages of postcentral somatic sensory areas. Each of these afferent chains, four in humans and three in monkeys, links to a different perceptual channel and function, a cortical and perceptual expression of the labeled line concept. Three classes of afferents innervating the glabrous skin have similar properties in humans and monkeys. The spectacular success achieved by microneuronography in humans has confirmed and extended many of the conclusions inferred by correlating activity in monkey nerves with human sensory experience.

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Experimental Sequence Research in somatic sensibility begins with psychophysical study of mechanoreceptive sensibility, in monkeys and in humans, and continues by describing the initial transduction and encoding of mechanical cutaneous stimuli in first-order afferent fibers innervating the glabrous skin of the hand. Neural codes are identified at the level of first-order fibers by a process of testing and elimination of hypotheses to find the code that varies in correspondence with psychophysical measures. This is followed by single-neuron studies of the afferent transition nuclei and cortical projection areas in waking monkeys as they execute somesthetic tasks. These combined experiments have revealed that transformations of the primary input patterns appear and are further elaborated in the primary sensory cortex. It is conjectured that these are the first steps toward more abstract and perhaps more efficient representations in the distributed cortical system serving somatic sensation. Methods now allow study of large samples of neurons in central populations, observed simultaneously via many microelectrodes. The hypothesis under study in these experiments is that subtle aspects of the neural reflection of sensory events may be signaled by the temporal and spatial relations between the impulse patterns of many neurons. More recently, efforts have been made to correlate discoveries made in studies of nonhuman primates with the results of imaging studies in normal, waking humans (Burton, 2002).

Neural Coding in the Somatic System Neural signals in the somatic system are commonly trains of nerve impulses that transmit information from one point to another, or from the periphery to central neural structures. Neural codes define and limit an observer’s capacity to detect and to discriminate between somatic sensory stimuli. Study of neural coding in the system involves seeking that set of neural signals from which one can predict the sensory experience evoked by the peripheral stimulus, and for which there is a correspondence between the variations in peripheral stimuli, the sensory experiences evoked by them, and the candidate code. Predictability and correspondence are the crucial tests for the validity of a code (Johnson et al., 2002). The second problem is to discover what neural operation links the input neural code to the observed behavior.

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Established codes in the somatic afferent systems may be: •

Intensive, in which variations in stimulus amplitude are signaled by changes in the differences in frequencies of discharge. The information for amplitude alone can in principle be derived from the action of a single fiber, but other attributes—orientation, shape, form, contour, and so forth— are signaled by populations.

•

Temporal, in which the temporal order of impulse discharge provides critical information about the stimulus, and predicts the evoked sensory experience, for example, the role of rapidly adapting (RA) afferents in signaling the low-frequency sense of flutter (Chapter 12).

•

Population, in which the relevant information is signaled by the spatial and temporal distribution of activity in a population of fibers in correspondence with the spatial and temporal attributes of the stimulus, for example, the function of the slowly adapting type I (SA-I) afferents in signaling the texture of mechanical stimuli to the glabrous skin. Neural populations are now intensively studied in neurophysiology; for reviews, see among many those by Doetsch (2000), Pouget et al. (2003), Sanger (2003), and Goodwin and Wheat (2004).

An important addition to each of these codes is the modal code of the labeled line. Afferent impulses in the mode-specific mechanoreceptive afferents innervating the glabrous skin of the hand evoke the same sensory experience no matter how they are activated, or how frequently they discharge. The concept of the labeled line originated from Bell (1811), and was defined explicitly by Muller (1840). The belief emerged that there are specific nerve endings and afferent axons that when active evoke specific sensory experiences and not others. The code of the labeled line has been confirmed in microneuronographic experiments in waking humans by electrical stimulation of single afferent fibers; for review, see Vallbo et al. (1984), Torebjork et al. (1987), and Macefield et al. (1990). In some instances what appear to be elegant neural codes at the input level of the nervous system evoke no conscious perception. For example, the SA-I afferents under drive by steady indentation of the skin may be entrained to rhythmic discharge by superimposed low-frequency

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mechanical sinusoids, at amplitudes an order of magnitude below the human or monkey thresholds for detecting those sinusoids. The rhythmicity in the SA-I afferent discharge is not perceived, and the signal is experienced as steady pressure. The rhythmic pattern fails the code tests of predictability and correspondence. It may be used in functions other than perception.

Cutaneous Afferent Channels of the Lemniscal System The ontogenesis, structure, and general biology of the Meissner, Merkel, and Pacinian afferents are described in Chapter 5; their general properties in humans are summarized in Figs. 11–2 and 11–3 (Vallbo & Johansson, 1984). These parallel chains of neurons project through the nuclei of the lemniscal afferent system to the postcentral somatic cortex. Their functional properties are preserved with limited cross-convergence through the early intracortical synaptic operations. One can then speak of the SA-I, RA, and Pacinian (PC) “systems” to describe the sets of neurons linking Merkel, Meissner, and Pacinian receptors, respectively, to the cerebral cortex, and one can also speak of SA-I, RA, and PC postcentral cortical neurons. These three systems serve different forms of mechanoreceptive sensibility on the glabrous skin of the hand. SA-I afferents adapt slowly to skin indentation by mechanical probes, and provide graded signals of the degree of skin indentation/pressure. They are especially sensitive to movement of stimuli across the skin, and signal in their population discharge the spatial form and surface structure of objects that reach or are grasped by the hand. They respond strongly to points, edges, and contours with high spatial resolution. The RA quickly adapting Meissner afferents are relatively insensitive to steady skin deformations, but signal with precision the details of stimuli that produce minute skin movements such as flutter. An important function is their sensitivity to slip, and they serve as feedback sensors regulating grip control. The quickly adapting Pacinian system resolves spatial detail poorly, but is exquisitely sensitive to high-frequency mechanical sinusoids, sensed either directly or through hand-held instruments. The filtering function of the Pacinian corpuscle isolates its nerve ending from low-frequency mechanical events encountered by the hand. The slowly adapting type II (SA-II) afferents are thought to terminate peripherally in Ruffini organs. They have been identified in

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Fig. 11–2 Characteristics of FAI (RA—Meissner’s) and SAI (SA—Merkel’s) primary afferents innervating the glabrous skin of the human hand, studied by microneuronographic recording in the peripheral nerves of waking humans. A—Receptive field sizes, for 15 of each type, determined with forces at 4–5 times threshold in each case. Graphs indicate cumulative curves of receptive field sizes for the four types; data based on sample of 255 afferents. Solid curves refer to FAI and SAI afferents, respectively. B— Microstructure of typical receptive fields of the two types; lines are isosensitivity curves; graphs plot thresholds determined along the straight lines shown on the field maps, ordinates are multiples of the lowest threshold (T). C—average density of the two types in the indicated skin areas. (From Vallbo and Johansson, 1984.)

recordings from human peripheral nerves by their functional properties, notably an exquisite sensitivity to skin stretch and to its direction. The SA-II system is well known for the hairy skin and the transitional skin on backs of the fingers and hand in humans, in whom it contributes to the perception of movement of the fingers at their joints, and to changes in hand conformation. However, Ruffini

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Fig. 11–3 Characteristics of the FAII (Pacinian) and SAII (?Ruffini) afferents innervating the glabrous skin of the human hand, studied by microneuronographic recording in the peripheral nerves of waking humans. Solid lines in graphs of A refer to FAIIs and SAIIs, respectively. For the SAIIs, arrows indicate the direction of skin stretch evoking increases in responses. Data display otherwise similar to that described for Fig. 14–2. (From Vallbo and Johansson, 1984.)

organs are not present in the glabrous skin of the monkey finger, and only one such receptor was identified in a study of the glabrous skin of human fingers (Pare et al., 2002b, 2003). There is no question of the validity of the identifications of these stretch-sensitive afferents made in microneuronographic recordings in waking humans, but uncertainty remains concerning the peripheral terminations of SA-II afferents in the glabrous skin of human finger pads. For reviews, see

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Vallbo et al. (1984), Vallbo and Johansson (1984), and Torebjork et al. (1987). SA-I afferents with receptive fields on the sides of the distal pads of the monkey finger, where there are no Ruffini organs, are sensitive to skin stretch (Bisley et al., 2000). The inference is that a subset of SA-I Merkel afferents in monkey respond to skin stretch because of the special relation of their terminals to the tissue strain produced by stretch. Pare et al. (2002b) describe linear chains of Merkel cells in the finger tip skin of the monkey, innervated by single myelinated afferents, which appear disposed to signal skin stretch. Until now, however, no neurons with SA-II properties have been observed in studies of the postcentral gyrus in waking monkeys. The exquisite stretch sensitivity of SA-II afferents innervating the human hand may contribute to the elegant control of the position and movement of the human fingers, and may represent an evolutionary change in the sensory innervation of the hand. The SA-II properties can be correlated with the fine control of finger movement and position in humans, which contrasts with rudimentary controls in the monkey, in whom fingers 2–5 frequently move in tandem, not individually. Direct electrical stimulation of SA-II afferents in waking humans evokes no conscious sensation. It is often suggested that this is because spatial summation in more than one fiber may be required to evoke perception, but there is no direct evidence for this speculation. Nevertheless, the close match between the functional properties of SA-II afferents and the exquisite sensitivity of humans to skin stretch and its direction provides strong inference that afferents with SA-II properties do project to central perceptual mechanisms (Goodwin et al., 1997). Neural elements of the different modality classes are grouped together from the level of the fascicles in peripheral nerves to the columns of postcentral somatic sensory areas. The Ranvier nodes of afferent axons in human nerves occur in clusters composed of axons of the same modality class (Ekedahl et al., 1997; Wu et al., 1998, 1999; Hallin et al., 2002; Hallin & Wu, 2002). The peripheral clustering by modality type and place presages the columnar organization of the postcentral somatic sensory areas, described in Chapter 10.

The Impact of Microneuronography The field of human somatic sensory physiology has been broadened and energized since the introduction by Vallbo and Hagbarth (1967,

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1968) of the method of microneuronography, in which recordings are made with microelectrodes from single axons in peripheral nerves of waking humans (Figs. 11–2 and 11–3). The use of this method first in Swedish laboratories and more lately elsewhere has produced a wealth of new knowledge, much of which is described in that which follows. A major discovery was made independently by Torebjork and Ochoa (1987) and by Vallbo (1981), that microstimulation of single afferent axons innervating the glabrous skin of the hand elicits a somatic sensory experience determined by the modality-specific nature of the single primary afferent stimulated; proof of singularity was given by proximal recording. In the study of Ochoa and Torebjork (1983), stimulation of 35 of 38 RA axons evoked the sense of flutter; a sense of pressure was evoked by stimulation of 28 of 39 SA-I axons; and a sense of vibration by stimulation of 13 of 13 PC axons. No sensations were evoked by stimulation of any one of 17 individual SA-II axons. Moreover, in many cases a single impulse in a single RA axon elicited in an attending human subject the sensory experience defined by the axon’s transducer function. The evoked sensations are quantal in nature, as Macefield et al. (1990) emphasized, and each stimulus to a single fiber generates a tactile perception that can be identified by the subject, and that he can project to a local peripheral receptive field. For reviews, see Vallbo et al. (1984) and Torebjork et al. (1987).

The Effect of Stimulus Movement Katz’s principle that “movement is the formative factor in tactual phenomena” applies from the level of peripheral transduction to central representations, and to human performance (Katz, 1925, translated, 1989). Katz’s principle is derived from Weber’s discovery of the effect on spatial acuity of movement of the skin over the object examined, or the object over the skin (see pp. 57–60 in De Tactu, Weber, 1834). It is common experience that the structural details of a surface that cannot be detected with a stationary finger become obvious when the finger is moved laterally over the surface. Lederman and her colleagues established that humans use a small set of stereotyped movements when examining two- or threedimensional objects, and that the movements are adapted to the haptic tasks. For reviews, see Lederman (1998) and Lederman and Klatsky (1998).

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Tactile Thresholds on the Glabrous Skin An aim in psychophysical studies of sensory systems is to determine whether the human threshold for the detection of a sensory stimulus is set by the threshold of first-order afferent fibers, or whether there is a (higher) perceptual threshold set by central operations. The answer for the somatic system is that both are true. Thresholds for tactile sensibility on the densely innervated finger pads are set by the thresholds of primary afferent fibers, while for the more sparsely innervated central palm some central summation mechanism may determine behavioral threshold for some somatic sensory modalities (Vallbo, 1985). Thresholds of the RA afferents are uniform over the hand; they match the psychophysical thresholds on the finger skin, but are only one third the human threshold measured on the palm (Johansson and Vallbo, 1979a,b). A single impulse in a single RA fiber innervating the finger pad often evokes a conscious perception, while similar stimulation of a fiber innervating the palm seldom does so (Torebjork et al., 1987). Stimulation of a single fiber innervating the finger elicits a robust hemodynamic response in both somatic cortical areas I and II in waking humans (Trulsson et al., 2001), and evoked potentials in the postcentral region in waking humans (Kunesch et al., 1995). Tactile thresholds on the human fingers measured with moving stimuli range between 2–4 µm, and are below 1 µm for a moving edge, independently of velocity, over the range of 10–40 mm/sec. The thresholds for minimal activation of mechanoreceptive afferents from the monkey fingers in LaMotte’s experiments were: for RAs, between 2 and 4 µm; for SA-Is, 8 µm (Johansson & LaMotte, 1983; LaMotte & Whitehouse, 1986). The records of Fig. 11–4 show the ON–OFF response of an RA fiber innervating the glabrous skin of a monkey hand, and the critical slope requirement. This response pattern is projected through the RA system and into the postcentral gyrus, where neurons of the RA columns in areas 3b and 1 respond similarly to step indentations of the skin.

Rating of Pressure Stimuli on the Glabrous Skin Humans adjust with delicacy the pressure of the fingers upon surfaces and objects examined to derive signals of surface structure and object form, and adjust that pressure accurately to avoid slip in lifting objects enclosed by the hand. Measures of the range and sensitivity of

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Fig. 11–4 Responses of a single rapidly adapting Meissner afferent (RA), innervating the glabrous skin of a finger of a macaque monkey; fiber isolated by microdissection of the median nerve. Stimuli delivered via a 2-mm rounded probe. Step indentations of 500 µm were delivered at a series of different indentation slopes, varied randomly in sequence at 5-sec intervals. The typical ON–OFF response of the fibers if the RA class persisted until the rate of skin indentation fell below a critical slope, here between 0.78 and 0.95 mm/sec. (From Mountcastle, unpublished experiments.)

the pressure sense on the glabrous skin are shown by the graph of Fig. 11–5, for which LaMotte (1977) used both subjective magnitude estimation (Stevens, 1970) and categorization to show a linear relationship between stimulus amplitudes of pressure stimuli and the human ratings of stimulus amplitudes. The linear relationship of Fig. 11–5 is predictable from the transducer function of the SA-I afferents in the glabrous skin. Figure 11–6 shows the discharge pattern of an SA afferent, a high-frequency onset transient merging into an early quasi-steady state in which frequency is maintained at a nearly constant rate, set by stimulus amplitude. The plot of individual responses to individual stimuli in Fig. 11–7A shows the low variability from trial to trial of the responses of the SA-I afferents under the experimental conditions of exact definition of receptive field, and the symmetrical location of a rounded stimulus probe covering the field, which minimizes the edge effect. SA-I and RA population

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Fig. 11–5 Human rating of touch-pressure stimuli. Subjects estimated subjective magnitude of pressure elicited by stimuli of different amplitudes by category estimation on a rating scale of 1 to 15, the same with scale of 1 to 30, and in subjective magnitude estimation. Ten naive subjects were used in each procedure. Stimuli were step indentations of the glabrous skin of the finger pad, each of 900 msec duration, varied over 15 steps in the range up to 1600 µm. They were delivered every 8 sec, in pseudo-random sequence, via a rounded probe tip 2 mm in diameter. Estimates expressed as average of percent of maximum judgment for each subject. (From LaMotte, 1977.)

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Fig. 11–6 Recordings from a single SAI (Merkel) afferent fiber innervating the finger pad of an anesthetized macaque monkey; the axon was isolated from the median nerve by microdissection. Stimuli were mechanical indentations of the glabrous skin by a 2-mm diameter probe tip, rounded to one third of a sphere. Stimuli of different amplitudes, all of the same duration, were delivered in random order. The period of the early steady state is particularly clear in the records at 276–926 µm indentation. The afferent was insensitive to skin stretch. (From Mountcastle et al., 1966.)

impulse rates, and the number of fibers activated by a 1-mm diameter probe, are also near linear functions of skin indentation depths (VegaBermudez and Johnson, 1999a). This pattern of response is propagated through the SA-I system and into the initial trans-synaptic levels of the postcentral gyrus (Fig. 11–7). The correspondence between stimulus amplitude, the linear response of SA-I axons innervating the glabrous skin, and human subjective magnitude estimations was also observed in a combined experiment in humans by Gybels and Van Hees (1972). There is a regular increase in sensitivity in the SA-I stimulus– response function with increasing processing time (Fig. 11–8). Maximal information transmission in humans is approached after 300 msec of stimulus time (Mountcastle et al., 1966). In normal life experiences the perception of the amplitudes of pressure stimuli are

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Fig. 11–7 Above: Stimulus–response relationship for a slowly adapting myelineated afferent innervating the glabrous skin of a monkey hand (SA-I), isolated by microdissection of the median nerve. Stimuli were step indentations of the skin of 600 msec duration, delivered at different amplitudes in a random order, at 12/min. Stimulator tip, 2 mm diameter, rounded to one-third spherical surface. The numbers of impulses evoked by each stimulus are plotted as a function of measured stimulus amplitudes. (From Mountcastle et al., 1966). Below: Results of a similar experiment made while recording from a single neuron in area 3b of the postcentral gyrus of a macaque monkey. Stimulating circumstances are the same. (From Mountcastle, unpublished experiment.)

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Fig. 11–8 Study of a single slowly adapting afferent (Merkel) innervating the glabrous skin of the monkey hand, isolated by microdissection from the median nerve. Stimuli of different amplitudes delivered in random order with a 2-mm diameter probe tip rounded to a one-third sphere. All stimuli were 600 msec duration; responses analyzed and plotted in 100-msec increments. (From Mountcastle et al., 1966).

rarely if ever determined by the action of single afferents, and never by the action of single cortical neurons. The shape of the distributed signals in first-order afferent fibers is suggested by the post hoc reconstruction of population events illustrated in Fig. 11–9; it represents the pattern of activity in neural space of the intensity, contour, and location of the peripheral stimulus projected through the lemniscal system to the postcentral cortex. Goodwin and Wheat (1999, 2002) suggested that the population response may be modified by variations in the sensitivity, thresholds, and receptive field overlaps of elements in the population; that of Fig. 11–9 represents the mean.

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Tactile Localization Place is an intrinsic property of the somatic afferent system; labeled lines at periphery and center signal the locations of tactile stimuli on the glabrous skin. Localization error is minimum at 1–2 mm on the finger pads, face, and tongue, and gradually increases on more proximal parts, reaching 30–40 mm on the back (Fig. 11–10). Schady and his colleagues combined the point localization method with microneuronography in humans by first mapping the receptive field on the glabrous skin of an isolated mechanoreceptive axon, and then the projected field of the sensation evoked by electrical stimulation of that same single afferent axon (Schady & Torebjork, 1983; Schady et al., 1983). The errors in point localization, and those in marking the projected field location are similar: for the finger pad, 3.2/2.6 mm; for more proximal finger, 5.7/5.7 mm; and for the palm, 6.4/6.0 3 mm. Tactile localization in humans is more precise than that measured by point localization, and is considerably better than that predicted from the sampling theorem on the basis of peripheral innervation density. For example, humans discriminate between the locations of a spherical object pressed into the finger tip skin at a stimulus separation threshold of 0.55 mm for an object with radius of 5.8 mm, and at 0.38 mm for one with a radius of 1.9 mm (Wheat et al., 1995).

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Fig. 11–9 Results of a receptive field study of a slowly adapting, SAI-Merkel type, mechanoreceptive myelinated afferent innervating the glabrous skin of the thumb pad of an anesthetized macaque monkey; axon isolated by microdissection of the radial nerve. The receptive field of this afferent extended across seven or eight dermal ridges, numbered on the left horizontal axis; the field measured about 2.4 mm in diameter. Mechanical skin indentations of just supramaximal amplitude were delivered through a tip 0.5 mm in diameter, machined to a one-third spherical shape. The threshold of this fiber was in the mid-range of the distribution of thresholds of the SAI class innervating the glabrous skin. Stimulus amplitude was constant; stimuli were delivered at 5-sec intervals. Impulse number counted in each 50-msec increment of stimulus time. The contoured lines mark one possible representation of the evoked activity in the entire population of afferents activated by the stimulus, on the assumption that as the stimulus is moved in steps from the edge to the center and to the edge again of the receptive field. The fiber under study occupied a series of different positions in each of the populations activated by each stimulus at those successive the field positions. The contours show a high-frequency onset transient followed by an early steady state. (From Mountcastle et al., 1966.)

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Fig. 11–10 Two-point touch and point localization thresholds for various body sites. Data are means of threshold values for left and right sides of the body; with few exceptions there is no laterality effect. Point localization thresholds are uniformly lower than the two-point thresholds; the two are highly correlated. (From Lederman 1998, modified from Weinstein, 1968.)

The place property of labeled lines provides a population signal at both peripheral and central levels of the location of a stimulus on the body surface. Shifts in the stimulus position on the skin are matched by shifts in the locations of the active population of neural elements, and allows for the mild hyperacuity beyond that limited by axonal innervation density. The place signal is clear in the SA-I population discharge, less so for the RAs, and is minimal for the PCs. The SA-I signal of stimulus location is not degraded by dynamic changes in the pattern of activity within the population; indeed, variations in those population patterns signal more complex stimulus attributes such as orientation, shape, texture, form, and movement.

Structure of Receptive Fields of Mechanoreceptive Afferents Innervating the Glabrous Skin of the Hand In earlier chapters the properties of the receptive fields of neurons at each level of the somatic afferent system, mapped with punctate

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stimuli, were used in descriptions of the representation of the body form in the system. They form the basis for descriptions of the representation of the hand in postcentral areas 3b, 1, and 2, and in the formulation of columnar organization. Quantitative studies at both peripheral and central levels with both moving and stationary stimuli have added new information important in considering the dynamic aspects of somatic sensory processing. Vega-Bermudez and Johnson (1999a,b) studied the receptive fields and stimulus–response properties of SA-I and RA fibers innervating the glabrous skin of the monkey finger pad, using an array of probes placed at 1-mm intervals in a 13-mm hexagonal plate, lowered into the skin until all probes made skin contact. The central 7 of the 155 probes were openings through which 0.5-mm diameter stimulating probes driven by linear motors could be passed. The array was first centered on the “hot spot” in a receptive field, and then moved successively in a systematic way so that the entire field was tested with stimulating probes. Both SA1 and RA fibers responded to punctate stimulation with linear increases in impulse frequencies to successively greater indentations by the stimulus probes. The RA response function saturated at about 100 µm indentation depth, while the SAIs produced linearly increasing response frequencies up to 500 µm indentations; they are known to do so for indentations up to 1500 µm. The mean receptive field area for RA afferents grew from 5.5 mm2 to 22.4 mm2 as indentation depth of the stimulus was increased from 50 to 500 µm, that for the SA-Is from 5.1 to 8.8 mm. A second stationary stimulus placed at the edge or just outside the receptive field of an afferent suppresses its response to a stimulus delivered to its hot spot, by up to 24 percent for SA-I afferents, and up to 12 percent for RA afferents. The suppressive edge effect increases linearly as increasing numbers of stationary stimuli are placed around the edge of the receptive field. The suppression is attributed to a redistribution of tissue strain on the terminals of the afferent by the skin indentation produced by adjacent probes. The phenomenon is one of skin mechanics, and is independent of any neural mechanism (Phillips and Johnson, 1981c). When tested with moving dot stimuli, the edge effect produces a fixed inhibitory receptive field trailing the excitatory field, for SA-I afferents. Peripheral suppression accounts in part for the acute sensitivity of the SA-I fibers to local stimulus features such as edges, points, and curvatures, and makes them less responsive to broad skin indentations. The receptive fields

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of PC afferents are large with ill-defined borders when mapped with optimal sinusoid stimuli at 100–300 cycles/sec; when determined with punctate stimuli those on the fingers may be limited to the middle and distal phalanges. Receptive fields of mechanoreceptive afferents innervating the human glabrous skin measured 6.2 mm2 for RA-I fibers, and 4.8 mm2 for SA-I fibers (Phillips et al., 1992). A new feature of these receptive fields was revealed, that those of both SA-I and RA afferents contain four to six loci of intense sensitivity within the field. There is evidence from study of RA afferents with moving stimuli that a single branch of the terminal array of the sensory axon, innervating a single “hot spot,” may dominate the afferent barrage, blocking entry of impulses from other branches to the parent axon (Gardner and Palmer, 1989).

Structure of Receptive Fields of Postcentral Neurons The dispositions of the excitatory and inhibitory receptive fields of postcentral neurons differ in the zones of representation of hairy and glabrous skins. Those related to the hairy skin of the arm are disposed in partial or completely superimposed Gaussian patterns (Mountcastle & Powell, 1959b). The impulse response pattern produced by the interaction of inputs from the two regions is illustrated in Fig. 11–11. The high-frequency “thin spikes” evoked by stimuli delivered to the inhibitory zones of the receptive fields, observed in these recordings, are thought to be those of γaminobutyric acid-ergic (GABAergic) inhibitory interneurons. Afferent inhibition preserves the signals of stimulus location on the hairy skin, where innervation density and central magnification factors are weaker than in the representation of the glabrous skin, where inhibition plays a more complex role. The role of inhibition for central processing in the hairy skin representations is shown by the increase in the receptive field size in the somatic sensory cortex produced by local cortical infusion of GABA blockers (Alloway and Burton, 1991). DiCarlo and Johnson (1999, 2000, 2002) and DiCarlo et al. (1998) studied the dynamic aspects of the responses of area 3b neurons with receptive fields on the finger pads of monkeys working in an alert-sustaining, attention-diverting, visual detection task. Neurons

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were activated by running streams of random dot stimuli scanned across the receptive fields on the finger pads, at different velocities and directions; dot heights were 400 um; diameters, 500 µm. For analysis, the 10 × 10 mm area of skin of the finger pad stimulated was divided into 625 (25 × 25), 400 µm × 400 µm, local regions. A modified linear regression analysis allowed direct correlations between the presence or absence of an action potential in the cortical response and the presence or absence of a raised dot over each local region of the skin. Spatial integration yielded a measurement parameter, the excitatory/inhibitory mass, defined as the total activity evoked/suppressed by the stimuli, summed over the receptive field. The results led to a three-component model that accounts for 95 percent of the receptive fields of 3b neurons. It contains a fixed excitatory, a spatially overlapped, temporarily coincident, fixed inhibitory field, and a delayed, “moving,” or “lagged” component whose variable location is determined by the direction and velocity of the scanning stimulus (Figs. 11–12 and 11–13). Fixed excitatory and inhibitory fields form a spatial filter generating selectivity for texture and orientation. The lagged inhibitory field preserves sensitivity to stimulus gradients and maintains spatial acuity over scanning velocities from 20 to 80 mm/sec. The mechanism of the lagged, moving inhibitory component is unknown. It is not known whether the integrative transformation between first-order fibers and postcentral neurons

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Fig. 11–11 Illustration of the interaction of excitatory and inhibitory effects on the response of a single neuron recorded in area 3b of the postcentral gyrus of an anesthetized monkey. The cell responded to mechanical stimuli delivered in a field on the preaxial side of the arm, and inhibited by stimuli delivered in a much larger, surrounding field covering the rest of the forearm; only dorsal half is shown. Graph plots impulse frequency versus time during excitatory-inhibitory interaction. The excitatory stimulus evoked a high-frequency onset transient that declined towards a quasi-steady-state until interrupted by application of the inhibitory stimulus. On removal of the latter, the sequence repeated in response to the continuing excitatory mechanical stimulus. (From Mountcastle and Powell, 1959.)

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Fig. 11–12 Model of the receptive field of cutaneous neurons of area 3b of the postcentral gyrus of macaque monkey, determined with moving dot stimuli stroked across the skin. Field contours independent of stimulus velocity. There are three components: a fixed excitatory field, a fixed inhibitory field of invariant position, and a lagged or moving inhibitory field whose position varies with stimulus direction. (From DiCarlo, 1998.)

occurs at intervening steps in transmission through the system, or is initiated at the first intracortical synapse. Three hundred and thirty neurons were studied by DiCarlo and Johnson; of these, 95 percent were related to complex receptive fields such as those described, with excitatory and inhibitory field components. Two hundred and ninety-eight neurons were tested with moving random dot stimuli and located in postcentral area 3b by histological analysis. A subset of 87 neurons was tested also with punctate stimuli; half adapted rapidly to sustained stimuli (“RA neurons”); half yielded sustained responses (“SA neurons”). The mean E-field size was 24 mm2, range 3–43 mm2; the mean I-field size was 18 mm2, range 1–47 mm2. Compare with the mean RF area of first-order SA-I afferents innervating the finger pads of 4.5 mm2. Increases in stimulus velocity over the range of 20–80 mm/sec evoke increases in response but do not affect the spatial distributions of the E and I fields.

Representations of Complex Features of Tactile Stimuli in the Somatic System Some complex features of tactile stimuli humans sense with ease are encoded weakly, if at all, in the responses of single afferent fibers.

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Fig. 11–13 Dynamic receptive field of a cutaneous neuron of area 3b, studied in a macaque monkey working in a visual detection tasks as the tactile receptive field on a finger pad was studied. In these experiments 298 neurons, located in area 3b by histological study, were tested with moving, random dot stimuli. The population studied was evenly divided between the RA and SA classes. The receptive field of this neuron was studied by scanning random dot stimuli at a spatial density of 10 dots/cm2; each dot was 400 µm high and 500 µm in diameter at the top, with sides that sloped away at 60o with respect to the base. The three squares in each group show the receptive field determined from the raw data (left), the receptive field predicted from the three component model of Fig. 11–12 (center), and the positions of the Gaussian components (right). Each receptive field is plotted as if viewed through the dorsum of the terminal digit, with the finger pointed toward the top of the figure. The locations of the model’s excitatory (solid ellipse) and the partially superimposed, fixed, inhibitory (dashed ellipse) components are not affected by stimulus direction; the lagged inhibitory component shifts with stimulus direction, trailing by a fixed distance in each direction. Increases in stimulus velocity over the range of 10–80 mm/sec evoke increasing frequency of neuronal response, but do not change the spatial distributions of activity; stimulus velocity here = 40 mm/sec. (From DiCarlo and Johnson, 2000.)

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They are signaled by the patterns of evoked activity in populations of those afferents. Complex stimulus features of orientation, shape, movement, direction, texture, and form are elaborated further by intracortical processing in the supra- and infragranular layers in area SI of monkeys, and in the transcortical projection targets of SI. Feature elaboration in the trans-granular layers of the somatic sensory cortex may be only the first in a series of increasingly abstract representations of peripheral stimuli. Absent the capacity to record simultaneously from more than a few sensory axons, experimentalists reconstruct post hoc the population responses of those afferents. Artificially constructed populations do not take account of differences in sensitivity of different afferents, the presence of neural noise, and so on, and provide no measure of information that might be embodied in the temporal relation between the trains of impulses in simultaneously active axons (Goodwin and Wheat, 1999, 2002). For a review of population coding and decoding in the standard model, see Pouget et al. (2003). Nevertheless, the artificially constructed population responses of the SA-I afferents in monkeys and humans represent with discriminable precision some complex stimulus properties.

Curvature (Shape) Population responses of SA-I afferents evoked by tactile stimuli with different curvatures have been studied in the laboratories of Goodwin and LaMotte (Goodwin et al., 1991, 1995; Goodwin and Wheat, 1992a,b; LaMotte and Srinivasan, 1993; LaMotte et al., 1994, 1998; Khalsa et al., 1998). Figure 11–14 gives the results of one such experiment in which objects with different curvatures were stepped across the peripheral receptive field of a SA-I fiber innervating the finger pad of a monkey. The population constructions are fitted by Gaussians, change with changes in curvature, rotate with changes in orientation, change position in the neural field with changes in stimulus position, and increase in discharge frequency with increases in contact force, while maintaining the population signal for shape, changes observed in both monkey and human SA-I afferents (Goodwin et al., 1997). Humans identify changes in curvature when the intensity of the discharge is changed simultaneously by changes in stimulus force, as if the variation in the frequency of discharge of

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Fig. 11–14 Reconstructed population responses of peripheral SAI (Merkel) afferents innervating the glabrous skin of the monkey’s finger, to spheres of different curvatures. Left: The mean responses of SAI afferents as a function of the proximodistal distance from the center of stimulus indentation. Stimuli were spherically shaped, with radii of curvature indicated, all delivered at the center of the receptive field, x = 0. Right: Responses for a single curvature, with stimuli of increasing amplitudes, delivered along axes at successive 0.5-mm intervals from x = 0. (From Goodwin et al., 1995.)

SA-I axons within the population functions as a population code for force, without loss of the distributed pattern for curvature.

Orientation The sensitivity and rapid reactions to the orientations of objects are essential for the function of primates for life in the trees, and for humans in grasping and lifting objects, and in the adjustment of the hand to tools. Orientation has been studied with a variety of objects impressed into or scanned across the glabrous skin, including bars of different orientations and diameters, spheres of different sizes, ellipsoids, toroids, and so forth. Humans discriminate 4- to 5-degree differences between the orientation of stationary rods grasped by the hand, make errors of 4–6 degrees in reproducing orientations (Lechelt & Verenka, 1980), and discriminate, at the 75 percent level, 10 percent differences in the curvatures of objects applied to their finger

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pads (Goodwin et al., 1991). Only the SA-I afferents provide the spatial acuity and have the innervation density required to encode the orientation of tactile stimuli. The orientation of bars pressed into or swept across their receptive fields is not encoded in the response of single SA-I afferents, but is signaled by the population response of those afferents, and in the response pattern of postcentral neurons upon which they project (Dodson et al., 1998; Khalsa et al., 1998; Hsiao et al., 2002b).

Movement and Direction The human capacity to detect movement and to discriminate between stimuli moving in opposite directions on the skin has been studied for more than a century (Hall and Donaldson, 1885). The methods used now include frictionless stimuli that do not stretch the skin, immobile stimuli that stretch it without lateral movement over the surface, and simulated motions produced by punctate stimuli sequentially displaced in space and time; for reviews, see Essick (1998) and Gardner (1998). The psychophysical observations are summarized as follows. 1. A liminal transverse length of movement is required for criterion performance; it is about 2–3 mm on the glabrous skin, and 10–15 mm on the hairy skin of the forearm (Whitsel et al., 1986; Essick et al., 1991; Olausson and Norrsell, 1993). 2. Knowledge of the start and stop positions of a frictionless, moving stimulus is not sufficient for detection of movement or for discrimination between directions of movement. Continuous stimulation or stepped punctate stimuli delivered along a movement path of minimal length are required (Gardner, 1998; Gardner and Sklar, 1994). 3. When the hairy skin of the forearm is stretched without horizontal movement of the stimulus over the skin, the threshold detection of movement and direction is on average 0.13 mm, an order of magnitude lower than the threshold when frictionless stimuli are used (Olausson et al., 1998). The direction of force delivered without movement is scaled linearly by human subjects (Pare et al., 2002a).

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4. Given suprathreshold stimulus force and adequate transverse length, sensory performance is unchanged over a velocity range from 2 to 40 cm/sec, the velocity range of human scanning movements (Essick and Whitsel, 1985a,b). 5. When tested with stimuli moving at different angles over the finger pads, humans detect angular changes of about 14 degrees (Keyson and Houtsma, 1995). Almost all stimuli reaching human hands or sensed by scanning movements combine lateral movement and skin stretch. The RA afferents provide reliable signals of frictionless movement/direction by the successive excitation of different populations successively overlapping in the line of movement, and in humans the SA-IIs provide exquisite signals of the degree and direction of skin stretch. Each class of mechanoreceptive afferents innervating the glabrous skin of the human finger may contribute to the sensing of the tangential direction of force. SA-IIs are biased for tangential force directed away from the tip of the finger pad, the SA-Is for force in the distal direction, and the RAs for forces in the proximal and radial directions (Birznicks et al., 2001).

Tactile Texture Humans perceive the texture of surfaces by scanning movements of the finger pads. The repetitive arrangement of the small constituent parts of textured surfaces have the dimensions of rough/smooth. and hard/soft, and perhaps also of sticky/slippery. Humans rate roughness over a continuum of subjective magnitude, and make fine discriminations between different grades of rough surfaces (see Hollins et al., 1993, 2002; Hsiao et al., 1993; Lederman, 1998; Lederman and Klatsky, 1998). The perceptions of surface textures with element spacings from 0.1 to 6 mm are accounted for by a spatial variation code in the population response of the SA-I afferents innervating the glabrous skin of monkeys and humans. These signals are independent of the applied force or scanning velocity of the moving fingers over a range of 10–70 mm/sec; that is, the distributed signal may be changed in overall frequency with preservation of the spatial pattern, and thus of spatial perception. Increase in the discharge rates of neurons in

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the population appears to brighten the distributed neural image. The results obtained reject for lack of consistency all codes based on the responses of PC, RA, or SA-II (in humans) afferents, and all codes for all classes of fibers based on impulse frequency or temporal variation. The “last code standing” after these analyses is that of the spatial variation between the evoked discharge rates in SA-I afferents with receptive field centers separated by about 2 mm. The correlations between this spatially distributed code and the double-ended human magnitude estimation functions are shown in Fig. 11–15. The consistency is invariant over changes in element spacing, height, or changes in contact force. These are the conclusions reached in a series of experiments by KO Johnson et al., described in papers (Connor et al., 1990; Philips et al., 1990; Connor and Johnson, 1992; Blake et al., 1997; Yoshioka et al., 2001) and summarized in reviews (Johnson and Hsiao, 1992; Hsiao et al., 1993, 2002a; Johnson et al., 2000; Johnson and Yoshioka, 2002). Katz suggested that roughness is served by two neural mechanism, a spatial one for surfaces with larger element separation, and a vibratory one for finer surfaces (Katz, 1925; translation 1989). This

Fig. 11–15 Perceived roughness as a function of neuronal discharge rates in four studies with surfaces of different textures. In each of the nine graphs, the left axis is the mean reported roughness; the right axis is the spatial variation in the discharge rate of single slowly adapting afferent axons (SAIs) innervating the glabrous skin of the monkey’s hand, isolated by microdissection of peripheral nerves. The pattern of the stimulating surface is shown beneath the graphs to which it applies. A: Results from Connor et al. (1990), who used 18 raised dot patterns with different mean dot spacings and diameters. B: Results from Blake et al. (1997), who used 18 raised dot patterns with different dot diameters and heights. C: Results from Connor and Johnson (1992), who varied pattern geometry to distinguish temporal and spatial neural coding mechanisms. D: Results from Yoshioka et al. (2001). The perceived roughness in each case, with element spacings > 1 mm, is based on the spatial variation in the discharge rates of slowly adapting SA1 afferents innervating the glabrous skin, determined by the surface pattern of the stimuli. For more finely spaced stimulus elements, the variation in discharge rates is determined by variation in spike rates. The relevant afferent input for very fine surfaces may depend upon signals in PC afferents. (From Yoshioka et al., 2001.)

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hypothesis has been revived by Hollins (Hollins and Risner, 2000; Hollins et al., 2000a,b, 2001, 2002), who suggested a role for Pacinian afferents in the perception of finer grades of roughness. Johnson and his colleagues tested this PC hypothesis and simultaneously whether the spatially distributed code in SA-I afferents could account for the human perception of surfaces whose spatial elements are more dense than the spatial innervation density of the SA-Is (Yoshioka et al., 2001). Trapezoidal gratings with spatial periods of 0.1–2.0 mm were used as stimuli. The consistency observed between the magnitude function and the spatial variation SA-I code is illustrated in Fig. 11–15, lower right. Candidate codes in PC afferents were rejected for lack of consistency. Hollins et al. (2000a,b, 2001, 2002) have adduced several lines of evidence favoring the role of the Pacinian system in the perception of textures with element spacings less than 0.1 mm: (1) human subjects cannot discriminate very fine textures without surface movement; (2) the subjective magnitude estimation function obtained with stationary stimuli is flat up to 100 µm element size, at which there is a point of inflection; but see other evidence that the subjective magnitude estimation rises over the full range from 16 to 905 µm (Verillo et al., 1999); and, (3) adaptation of the Pacinian channel disrupts the perception of fine textures. Some of these observations support Katz’s duplex theory of texture perception. Other evidence indicates that a frequency code in single SA-I afferents is not sufficient for the sensing of different textures. Electrical stimulation of single SA-I afferents in human nerves elicits a contact sense of pressure. At frequencies of 5–6/sec individual contact sensations merge into a sense of smooth, uninterrupted pressure. Increasing frequencies of stimulation elicit increasingly more intense perceptions of pressure, and no sensations of texture. Stimulation of RA or PC axons elicits sensations of flutter or vibration, respectively, and never texture or form (Ochoa & Torebjork, 1983; Torebjork et al., 1987).

Spatial Form and Pattern Form is a shape or arrangement of parts; it differs from texture in that surface details vary from place to place, and together compose the two-dimensional geometric structure of objects. Sensing of the

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details of the surface shapes of objects, beyond the regularities of texture, is part of the haptic sensing of three-dimensional objects. The capacity for pattern perception is set by the resolving power of the somatic system, limited on the finger pads by the innervation density of the mechanoreceptive afferents innervating the glabrous skin. Densities on the monkey finger are 178/cm2 for RA afferents, 134/cm2 for SA-I afferents, and 13/cm2 for the PCs (Darian-Smith & Kenins, 1980). Comparable figures for the distal finger pad in humans are 140/cm2 for RAs, 70/cm2 for SA-Is, and 21/cm2 for PCs ( Johansson & Vallbo, 1979b). Phillips and Johnson (1981a,b) measured the spatial resolving power of the tactile system on the human finger tip by asking subjects to recognize gaps of different widths, to discriminate the orientation of gratings of different periods, and to recognize embossed English letters, all pressed into the skin without lateral movement, with control of stimulus force. The results of the three experiments converge to threshold measurements of about 0.9 mm (Fig. 11–16), the level predicted by axonal innervation density. Thresholds fell to about 0.7 mm with moving stimuli. When tested with these same periodic bar and groove stimuli only the SA-I afferents innervating the

Fig. 11–16 Measures of the human performance in gap detections, grating orientation discrimination, and letter recognition tasks. Abscissa—element width for each task, which was gap size for the gap detection task (above left); bar width, half the grating period for the grating orientation task (above center), and the average bar and gap within letters (about one-fifth the letter height) for the letter recognition task (above right). Threshold is defined as the element size producing performance midway between chance at 50 percent correct for the first two tasks, and 1/26 for letter recognition. (Adapted by Johnson et al., 2000 from Phillips and Johnson, 1981c.)

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monkey finger pad responded with discriminable signals matching these thresholds. RA fibers responded only to 3.0 mm grooves and wider, the PC neurons not at all. The most intensely studied of human somatic sensory form perceptions is that of the blind reading Braille, described in Chapter 16. Fig. 11–17 shows the spatial event plots of the reconstructed population responses of each of the four mechanoreceptive afferents innervating the human finger pads to Braille type scanned across their receptive fields on the glabrous skin of the hand (Phillips et al.,

Fig. 11–17 Responses of mechanoreceptive afferent fibers innervating the glabrous skin of the human hand, recorded from axons in human peripheral nerves by microneuronography. Top: The stimulus is the Braille pattern, swept across the receptive fields of the afferents at 60 mm/sec; shifted 200 µm from one pass to the next; the results are shown as spatial event plots of the reconstructed populations. Dots represent individual action potentials. The responses of the SAI afferents (Merkel) provide a discriminable neural image of the stimulus patterns, the RA a less discriminable set. The responses of the SAII and Pacinian afferents provide no useful input. (From Phillips et al., 1990.)

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1990). The SA-I response is a robust, isomorphic neural image of the Braille pattern, that of the RA population is somewhat less precise, while those of the SA-II and PC afferents provide no Braille image. The spatial image embedded in the SA-I population response is virtually unaffected by stimulus force or horizontal velocity, over a range up to 70–80 mm/sec, which covers the human scanning speeds. RA afferents are three time less sensitive to spatially varying stimuli than are the SA-Is.

Postcentral Processing of Complex Features of Tactile Stimuli Area 3b of the postcentral gyrus is both a neuronal processing and a distribution center. It is a major source of input to postcentral areas 1 and 2, projects through them to areas 5 and 7b of the posterior parietal cortex, and to areas SII and parietal ventral (PV) of the lateral fissure. In primates this funnel is almost absolute, for a selective removal of area 3b denervates areas 1, 2, SII, and PV of tactile input and eliminates all aspects of tactile sensibility other than simple detections, while a restricted removal of area 1 or 2 results respectively in defects in tactile texture or form perception. The general hypothesis is that the quasi-isomorphic representations of complex somatic sensory stimuli are encoded in the population responses of SA-I afferents and are projected over the lemniscal system to the postcentral cortex. At that first cortical transfer in layer IV these signals are transformed into a frequency code in the responses of cortical neurons; they appear more robustly in the supra- and infragranular layers. It is conjectured that they are further modified in the cortical projection targets of 3b into forms more efficient for perceptual processing. The experimental aim is to discover what those transformations are, and to follow them through the several stages of further abstraction. The convergent creation of frequency codes at the cortical level for these stimulus parameters does not rule out other and still unknown signals embedded in the population that may be of importance in evoking the overall perceptual experiences. So far as presently known, all of the complex tactile properties described above, directionality excepted, are signaled selectively in the population patterns of discharge of the SA-I afferent fiber set. I describe here some examples of the mode-specific convergence of population signals of peripheral afferents onto 3b neurons, the responses of those cells to complex stimuli in a frequency code; and, for the

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properties of texture and orientation, a mechanism of the transformation.

Tactile Texture Afferent impulses in members of the population of SA-I afferents that encode tactile texture (roughness) project to and converge upon single neurons of area 3b that signal differences in texture by differences in their discharge frequency. The spatial displacement of the fixed excitatory and inhibitory fields of 3b neurons is shown in the three-component model of Fig. 11–12, and by several of the receptive fields of Fig. 11–13. It is proposed that the spatial displacement of the two fields forms a spatial filter for activity reaching the cortex from skin locations separated by about 2 mm. This converts the spatial variation signal to a frequency signal in single 3b neurons, which varies with the textual roughness (Yoshioka et al., 2001). A number of earlier studies were made of the activity of 3b neurons in monkeys working in tasks that required the detection of or discrimination between textural stimuli. In all of these, sets of 3b neurons coded the variation in the textural stimuli, the intensity of roughness, in the frequency discharge of 3b neurons (Darian-Smith et al., 1984; Sinclair and Burton, 1991a,b; Burton and Sinclair, 1994; Sinclair et al., 1996; Tremblay et al., 1996; Jiang et al., 1997; Meftah et al., 2000; Chapman et al., 2002).

Stimulus Orientation Orientations of unmoving bars pressed into the finger pad skin of monkeys are not signaled in the vigorous responses they evoke in single SA-I afferents to those stimuli. They are differentially signaled in the population response of those afferents. That embedded pattern yields by projection and convergence the signals for stimulus orientation observed by Hsiao et al. (2002b) in 75 percent of single neurons in areas 3b and 1 with receptive fields on the distal finger pads, and in 30 percent of a population of neurons studied in area SII. How the convergence over the system from the population signal at the level of entry to the frequency code for cortical neurons is thought to be similar to that for texture, described above. The threecomponent model accounts for the preferred selectivity for the orientation of a scanned bar, a property displayed most strongly when

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the fixed inhibitory and excitatory components of the receptive fields are of near equal value (DiCarlo and Johnson, 2000). Orientation selectivity is stronger in the supra- and infragranular layers of area 3b than in the recipient layer IV. Hsiao et al. (2002a,b) also observed the powerful facilitatory effect of attention upon the responses of cortical neurons to different stimulus orientations. The orientation selectivities in SII neurons with receptive fields covering the digits of both hands are identical for both contralateral and ipsilateral finger pads (Nakama, 2003). It is still uncertain how a signal for a complex tactile property such as orientation, not signaled in the responses of single afferent fibers innervating the glabrous skin, is generated in the population response of those same afferents. It is proposed that this results from the overlapping coding for the bar in the responses of different single afferents, and generation of a neural vector for orientation in the population, but there is no direct evidence for this conjecture.

Spatial Form and Pattern Recognition The recognition of spatial form and pattern is a complex cerebral operation we execute rapidly and subconsciously in all sensory modes; for example, the recognition of each Braille pattern by a skilled reader is executed in something less than 100 msec. Two inferences follow: first, the afferent input must access the several nodes of the cortical somatic sensory processing system virtually simultaneously; second, the sustained discharge by which we identify the SA sets of afferents innervating the glabrous skin can be of little importance in this rapid and repetitive pattern recognition. It is the early-onset response that counts. The neural mechanism of pattern recognition has been studied in humans and in monkeys using raised outlines of letters of the English alphabet as stimuli (Phillips et al., 1988). Letters are readily identified by human subjects when felt with the finger pads, and monkeys can be trained to recognize them and match them to one among alternatives presented on a monitor screen. The method of population reconstruction by creating spatial event plots is illustrated for a single letter in Fig. 11–18, for a peripheral SA-I afferent. Figure 11–19 shows, above, the strongly isomorphic images of letters in a first-order SA-I innervating the glabrous skin of a distal finger pad; and below, similar results obtained for two area 3b neurons studied in a waking monkey working in a alertness-maintaining

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Fig. 11–18 Model of how a spatial event plot is made. Left: Three of the many traverses of the embossed letter stimulus across the receptive field of the afferent fiber or cortical neuron; close correlation with impulse discharge (short upstrokes) with letter configuration. Middle: Full result for a SAI fiber innervating the glabrous skin of the distal finger pad of a monkey. Right: Similar result for a neuron of postcentral area 3b, recorded in a waking monkey. (From Johnson et al., 1990.)

Fig. 11–19 Above: Spatial event plots of the responses of a SAI Merkel afferent innervating the glabrous skin of the distal finger pad of a monkey. Plots constructed as for Fig. 11–18. Below: Spatial event plots for two neurons of area 3b of the postcentral gyrus of a waking monkey, working in an attention maintaining visual detection task. The isomorphic relationship is strongest in the middle layers of the cortex, and is much less so in both supra—and infragranular layers, which implies a transformation to some, perhaps more efficient, spatial code. (From Phillips et al., 1988.)

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visual detection task. The first record is that of a neuron in the middle layers, the second and less isomorphic one for a neuron in the supragranular layer. This suggests that with further intracolumnar processing from the middle to the supra- and infragranular layers of area 3b, and in area 1, there is a rapid decrease in isomorphism, but with retention of structure. These structures have not been studied in detail; they are conjectured to be the initial steps in the central transformations of the initial central representations into abstracted forms used in the perceptual operations. Little is known of the latter.

The Manual Sensing of Three-Dimensional Form Perhaps the most elegant of the perceptual functions of the hand is the capacity we have to sense the size, contour, and surface texture of objects we palpate. We commonly do this in a succession of gentle grasps and movements before reaching an identification of three-dimensional form and surface texture, and it is this successive spatial and temporal integration that makes form perception at once the most interesting and the most difficult of somatic sensory capacities to study. This capacity is commonly referred to as haptic or kinematic touch, by which is meant the somatic sensory information obtained by the simultaneous stimulation of several classes of mechanoreceptive afferents innervating the hand. Klatzky and Lederman (1995) found that blindfolded human subjects were able to identify 100 common objects with an accuracy of 95 percent, when responding within 5 sec. We have no idea how the brain synthesizes such successive population images to yield perceptual wholes. What we do know, at least for the hand, is that the unified perception depends on the simultaneous activation of several quite different sets of afferents from skin, muscle, and joints, and that elimination of any one of these leads to degradation but not elimination of threedimensional form perception (Ferrell and Smith, 1989; Collins et al., 2000). Whether the sensing of the three-dimensional objects we palpate is signaled exclusively by afferent signals is still uncertain, and it may be that in addition to peripheral input, central re-entrant signals of the output producing the movements play a supplementary role in this perception, or, indeed, none at all. It is important to note what Lederman and her colleagues have shown, that humans commonly employ only a small set of patterned movements in

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manual explorations (Lederman, 1998; Lederman and Klatzky, 1998). I restrict this discussion to the kinesthetic function of the hand, a part of a larger subject, the senses of the position and movement of the limbs in general, of the body form, and of the position of the body in space. A number of experiments have been made on human hands, aimed at defining the contributions of the different sets of mechanoreceptive afferents to stereognosis, whether cutaneous, joint, or muscle in origin. In one class of experiments the remaining sensory capacity is observed after removal of one or two of the three sets of afferents. The results obtained are clear: removal of the input from the joint afferents, or from the stretch afferents from the skin, or from muscle afferents, may in any one of these cases degrade the sense of the position and movement of the fingers at their joints, but in no case eliminate it entirely. The technical difficulty of these experiments has undoubtedly contributed to the differences obtained by different investigators. Moberg (1983) studied 50 patients operated for carpal tunnel syndrome, and in the procedure isolated the tendons of the long muscles of the hand. Pulling on those tendons elicited sensations only when the pull activated nearby cutaneous afferents, or came to full stop against the muscle origins. Others have obtained quite different results and emphasize the important—but not the exclusive— function of muscle afferents in haptic sensibility, based largely on the illusions of movement produced by vibratory stimulation of muscle tendons (McCloskey et al., 1983). Several experimental results question the exclusive importance of muscle afferents in signaling finger joint position. Taylor and McKloskey (1990) found that tensing the muscles acting at a particular finger joint position had no effect on the sense of finger position, and that functional disengagement of the muscles acting at the proximal or distal interphalangeal joints of the fingers produced no changes in the perception of finger position. Microneuronographic studies of the human hand afferents revealed that intraaxonal stimulation of spindle afferents never evoked any sensation, while similar stimulation of the majority of joint afferents evoked deep sensation relevant to joints, and in about half the cases a sense of joint movement (Burke et al., 1988; Macefield et al., 1990). Moreover, spindle afferents of finger muscles are silent during accurate position holding of the fingers (Hulliger et al., 1979). It is possible

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that muscle afferents are important during finger movement, and not for position. Each of the four classes of mechanoreceptive afferents innervating the glabrous skin of the human hand is active during voluntary isotonic finger movements, and 50 percent continue to discharge at steady joint positions (Hulliger et al., 1979). This sensitivity of the skin to even minute stretches is marked for the afferents innervating the skin on the dorsal surfaces of the fingers, where they are disposed to signal movement of the underlying joints (Edin and Abbs, 1991). It has been known for nearly a century (Head, 1920; Holmes, 1927) that lesions of the parietal lobe may produce defects in form perception by the contralateral hand, an astereognosis frequently associated with tactile apraxia. In earlier studies it was difficult to localize lesions exactly, and it remained uncertain whether a lesion of the posterior parietal cortex without damage to the postcentral somatic areas could by itself produce these defects. The opinion gradually emerged that this is indeed the case. Recently, more precise methods for locating lesions and the study of small ones soon after onset has lent further support to the idea that the posterior parietal areas, particularly area 5, are essential for normal form processing by the contralateral hand (Binkofski et al., 2001; Freund, 2003). Tomberg, Desmedt and their colleagues have used the evoked potential method to show that area 2 is selectively activated in humans by stimulation of joint afferents (Tomberg and Desmedt, 1999; Desmedt and Ozaki, 1991), as it is in monkeys, and that small lesions centered on area 2 may selectively eliminate stereognosis in the contralateral hand (Mauguierre, et al., 1983). These observations in humans are congruent with the repeated observation made in waking monkeys that many neurons in the area 2–5 transition zone are selectively sensitive to the three dimensional form of the contralateral hand and fingers. The appearance of such neurons in such experiments is a certain sign that the recording locus has passed from area 2 to area 5 posteriorly (Sakata, et al., 1973; Mountcastle et al., 1975).

Concluding Remarks Research of the last decades executed largely with neurophysiological methods has yielded an understanding of the dynamics of the

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transduction and encoding of relatively simple stimuli at the peripheral interface between the somatic system and the external world. Much remains to be learned, in particular, how a stimulus property, never seen in the evoked responses of any single fiber of a group, is encoded with discriminable clarity in the population response of a set of fibers of that group. It is only for the spatially distributed properties of textured and oriented stimuli that we know how those properties are signaled in the population discharge of a certain of class of afferents, the SA-I set. How is it that two or even more complex properties of somatic stimuli can be embedded in the same population discharge, and are still identified and discriminated by central operations? Beyond that, we need to learn the dynamic temporal relations between the afferent responses in different sets of afferent axons, for it is clear that in normal life it is the combined action that often provides the critical information, for example, the role of skin, joint, and muscle afferents in signaling the position and movements of the fingers at their joints. These problems all require recording of many afferents, simultaneously. The first surge (30 years’ duration) of the use of the combined experiment in study of the somatic sensory cortex in monkeys working in somesthetic tasks has now run its course. Attention turns to other and increasingly difficult aspects of the experiment. First among these is to devise ways of knowing the exact laminar location of the neurons observed, and their cell types, when recording from the extracellular position. The overall aim is to identify the dynamic operation in the vertically linked chains of the cortex, to define the neuronal transformations executed in that dynamic processing. It is conjectured that each cortical neuron occupies a position in the processing chain with specific input and output connections, and with a specific role to play in that operation. A second matter of importance is to test a wide spectrum of these response characteristics, for surely most 3b neurons in a particular mode-specific channel participate in processing all mechanoreceptive inputs in that channel. Considering the SA-I channel, for example, it is unlikely that there are separate cell populations for texture, force, directionality, and so forth. It is a difficult experimental task to find means for testing the full panorama of neuronal responsivity in what is frequently a short recording period.

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Dynamic Neural Operations in the Sense of Flutter-Vibration

Mammals detect and discriminate between different amplitudes and frequencies of oscillating mechanical stimuli that reach the body surface either directly or by transmission from vibrating objects such as tools. Mechanical sinusoids in the range of 2–50 Hz evoke a localized cutaneous flutter; those in the range of 50–500 Hz evoke the familiar hum of vibration, which spreads through the body tissues as stimulus amplitudes rise. Flutter is evoked in primates by cyclic entrainment at impulse frequencies in the range of 2–50/sec in the rapidly adapting (RA) nerve fibers innervating the glabrous skin of the hand. Vibration is evoked by mechanical sinusoids in the range of 50–500 Hz that entrain impulses in Pacinian (PC) afferents. Each of the two components is served by a separate peripheral and central neural channel, and each covers separate but overlapping frequency ranges. The two modes are readily dissociated by a number of experimental procedures. Vibration is unique among somesthetic modalities in that its high sensitivity enables it to function as both a local and a distant sense. Mechanical oscillations in the range of 200–300 Hz can be detected by mammals for hundreds of meters; the distance depends on the amplitudes of the disturbances and the conduction properties of what intervenes. In some animals, ground-transmitted signals serve as guides for escape or attack. Humans and monkeys have virtually identical capacities to detect and to discriminate between flutter or vibratory stimuli of slightly different amplitudes or frequencies. The sense of flutter is well suited

12

for studies of the dynamic neuronal operations in the transitional nuclei and cerebral cortical areas of the somatic system, in combined experiments in monkeys. The cyclically entrained activity evoked by mechanical sinusoids delivered to the body surface provides a tell-tale sign of the relevant neural activity, which can be traced through the early stages of the system and its modifications defined. Each of the three classes (four in humans) of large-fibered mechanoreceptive afferents innervating the glabrous skin of the hand project to the cortex over relatively isolated, parallel channels, and each has privileged access to perception.

Psychophysical Studies of Flutter-Vibration in Humans and Monkeys Flutter-vibration has been studied intensively since the early days of Psychophysics, in the last century by Geldard (1940a,b), Keidel (1956), Stevens (1959, 1968), Bekesy (1960, 1965), Verrillo (1985), Gescheider and Verrillo (1980), and Bolanowski et al. (1988, 1994). The result is knowledge of the performance of human subjects as they detect, discriminate between, and rate mechanical sinusoids, and of other factors that influence performance, including adaptation, summation, enhancement, and masking, which reveal some of the operating properties of the neural mechanisms involved. The identity of detection thresholds and discrimination limens in monkeys and humans supports the inference that the neural events observed in the somatic systems of monkeys resemble those of humans. Knowledge supporting this inference has come from studies of humans and monkeys with brain lesions, from studies of humans with peripheral neuropathies, imaging studies of the human cortex, psychophysical studies in primates, and from electrophysiological studies of the relevant sets of primary afferent fibers in both humans and monkeys. Parallel results have been obtained in experiments in which monkeys are trained to detect and to discriminate between the frequencies or intensities of mechanical sinusoids delivered to their hands, while electrophysiological recordings are made simultaneously of the central neural activity evoked by those same stimuli. Correlations are observed, and the link to causality is sought on other grounds: for example, a close correspondences between behavioral and neural events as they change together over some

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continuum, the defects in flutter-vibration produced by brain lesions, differential block of particular sets of afferent fibers, and knowledge of the transmission capacity of the lemniscal system linking the periphery to the postcentral gyrus. Nevertheless, in this, as in all combined experiments, the possibility cannot be disproven that some other set of unrecorded central neural activity is essential for the sensory performance observed. Threshold functions for the glabrous skin of the hand, determined with the methods of Fig. 12–1, in monkeys and humans are shown in Fig. 12–2. They are lowest in the range of vibration, rising gradually at successively lower frequencies through the range of flutter; they are higher on hairy than on glabrous skin. Bekesy proposed that two processes determine the frequency-threshold function for vibratory sensibility in humans (Bekesy, 1960, 1965). This was supported by the investigations of Verrillo and his colleagues (Verrillo, 1963, 1968, 1985; Gescheider, 1976; Bolanowski et al., 1988, 1994), paralleled by the electrophysiological study of firstorder afferents innervating the hands of monkeys, and by correlation of the properties of the Meissner (RA) and Pacinian (PC) afferents with the performance of humans and monkeys as they detected and discriminated between frequencies over the range of flutter-vibration (Mountcastle, 1967; Mountcastle et al., 1967, 1972; Talbot et al., 1968; LaMotte and Mountcastle, 1975). The Meisner rapidly adapting (RA), Pacinian (PC), and Merkel slowly adapting (SA-I) afferents are also activated by brief tactile contacts and contribute to other complex aspects of tactile sensibility (Chapter 11). SA-I afferents innervating the glabrous skin do not contribute to the sense of flutter-vibration; they signal the spatial pattern of afferent signals for form and texture of surfaces palpated by the hand. The SA-II Ruffini afferents, present in the human but not in the monkey hand, are exquisitely sensitive to skin stretch, and are important in the control of the positions and movements of the fingers in humans (Chapter 13). They rarely evoke any conscious perceptions when stimulated in isolation in human peripheral nerve experiments, and how they access the central somatic system is uncertain (Vallbo and Johannson, 1984; Torebjork et al., 1987; Macefield et al., 1990). Afferent fibers identified as SA-IIs, isolated in human peripheral nerves, entrain at low (1–8 Hz), but not at high frequencies of cutaneous sinusoids (Johansson et al., 1982).

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Fig. 12–1 Schematic outlines of active and passive detection and discrimination tasks used in studies of flutter-vibration in humans and in monkeys. A mechanical stimulator generated axial movements of a Lucite probe of 1, 2, or 3 mm diameter, shaped to a one-third spherical surface, oriented normally to the skin surface of the stimulated hand, in the passive discrimination task. The subject initiated a trial on sensing the initial step indentation of the skin of his hand by inserting his opposite hand into the path of a light key. The two stimuli follow, with variable delays between them (not shown). Subjects then indicated detection within the time period shown by removing the unstimulated hand from the light path and their forced choice by projecting that hand to one of two buttons to indicate their decision that the frequency of the second stimulus was higher or lower than that of the first. In the active discrimination task, the subject initiated a trial on light signal by exerting force with his finger pad upon a 6-mm diameter platform, driven by the mechanical stimulator, and maintaining force within a window indicated to him by lighted lines. The task then follows as described, with detection indicated by release of force, and so forth. The two detection tasks are similar, save that only one stimulus, which varies in amplitude from trial to trial, is delivered, and the subject indicates its presence by removing his hand from the light gate (passive), or releasing force (active). (From Mountcastle et al., 1972.)

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Fig. 12–2 Humans and monkeys have identical thresholds for detecting flutter-vibration stimuli delivered to their hands. Left: Averaged psychometric functions for five monkey and six human subjects working in the passive discrimination task of Fig. 12–1. Mechanical sinusoid at 40 Hz delivered to finger pads through a linear motor simulator bearing a rounded probe tip of 3 mm diameter, oriented normally to the skin surface. Right: Frequency-threshold functions for the same subjects who repeated the experiment at a number of frequencies. (Data from Mountcastle et al., 1972.)

Threshold Functions for Flutter-Vibration Are Similar in Humans and Monkeys Whether the neural operations in flutter-vibration are similar in humans and monkeys requires repetition of experiments under similar conditions, in the tasks outlined in Fig. 12–1 (Mountcastle et al., 1972, 1990; LaMotte and Mountcastle, 1975). Averaged psychometric functions for five human and six monkey subjects working in the passive-detect paradigm at 30 Hz are shown in Fig. 12–2, left. Repetition of the experiment at several frequencies yields the averaged frequency-threshold functions of Fig. 12–2, right. Analysis of the individual functions for these primate observers showed no significant differences either within or between the two groups.

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Until recently, nearly all studies of flutter-vibration have been made with stimuli delivered through punctate probes mounted normally to the skin surface. Brisben et al. (1999) measured these thresholds in humans in a way resembling everyday experience, by asking subjects to grasp a vibrating rod (32 mm diameter), the frequency and amplitude of which were controlled and changed. They found absolute thresholds in the range of vibration to be nearly an order of magnitude lower than any previously described; and, for some subjects, to be as low as 0.01 µm, at 300 Hz. This extreme sensitivity is interpreted as due to spatial summation and the free choice of contact area and force. Whether the spatial summation of Pacinian afferents is the only factor contributing to this threshold is uncertain, and it may be that the wide stimulus area found the most sensitive Pacinian afferents for the lower envelope. In this experiment the grasp of the vibrating rod certainly activates the large PCs in deep tissues whose thresholds are unknown.

Frequency and Amplitude Discrimination Thresholds for Flutter and Vibration Are Similar in Humans and Monkeys Psychometric functions for humans and monkeys making frequency discriminations are shown in Fig. 12–3. The human subjects had long experience in these tasks, and the monkey was trained in them for 5 days per week for 3 months. Such intensive training may lower discrimination limens by one half (Recanzone et al., 1992). The active acquisition of stimuli in these simple tasks provides little advantage over their passive reception. Human thresholds for discriminations between the amplitudes of mechanical sinusoids delivered to the skin are in the range of 1–2 dB, are independent of frequency (25 Hz and 250 Hz were tested), and rise by factors of 1.3 times at lower sensation levels, yielding a “near-miss” fit to Weber’s law (Gescheider et al., 1990). The capacities of experienced humans and a well-trained monkey for amplitude discriminations are shown in Fig. 12–4. Discrimination was measured at 30 Hz, at a sensation level 31 dB above averaged thresholds. The discriminable increments for the two primates are the same (10–11 µm above a base level of 102 µm), and remain so when tested over a range of sensation levels. Weber fractions in these studies clustered around 5–10 percent. In a control experiment

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Fig. 12–3 Humans and monkeys have similar capacities for frequency discrimination in the senses of flutter and vibration (the latter not shown). Left: Averaged results for three male humans, ages 25, 34, and 71 years, working in the passive discrimination task of Fig. 12–1 with base frequencies of 20, 30, and 40 Hz. Data points are means of 60–90 trials; they indicate percentage of trials on which subjects identified the comparison stimulus as of a higher frequency than that of the base stimulus. Curves are logistic functions fitted to those data points. Difference limens calculated as one-half the 25 percent and 75 percent levels on those functions. Weber fractions were in the range of 5–10 percent over the range of flutter and vibration. Right: Performance of a monkey working in similar tasks in the combined experiment, with head fixed and intracortical microelectrode recording. The difference limens and Weber fractions are similar in the two primates. (From Mountcastle et al., 1990.)

variations in frequency of the test stimuli, up to 4× the human difference limens (DLs), introduced randomly in different trials in the amplitude discrimination task, had no effect on performances in amplitude discriminations of mechanical sinusoids by humans or monkeys, yet they produce marked differences in mean frequencies of discharge in first order afferents produced by the test stimuli, with preservation of periodicity (LaMotte and Mountcastle, 1975). The postcentral neural activity evoked by mechanical sinusoids delivered to the glabrous skin of the hand contains one code for stimulus frequency, periodicity, and a population signal for stimulus intensity. What has gone before summarizes in abbreviated form a portion of the field of psychophysical research in vibratory sensibility. The result is that humans and macaque monkeys, though

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Fig. 12–4 Monkeys and humans have similar capacities for discriminating between mechanical sinusoids of different amplitudes delivered to the glabrous skin of their finger pads. Left: Results of a study of a trained monkey subject working in a passive discrimination task similar to that of Fig. 12–1 but here for amplitude differences. Dots give values for comparison stimuli called greater than base stimuli. Twenty-two runs for this monkey yielded 22 logistic functions, averaged for the solid line. DL = 10.2 µm; Weber fraction, 9.2. Right: Results of study of an experienced human subject, working in the identical task. DL = 10.8 µm; Weber fraction 10.0. (From LaMotte and Mountcastle, 1975.)

separated by several million years of divergent evolution, have nearly identical capacities in these somesthetic modalities. This similarity provides an opportunity for study of the brain mechanisms in somatic sensibility in experiments designed for the two primates under identical conditions, with the addition of electrophysiological recording of the relevant neural events in the monkey nervous system, and, with the development of new methods, in human brains as well. A central problem is that of neural coding; that is, which aspect of the neural activity observed is uniquely related both to the stimuli evoking it and to the sensory performance, and can be shown to correspond the latter? A set of problems of general significance is, what are the neural mechanisms of the perceptual decision processes linking the initial neural displays of stimulus properties in the somatic

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sensory cortex and the differential motor responses? These latter are now studied in combined experiment in monkeys (Romo et al., 2002a,b) and in imaging studies in both humans and monkeys (Seitz and Roland, 1992; Burton and Sinclair, 2000).

Peripheral Transducer Mechanisms in Flutter and Vibration. Neural Coding in First-Order Afferents The RA and PC afferents innervating the monkey hand are sensitive to mechanical sinusoids delivered to the glabrous skin of the hand over different but overlapping ranges of frequency. Each entrains the sinusoids in the phase-locked mode in its own range of frequency sensitivity. Entrainment thresholds for fibers in each group vary over an order of magnitude of stimulus amplitudes. Tuning thresholds for the most sensitive fibers in each group blanket the frequency-detection functions for monkeys, providing a strong example of the lower envelope principle; that is, that threshold is set by one or few fibers of a population with the lowest threshold(s) (Parker and Newsome, 1998). The typical response pattern of RA and PC fibers, as the amplitude of a cutaneous mechanical sinusoid rises from zero, is the appearance of a single nerve impulse phase locked to one or a few, randomly sequenced, sine waves in a stimulus of 400–1000 msec duration. This is the absolute threshold. As stimulus amplitude is further increased, the number of sine-waves with single phase-locked impulses increases linearly until, at a critical amplitude, most of the sine-waves evoke one impulse (criterion is p = 0.9 or better). This tuning threshold is illustrated by the impulse records of Fig. 12–5 for one RA and one PC fiber. The upper record of each set was evoked by stimuli just below the tuning points, the lower by stimuli just above it. Increases in stimulus amplitudes beyond the tuning point produce no change in the afferent response other than a phase advance. This tuning plateau is shown for a fiber of each class by the interval and cycle histograms of Fig. 12–6. Tuning point measurements over the relevant frequency ranges are compared with the average monkey detection function in Fig. 12–7. These graphs illustrate the order-of-magnitude range in the sensitivities of these sets of afferents. The fibers of Fig. 12–6 are from the mid-range of these sensitivity distributions. Tuning curves of first-order fibers shadow

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Fig. 12–5 Recordings of nerve impulses in the two types of rapidly adapting large mechanoreceptive afferents innervating the hand of the monkey. Single axons isolated for recording by microdissection of the median nerve. For each set of records, the upper trace is the analogue electrical signal of the position and movement of the stimulating probe tip, first its 550-µm indentation of the skin, and then the superimposed sinusoid. The two upper sets of records obtained from a Meissner rapidly adapting afferent, with stimuli at 40 Hz, and amplitudes just below (16 µm) and just above (19 µm) its tuning point. Stimuli delivered to distal pad of third finger. The two lower sets of records obtained from a Pacinian afferent innervating the hand; stimuli delivered to the palm. The two sets of records, obtained at stimulus frequency of 150 Hz and amplitudes of 14 µm and 18 µm, just straddled the tuning point of the fiber. Many other Pacinians have lower tuning points. (From Talbot et al., 1968.)

the lower edge of the detection functions. In such a correlation, response variability, from trial to trial, suggests that different afferent fibers might occupy the lower envelope in successive trials. In this case, it is likely that more than one fiber is active in the lower envelope, for several have low and almost identical tuning curves.

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Fig. 12–6 Interval and cycle histograms constructed from the responses of a Meissner, rapidly adapting, peripheral afferent fiber with a receptive field on the glabrous skin of a monkey’s distal finger pad. Stimuli at 40 Hz. Peak-to-peak amplitudes of mechanical sinusoid shown by numbers alongside each histogram. The histograms were constructed with 0.5-msec bins for the interval histograms shown to the left, and 0.25 msec for the cycle histograms, to the right. The absolute threshold is about 10 µm, followed by the tuning point at 17–19 µm, and then by a long plateau over which increasing stimulus amplitudes produce no change in the response, up to 99 µm at which some cycles evoke more than 1 impulse/cycle. Over the plateau there is a slight shortening of the phase lag, shown in the cycle histograms.

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Fig. 12–6 (continued) A similar analysis for a rapidly adapting Pacinian afferent fiber innervating the palm of a monkey’s hand. Stimuli delivered as described above, but at 300 Hz. Threshold, at 0.6 µm, followed by the tuning point, at 0.9 µm, and by a plateau of no response change with stimulus increases up to about 80 µm. Both sets of histograms constructed with 0.125-msec bins. The slight increase in the phase lag shown in the cycle histograms for responses to stimuli of high amplitudes is attributed to slowed conduction in an axon conducting at 300/sec. (From Talbot et al., 1968.)

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Fig. 12–7 Correlation between tuning points for Pacinian (left) and Meissner (right) afferent fibers, innervating glabrous skin of monkey’s hands with frequency detection functions, shown by solid curves connecting open circles, repeated in each panel. It plots thresholds averaged for 6 monkey subjects working in the passive detection task of Fig. 12–1; vertical lines = 1 SEM. Filled circles indicate tuning points for Pacinian and Meissner afferents. The lower envelope of the most sensitive fibers in each class matches the detection function in a particular range of frequency, with overlap in the range of 40 Hz. (From Mountcastle et al., 1972.)

Central Neuronal Mechanisms in Flutter and Vibration The RA, slowly adapting type I (SA-I), and PC sets of mechanoreceptive afferent fibers innervating the glabrous skin of the hand project through parallel channels of the lemniscal system with preservation of their specific modality and spatial properties. While there is some degree of segregation of SA-Is to area 3b and of RAs to area 1, this is not exclusive, and columns of these and of PC neurons occur throughout these two areas. The proportions of the three classes in areas 3b and 1 are given in Table 12–1. Areas 3a and 2 receive relayed afferent input from primary afferents innervating joints, fascia, and muscle; area 2 also contains a representation of the glabrous skin of the hand, which extends posteriorly from area 1 (Chapter 10).

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Table 12–1 Numbers of Neurons of Cutaneous Modalities Observed in Areas 3b and 1 of the Postcentral Somatic Sensory Cortex, Activated by Mechanical Stimulation of the Contralateral Hand, Under Different Experimental Conditions Source 1969* 1990** Totals

Rapidly Slowly Pacinian Number of adapting—RA (%) adapting—SA-I (%) —PC (%) neurons 78.6 77.3 78.9

14 14.2 14.1

6.4 8.5 7.0

720 331 1051

*(From Mountcastle et al., 1969.) **(From Mountcastle et al., 1990.) No neurons with SII properties were observed.

Postcentral Cortical Mechanisms in the Sense of Flutter Phase-linked neural signals evoked by low-frequency mechanical sinusoids delivered to the skin of the contralateral hand are transmitted through the RA channel of the lemniscal system and into areas 3b and 1 of the postcentral somatic sensory cortex, in macaque monkeys. The low-frequency activity evoked by flutter stimuli appears in the responses of the stellate cells of layer IV, and in many pyramidal cells at different positions in the intracortical processing chains. For RA neurons, phase-locked coding is transformed into periodicity in the discharge of cortical pyramidal cells across early synaptic transfers in the cortex. In this pattern, action potentials are clustered to a portion of the stimulus sine wave, and each cycle evokes a number of action potentials in a rhythmic waxing and waning in the density of neuronal discharge. There is a gradual growth in the intensity of the cortical cell discharge with gradual increases in stimulus amplitudes, without the abrupt tuning threshold characteristic of first-order RA afferents. Humans and monkeys make frequency discriminations in the sense of flutter with difference limens of 2–3 Hz, at base frequencies of 20, 30, and 40 Hz (Fig. 12–3). Results obtained in a macaque monkey as it worked in the combined psychophysical–neurophysiological experiment are shown in Fig. 12–8. The records and analyses of Fig. 12–9 show that the dominant periodicities evoked by the test stimuli are due to the sequential order in which impulses occur, and not to the presence of impulse intervals matching stimulus period

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Table 12–2

Primate Frequency Discrimination in Flutter Vibration:Difference Limens and Weber Fractions Base (Hz)

DL-Down (msec)

Weber (Hz)

Fractions (msec)

17%* 7.4 6.7 10.1 10.8 6.5

14.5% 7.0 6.3 9.2 9.7 6.2

Human, passive (1990)

20 30 40 60 100 200

2.9 2.1 2.5 5.5 9.7 12.4

8.49 2.48 1.67 1.69 1.08 0.33

Human, active (1990)

30 40 60 100

1.1 1.6 4.0 4.0

1.13 1.04 1.19 0.42

3.9% 4.2 7.1 4.2

3.7% 4.0 6.7 4.0

Monkey, experimental (1990)

20 30 40

1.3 1.6 1.7

3.46 1.83 1.08

6.5% 5.3 4.3

6.9% 5.5 4.3

Monkey, passive (1975)

30 30

2.7 1.8

3.3 2.13

9.0% 6.4

9.8% 6.0

Averages:

7.4%

6.8%

*Outlier included.

lengths. The periodicities are shown for a group of postcentral neurons, each studied individually, all in area 3b of a single hemisphere, by the spectral analyses of Fig. 12–10. This set of neurons responded to the base stimulus of 20 Hz with periods containing 8–10 percent of the total power, at that frequency. These same neurons responded after a 1-sec interval to the test stimulus with an equally powerful signal in which the harmonic content shifted to that of the test frequency. The cycle lengths of the two stimuli compared in this discrimination task are reproduced by the periodicities in the neural signals, and success in discrimination can be predicted by the difference in the periodicities in the neural activity evoked by the two stimuli compared. The analysis shows a similar periodicity produced in postcentral neurons in a monkey not working in the discrimination task. The operation of discrimination does not occur in the postcentral somatic sensory cortex. Other observations and control experiments support the hypothesis that periodicity is a candidate neural code for frequency in the sense of flutter, through the input level of the cortical processing

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Fig. 12–8 Results of a frequency discrimination study in a monkey working in the passive discrimination task of Fig. 12–1, as recording was made simultaneously of the activity of a rapidly adapting neuron of area 3b of the postcentral somatic sensory cortex, driven by the stimuli discriminated. The psychometric function to the right shows the behavioral performance. Data points show percent trials on which the frequency of the comparison stimulus, S2, was identified as higher than that of the base stimulus, S1; 10 trials per point. Curve is logistic function fitted to those points; DL 4.58 msec, Weber fraction 9%. Replicas of impulse discharges to the left obtained simultaneously with the behavioral performance. Each line is record of a single trial, each up stroke the time of an impulse discharge; steps show onset and offset of 550 µm, steady skin indentation of distal pad of contralateral third finger, upon which mechanical sinusoid were imposed. Stimuli delivered with probe oriented over the peripheral receptive field. There were no significant differences in impulse frequency between any of the comparison stimuli. Only six of eight classes delivered are shown. The difference in period lengths is the candidate cortical discriminandum for frequency discrimination, at the level of the first somatic cortex. (From Mountcastle et al., 1990.)

operation. There are no significant differences in the rates of impulses discharged by stimuli between which discriminations are made with certainty. It was established in a control experiment that random variations in the amplitudes of the comparison stimuli, which evoke different rates of discharge but that retain the periodic signal, do not

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Fig. 12–9 Results of a study of a rapidly adapting neuron of the postcentral somatic sensory cortex, made in a waking monkey, working in no task. Stimuli delivered as for the passive task of Fig. 12–1, with probe tip centered over the receptive field on the distal pad of the contralateral second finger. Columns from left to right: Columns 1 and 2 show spike replicas of the responses evoked by the base (S1) and comparison (S2) stimuli. Each line is the record of a single trial—continuous from the base to the comparison stimuli with variable inter-stimulus intervals, not shown; each up stroke is the instant of an impulse discharge; step functions indicate onset and offset of steady skin indentations of 550 µm, on which mechanical sinusoid were imposed. Columns 3 and 4, expectation density histograms obtained by analysis of records of columns 1 and 2; they show the strong periodic entrainment of neural activity with periods equal to cycle lengths of stimuli. Column 5, renewal density histograms of responses of column 2 show that periodicity is greatly reduced by random shuffling of impulse interval sequences. The inset histograms of column 5 show that the periodic signal is not due to the presence of large numbers of intervals at or near the stimulus cycle lengths. The differences in the period lengths in the entrained neural activity is regarded as the neural discriminandum for frequency at the level of the postcentral somatic sensory cortex. (From Mountcastle et al., 1990.)

degrade discrimination performances. A similar experiment in humans yielded the same result (Sinclair and Burton, 1996). In a second control experiment, two stimulus sets were convolved, one with 30 Hz as base and 32–38 Hz; as comparisons, in 2-Hz steps, and a second with 40 Hz as base and 32–38 Hz as comparisons. Trials from the two sets were sequenced randomly, so that, for example,

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Fig. 12–10 Results of Fourier analysis of the responses of 17 rapidly adapting neurons of areas 3b and 1 of one hemisphere in a monkey as he worked in the passive discrimination task of Fig. 12–1. Base stimuli at 20 Hz. Light columns show percentage of total spectral power (range of analysis 1–500 Hz) in responses evoked by the base stimuli. Dark columns show the percentage total power evoked by the comparison frequencies from 12 to 28 Hz, in different rows. At 12 and 14 Hz second harmonic is significant; human subjects report that they sense this second harmonic, but that it does not interfere with frequency discrimination. The same set of cortical neurons delivers, within a 1-sec interval, robust signals of the frequencies of the base and comparison stimuli delivered for discrimination. The difference between the two power spectra is a candidate neural discriminandum at the level of the postcentral somatic sensory cortex. (From Mountcastle et al., 1990.)

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Fig. 12–11 Results of frequency discrimination test in one human subject working in the passive task outline in Fig. 12–1, but here two sets with different base stimuli and two sets of comparison stimuli were intermingled randomly on successive trials. The subject was required to identify the base stimulus by its frequency. A number of comparison frequencies could be higher or lower than that of the base frequency in an unpredictable way. The results show periodicity is detected and discriminated, and not overall response frequency. (From Mountcastle, unpublished experiment.)

comparisons in the range of 32–38 Hz were low on some trials, high on others, in an unpredictable sequence. The performances of a human subject in this combined set, and on the two sets delivered separately, are shown in Fig. 12–11. His performance in the combined set was 89 percent of that in the two sets delivered separately. Both humans and monkeys can make frequency discriminations when working in such mixed sets containing two or even more different base stimuli and related comparisons (Mountcastle et al., 1990).

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Frequency discrimination in the sense of flutter depends on different periodicities evoked in postcentral neurons by the frequencies discriminated, and is not based on uncontrolled cues, or on any differences in subjective magnitude or overall frequency. The periodicity code persists through the early stages of processing in the primary somatic sensory cortex.

Postcentral Cortical Mechanisms in the Sense of Vibration A smooth transition is maintained in primate performances in the frequency discrimination task, as the frequencies to be discriminated are raised from the range of flutter to that of vibration. Over this transition, the Weber fraction remains in the range of 5–10 percent. Cutaneous sinusoids in the range of 100–300 Hz, delivered via punctate probes oriented normally to the surface of the glabrous skin of the hand, at amplitudes just above the atonal interval, evoke cyclically entrained activity in PC thalamocortical fibers and PC neurons of the middle layers of areas 3b and 1 in the postcentral gyrus of waking monkeys (Fig. 12–12), and entrain some of the pyramidal cells of the supra- and infragranular layers. Nelson and his colleagues took advantage of the strong spatial summation within the peripheral Pacinian population, and of the central neural convergence within the PC channel, by delivering vibratory stimuli (127 Hz) via a plate covering the full glabrous skin surface of a waking monkey’s hand (Lebedev et al., 1994; Lebedev and Nelson, 1995, 1996). They identified 4–5 percent of the neurons in the cytoarchitectural areas of the first somatic area (SI) with PC properties, and used stimuli at amplitudes likely to engage the majority of PCs innervating the hand to produce a strong entrainment of cortical PCs. The latency to activation of PCs in area 2 averaged 35.6 msec, vs 16.5, 19.8, and 21.4 msec, respectively for PC neurons in areas 3a, 3b, and 1. This suggests that area 2 receives its major input by transcortical projections from more anterior postcentral areas, and may function as a higher-order processing area in somatic sensibility, a suggestion consonant with the observation that ablation of areas 3a, 3b, and 1 denervates area 2. Activation of the RA and PC channels by low- and high-frequency cutaneous sinusoids, respectively, produced in the squirrel monkey spatially congruent increases in light absorbency and neuronal

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Fig. 12–12 Study of a thin spike of a presumed Golgi neuron, 860 µm below the surface of area 1 in the postcentral gyrus of a monkey. The neuron had all the properties of the Pacinian class, and was driven from any spot on the contralateral hand. The expectation density histograms show an entrainment threshold of 2–3 µm at 200 Hz, but only for much higher stimulus amplitudes at 300 Hz, and never at 400 µm for any of the amplitudes used. The stimuli were mechanical sinusoids; values given are peak-topeak amplitudes. The neuron did not entrain to any stimulus frequencies below 60 Hz. (From Mountcastle et al., 1969.)

activity in local regions of areas 3b and 1 of SI (Tommerdahl et al., 1999). High-frequency stimulation of contralateral fingers in humans evokes increases in blood flow in local regions of SI (Fox et al., 1987), in the second somatic area (SII), and in adjacent regions of the superior bank and fundus of the Sylvian fissure (Burton et al., 1993; Coghill et al., 1994). The conclusion is that cyclically entrained activities for both flutter and vibration are projected through the lemniscal system and into the postcentral cortex. Periodic entrainment appears to be the neural code with predictive power for frequency discrimination in the sense of flutter. This is transformed to frequency codes in transpostcentral areas of the cortical somatic system. The code used in the frequency range of vibration remains less certain.

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Transcortical Neural Mechanisms in Flutter Discrimination: Postcentral Sensory to Contralateral Motor Cortex The neural mechanisms of discrimination have been studied in the postcentral sensory and the precentral motor cortex of monkeys. The circumstances of the task require projection of the responding arm contralateral the stimulated hand, which allows study of the cortical processes operating in both hemispheres. A major hypothesis for these studies is that the discrimination operation is executed in the dynamic activity of the multinoded, distributed transcortical system linking the sensory cortex of one hemisphere to the motor cortex of the other, and that the neural activity on which the final discrimination output is based is not generated in any single intervening stage, but in the distributed system as a whole. The phrase “distributed system” includes both the cortical areas and reciprocal loops with such subcortical structures as thalamus, basal ganglia, and cerebellum, and so forth. The experimental aims are to differentiate the neural activity evoked directly by the sensory stimuli, at the input level of the postcentral sensory areas, from those which follow in both hemispheres. They are inferred to be: (1) the activity evoked directly by the first stimulus; (2) neural signals of a short-term or working memory of the responses to the first stimulus thought to persist in the interstimulus interval; (3) the neural signals evoked by the second stimulus, which may also be influenced by the first stimulus; (4) the decision process following the second stimulus; and (5) activity related directly to the overt motor responses. Attention turned first to two near-range transcortical projection targets of areas 3b and 1, the immediately adjacent area 2 of the postcentral area, and SII on the superior bank of the Sylvian fissure, in monkeys. Restricted ablations of the hand regions of areas of 3a, 3b, and 1 effectively deactivate the hand areas of both postcentral area 2 and SII. (Burton et al., 1990; Garraghty et al., 1990a,b). Under normal circumstances, many neurons of area 2 respond to mechanical sinusoids delivered to their multifingered receptive fields on the contralateral hand, but only 13 percent of those otherwise typical RA neurons are cyclically entrained by the stimuli of Fig. 12–1, in contrast to the 72 percent of neurons of areas 3b and 1 that are (Mountcastle et al., 1969, 1990). The general role of the SII areas in somatic sensibility is described in Chapter 14. A major difference exists in the connectivity of SII

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between Old World monkeys and many other species, for while the major input to SII is from SI in the macaque monkey, carnivores, rodents, and prosimians receive parallel and independent thalamocortical projections directly to SII from the thalamic ventral posterior lateral (VPL) nucleus (Rowe et al., 1996). The partial modality segregations and the proportions between neurons of different modality classes in SI should, by this direct projection, determine similar modality segregation and proportionate numbers in SII (Pons et al., 1992). There is some spatial divergence within the cutaneous modalities, for their receptive fields are larger in SII than in SI, but submodality specificity persists into SII. Some SII cutaneous neurons subtend bilaterally symmetrical receptive fields, produced by reciprocal trans-callosal projections between the two SII areas, rather than by ipsilateral input (Whitsel et al., 1969a,b; Nakama, 2003). The sequence outlined above has been studied in several of the nodes of the distributed cortical system in the combined experiment described in Chapter 1, particularly in a series of experiments by Romo and his colleagues in Mexico City. Their experiments are marked by a careful correlation between psychophysical and neurophysiological observations, by study of large numbers of neurons in each of the cortical areas, and by a statistical analysis of the neuronal activity recorded. For reviews, see Romo et al. (2002a,b, 2004), Brody et al. (2003), and Romo and Salinas (2003). Postcentral areas 3b and 1. Romo et al. discovered that in addition to the two thirds of postcentral neurons that are cyclically entrained by the mechanical sinusoids, many of the remainder discharge with increased frequencies as the stimulus frequency rises (Hernandez et al. 1997; Salinas et al., 2000). This suggests that in such a task a subject may have the alternatives of working on two or more neural discriminanda, in this case on cyclically entrained or overall frequency of response; or, indeed, on some aspect of the neural activity yet to be identified. Experiments have shown that in some cases discrimination depends on the first, described above, but in others on the frequency of discharge, per se, without entrainement. No sign of the putative short-term memory process was observed in the delay period between the two stimuli. There is no evidence concerning neuron types or their positions in the intracolumnar processing operations within the postcentral areas, in

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relation to these response properties, which may reflect the sequential intracolumnar processing. Second somatic area. Only rarely are SII neurons with receptive fields on the glabrous skin of the hands entrained to cyclical discharge by mechanical sinusoids, but many show frequency changes with changes in stimulus frequency. However, in contrast to the pattern of response of SI neurons, some SII neurons carry information about the first stimulus into the inter-stimulus delay period; this activity may persist for many hundreds of milliseconds in some neurons (Romo et al. 2002a). This is interpreted as an early sign of the short-term memory process. Premotor cortex. Transitional neural operations have been studied by Romo et al. (2002a,b, 2004) in the ventral and medial premotor cortex of the frontal lobe, and in the motor cortex itself. Several observations are relevant to the question of the cortical mechanisms of decisions made in the frequency discrimination tasks in flutter. The strong periodicity observed in the early stages of the intracortical processing chains in areas 3b and 1, illustrated above, appear only rarely in any of their trans-cortical targets. Neurons of the ventral premotor cortex reflect the full pattern of events in the sensory discrimination to motor transition. Romo et al. (1999) also observed strong and sustained activity between base and comparison stimuli, even when the two were separated by 6 sec or more, and interpreted this as the neural correlate of short-term memory, containing information of the frequency of the base stimulus. This premotor neural correlate of short-term memory has been observed in many different experiments. It is followed by neural signals of the decision process after the second stimulus, and the motor response. For reviews, see Fuster (2001); for a summary of the experiments of Romo et al., see Fig. 12–13. The motor cortex. The patterns of activity of the motor cortical neurons during execution of the frequency discrimination task contain both the output signals of the discriminative operation, and the efferent discharge driving the contralateral arm. Fig. 12–14 shows the discharge pattern of a motor cortical neuron selectively active during the time of the comparison stimulus. There is no periodicity in the activity of the motor cortical cell; the increase in

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Fig. 12–13 Summary of the studies of Ranulfo Romo and his colleagues of the somatic sensory and trans-cortical areas active in monkeys making frequency discriminations in the sense of flutter. SI— postcentral area 3b; S2—somatic sensory area 2; VPC—ventral promoter cortex. M.C.—medial promoter cortex; M1— precentral motor cortex; N = number of neurons studied in each area; the graphs show the percentage of the neurons that showed significant relationships between the frequencies of the base (f1) and comparison (f2) stimuli in the frequency detection task. Graphs are plots of coefficients that serve as direct measures of the dependence of the discharge rates of neurons as functions of the frequency of either f1 or f2. The light gray line plots the average coefficients as functions of the f1 frequency; they show the powerful surge of activity in the inter-stimulus interval. Dashed line shows dependence on the frequency of f2. The line reaching its peak during f2 plots the number of neurons with equal but opposite dependence, and the heavy black line the switch to the decision response. (From Romo et al., 2004.)

activity begins about 300 msec after onset of the comparison stimuli, continues to and through the reaction time, and ceases abruptly with movement onset. The distribution of latencies of these motor cortical cells is broad relative to the onset of the comparison stimuli (Fig. 12–15), but peaks of activity occur well before onset of activity in motor cortical neurons relative to the upcoming movement

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Fig. 12–14 Results of study of a neuron in the motor cortex ipsilateral to the stimulated hand and contralateral to the responding arm as a monkey worked in the passive frequency discrimination task of Fig. 12–1. Mechanical sinusoid delivered at 10 × thresholds, determined for each frequency. The standard stimulus, S1, at 30 Hz coupled with the comparison stimuli, S2, of different frequencies, delivered in randomly ordered trials. First column left: each line is record of a single trial, each up stroke the time of occurrence of a nerve impulse; step changes are indentations of skin, on which mechanical sinusoid were superimposed. Second column, responses to S2 are aligned to the onset of the reaction time. Third column (Hist-S2) shows peristimulus time histograms, and the fourth the expectation density (autocorrelation function) for the responses to S2. This neuron discharged selectively only to comparison stimuli lower in frequency than that of the base, during and after the comparison stimuli, and ceased abruptly with onset of the reaction time. Ordinates: for frequency histograms, 50 impulses/sec/large scale division; for ED, 10 impulses/sec/large scale division. (From Mountcastle et al., 1992.)

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itself. The delay in the discharge of motor cortical cells during the comparison stimuli is independent of change in the inter-stimulus period, or variations in the duration of the comparison stimuli (tested from 400 to 1000 msec; Hernandez et al., 1997). Analysis of error trials revealed that errors are most commonly made in the discrimination process, followed by a correctly matched arm movement to the wrong target (Mountcastle et al., 1992). On the assumption that the early selective activity of motor cortical neurons is generated by the output of a completed discrimination process, and taking into account afferent transmission and postcentral operation time, it appears that the discrimination operation within the distributed system of the cortex takes no more than 200–250 msec, which fits with the reports of human subjects that they reach a decision early in the comparison stimulus time.

Fig. 12–15 Latency histograms of a population of neurons of the motor cortex, recorded in waking monkeys in the passive frequency discrimination task of Fig. 12–1. in experiments like that of Fig. 12–14. Times are plotted as lead from onset of discharge to the end of the comparison stimuli. Cross-hatched bars indicate lead times for neurons discharging selectively during the period of the comparison stimuli: mean lead time 691+/—18 msec, SEM; n = 180 neurons. Open bars indicate lead times for motor cortical neurons discharging selectively during the reaction time and/or the movement period: mean lead time 19 msec  SEM 12 msec; n = 356 neurons. The latter group displayed the well-known activity pattern of motor cortical neurons during reaching with the contralateral arm. (From Mountcastle et al., 1992.)

Central Nervous System Lesions and Flutter-Vibration Spinal Cord Lesions in Humans and Monkeys The convoluted history of the effect of spinal cord lesions upon somatic sensibility is described in Chapter 6 (see Ross, 1991). Those defects can now be understood in terms of which defined sets of dorsal root afferents project into which spinal funiculi, or into more closely defined ascending pathways of the primate spinal cord. In both humans and monkeys high cervical transections of the dorsal columns produce severe defects in proprioception and motor control

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in the arm, but much milder changes in the leg, while defects in some dynamic aspects of cutaneous sensibility appear in both limbs. The critical discovery was made by Whitsel et al. (1969a,b, 1970), that the gracilis tract at the upper lumbar level contains a full complement of large-fibered afferents from the lumbosacral dorsal roots, but that this same tract at the high cervical level contains only quickly adapting cutaneous afferents. Slowly adapting cutaneous afferents and mechanoreceptive afferents from muscle and joints of the leg transit through the dorsal horn in the low thoracic region, and project second-order axons into the dorsolateral column. Some of these are destined for the dorsal column nuclear complex, and a large contingent for the cerebellum. These findings predict the differential effects of high cervical transections on the arm and leg in humans, and those described by Vierck in monkeys with high cervical transections Vierck (Chapter 6) Direct tests have not been made of the capacities of monkeys with high cervical lesions to discriminate between the frequencies or amplitudes of mechanical sinusoids to the skin. The conclusion is that the re-sorting of primary afferent fibers of different modalities, and their redirection into different ascending pathways of the spinal cord, can account for the effects of lesions of those pathways made at different segmental levels.

Cortical Lesions in Humans and Monkeys It is a long-standing dogma in clinical neurology that suprathalamic lesions in humans produce little or no change in thresholds for vibratory stimuli delivered by tuning forks held to the side of the body opposite the lesions (Head and Holmes, 1911–1912). In the classical age of neurology this was attributed to “thalamic integration,” which now seems unlikely. This observation has been confirmed many times; for example, Roland and Nielsen (1980) found no threshold changes for detecting vibratory stimuli delivered to the hands of humans with contralateral, circumscribed, suprathalamic lesions. These observations are consonant with those made in monkeys, described below. LaMotte and Mountcastle (1979) studied 17 monkeys (20 hemispheres) before and after a variety of lesions of the cerebral cortex, with pre- and postoperative measures of thresholds for detecting

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flutter-vibration stimuli delivered to their hands, and for discriminating between mechanical oscillations at different frequencies (5 monkeys) and amplitudes (2 monkeys). Their results were as follows: 1. Removal of the hand and arm areas of SI, cytoarchitectural areas 1, 2, and 3, produces an immediate elevation of detection threshold by 3–6 times for frequencies at 10, 30, or 200 Hz, compared to thresholds on the ipsilateral hand opposite an unlesioned hemisphere. Thresholds dropped to 2.0–2.5 times preoperative thresholds over 6–8 days of postoperative training and remained elevated at that level thereafter. Simultaneous removals of SI and SII produced no greater elevations of thresholds than did removal of SI alone. No change in threshold was ever seen on a hand ipsilateral to any cortical lesion. 2.

Addition of the posterior parietal areas and the precentral motor cortex to the removals, either separately or together, produced no greater elevation of thresholds than did lesions of SI alone. Monkeys with even the largest of these lesions quickly relearned the motor components of the detection and discrimination tasks. A lesion restricted to SII and adjacent somatic sensory areas of the parietal operculum, or of areas 5 and 7 of the parietal lobe, caused no elevations of thresholds.

3. Any combination of lesions of the cortex that included the arm and hand areas of SI together with SII reduced to chance the monkey’s capacity to make frequency discriminations (Fig. 12–16). These lesions also decreased the capacity to categorize stimuli of different frequencies, and to discriminate between the wide ranges of flutter and vibration. 4. Monkeys with removals of SI + SII, or with these plus large parietal lobe and motor cortex removals, were defective in making amplitude discriminations between stimuli of the same frequency. Difference limens were elevated by factors of 4–5 times. 5. Monkeys with isolated lesions of SII have not been studied for changes in amplitude or frequency discriminations in

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Fig. 12–16 Frequency discrimination in a monkey before and after removal of somatic sensory areas SI, SII, and area 5 of the parietal lobe, contralateral to the tested hand. The preoperative psychometric function is shown by the line connecting filled circles. Each symbol is weighted average of data from three to nine test runs. Tests were made on postoperative days 10–16 (closed dots) and 79–81 days (open circles with X). The animal was unable to discriminate between frequencies in the range of flutter, up to 70 Hz, and the standard of 40 Hz. (From LaMotte and Mountcastle, 1979.)

flutter-vibration. The major source of input to the hand area of SII comes from the hand area of SI, in macaques, so that a lesion of SI that eliminates frequency and amplitude discrimination removes the funnel of activity to projection targets, and does not imply that the discrimination operations are executed in SI. In summary, detection thresholds are elevated by about 2.5 times when SI is removed, in monkeys, and the addition of areas of parietal and frontal lobes does not add to this defect. What mechanisms are

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responsible for detection in these widely lesioned hemispheres is unknown. Any lesion of the cortex that includes SI + SII eliminates permanently a monkey’s capacity to discriminate between or to categorize flutter-vibration stimuli of different frequencies, and produces increased difference limens for discrimination between stimuli of the same frequency but different amplitudes. The conclusion is that the neuronal processing mechanisms of SI and SII are essential for the cortical processing of the dynamic aspects of the neural activity evoked by mechanical sinusoids delivered to the glabrous skin of the hand.

Subjective Magnitude Estimation and the Primary Population Code for Stimulus Amplitude in Flutter-Vibration Subjective magnitude estimation (SME) is a measure of a subject’s perception of the intensities of sensations evoked by peripheral stimuli of different amplitudes. This measure allows construction of testable hypotheses concerning the relevant peripheral and central neural processes leading to these perceptions. Humans rate the intensities of mechanical sinusoids delivered to their hands along linear continua, when measured by Stevens’ method of direct scaling. After logarithmic transformation, the SME functions have slopes of 0.9 in the frequency range of flutter. In some (Stevens, 1968), but not all (Verrillo et al., 1969; Verrillo, 1970), studies the slope declines to about 0.6 at 300–350 Hz (Stevens, 1959a, 1968; Talbot et al., 1968). The SME is proportional to perceived stimulus intensities as stimulus amplitudes are reduced to levels close to threshold (Verrillo, 1970). There is a striking mismatch between these psychophysical measurements and the responses of the relevant first-order, the mechanoreceptive afferent fibers innervating the primate hand. The intensity functions of RA and PC afferents innervating the glabrous skin of the monkey’s hand do not change over an extended range of increasing stimulus amplitudes. Over this plateau, action potentials are phase locked to the stimulus sine wave, with no other change in the signal in single fibers except for a shortening of the phase lag; yet over this same range of stimulus amplitudes the human subjective magnitude estimation function increases steadily. The perceptions of the intensities of flutter or vibration stimuli cannot be accounted for by the pattern of afferent discharge in any single RA or PC afferent.

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A solution to this problem evolved from the studies by KO Johnson of the population responses of RA and PC fibers innervating the monkey hand to flutter and vibratory stimuli of different amplitudes (Johnson, 1974). The open circles of the upper panel of Fig. 12–17 show the nearly linear human SME of the amplitude of mechanical sinusoids at 40 Hz, delivered to their hands; the dashed line and closed circles plot the total RA population responses evoked by stimuli of the same amplitudes. The lower panel plots the average course of events in a single RA afferent under similar stimulus conditions. There is a nearly linear increase in the probability that the stimulus will evoke a single impulse, from the absolute threshold at I-0 to the tuning point at I-1, at which the probability is 1 that each sine wave will evoke a phase-locked impulse. This is the point humans identify as the upper level of the atonal interval. There follows an extended range of increasing stimulus amplitudes over which the only change in the response is a shortening of the phase lag; over this same range the SME continues a linear increase. Then, at stimulus amplitudes that vary for different fibers (I-2) the majority of RA afferents begin to discharge two impulses on at least some sine waves; and, with still further stimulus increments, a few discharge 3 impulses on some sine waves, I-3. The dashed line and open circles of the upper panel of Fig. 12–17 show the linear increase in the total number of impulses in the afferent population as stimulus amplitude rises, derived from Johnson’s population reconstruction; it matches the nearly linear SME, obtained under similar stimulating arrangements. This intensive recruitment is paralleled by a spatial recruitment, a linear increase

Fig. 12–17 Above: The dashed line and open circles show the linear increase in the total number of impulses in the population of Meissner afferents innervating the glabrous skin of the monkey finger activated by increasing sine wave amplitudes, at 40 Hz; it matches the nearly linear subjective magnitude estimation of humans, determined under the same circumstances. Below: The average time course of events in a single Meissner afferent, studied under the same circumstances. Io = threshold; I1 = tuning point at 1 impulse per cycle; I2—threshold for increment in number of impulses per stimulus cycle; I3—some fibers begin to discharge 3 impulses per cycle. The linear subjective magnitude estimation cannot be based on the properties of single afferents, but upon the summed population signal. (From Johnson, 1970, 1974.)

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in the total number of fibers in the active population. Analysis and reconstruction led to similar results for the PC population (Johnson, 1970). Flutter stimuli of different frequencies are judged by human observers to be of equal intensities at stimulus amplitudes that recruit nearly equal numbers of fibers to the response populations. This suggests that the recruitment of increasing numbers of fibers is the likely code for intensity in this sensory mode, although the parallel recruitment of increasing numbers of impulses in an unchanged active population remains a candidate (Johnson, 1977). These parallel functions for the population response of the firstorder afferent input and the human subjective magnitude estimation indicate that the spatial and perhaps also the intensive recruitments within the first-order afferent population compose neural codes for intensity in the senses of flutter and vibration. That possibility is strengthened by the facts that no other large-fibered mechanoreceptive input from the hand evokes when stimulated the senses of flutter or vibration, and that no set of smaller afferents responds to cutaneous mechanical sinusoids. In either case, the population code proposed for the intensity of flutter-vibration stimuli meets the first requirement for any neural code: it predicts the subject’s response.

Postcentral Neural Activity and the Atonal Interval Observations in both humans and monkeys show that in a zone of 6–8 db of increasing amplitudes above absolute threshold, subjects can detect a peripheral event, but cannot make frequency discriminations in the frequency range of either flutter or vibration. A similar atonal interval exists in audition (Pollack, 1948). No double threshold exists in the responses of postcentral RA neurons driven by these stimuli. Even the weakest perceptible peripheral flutter stimulus evokes a periodic neuronal discharge of regular cortical neurons. Further increases in stimulus amplitudes through the behavioral range of atonality, between the peripheral absolute and tuning thresholds, evokes a smooth increase in the strength of the periodicity in cortical neuronal activity. Humans and monkeys show parallel performances, as they work in frequency discrimination tasks with stimuli gradually rising over this range of amplitudes (Fig. 12–18). There is a gradual, not a sudden, increase in the accuracy of frequency discrimination to an arbitrarily chosen criterion level (LaMotte and Mountcastle, 1975; Mountcastle et al., 1990).

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Fig. 12–18 Psychometric functions for a human and a monkey subject working in the passive flutter discrimination task outlined in Fig. 12–1. Performances drop below criterion value as amplitudes of stimuli drop below 7–8 dB above thresholds. This is the atonal interval, in which subjects can detect the presence of mechanical sinusoid delivered to the skin of their hands, but cannot discriminate between the frequencies of those stimuli. (Data from LaMotte and Mountcastle, 1979.)

Slowly Adapting Mechanoreceptive Afferents Innervating the Glabrous Skin Do Not Contribute to Flutter-Vibration Both the SA-I and RA sets of postcentral neurons are periodically entrained by cutaneous mechanical sinusoids in the frequency range of flutter, driven by similarly entrained activity in systems that link them to SA-I and RA first-order afferents. Yet the evidence indicates that the RA system serves the oscillatory sense of flutter; the SA-I system serves the sense of pressure, and more complex aspects of tactile sensibility, without an oscillatory component. This conclusion is supported by

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several lines of evidence. The first is the low thresholds at which SAI neurons are entrained by cutaneous sinusoids when the stimulus frequency matches the steady discharge of SA-I peripheral fibers, which varies with the depth of skin indentation. These afferents and their postcentral neuronal targets can then be entrained at stimulus amplitudes an order of magnitude below primate thresholds in the frequency range of flutter. Second, stimulation of isolated, identified, SA-I afferents in human nerves evokes the sense of pressure, never flutter, no matter what the frequency of stimulation. Stimulation of RA afferents evokes the sense of flutter; of Pacinians, vibration. Changes in the frequency of stimulation of a QA fiber evoke changes in the frequency of flutter perceived; changes in the frequency of stimulation of SA-I afferents evoke changes in the intensity of the pressure perceived. Stimulation of SA-II afferents in human nerves, thought to innervate Ruffini receptors in the human hand, evokes no conscious perception (Torebjork et al., 1984b, 1987; Vallbo et al., 1984; Macefield et al., 1990). These facts indicate that the periodic signals in SA-I neurons, peripheral or central, are not used for frequency detection or discrimination in the sense of flutter.

Flutter and Vibration Can Be Dissociated Perhaps the strongest evidence for the dual nature of fluttervibration is the different subjective experiences evoked by low, as contrasted to high-frequency mechanical sinusoids, a difference to which all human subjects with normal nervous systems attest. Local anesthesia of the skin selectively eliminates the sense of flutter, leaving the vibratory sense intact (Talbot et al., 1968). The selective elimination of the Meissner afferents by cutaneous anesthesia has also been observed on the thenar eminence of the monkey’s hand (Mountcastle et al., 1972), and on the hairy skin of the human arm (Merzenich and Harrington, 1969). A similar dissociation is produced on the fingertip by transection of a purely cutaneous digital nerve (Morley et al., 1988).

Enhancement and Masking Intrinsic variables of enhancement and masking influence human subjective estimates of the magnitude of leading or trailing stimuli in the mode of flutter-vibration (Verrillo and Gescheider, 1979; Geschei-

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der et al., 1983, 1985; Hammer et al., 1983; Verrillo, 1985). The channel specificity of the enhancement effect, together with the masking phenomenon, has been used to raise the still unsettled question whether other sets of mechanoreceptive afferents innervating the hand may also contribute to this somesthetic modality (Bolanowski et al., 1988; Gescheider et al., 2001). Masking is the suppression of a subjective estimate of stimulus magnitude by a stimulus in the same frequency range that begins before and continues through and after the following test stimulus. The effect is increased by increasing intensity of the masker, remains channel specific in terms of mode and frequency, and can be evoked between fingers of the same hand, or between locations on opposite sides of the body (Craig, 1976; Gescheider and Verrillo, 1980). Burton and Sinclair (1998) found in monkeys that the response of SI neurons to a 125-Hz vibratory stimulus is depressed by a similar, preceding stimulus, delivered to the same location on the contralateral body surface. Neurons of SII and 7b, with bilateral receptive fields, were suppressed by stimuli delivered in either ipsi-contra or contra-ipsi sequence to mirror image locations on the two sides of the body.

Concluding Remarks What has been described here are preliminary samplings of what is necessary for understanding the cerebral cortical mechanisms in somesthetic perceptions, even relatively simple ones such as frequency or amplitude discriminations in the sense of flutter. The consistent parallel between measures of primary afferent input, and of the perceptual experiences evoked by them, establishes at the first level of analysis a metric base for perceptual operations. Working on the hypothesis that the discrimination operation is executed in the dynamic operations in the multinoded and widely interconnected distributed system linking input to output, it is necessary to go beyond the step-by-step observation of one candidate node after another, with the hope that a later reconstruction will yield some image of the activity in the system during perceptual events. This seems almost certainly doomed to be incomplete, for it is just those timing relations between events that are important, and it is just those relations that are lost in such a reconstruction. Methods are now available that allow direct attack on the problem: the chronic implantation of dozens—even hundreds—of microelectrodes at lo-

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cations throughout the system, each movable in the z-direction, and recording for days and weeks as an animal learns and finally executes perceptual tasks. Such a program will also allow study of extraneous factors that influence perception; for example, the motor responses, diversion of attention, emotional overtones, and so forth. Such a program has all those problems involved in the transition of central neurophysiology from small to large science.

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Parietal Lateral System and Somatic Sensibility

Evoked neuronal activity in the major sensory systems of the brain transits through the primary sensory areas, undergoing in them processing, elaboration, and abstractions from the quasi-isomorphic representations of peripheral stimuli that reach them over thalamocortical pathways. From thence these transformations are projected into widely interconnected areas of the cerebral cortex where hierarchy quickly disappears. Processing in the system abstracts/constructs complex properties of peripheral stimuli, yielding representations presumed suitable for perceptual operations and, at choice, behavioral response. These cortical areas are not restricted to any one somesthetic mode, and some of them function in generating the cognitive and affective components of many aspects of somesthesis, and indeed for other sensory systems as well. Much of what we know of these distributed systems comes from anatomical experiments, in which the corticocortical connections and the linked cortical–subcortical loops were traced; and from electrophysiological experiments in monkeys working in somatic sensory tasks that reveal the functional properties of populations of neurons in these cortical areas. More recently, imaging studies in normal humans have revealed the previously unpredictable roles of several cortical areas as members of the cortical somatic sensory system. The cortical systems engaged by the efferent projections from the postcentral gyrus compose two large sets defined on the basis of their locations and connectivity, and the particular aspects of somatic sensibility they serve, with the qualifier that the division is

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somewhat arbitrary and that the two sets are heavily interconnected at many levels. The first projection is from the postcentral gyrus into areas 5 and 7 of the parietal lobe—the “posterior system,” which generates somatic sensory functions, including the recognition of the form of objects enclosed by the hand, knowledge of the position and movement of the limbs in space, the generation of an internal schema of the body form, and the generation of movements of arm and hand directed at targets within reach. This posterior parietal system generates the trans-cortical projections linking the parietal and frontal lobes that initiate and govern those projected movements. I describe the function of this system in Chapter 14. The second major efferent projection from the postcentral areas is into the cortex of the Sylvian fissure—the “lateral system”— including as immediate targets the second somatic and insular areas that serve particular aspects of tactile, pain, and thermal sensibilities. These regions serve as processing-projection regions into the systems of the frontal and temporal lobes concerned with cognitive functions, including memory and learning, but are also interconnected with the posterior parietal and premotor areas of the “posterior” system. The lateral component of the distributed system is the topic of the present chapter. Electrophysiological experiments in monkeys and imaging studies in humans reveal overlap between those cortical areas of the lateral fissure activated by innocuous mechanical stimuli and those responding to noxious and/or thermal stimulation of peripheral tissues. These responses are context dependent, determined both by afferent input evoked by peripheral stimuli and by the convergent input from interconnected cortical areas (Friston, 1998, 2002), and may reflect the general set of the subject in terms of attention, stimulus novelty, immediate past history, and the affective and cognitive implications of the stimulus to the subject in the overall behavioral context. The convergence of innocuous and noxious inputs poses the problem of how the same intracortical networks could produce through their outputs such different and clearly identifiable, modality specific, experiences. In each case the neural activity leading to either mechanoreceptive or painful experiences is embedded in the ongoing activity in the distributed system, and, it appears, in some of the same components. The caveat remains that in some areas noxious and innocuous activity may be closely interdigitated in parallel processing

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streams, but may appear to be completely superimposed in imaging studies. The spatial and temporal resolving powers of event-related functional magnetic resonance imaging (fMRI) methods now approach the sub-millimeter dimensions of columns and the temporal cadences of neuronal activity. Use of these methods may solve the problem of whether interdigitation and parallel processing, or convergence and “integrated” activity, prevails with progression into the distributed cortical system for somesthesis (Ogawa et al., 2000; Kim and Ogawa, 2002; Urgurbil et al., 2003). Parallel processing dominates through the thalamic relay nuclei and into the first-order somatic sensory areas, but convergence appears on present evidence to occur to one degree or another in far-cortical targets of the system. Evidence from lesion studies in humans, imaging studies in humans, and both surface and dural recording of evoked potentials indicate that pain projects to two areas within the lateral sulcus, and some fMRI studies in humans suggest that the areas in the cortex of the lateral fissure activated by mechanical or noxious stimulation may be interdigitated rather than overlapping (Gelnar et al., 1999; Apkarian et al., 2000; for review see Treede et al., 2000). Studies of the cortical mechanisms in tactile, pain, and temperature sensibilities in humans and monkeys have yielded a rapidly changing picture of the relevant cerebral networks. The components of the cortical somatic sensory system described in later sections are those most commonly identified in experimental or clinical studies. The variable natures of somatic sensory experiences, particularly that of pain, are matched by variations in the distributions of the associated cerebral activity, which differ as the sensory experiences differ in affective or cognitive components, or in accompanying motor responses. A question of current interest is whether activity in the smallfibered afferent systems projected to the forebrain over ascending intrinsic pathways, ordinarily serving pain and temperature, may also contribute to the mechanoreceptive aspects of somatic sensibility, for example, through the low-threshold tactile C-fibers that innervate the hairy skin and project to the insula. In a patient lacking large myelinated afferents, Olausson et al. (2002) observed that light tactile stimulation of hairy skin of the forearm innervated only by C-fiber mechanoreceptive afferents elicited a sensation of pleasant touch. See also Pride and a Daily Marathon (Cole, 1995). fMRI studies showed that selective stimulation in regions innervated only by these

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C-tactile afferents produced activation of the most posterior insular region, but not the first or second somatic areas. Rolls et al. (2003) used the fMRI method in normal subjects to show a preferential activation of regions of the orbitofrontal and anterior cingular areas by pleasant tactile stimuli delivered to the glabrous skin of the hand; but until now low-threshold tactile C-fiber afferents have not been identified in the innervation of the glabrous skin of the hand.

Discovery of Multiple Cortical Sensory Areas A major discovery in cortical neurobiology was made in the late 1940s, that each of the somatic sensory, auditory, and visual systems is represented in more than one cortical area, now an established principle of cortical organization. Adrian (1941) recorded responses in the cat second somatic area (SII) evoked by stimulation of the forefoot, and suggested that the area was specialized in carnivores for the sheathing and unsheathing of the claws; he later observed this area in other mammals. Woolsey defined the location and somatotopic pattern within the second somatic area; showed that this area contains a separate, complete representation of the body form, in many cases with bilateral overlay; and that it exists in mammals from rodents to primates, including humans (Woolsey, 1943, 1947, 1981; Woolsey and Fairman, 1946; Woolsey et al., 1979). The SII is located on the upper, inner bank of the Sylvian fissure in macaque monkeys (Fig. 13–1); it has since been identified in analogous locations in every eutherian and marsupial mammal examined. The general location of the SII in the human brain was first identified by electrical stimulation of the exposed cortex in waking patients (Penfield and Rasmussen, 1950), and since then in imaging studies in human subjects (Polonara et al., 1999; Disbrow et al., 2000b; Burton, 2002). The meaning for function of multiple representations is still uncertain, as well as the nature of the contribution of each to the final perceptual image. Several elements of the cortical system for tactile sensibility contribute to the complex aspects of somatic sensibility. One hypothesis is that each of the component cortical areas, by virtue of its own unique pattern of extrinsic connections and intrinsic operations, contributes a particular attribute to the final perceptual image, which attribute can be integrated with neural activity evoked by more than one mode of somatic sensory stimulation. On this hypothesis, the integrated combination is embedded in the

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Fig. 13–1 Drawing of the left hemisphere of a macaque monkey; the lateral fissure has been opened to reveal the insula and the opercula. The general region of the SII areas shown on the superior bank.

activity within the distributed system as a whole. A necessary corollary to this idea is that the processing networks of the somatic areas of the postcentral gyrus have direct access to perceptual operations to provide precise signals of mode and place.

Structure and Connectivity of the Second Somatic and Insular Areas The location of the SII areas in the upper bank of the Sylvian fissure has been confirmed in imaging studies in humans with a variety of methods, including positron emission tomography (PET), fMRI, magnetoencephalography (MEG), and directly recorded evoked potentials. These studies have confirmed the bilateral input to these areas, but until now have not revealed the detailed somatotopic pattern nor the existence of two separate areas described in the macaque monkey, and predicted to exist also in the human brain. For a review of the imaging literature, see Burton (2002).

Cytoarchitecture and Connectivity On the basis of cytoarchitecture and connectivity the Sylvian cortex of the macaque contains at least five areas that receive somatic sensory input: the granular insular area (Ig); the parietoventral area

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Fig. 13–2 Left: Projection fields of the posterior nuclear complex in the rhesus monkey. The cortex of the Sylvian fissure is shown as if drawn out laterally (inset), lower right. STS = superior temporal sulcus. The granular insular area receives fibers from suprageniculate-limitans (SG-Lims); the retroinsular (RI) and postauditory (Pa) fields from posterior nucleus (Po); somatic sensory areas (3, 1–2, SII) from ventral posterior nucleus (VB); the auditory fields from medial geniculate nucleus (MG); the gustatory cortex (G) from basal ventral medial nucleus (VAB); and the dysgranular insular field (Id) from ventral posterior inferior (VPI). (From Jones and Burton, 1976.) Right: A composite summary of patterns of representation of body in second somatic area of monkey and in several surrounding areas that receive somatic sensory input. (From Burton and Robinson, 1981.)

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(PV), also termed SIIa; the second somatic area (SII) (also termed SIIp), the retroinsular area (Ri); and a portion of area 7b. Figure 13–2 shows them in a scaled diagram of the intrasylvian fissure (Jones and Burton, 1976). The SII areas (PV + SII) lie on the upper and inner banks of the Sylvian fissure of the macaque brain, bordered medially by the face and head regions of the postcentral somatic areas, posteriorly by the retroinsular area Ri and parietal area 7b, and ventrally and anteriorly by insular areas of decreasing granularity, Ig, Id, and Ia. So far as presently known, PV and SII have a similar cytoarchitecture, distinct from that of the adjacent insular areas and from that of the postcentral sensory cortex. The cortex of the SII areas is thicker than that of surrounding fields, is characterized by a prominent granular layer IV where the packing density is somewhat less than in area 3b, by a blurring of layers II and III, by small to medium sized pyramids in layers III and V, by a cell-sparse layer VI, and by radially coursing axons which give it a columnar appearance in fiber stained sections. The posterior insula is markedly granular, with small neurons packed in layers II and V; layers III and IV are partially fused.

Direct Lemniscal Input to the Parietoventral and Second Somatic Areas Through the Ventral Posterior Lateral and Medial Nuclei At the level of the thalamocortical projections the lemniscal and spinothalamic and spinotrigeminothalamic (ST/STT) systems converge to common nuclear and cortical areal targets. The SII areas receive a direct thalamocortical projection from major lemniscal thalamic relay nuclei, ventral posterior lateral/ventral posterior medial (VPL/VPM). The two sets of thalamic neurons projecting separately to SI and SII areas are interdigitated in the horizontal rods of VPL/VPM; they have similar properties of place and modality, but those projecting to SII are less numerous than those projecting to SI (Zhang et al., 2001).

Posterior Thalamic Projections to SII and the Insula The thalamic region posterior and ventral to VPL/VPM contains within a calbindin-labeled matrix several nuclei that make separate projections to the cortical areas within the lateral fissure. The

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suprageniculate-limitans nuclei project to the granular insular area, Ig; VPI projects to the SII areas; and VMb to the gustatory area in the medial insula. In the macaque each of these insular fields receives overlapping projections from each of these nuclei (Friedman and Murray, 1986). The cells of origin of these more diffuse projections have not been specified, but the diffuse pattern of projection suggests that they are thalamic matrix cells (Jones et al., 2001; Jones, 2002). The lamina I components of the ST/STT systems project to several brain stem and thalamic targets, including the ventral posterior inferior nucleus, the magnocellular part of the mediodorsal nucleus, and perhaps also to VPL/VPM; a major thalamic target of the lamina I ascending system in primates is VMpo, which extends from the posterior edge of the gustatory nucleus VMb posteriorly to the level of the magnocellular medial geniculate nucleus. The properties of VMpo neurons reflect those of the three major classes of lamina I ascending axons: a selectively thermoreceptive set in which the majority are cooling neurons and warming neurons are rare, a selectively nociceptive set, and a polymodal set sensitive to both thermal and mechanical stimulation of peripheral tissues. The nucleus is organized with head anteriorly and legs posteriorly, orthogonal to the general mediolateral pattern in VPL/VPM. The cortical projection targets of VMpo are still uncertain, but there is some evidence that it projects to the dorsal insula, posterior to the gustatory projection from VMb, and to the 3a/3b border in the postcentral gyrus (Craig, 2003). Nociceptive and thermoreceptive neurons have been recorded in VMpo in the human thalamus, and noxious and/or thermal experiences are evoked in humans by electrical stimulation in this region (Lenz et al., 1993; Dostrovsky, 2000).

Cortical Connections of SII Areas The SII areas are reciprocally connected with the postcentral somatic areas 3b and 1 in matching somatotopic patterns, with column-tocolumn congruence of efferents and afferents. The connections of areas 3a and 2 with the SII areas are less certain. Removal of the postcentral somatic areas denervates the SII areas in monkeys (Pons et al., 1987, 1992; Garraghty et al., 1990, 1991). This serial projection

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Fig. 13–3 Summary of corticortical and corticolimbic projections of somatic sensory fields. The SII areas are in a key position in the distributed system to project somatic sensory information to the amygdala (A) and hippocampus (H) through the granular and dysgranular fields of the insula. Forward projections terminating heavily in Layer III, solid lines; backward projections terminating heavily in Layer I are indicated by dashed or dotted lines. (From Friedman et al., 1986.)

is not dominant in the marmoset (Rowe et al., 1996; Zhang et al., 1996), and the evolutionary shift from parallel to serial processing for the large-fibered projection systems does not occur for the smallfibered ST/STT systems, which are parallel in higher simians and humans. Figure 13–3 shows the reciprocal connections between the SII areas and other cortical areas in addition to its connections with the postcentral somatic sensory areas (Burton et al., 1995), and Fig. 13–4 lists the reciprocal corticocortical connections of the insula (Burton et al., 1995; Augustine, 1996). These connections form a cascaded pathway from the SII areas through the insular regions to brain structures essential for tactile learning and memory, including the amygdala, perirhinal cortex; and, through relay, to the hippocampus (Mishkin, 1982; Murray and Mishkin, 1984a,b; Friedman et al., 1986). Reciprocal connections between the SII areas and the frontal lobe suggest a role of the SII areas in the processes of decisionmaking leading to motor action (Preuss and Goldman-Rakic, 1989; Romo et al., 2002a).

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Fig. 13–4 Chart of the projections from the insular areas of the human brain to other cortical areas, above; and from other areas to the insular cortex, below. (From Augustine, 1996.)

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Dual Somatotopic Representation in the SII Areas Since Woolsey’s evoked potential studies the second somatic sensory areas have been examined with the methods of single neuron analysis, in anatomical tracing experiments in monkeys, and in imaging studies in humans (Burton, 2002). Early electrophysiological experiments in macaques confirmed at the level of single neurons the topographical pattern of representation, and the bilateral input to the SII areas (Whitsel et al., 1969a,b; Robinson and Burton, 1980a–c; for reviews see Burton and Robinson, 1981; Burton and Sinclair, 1990, 1991; Burton, 2002). Robinson and Burton’s map of the representation of the face, head, and body in SII of the macaque monkey (Fig. 13–2) suggests that there are two representations of the face separated by that of intraoral structures, and two representations of the foot separated by those of arm, trunk, and leg, etc. A dual representation of the body form in the SII areas has since been defined in micromapping experiments in squirrels (Slutsky et al., 2000), bats (Krubitzer et al., 1993), marmosets (Krubitzer and Kaas, 1990), and macaque monkeys (Krubitzer et al., 1995) and by tracing of cortico–cortical connections (Burton et al., 1995). Studies in humans with imaging methods have confirmed the location of the SII areas on the upper bank of the Sylvian fissure, and suggested an outline of the somatotopic patterns within them (Burton et al., 1995; Disbrow et al., 2000b; Ruben et al., 2001) but have not yet demonstrated clearly a double representation in the human SII areas. A small zone lateral to these SII areas called VS was described in the owl monkey by Cusick et al. (1989), and in the macaque by Krubitzer et al. (1995). Little further is known of VS. Fitzgerald and Hsiao (see Fitzgerald et al., 2004) have completed a detailed mapping of the SII areas using microelectrode recording of multiunit responses in waking monkeys, with anatomical correlations. Their map, shown in Fig. 13–5, confirms the double representation of all parts of the body, one in each of SII and PV (SIIp and SIIa in their terminology). The patterns are dominated by the representation of the hand, especially the fingers. This map was constructed by superimposing those obtained in five hemispheres studied with the microelectrode mapping method. It extends for 10 mm in the anteroposterior dimension, but the map shown includes only the representation of the hand, and both SII and PV are surrounded by cortex activated from other body parts, so that the true extent of these areas may be larger than that depicted. The map is angled with

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Fig. 13–5 Summary map of the representation of the body in areas SIIa and SIIp (equivalents: SII and PV). Map constructed by convolving the results of multiple microelectrode experiments in five hemispheres in waking monkeys. The topographic map of cutaneous input was much clearer in SIIp than in SIIa, but was present in both. Afferent input from deep tissue commonly observed in SIIa, but rarely in SIIp. Separation of digit skin clear in SIIp, vague in SIIa. UBLS—upper bank lateral sulcus; LBLS—lower bank. A—responses from the arm; M—responses from the mouth. Anterior to the left, lateral is down. Diagonal line, estimated divsion between the two areas. (From Fitzgerald et al., 2004.)

respect to the line of the lateral sulcus. The fingers are mapped in SII with digit 1, most medial, to digit 5, most lateral. The receptive fields in SII have been studied by both Fitzgerald et al. (2004) and Nakama (2003) in terms of the number of pads of the phalanges of the fingers from which cortical neuronal responses are evoked. The plot of Fig. 13–6 gives the distribution of SII fields in terms of numbers of pads included in the fields.

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Fig. 13–6 Histograms of the receptive field sizes of neurons in the SII cortex. A: Receptive fields for neurons that did not show orientation selectivity; fields are measured in number of pads of the phalanges from which significant responses were obtained to indentation of a small bar at supramaximal indentation. B: Receptive field sizes for neurons that showed orientation tuned responses. Black bars for orientation selective responses; gray bars for responsive bars without orientation tuning within fields in which some did. The orientation tuned pads appear to be in the center of the fields. (From Hsiao et al., 2002b.)

Functional Properties of Neurons of the SII Regions The general result of many single-neuron studies of the SII areas in waking monkeys is that SII and PV are further processing nodes of a “higher order” in the cortical somatic system. The transformation from the quasi-isomorphic representation of peripheral events in the afferent lemniscal system to the entry level layer IV of SI to an abstracted form that begins in the supra- and infragranular layers of SI is further elaborated in the Sylvian cortex. Complex properties of stimuli appear; SII neurons are more powerfully affected by attention than are those of SI; and neuronal signs of the discrimination process in complex somesthetic tasks appear in SII and not in SI, and in the precentral cortex as well, where the efferent response in

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such tasks is generated. For details of these experiments, see Chapter 12, and Romo et al. (2002a,b). Lesions that include both SII areas eliminate the complex aspects of somatic sensation, including tactile learning and memory, leaving the primitive capacity for detection intact. The majority of SII neurons are activated by innocuous mechanical stimuli delivered to cutaneous receptive fields somewhat larger than those of SI; the fields of SII are larger than are those of PV, and in the hand region they commonly cover several fingers. Bilateral fields are common, and those on the apices of the limbs are often symmetrical (Whitsel et al., 1969a,b). Some neurons in SII appear to conserve the properties of the slowly and rapidly adapting neurons of 3b and 1, but this is not universal, and is seldom the case in PV. Many neurons in PV can only be activated by stimulation of deep tissues, but their functional properties have not been further defined. Fitzgerald et al. (2004) observed that the neurons of PV thought to be related to deep receptors were active during spontaneous movements of the hand, but they were not tested in the reach to target maneuver. The dense connections between PV and the posterior parietal cortex suggests that PV may be a node in the distributed system controlling projected movements of the hand and arm, but there is no direct evidence that this is so. About 5 percent of SII neurons have Pacinian properties, a proportion that appears to be constant in primates throughout the system. Nociceptive neurons are uncommon in the SII areas, but noxious search stimuli were not used systematically in these experiments, so the negative observations leave the problem unsettled. Until now, experimental observations have not revealed the strong nociceptive properties of SII neurons expected from its input from posterior thalamic regions. Several complex aspects of tactile stimuli important for form and texture perception are processed through SII. For example, about 30 percent of SII neurons are selective for the orientation of bars pressed into their fingers (Hsiao et al., 2002b; Nakama, 2003; Fitzgerald et al., 2004). The remarkable observation is that for neurons with receptive fields on two or more fingers, the orientation selectivity is similar on all. Indeed, for neurons with receptive fields on the finger pads of both hands, the orientation selectivity is virtually identical for all the contralateral and ipsilateral fingers, a remarkable example of positional invariance in the somatic system. This implies that the afferent signals for orientation selection are maintained through the long

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circuitry from the cortex contralateral to the stimulated finger and back through the callosum to the ipsilateral SII, for there is no known ipsilateral projection over the lemniscal system. All orientations were represented in the population of orientation selective neurons. The further observation made by Hsiao et al. (2002a) and by Nakama (2003) is the powerful effect of directed attention in increasing the response to somatic sensory stimuli, illustrated in Figs. 13–7 and 13–8. Attention not only increments the magnitude of the response, but also accentuates the orientation selectivity observed. This result is similar to many others made in experiments in waking monkeys working in sensory detection and discrimination task, in all the major sensory systems. Until now, experiments in waking

Fig. 13–7 Effects of attention on the orientation sensitivity of a neuron of the second somatic area, recorded in a waking monkey working in alterative tactile and visual tasks, each of which required close attention for success. The left panel shows replicates of the impulse discharges of the cell in runs in which the animal first attended to somatic stimuli and then to the visual task, as somesthetic stimulation were delivered simultaneously. The stimuli were oriented bars at eight orientations, 22.5 degrees apart, delivered in random order, first at one orientation for 500 msec (S1), raised for 1000 msec and then delivered again at either the same or the orthogonal orientation (S2). Rasters sorted by the orientation of the first bar; orientations indicated by the short lines to the left of each set of responses. Each horizontal line shows a single trial, each short up-stroke the instant of impulse discharge. The right panel shows by the upper graphed line that the mean impulse discharge rate was markedly enhanced in the presence of directed attention, as compared with the responses when attention was diverted to the visual task, shown by the lower graphed line. (From Hsiao et al., 2002b.)

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Fig. 13–8 Attentional modulation of the responses of neurons of the second somatic area of waking monkeys; the cortical SII neurons had receptive fields including both the contralateral and ipsilateral digits. Attention directed to the particular digit stimulated or away from it by a visual task requiring attention. Summary of results of study of 151 neurons of the second somatic area in waking monkeys. Ordinate: mean discharge rate of the cortical neurons; abscissa: stimulated digits: ID2, ID3, ID4—ipsilateral digits; CD2, CD3, CD4—contralateral digits. The curves plot responses to the orientation of bars at +45 degrees (circles), and −45 degrees (squares). The three horizontal lines (two are superimposed) plot the mean spontaneous rates of discharge under the three behavioral conditions. (From Nakama, 2003.)

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monkeys and the extensive psychophysical studies of attention in humans have revealed the results of directed attention, not its mechanism.

Properties of Insular Neurons The majority of Ig neurons respond to gentle mechanical stimuli delivered to large receptive fields; 60–80 percent are bilateral. They compose an indistinct somatotopic representation of the body form (Robinson and Burton, 1980a–c). Ig receives major afferent inputs from SI after relay through the adjacent S-II areas. Ten percent of Ig neurons are selectively sensitive to noxious thermal stimuli. Nociceptive neurons are more common in Ri/7b than elsewhere in these regions. A few of those in 7b code the intensity of thermal noxious stimuli in parallel with the reduction in escape reaction times (Dong et al., 1994). These cells, like others of 7b, however, show many of the properties of posterior parietal neurons: lability of receptive fields, multimodal convergence, variations of activity with changes in behavioral state, and so forth. Ri is only 1–2 mm in tangential size and whether it is congruent with the cortical projection of the lamina I stimulus-selective nociceptive afferent system is unknown. Areas Ig, PV, SII, Ri, and the anteroventral part of 7b in the Sylvian fissure meet the definitions of somatic sensory fields. The functional properties of the three major classes of mechanoreceptive afferents innervating the glabrous skin of the hand, so clear for neurons of the postcentral somatic areas, are seldom preserved in the transitions to the areas of the Sylvian fissure. It is not possible to define the function of these cortical areas more precisely than that they are somatic sensory. The results obtained give minimal support for the hypothesis derived from imaging studies in humans, that the cortex of the Sylvian fissure contains one and perhaps two areas that are nodes in the distributed cortical system serving pain and temperature.

Defects in Mechanoreceptive Somatic Sensibility Produced by Lesions in the Sylvian Cortex The results of lesion experiments in primates have not produced precise definitions of the function of the SII areas, perhaps because

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exact lesions there are difficult to produce in monkeys, and rarely occur naturally in humans. Ettlinger proposed that the region is critical for tactile learning and retention, functions in some aspects of hemispheric specialization, contributes to bimanual tactile dexterity, and to an incipient handedness in this species (Ridley and Ettlinger, 1976, 1978; Garcha and Ettlinger, 1978; Ettlinger, 1988). Macaques with bilateral lesions of the SII regions are impaired in tactile shape and texture discriminations, and show elevated thresholds for size and roughness discriminations (Murray and Mishkin, 1984a). Mishkin proposed that SII functions in a pathway that projects from SI to SII to IG and from thence to the memory and learning circuits of the medial temporal lobe, the amygdala and hippocampus (Mishkin, 1982; Murray and Mishkin, 1983, 1984b; Bonda et al., 1996). Removal of the amygdala and hippocampus produces severe defects in tactile and well as visual memory formation in monkeys. It is unlikely that the SII areas function only as throughput funnels. The region is a constant in mammalian phylogeny; it has been shown to exist in every mammal examined, from monotremes to primates, and is usually positioned in about the same spatial relationship to SI, with the same pattern of extrinsic connections. It seems reasonable to conjecture that the SII areas add some important and perhaps unique attribute to the sensory evoked activity that reaches it. Changes in somesthesis in humans caused by lesions in the lateral fissure are difficult to interpret (Knecht et al., 1996). A literature search does not reveal a case in which a naturally occurring or surgically produced lesion has been documented to have completely removed the SII areas without damage to adjacent areas or subjacent fiber pathways. The result is that a variety of abnormalities have been attributed to lesions thought to have included the second somatic areas, but that almost certainly injured adjacent areas as well. 1. There are defects in texture and shape discrimination, and elevated thresholds for detection of painful stimuli, in patients with lesions of Sylvian cortex that included SII and the posterior insula. 2. Lesions in the SII areas produce the syndrome of tactile agnosia, in which the brain-injured patient can no longer recognize by tactile examination familiar objects, while

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retaining primary somesthetic capacities (Tranel, 1991; Caselli, 1993; Platz, 1996). 3. Some patients with such lesions no longer recognize the import of painful stimuli, and do not seek to avoid or escape from them, the syndrome of pain asymbolia (Berthier et al., 1988). 4. Lesions in the SII areas eliminate the capacity to access stored tactile memories, or to store newly learned ones. 5. The bilateral property of neurons in the SII areas contributes to the bimanual integration of tactile inputs (Disbrow et al., 2000a). 6. The SII areas, and perhaps adjacent areas of the insula, are important nodes in the distributed cortical system serving pain and temperature, and contribute a particular attribute to the overall pain experience. Although some evidence can be adduced to support each of these propositions, it is not compelling for any. Any one or perhaps all may be true, but after more than half a century of study the function of the SII regions remains uncertain. It is relevant to note that one review of patients with lesions in the Sylvian areas indicated that they showed no deficiencies in the detection thresholds for several varieties of somatic sensibility (Roland, 1987).

The Cortical System for Pain and Temperature Electrophysiological experiments in monkeys and anatomical tracing experiments and imaging studies in humans have identified a number of forebrain pathways and structures activated by noxious or thermal stimuli, some of which are convergent with cortical areas also receiving mechanoreceptive afferent input over the largefibered systems. The neural activity associated with a painful experience is embedded in the ongoing activity in the linked populations of the system; and no single neuron, nor any small group of neurons, nor any single thalamic nucleus or cortical area, is uniquely essential for it. How activity in such a system evokes the experience of pain with its unique qualia and powerful response-evoking property is as mysterious for pain as for other modes of somatic sensibility. So

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far as present evidence is telling, several nodes of the system receive convergent input from both small- and large-fibered afferent systems. These systems contain the essential neural circuits for the higher order aspects of somatic sensibility, and how they operate to yield different and readily discriminable somatic sensory experiences remains a matter of much study and speculation. Afferent pathways serving pain from the level of peripheral transduction to the dorsal thalamus are described in Chapters 7, 8, and 9. There is a long and convoluted history of the question whether any cortical areas are involved in the central processing operations for pain and temperature. A positive conclusion was reached by Perl (1984), and by others since then, that there are nociceptive-specific primary afferents, that the pathways they enter project to the cerebral cortex, and that cortical areas play essential roles in the overall perceptual experiences of pain. These generalizations have since been confirmed and extended in a number of studies, so that it is now possible to make the following assertions: 1. Electrical stimulation of the postcentral gyrus in some humans may evoke painful sensations. 2. Lesions of the postcentral gyrus may result in some cases in elevations in the threshold for detecting noxious stimuli and a lowered ability to discriminate between noxious stimuli of different intensities. 3. The ST/STT systems project through thalamic nuclei to several cortical areas including the postcentral gyrus. 4. The neural activity producing a painful experience is embedded in the ongoing activity of the linked populations of the system, and no single thalamic nucleus nor any single cortical area is uniquely essential for it. 5. Electrophysiological experiments in monkeys, imaging studies in humans, and anatomical tracer studies have revealed that a number of afferent pathways and structures activated by noxious stimulation are also responsive to afferent input from the large-fibered mechanoreceptive afferent system. The uncertainty on these points may have been due to what recent electrophysiological studies in monkeys have shown, that

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nociceptive neurons in the ventral posterior nuclei of the thalamus and in the postcentral gyrus are relatively few in number, on the order of 5 percent, which raises the question of what these small populations contribute to the central processing of nociceptive inputs. This uncertainty may be explained by the discovery that cutaneous neurons in area 3a, in the depths of the central fissure, are selectively activated by noxious heat stimuli delivered to the hand, in squirrel monkeys (Tommerdahl et al., 1996), recently confirmed with electrophysiological methods (BL Whitsel, personal communication, 2003). This is matched by the finding that the thalamic relay nucleus for the stimulus selective nociceptive and thermoreceptive component of the ST/STT systems of lamina I origin, VMpo, described Chapter 9, is thought to project both to the dorsal, posterior part of the insula, and to area 3a (Craig, 2003). The small-fibered afferent systems of the spinal cord and the trigeminal systems terminate in several targets in the brain stem, midbrain, and dorsal thalamus, and engage the cerebral cortex through three major thalamocortical pathways: through the posterior thalamus to the cortex within the Sylvian fissure, through VPL/VPM to the postcentral areas, and through a medial pathway via the intralaminar nuclei. This third pathway allows access by the fine-fibered systems to wide areas of the cortex, including the cingular gyrus, and to the basal ganglia (Chudler and Dong, 1995).

Thalamic Ventral Posterior Nuclei and Postcentral Somatic Areas Two early electrophysiological experiments made in anesthetized macaques confirmed the anatomical evidence that the ST system projects upon the lemniscal thalamocortical structures in topographic conformity with that of the medial lemniscus (Perl and Whitlock, 1961; Andersson et al., 1975). Studies of the thalamic nuclei VPL/VPM have been made in anesthetized and in waking monkeys with the aim to identify neurons responsive to noxious stimulation of peripheral tissues (Kenshalo et al., 1980; Apkarian, 1995). Similar studies have been made in the postcentral somatic areas by Kenshalo et al. (1988, 2000), Bushnell et al. (1999), and Iwata (1998). The results establish that a nociceptive afferent system projects through VPL/VPM to the postcentral cortex, in parallel somatotopy with the mechanoreceptive inputs to those same structures, via the same lemniscal thalamic relay nuclei. The evidence is as follows:

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1. About 5–10 percent of VPL/VPM neurons are sensitive to innocuous mechanical and to noxious heat stimuli. Polymodal neurons outnumber selectively nociceptive neurons by 4 to 1. Nociceptive cells are arranged in longitudinal rods, interspersed with those containing mechanoreceptive thalamocortical neurons. 2. The polymodal nociceptive neurons of VPL/VPM receive synaptic inputs from axons of the ST/STT systems, and project to the superficial and middle layers of the postcentral somatic sensory areas, mainly but not exclusively in area 1. 3. The polymodal cells of VPL/VPM and of the postcentral areas grade the intensity of noxious stimuli with steeper stimulus–response functions than do the selectively nociceptive cells. 4. The polymodal and selectively nociceptive neurons of the cortex are located in vertical arrays, extending from layer II though V, interspersed with the low-threshold mechanoreceptive neurons. They subtend small, contralateral receptive fields. 5. The probability of encountering a nociceptive neuron in the postcentral cortex in any given microelectrode penetration is between 1 in 5 and 1 in 7 (Kenshalo et al., 2000).

Posterior Thalamus and Cortex of the Lateral Fissure The ST/STT systems transit through several nuclei in the matrix region of the posterior thalamus to the cortex of the lateral fissure (Chapter 9). The insular and SII areas receive a relayed projection from the convergent components of the ST/STT systems. There is tentative evidence that the stimulus selective nociceptive and thermoreceptive axons of lamina I origin transit through VMpo to a local region in the dorsomedial insula, and to area 3a of the postcentral gyrus. Evidence has accumulated that this nucleus is a specific relay for some components of the ST/STT (Craig et al., 1994, 2000; Craig, 1996, 2000, 2002). based on electrophysiological and tracing experiments in monkey experiments, and on recording, stimulation, and ablations made in humans (Lenz et al., 1993a,b;

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Craig, 1996, 2000; Lenz and Dougherty, 1997, 1998; Blomqvist et al., 2000; Hua et al., 2000; Frot et al., 2001).

Medial Thalamic Nuclei and the Frontal Cortex The third thalamocortical pathway of the ST/STT system projects through the intralaminar nuclei, called the medial thalamic pain pathway. ST/STT axons of the polymodal, convergent class of dorsal horn neurons of laminae V-VII that project into the medial pain pathway are driven by activity in A-delta and C-fiber nociceptive afferents innervating peripheral tissues. They project to the central lateral and parafascicular nuclei, to the ventral portion of mediodorsal nucleus, and to the medial portion of centre median. Nociceptive neurons have been identified in these nuclei in cats and monkeys (Nishikawa et al., 1999), and in humans (Ishijima et al., 1975; Tsubokawa et al., 1975). Some nociceptive projections reach these nuclei after transition through the central cores of the brain stem and mesencephalon. Intralaminar neurons are driven from large and frequently bilateral peripheral receptive fields; they do not compose a somatotopic pattern. Intralaminar nuclei make diffuse projections to the frontal cortex, including the cingular gyrus (Vogt et al., 1987; Vogt and Sikes, 2000), where nociceptive neurons have been identified in monkeys and humans (Koyama et al., 1998; Hutchison et al., 1999). Lesions placed in the intralaminar nuclei and in the cingular gyrus are frequently successful in relieving intolerable pain in humans, and are sometimes followed by a syndrome in which subjects report that they are still aware of their pain, but that it is no longer of much concern to them. This led to the idea that the intralaminar–cingular gyrus system does not deal directly with the sensory aspects of pain, but with its motivational–affective components.

Imaging Studies of the Cortical Pain System in Normal Humans Imaging studies in normal humans directed at study of the topography of the cortical somatic sensory system, particularly of the representation in the postcentral gyrus, are summarized in Chapter 10. In general, the classical topography established in studies with older methods has been confirmed, and two new observations of importance made. First, the topographic representation in the postcentral

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gyrus may vary considerable from one individual to another. Second, imaging opens the study of how the topographic representations are changed by imposed changes in sensory experience, or by lesions of afferent pathways, described in Chapter 15. Imaging studies have documented that neural activity generated by noxious stimulation of peripheral tissues is processed in a distributed system linking a number of cortical areas and subcortical structures. The several trans-thalamic entries to the system, described above, are activated in parallel. The signals of pain intensity are preserved to some degree in several of the cortical components of the system (Coghill et al., 1999), which accounts for the preservation of a reduced awareness of different intensities of pain in humans after a variety of brain lesions, including hemispherectomy. The stimulus–response functions differ between areas: that for SI is directly related to stimulus amplitudes; those for the SII insular and ventral anterior cingular gyrus code for pain intensity; and that for the posterior cingular gyrus appears to code the simple occurrence of a painful event and its affective overtone (Bornhovd et al., 2002). The following areas are listed in order of decreasing incidence with which they were activated by noxious stimuli in the studies included in a meta-analysis by Peyron et al. (2000): SII and insular cortex, in both hemispheres; areas 24 and 32 of the anterior cingular gyrus; dorsal thalamus, often bilaterally; contralateral postcentral area SI; areas 10 and 45–47 of the frontal cortex; and area 40 of the parietal cortex. Several regions ordinarily regarded as motor in function were less commonly activated: the striatum, cerebellum, periacqueductal gray, and the supplementary motor cortex, area 6. Areas within the Sylvian fissure were activated by noxious stimuli in 27 of 30 studies included Peyron’s meta-analysis. In many of these experiments broad areas within the Sylvian fissure were activated, while in others two maximal peaks were observed, one in the anterior insula and a second in the SII-retroinsular-area-7b region, but these localizations are uncertain. The results of experiments made in waking monkeys up to now have been of little help, for neurons activated by noxious stimuli have rarely been identified in Sylvian cortical areas; for example, in the study of Robinson and Burton (1980c), 1.5 percent in SII, 2.0 percent in Ri, 7.7 percent in 7b, and 8.6 percent in Ig. Areas activated by noxious stimuli in imaging studies appear to converge with regions activated by non-

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noxious sensory stimuli: with a gustatory region in Ia, with a region in the middle/posterior insula activated by cooling stimuli (Craig et al., 2000), and with mechanoreceptive modes of somatic sensibility in the SII areas. Peyron et al. (2002) used PET, fMRI, and the evoked potential method to study normal volunteers and epileptic patients, the latter with presurgical electrodes implanted in the operculo–insular cortex. The laser stimulus used evoked a brief, sharp pain with no mechanoreceptive components; responses appeared in the cortical leads with latencies of 150–250 msec, with slight ipsilateral delay. Spatial congruence between the cortical regions activated by the several methods was observed, but clear differentiation between the SII and insular areas was not possible. Some convergence in the SII area of activity evoked by painful and nonpainful cutaneous stimulation has been observed directly by recording evoked potentials through electrodes implanted in the SII areas in epileptic patients, in presurgical studies (Ostrowsky et al., 2000; Frot et al., 2001; Peyron et al., 2002). These results seem to favor the convergent hypothesis, but the problem remains unsolved. Area SI was activated in 15 of the 30 experiments reviewed by Peyron (2000). SI activation depends on the spatial extent of the peripheral stimuli, for large-area thermodes or immersions of the hand in water at noxious cold or hot temperatures are most effective. This is attributed to the rarity of nociceptive neurons in SI, so that considerable spatial summation is required to reach a population activity level detectable with imaging methods. Experiments in waking monkeys suggest that these uncommon nociceptive neurons scale stimulus intensities by changes in impulse frequency discharge, and provide signals for place by their small, contralateral receptive fields. This scaling has been observed also in imaging studies in humans (Torquati et al., 2002). Attention to and anticipation of somatic sensory stimuli facilitates the responses of SI neurons to those stimuli, including noxious ones. The present hypothesis is that the signals of nociceptive events processed through the postcentral somatic sensory areas provide signals for the location and intensity of noxious stimuli. This suggests that the SI nociceptive processing channels have a direct access to perceptual operations, in parallel with those to convergent trans-postcentral areas. The cingular gyrus is a component of the forebrain systems regulating many heterogeneous aspects of behavior, including emotional behavior and the selection of responses to emotionally

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disturbing stimuli (Vogt et al., 1987, 1992; Kwan et al., 2000). Almost all imaging studies of cortical activations by painful stimuli in normal humans have revealed one or more activated regions in the cingular gyrus, commonly in area 24 (Vogt et al., 1996; Vogt & Sikes, 2000). This “medial pain system” receives afferent activity from lamina V–VI through the ST/STT systems via the intralaminar nuclei, particularly the central lateral nucleus. Neurons in the cingular gyrus activated by noxious stimulation of the skin have been observed in monkeys (Koyama et al., 1998) and humans (Hutchison et al., 1999). It has long been thought that the medial system deals with the affective aspects of the pain experience because patients with long-standing and intractable pain report that after medial thalamotomy, or removal of the cingular gyrus, they are indifferent to their persisting pain (Jeanmonod et al., 1994). A major objective in imaging studies of pain has been to assign different components of the overall pain experience to different neuronal elements in the distributed cortical system for pain. Some evidence suggests that the lateral pain system terminating in SI and SII is responsible for the sensory aspects of pain: intensity, location, and quality. This is not exclusive, for intensity functions of one type or another have been observed in other parts of the system, and humans with lesions of SI can still discriminate between different amplitudes of noxious stimuli. The “medial” pain system, which flows through the intralaminar nuclei to the frontal lobe and to the cingular gyrus, is thought to be essential for the affective and/or the cognitive aspects of pain. Imaging studies of pain now turn to the more dynamic aspects of neuronal processing in the distributed pain system. None of what has gone before gives any hint of what dynamic neural mechanisms might be involved in producing the powerful, emotion-laden, response-evoking, suffering aspect of the pain experience.

Thalamocortical Mechanisms for Innocuous Thermal Sensibility The response properties of the A-delta cooling and C-fiber warming afferents innervating the glabrous skin of the monkey hand are described in Chapter 7; for review see Darian-Smith et al. (1984). The intensity functions of these sets of afferents correspond to the subjective magnitude estimations of humans of the amplitudes of

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cooling or warming stimuli, over identical ranges of stimulus amplitudes. Primary afferents project to the thermospecific sets of spinothalamic neurons of lamina I, whose axons project through the most dorsal part of the spinothalamic tract, largely on the contralateral side, and terminate in the brain stem and mesencephalon, and in the VMpo nucleus of the posterior thalamus. Electrical stimulation in this region in waking humans via microelectrodes evokes at different locations thermal or noxious sensory experiences referred to the contralateral side. Thermospecific neurons have been recorded in VMpo in monkeys and humans, and local lesions in this region produce deficiencies in thermal and noxious sensibilities in humans (Lenz et al., 1993; Dostrovsky and Craig, 1996; Davis et al., 1999; Dostrovsky, 2000). In monkeys this nucleus projects to a local region in the dorsal, posterior insula, and imaging studies in humans show activity in the middle-posterior insula, produced by nonnoxious thermal stimulation of the contralateral side; this area may be analogous to the cortical projection of VMpo in monkeys (Craig, 2003; Craig et al., 2000). Controlled laser beams allow differential activation of A-delta plus C-fibers, or of C-fibers alone. Selective activation of C-fiber warming afferents evokes cortical potentials at latencies that vary in different studies from 400 to 1000 msec in the anterior cingular gyrus, and in the cortex of the Sylvian fissure, on both contralateral and ipsilateral sides (Iannitti et al., 2003).

The Convergent Problem It remains uncertain which areas in the Sylvian fissure are activated by noxious and which by non-noxious stimuli, or if some or all are activated by both. The regions of the Sylvian cortex activated by mechanical stimuli were re-examined by Burton et al. (1993). They stimulated hands and feet of 22 volunteers with vibration. PET scanning revealed two distributions of increased activity evoked by the vibratory stimuli, one posteriorly thought to center in the SII region, and a second in the middle/posterior insula. No somatotopic pattern could be determined in either with the PET method, nor could the two SIIs be differentiated clearly. Which of the Sylvian areas activated in the imaging study in humans is not clear. However, the results presently available must be taken to show that there is a convergence of noxious and innocuous evoked activity in the Sylvian fields.

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If so, the question is how the intracortical processing circuits receiving such convergent inputs could produce outputs that lead to different perceptual experiences. What is needed is to discover the degree and nature of the convergence. It may be that parallel streams through the convergent areas allow preservation of isolated line signals of modality. If the convergence is upon single neurons, then it seems logical to test the hypothesis whether such a converged channel can provide specific signals about either of the converged modalities, or produces an attribute of perception accessible to inputs of different specific modalities. This seems likely for such nodes in the system as the cingular gyrus and prefrontal cortical areas activated in humans in some of the imaging experiments. Earlier imaging methods used in most of the reported studies are remote measures of neural events, trailing in time on a scale of seconds, delayed by the linkage between neural activity and vascular response, the increased blood flow and oxygen levels measured with PET and event-related fMRI. The same linkage problem, but without time delay, attends the identification of neural events from electrical signals recorded from the surface of the head with EEG or MEG methods. One aim of much current research is to discover how to interpret events recorded in these ways, with new and improved spatial and temporal resolution of imaging methods. One general conclusion is obvious, as Paulesu et al. (1997) have emphasized, that no particular nucleus or cortical area is the nucleus or area for pain or temperature sensibilities. Each of the components, which we separate and identify for experimental analysis, contributes simultaneously to the overall experience of pain and temperature, and no one is uniquely essential for those sensations. This may account for the fact that local lesions of the systems at the level of the forebrain may degrade but seldom eliminate pain and temperature unless placed at the input funnel to the systems, just posterior to the lemniscal relay nuclei, VPL/VPM.

Hierarchical and Parallel Processing in the Somatic Afferent System Some thalamocortical projection patterns in the somatic system have evolved from the parallel arrangements in nonprimates and

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prosimians to a serial system in simians. Projections from postcentral areas reach SII areas of the parietal operculum directly. Removal of SI in macaques denervates SII (Pons et al., 1987, 1992; Garraghty et al., 1991). The SI to SII projection is thought to form a cascaded corticolimbic tactile pathway, and to provide via insular areas tactile access to brain structures involved in learning and memory: the amygdala, hippocampus, and perirhinal cortex. It is uncertain whether the transition from a parallel to a serial arrangement has occurred in the marmoset, the most primitive simian studied. Removal of SI appears to inactivate SII as a serial model predicts (Garraghty et al., 1990b), while inactivation by cooling of either SI or SII leaves afferent activation of the other intact (Rowe et al., 1996; Zhang et al., 1996). Rowe and his colleagues provide evidence in marmosets for a parallel activation of SI and SII from VPL/VPM (Zhang et al., 2001). They recorded from single VPL/VPM thalamic neurons, and identified the cortical target of each by electrical stimulation of SI or SII. The two sets of neurons were identical in properties of place and mode, and each population contained neurons activated selectively by each of the three lemniscal mechanoreceptive types—RA-I, RA-IIs, and PCs. There is little doubt that when all components are considered the somatic thalamocortical system is massively parallel. Significant numbers of neurons in VPL/VPM project exclusively to SII, and have functional properties similar to those of the larger set that projects exclusively to SI. The several thalamic nuclei receiving the ascending spinal cord systems of intrinsic origin project in parallel to both SI and SII areas, as well as via the medial thalamic nuclei to wide areas of the cerebral cortex. These facts imply that the mode of parallel processing in nonprimates and prosimians persists in the thalamocortical projections of the small-fibered afferent systems in simians, including humans. Ploner et al. (1999, 2002) recorded with magneto-encephalography (MEG) the cortical responses evoked by brief laser heat stimuli delivered to the dorsum of the hand in waking humans. They found a parallel activation of SI and SII at indistinguishable latencies of about 130 msec. A detailed study of patients with an extended battery of somesthetic tests before and after surgical lesions of the parietal cortex has provided further evidence for combined serial and parallel processing in the somatic thalamocortical system (Knecht et al., 1996).

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Hypotheses Concerning Synthesis in Somatic Sensory Systems I state explicitly two hypotheses concerning synthesis in the somatic afferent system. The first is that the mechanoreceptive experiences we isolate and control in the laboratory, useful as they are for experimental purposes, are artifacts, isolated aspects of what in ordinary life are amalgams of afferent inputs in both large- and small-fibered systems, and in their overlapping and convergent thalamocortical projection targets. The hypothesis is that virtually all of our mechanoreceptive experiences are accompanied by some—sometimes barely minimal— aspects of pain and temperature, and/or that aspect of mechanoreceptive sensibility transmitted via the small-fibered ST/STT systems (“limbic touch”), which may contribute the affective overtones to the synthesis of many mechanoreceptive sensations (Vallbo et al., 1993; Olausson et al., 2002). The second is the hypothesis of attributes, which allows some functional interpretation of the facts that the lemniscal and ST/STT afferent systems converge onto central processing targets at some levels of the system, particularly in the far-targets of the distributed cortical system for somesthesis. To state the problem explicitly, if two different mode specific sets of activity converge onto single cortical neurons then it is unlikely that any differences in dynamic pattern of activity in the converged elements can carry the specific signal of either. What is more likely is that the region converged, by its intrinsic processing, confers in a modality-indiscriminate output some other aspect of sensation, an attribute, common to the specific perceptions evoked by the mode-specific inputs through other channels. For example, the affective and cognitive components accompanying somatic sensory stimulation, may be independent of mode-specific inputs, and assignable to any afferent input reaching an area that generates the described attribute. The form in which general attributes in somesthesis are signaled is unknown, as it is for other sensory systems. A corollary is that the areas of the postcentral gyrus must have a privileged access to the perceptual process to account for the preservation of the rudimentary aspects of somatic sensibility in monkeys after removal of both posterior and the lateral projecting systems.

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Parietal Frontal Sensory–Motor Transition

Primates spend much time operating in immediately surrounding space, the working arena reached by the hand, a behavioral spatial frame with head/body as center, symmetric as regards the midline, and polarized in the anterior to posterior direction (Trevarthen, 1968). Humans frequently engage in complex, sequentially linked movements of hand and fingers within this space when using small objects, writing, handling tools, or winkling. Their manipulative skills are unmatched by those of other hominids. Skilled movements are improved by training and are thought then to be initiated from stored motor patterns. Movements of reaching toward and grasping objects are initiated and guided by visual identification of the location and nature of objects and, after contact, by somatic sensory signals, with an adjustment of hand posture to the form and texture of the object grasped. Grasping movements are controlled in part by reflex actions evoked by afferent signals in the large mechanoreceptive afferents innervating the glabrous skin. Transitions from sensation to action are initiated by the activity in parietal frontal systems; they are neither sensory nor motor in the usual sense. They are cortical systems in which integrative and planning operations are generated and expressed in the patterns of discharge of their constituent neurons. In each of these systems a signal for the relevant movement is followed by a pattern of neural activity that is selective, for example, in the lateral intraparietal area (LIP) for the movement of the eyes in one direction and not its opposite; in the parietal reach region (PRR) for the movement of the arm and

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Fig. 14–1 Cytoarchitectural maps of the lateral surface of the hemispheres of monkey and human, after Brodmann (1909). In monkeys, Brodmann area 5 occupies all of the superior parietal cortex, posterior to area 2, and area 7 occupies the entire parietal cortex posterior to the intraparietal sulcus, while the inferior parietal lobule is occupied in his map by areas 39 and 40. Contrast this map of nearly a century ago with that of Fig. 14–2. (From Zilles and PalomeroGallegher, 2001, after Brodmann, 1909.)

hand to one of several possible projection targets, and in the anterior intraparietal area (AIP) for the preformation of hand posture to match the three-dimensional structure of the target. These predictive neuronal patterns have the properties of plans, and it seems likely that when repeated many times may be stored as motor programs. Activity in these systems is projected to the targeted premotor areas shown in Figs. 14–1,14–2, and Fig. 14–3 and from them is projected to the precentral motor cortex, where some of the many descending corticospinal signals initiating and controlling movements of the eyes, hand and arm are generated (Lemon, 1993; Lemon et al., 2004). Although these three are the most clearly identified parietal frontal systems, the current view in the field is that the posterior parietal cortex contains several areas, some quite

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Fig. 14–2 Upper left: Diagrams of the cortico-cortical connections linking the parietal and frontal lobes in the macaque monkey that underlie the operations of reaching and grasping in both humans and monkeys. Double-ended arrows indicate reciprocal connections. Upper right: The medial aspect of the monkey hemisphere, with the cingular sulcus opened to indicate the cingular motor areas. Lower left: Large parts of the parietal and occipital lobes have been removed to show areas buried in the medial bank of the intraparietal sulcus, and the medial bank of the parieto-occipital sulcus. Lower right: An enlargement of the parietal region in and around the intraparietal sulcus, opened to reveal areas buried in its banks. PS, AS, CS, IPS, SF, STS, LS, IOS, POS, indicate principal, arcuate, central, intrparietal, Sylvian, superior temporal, lateral, inferior occipital, and parieto-ocipital sulci. M1—motor cortex; S1— postcentral somatic sensory cortex. CMJae, CMAd, CMAv indicate rostral, dorsal, and ventral motor areas of the cingular gyrus. MIP, LIP, VIP, and AIP indicate medial, lateral, ventral, and anterior intraparietal areas. (From Battaglia-Mayer et al., 2003.)

small, each defined by the functional properties of its neurons and by a distinctive pattern of cortico–cortical connections. Many observations suggest that in addition to this parcellation, neurons with the defining properties of a given area are also distributed less densely but more widely in the parietal cortex, and are not confined to the area

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Fig. 14–3 Diagram outlining the connections between areas of the parietal and frontal lobes, indicated by arrows. Dark gray arrows indicate somatic sensory and light gray arrows indicate visual connections; medium gray arrows indicate somatic sensory and visual connections. White arrows indicate connections between the premotor and more rostral frontal areas. AIP, MIP, VIP—anterior, medial, and ventral intraparietal areas; AFC—agraular frontal cortex; F2d, F2—areas around the frontal dimple; F2vr, ventrorostral part of F2; F4b, F5—areas of the arcuate bank; F5c, F5— areas of the cortical convexity; PE, PEci, PEc—von Economo fields in Brodmann area 5; PFC—“prefrontal” cortex; PGm, PF, PFG—von Economo fields in Brodmann area 7; PPC—posterior parietal cortex; SEF— supplementary eye field; V6A—a visual field in Brodmann area 19. 8A/8B, 45/12, 46d/46v—Brodmann areas; Information collected from several sources. (From Zilles et al., 2003.)

they are thought to define. It may be that there exists a more complex pattern of functional organization of the posterior parietal cortex that includes both parcellation and distribution. Certainly the visual grasp of an object and the projection of arm and hand to enclose it require detailed spatial and temporal correlations of activity in all of these systems. There is scarcely a comparable example of such exquisite sensory– motor linkages as those related to the human hand. They imitiate

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and guide the pre-conscious shaping of hand and fingers to fit an object about to be grasped, in gripping and lifting that object, in the manipulation of small tools, in the use of the hand in gestures, in formal sign languages, and in the manual expression of affective states. The exquisite manipulative capacity of the human hand has been the subjects of intensive study by neuroscientists working in the field of motor control. For reviews, see Wing et al. (1996); Witney et al., 2004. Positive neural images of some of the functional defects produced in humans and monkeys by parietal lobe lesions have been discovered in neurophysiological recordings in the parietal lobes of waking monkeys. These show that there exist in this system representations of space based on the integration of somatic sensory, visual, auditory, and vestibular signals, and it is in the sense of space that the parietal system functions in perception as well as in linking afferent input to efferent action. The parietal lobes are sensory integration centers, and the left and right parietal lobe systems play different but overlapping roles in high-level cognitive functions. Manipulative operations engage many parts of the nervous system intercalated in distributed and re-entrant systems between the primary afferent inputs and the discharge of spinal motoneurons; for example, cerebellar and basal ganglia circuits are active in the movements of reaching and grasping, as they are in almost all bodily movements (Houk and Wise, 1995; Mason et al., 1998). The posterior parietal cortex is located at an intermediate level between sensory input to and motor output from the cerebral cortex. Skilled manipulative operations depend also on a readily available and continually freshened neural image of the body form and of the body position relative to surrounding space and to the gravitational field, images embedded in the parieto-frontal systems. Recent work suggests that from time to time the brain may use different strategies for reaching and grasping, depending on context, nature of the task, and nature of the objects. The planning and execution of reaching movements involve sequential transitions of neural activity, perhaps through a series of overlapping egocentric and allocentric frames of reference, linked from eye-centered to body-centered to target coordinates. For reviews, see Soetching and Flanders (1992), Paillard (1995), Soetching, et al. (1996), Vallar (1997), Colby (1998), Behrmann (2000), Graziano (2001), Andersen and Buneo (2002, 2003), Cohen and Andersen (2002), and Kalaska et al. (2003).

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The peripheral signals from deep receptors reaching the postcentral somatic sensory areas are relayed to the posterior parietal cortex, in the main to area 5, and together with cutaneous afferents serve kinesthesis and position sensibility. It has long been conjectured that the posterior parietal cortex generates from all afferent inflows an internal image of the body form, which is frequently disordered by lesions of this region. This “body schema” has been a subject of much interest and speculation since the time of Head and Holmes (1911–1912). I give in a following section brief summaries of the abnormalities produced in primates by lesions of the parietal lobe. I shall describe limited segments of the wide spectrum of parietal lobe functions; namely, the psychophysics of reaching and grasping movements of the hand, the praxic control of small manipulations and the precision grip, and the dynamic neural mechanisms involved in these manipulations. The parietal frontal linkage is an example of a distributed cortical system serving a higher order function, in the original sense of Brodmann (1909, 1999).1

Cytoarchitecture and Connectivity of the Parietal Frontal System The parietal lobe occupies 20–25 percent of the surface area of the human cerebral cortex. Parietal areas differ in cytoarchitecture, in patterns of extrinsic connections, in the changes in function after cortical lesions in primates, and by differences in the functional properties of their neurons defined in electrophysiological experiments in waking monkeys. Uncertainty and variety have characterized cytoarchitectural descriptions of the posterior parietal cortex for a century since Brodmann first located areas 5 and 7 in the superior parietal lobule in the human brain, but separated the two by the intraparietal sulcus in the monkey, placing area 5 in the superior lobule and area 7 in the inferior (Fig. 14–1). Some interpret Brodmann as having implied that the most lateral and posterior portions of area 7 in the monkey brain are homologous to areas 39 and 40 in the human brain, but this is still uncertain. Zilles et al. (2003) have emphasized that the area 7’s in the two brains should not be regarded as equivalent. Parietal areas contain cortex of a balanced lamination, with medium and large pyramidal neurons in layers II and V, respectively.

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Variations in cell types and densities from place to place have led to a number of somewhat dissimilar maps. More recently, several previously unrecognized areas have been identified in the cortex lining the banks and depths of the intraparietal sulcus in electrophysiological experiments in waking monkeys. These areas have different and clearly identified functional properties. Lewis and Van Esssen (2000a) identified 17 architecturally different areas in the intraparietal and occipitoparietal sulci of the macaque monkey, on the basis of fiber, cell, and immunological staining of serial sections. It is possible for some but not all of these areas to make correlations between the areal parcellation and the functional properties of parietal neurons. The reciprocal connections between some areas of the parietal cortex and premotor cortex of the frontal lobe are listed in Fig. 14–3. The evidence suggests that these parietal frontal pathways are to some degree independent of each other (Battaglia-Mayer et al., 2003). Zilles and his colleagues have studied the human parietal cortex using a method of observer-independent histological analysis combined with mapping of receptor proteins for the neurotransmitters known to be present in the cortex. They identified two areas in the human intraparietal sulcus, ip1 and ip2, thought to be homologous with areas ventral intraparietal (VIP) and lateral intraparietal (LIP) in the monkey parietal cortex (Zilles and Palomero-Gallegher, 2001; Zilles et al., 2003). Areas 5 and 7 in the monkey brain are estimated to be nearly an order of magnitude larger in surface area than are the somatic sensory areas of the postcentral gyrus, areas 3a, 3b, 1, and 2. The posterior parietal areas receive heavy trans-cortical projections; area 5 from the postcentral somatic sensory areas, notably from area 2. Area 7 receives both directly and from area 5, from the sensory cortex, and from the prestriate visual areas, including medial temporal (MT) and medial superior temporal (MST). Area 5 is the cortical projection target for the lateral posterior nucleus of the thalamus, which receives no ascending sensory input, and is thought to function in a corticothalamocortical network. Area 7 receives thalamocortical projections from the region of the anterior pulvinar targeted as an output pathway from the superior colliculus. Area 7 is thus a convergent target for both the geniculostriate and collicular visual systems. Both areas 5 and 7 are reciprocally linked with homologous areas of the contralateral hemisphere, connections thought to account for the bilaterality of somatic sensory and

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visual representations in areas 5 and 7. The strong reciprocal connections between the parietal and frontal nodes of the parietal frontal systems are shown in Fig. 14–2 and charted in Fig. 14–3. They form mirror-reversed patterns of rostrocaudal organization spanning the central sulcus, a reciprocity that allows re-entrant signal processing between the frontal and parietal areas. Whether the systems form overlapping gradients of connection or are selective and isolated is a subject of continuing study.

The Parietal Lobe Syndrome in Humans Study of the functional abnormalities produced in humans by brain lesions is one of the most difficult in all of neurobiology, particularly so for study of changes in higher functions. It is a remarkable tribute to the neurologists of the last century that many of their observations and formulations made in studies of humans with parietal lobe lesions have stood the test of further analyses. The field is difficult because naturally occurring vascular accidents, cortical injuries, or cerebral tumors are unconstrained by architectural or functionally defined boundaries, because many signs of parietal lobe lesions regress rapidly after lesion, and because in earlier times exact localization was seldom achieved, absent neurosurgical exploration; for an exception.2 High-resolution magnetic resonance imaging now produces better definition of the locations of lesions. Study of small or early lesions, combined with objective methods of measuring behavioral and sensory motor defects, allows more exact correlations between lesion locations and size with the behavioral and sensory– motor defects they produce, as Freund has emphasized (Freund, 2003). Electrophysiological studies in waking monkeys have contributed to knowledge of the dynamics of the neural activity in the relevant parietal frontal systems. Recent use of trans-cranial electromagnetic stimulation to produce reversible inactivation of local cortical regions in normal human subjects, presumably without injury, and chemical methods are available for producing reversible lesions in small parietal regions in normal monkeys. These add to the tools available for the direct correlations between cortical regions and functional attributes. Parietal lesions result in cognitive disorders, and lesions in the posterior parietal areas of the two hemispheres produce different changes. Lesions of the somatic sensory areas of the anterior parietal

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cortex, areas 3a, 3b, 1, and 2, produce contralateral defects in haptic sensibilities, described in earlier chapters. Lesions of the superior parietal lobule leaving the postcentral areas intact result in more complex disorders; in either hemisphere they may produce two frequently associated defects, asterognosis and tactile apraxia (Binkofski et al., 2001). They may also produce errors in reaching and grasping with the contralateral arm and hand, a defect in sensory–motor transition between parietal and frontal lobes called optic or visuomotor ataxia. Lesions of the inferior parietal cortex in humans, areas 39 and 40, provide an example of hemispheric specialization present in humans and probably not or not to the same degree in monkeys. Lesions of the right but only rarely of the left angular gyrus, area 39, of the inferior parietal lobule, in right-handed persons, produce complex defects of spatial perception and directed attention, including the visual unilateral neglect syndrome (Table 14–1, Vallar et al., 2003). Contralateral neglect appears infrequently with lesions in other regions of the forebrain. Lesions of the supramarginal gyrus, area 40, in the left but rarely in the right parietal lobe in right-handed humans produce apraxic defects of motor attention and in the correct ordering of movements in time, particularly for skilled movements of the hand and fingers. Gazzaniga and his colleagues emphasize that functional lateralization in the parietal lobe system is not as exclusive as it is for language: “—the left parietal lobe governs motor attention throughout visual space, as well as spatial attention in the right visual field. Similarly, the right parietal lobe governs spatial attention throughout visual space, as well as motor attention in the left visual field.” (Colvin et al., 2003, p. 324). Positive neural images of some of the functional defects produced in humans and monkeys by parietal lobe lesions have been discovered in neurophysiological recordings in the parietal lobes of waking monkeys. These show that there exist in this system representations of space based on the integration of somatic sensory, visual, auditory, and vestibular signals, and it is in the sense of space that the parietal system functions in perception as well as in linking afferent input to efferent action. The parietal lobes are sensory integration centers, and the left and right parietal lobe systems play different but overlapping roles in high-level cognitive functions. A large literature has accumulated on the human parietal lobe syndromes; for reviews see Jeannerod (1990), Jeannerod et al., (1995), Karnath (1997), Bisiach and Vallar (2000), Vallar (2001), Freund

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Table 14–1

A Taxonomy of the Clinical Syndrome of Spatial Unilateral Neglect (USN)

Dimension (input/output)

Defective manifestations extrapersonal space

Personal/bodily space

Variety

Hemiasomatognosia b

Perceptual USN a premotor/intentional USN, directional hypokenesia d

Anosognosia c Motor neglect e

Sectors of space (with reference to the body)

Lateral external USN Lateral internal (marginal) USN f altitudinal g

Reference frames

Egocentric USN h Allocentric/object-based USN

Sensory modality i

Visual USN (pseudo-hemianopia) auditory USN Olfactory USN

Processing domain (material-specific forms of neglect)

Facial USN

Somatosensory USN

Neglect dyslexia Productive manifestations

Extrapersonal space Avoidance hyperattention, magnetic attraction toward ipsilesional targets Perserveration

Personal/bodily space Somatoparaphrenia k

(From Vallar et al., 2003.)

(2003), Jeannerod and Farne (2003), Vallar et al., 2003; for a major historical source, see Critchley (1953). The defects produced in humans by parietal lobe lesions can be divided into four groups. Many patients exhibit only a subset of the following.

Disorders of Attention Cardinal signs of the parietal lobe syndrome in primates are the contralateral neglect and inattention produced by lesions of the right hemisphere, rarely by those in the left hemisphere. The inattention obtains for all sensory stimuli and includes a reluctance to move into the contralateral half-field, with errors when doing so. The unilateral spatial neglect syndrome is regarded as more a defect in spatial awareness than a specific sensory or motor defect, for it may occur in patients with intact visual fields, normal visual acuity,

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and with no sign of motor incapacity. A common sign is sensory extinction with double simultaneous stimulation; that is, if two identical tactile, visual, or auditory stimuli are delivered to identical field positions in the right and left halves of immediate extrapersonal space, the subject may report only the stimulus opposite his intact hemisphere, although he has no primary sensory defect on either side.

Disorders of Motor Control Patients with parietal lobe lesions may be reluctant to project arm and hand opposite the lesioned hemisphere into immediately surrounding space, with errors in reaching to targets and in forming a hand grasp matching target form. These form the syndrome of optic or visuomotor ataxia (Balint, 1909; Prablanc et al., 2003). The defect in grasping in patients with posterior parietal lesions includes a severe loss of the exploratory and manipulative finger movements essential in active touch and haptic search, with preservation of the elementary capacities for somatic sensibility and finger motion (Pause et al., 1989). The homologue of area AIP in the anterior wall of the intraparietal sulcus in monkeys has been identified in imaging studies in humans, and the two components of reach and grasp dissociated by lesions in it (Binkofski et al., 1998, 1999). In these cases the formation of the hand aperture and target acquisition were less disturbed than was any manipulative behavior that required skilled movements of the fingers, such as those used in active palpation. Oculomotor function after a parietal lobe lesion is marked by a slowness in foveating peripheral targets, a difficulty in disengaging fixation once achieved, and cogwheel like smooth pursuit movements toward the side of the lesion. Apraxias are disorders of movement initiation or control, and in the proper temporal and spatial sequencing of movements, with preservation of the primary aspects of motor and mechanoreceptive function. Some of them occur commonly but not exclusively with lesions in the left parietal lobe of right-handed humans, while others may follow lesions elsewhere, usually when lesions are very large so that the critical local defect is difficult to define. For reviews, see Leiguarda and Marsden (2000) and Leiguarda (2002). The two classical syndromes of ideational and ideomotor apraxia are often produced by lesions of the left inferior parietal cortex in right-handed

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individuals. With ideational (or conceptual) apraxia the patient is unable to sequence correctly the movements required for the use of tools, or the execution of manual tasks. Ideomotor ataxia is characterized by the patient’s inability to pantomime movements on command. Constructional apraxia is the inability to reconstruct a model from its disassembled parts, considered to be a defect in spatial perception as well as a motor apraxia; it occurs most often after left inferior parietal lobule lesions in right-handed individuals.

Disorders of Visual and Spatial Perception The syndrome of visual disorientation described by Holmes (1918) includes defects in localizing single objects, and in discerning the spatial relation between two or more objects, without primary sensory defect. These patients have difficulty in perceiving entire scenes, or in discriminating figure from ground, and in stereopsis and depth perception. Some patients with parietal lobe lesions, particularly of the inferior parietal cortex, may lose the topographical sense, and may be unable to read a map. Such a patient may be unable to find his way from one place to another through previously well known spaces; for example, within his house or his local neighborhood, although he does not display blindness, global amnesia, or dementia. This disorder was termed egocentric disorientation by Aguirre and D’Esposito in their comprehensive review of 1999.

Lesions of the Two Trans-Cortical Visual Streams Produce Different Behavioral Defects in Humans Ungerleider and Mishkin (1982) proposed that a ventral occipitotemporal trans-cortical visual system is essential for the visual identification of objects. They observed that inferotemporal lesions in monkeys degraded their visual discrimination capacity, without affecting their spatial discrimination performance. Lesions of the occipitoparietal pathway and its targets in the parietal cortex produced the reverse. This generality has been modified in the light of further research in humans with brain lesions. An important result came from neuropsychological studies of humans with bilateral lesions in the occipitotemporal system and in others with bilateral lesions in the occipitoparietal system, and the determination of the locations and sizes of the lesions by high-resolution fMRI imaging.

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The patients were studied for many years, and their defects remained stable for long periods of time. One patient with bilateral lesions in the occipitotemporal visual stream could no longer recognize by visual inspection previously familiar objects, but could project her arm accurately toward such objects and form an appropriate hand posture for grasping them (Goodale et al., 1991; James et al., 2003). Conversely, a patient with bilateral lesions of the occipitoparietal stream could recognize common objects perfectly by visual inspection, but could not project an arm accurately toward them, or form an appropriate hand posture to the objects for grasping them (Jakobsen et al., 1991; Jeannerod et al., 1994). A number of imaging studies in normal humans have produced complementary evidence by showing activation of the temporal system during object recognition, and of the parietal system during reaching and grasping. Milner and Goodale (Goodale and Milner, 1992; Milner and Goodale, 1995) modified the concept of the functions of the two visual systems to account for the transitions to action driven by the parietal lobe system, “–processing in the ventral stream delivers our perceptual representations of objects, whereas processing in the dorsal stream mediates the visual control of action at those objects” (Goodale and Haffenden, 2003). The weight of evidence from a large body of current investigations supports this formulation of the two-visual system hypothesis; see also Rizzolatti and Matelli (2003). Sakata (2003) suggested a further division of the dorsal stream into two components based on studies of grasping in monkeys, copies a more medial one projecting through the medial region of the superior parietal lobule (PEc, MIP, and V6A) and controlling the reaching phase of the arm projection movement, and a more lateral projection through CIP to LIP controlling the grasp.

The Parietal Lobe Syndrome in Monkeys It is uncertain whether the monkey parietal lobe contains areas homologous to areas 39 and 40 of the human parietal lobe, but the abnormalities displayed by monkeys after complete posterior parietal lobe lesions, compose a nearly complete though somewhat pallid version of the human syndrome. No case has been described in which a unilateral lesion in the monkey produced bilateral defects in behavior. Animals with unilateral lesions neglect their contralateral

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limbs, display a decrease in the spontaneous movements of those limbs, and make errors in reaching and grasp formation with the contralateral arm and hand into either half-field of space (LaMotte and Acuna, 1978). This optic ataxia in the monkey differs from that in humans, in whom the error in reaching is related to the contralateral half-field of space when reaching with either arm. A syndrome of profound neglect and withdrawal is produced in monkeys (and in humans) by bilateral lesions of the parietal lobes, characterized by continued avoidance of any stimulus to the limbs or the head (Denny-Brown and Chambers, 1958; Mori and Yamadori, 1989). Such an animal behaves as if it can no longer gain access to an internal neural construct of the shape and position of its own body and its limbs, and their relation to each other to surrounding space. A monkey with a bilateral parietal lesion huddles in the back of his living space, avoiding all events in the surround. Even the gentlest contact with the face or mouth evokes vigorous withdrawal, so that feeding becomes a problem for survival, in both monkeys and humans. The bilateral withdrawal syndrome is interpreted as a loss of exploratory actions into the immediately surrounding space, replaced by active withdrawal. In sum, the results of lesions in humans and in monkeys indicate that the parietal lobe systems contain essential neural mechanisms for the direction of attention into and the manual exploration of and orientation within immediately surrounding extrapersonal space, and for the skilled organization of movements, particularly of the hand and fingers.

Psychophysics of Reaching and Grasping in Humans During the last three decades psychophysical methods have been applied successfully in many studies of sensory, motor, and higher functions of the brain in waking monkeys (Stebbins, 1970), and particularly in study of parietal lobe function (Jeannerod, 1997). Neuropsychological studies in humans and in monkeys have documented the separation of the projection of the arm and hand to a target into a transport phase of arm projection and a grasping phase that begins while the hand is the air as it adapts to the visually observed or remembered spatial contour of the object (Jeannerod, 1988, 1997; Perenin and Vighetto, 1988; Paillard, 1991). It was Jeannerod

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who first described the pattern of the reach and grasp movements of the arm and hand in humans by analyzing photographic films made at high frame frequency (Jeannerod, 1984, 1988). Electrophysiological studies of the parietal frontal systems in waking monkeys engaged in reaching and grasping have revealed a coherent distributed network in which different nodes are specialized for generating/ governing different parts of the overall behavioral act shown in Jeannerod’s films. These activities are present in the network before movement begins. How they are combined to generate the temporally and spatially ordered outcome is the formidable and still unsolved problem of integration. The acts of reaching and grasping are usually preceded by a saccadic fixation of the object of interest, a direction of gaze usually but not always accompanied by a strong colinear direction of attention, a parietal lobe function shown both by the defects in attention after parietal lobe lesion, and by the activity of parietal neurons in waking monkeys. Accurate reach and grasp movements can be made to objects in the extra-foveal visual fields, however, and accurate reaching movements can be made in darkness to previously identified objects. Reaching or pointing movements are most accurate when made under binocular visual control; reach movements with monocular viewing are slow and inaccurate (Soros and Goodale, 1994). A reach to grasp movement by a human is shown in the successive frames of a film made by Jeannerod at 5 frames/sec (Fig. 14–4A). The movement begins with a rapid acceleration to a peak velocity of about 100 cm/sec in mid-reach at about 200 msec after onset, followed by a slowing and in-flight shaping of the hand and fingers to the three-dimensional form of the object, shown by the records of wrist, thumb and finger in Fig. 14–4B. The opening of the hand occurs before grasping starts. It begins with a wide fanning of the fingers, which then close to an aperture appropriate for the size of the object to be grasp. Grasp aperture varies linearly with object size. If the position of the object is suddenly moved, after the reach movement has begun, a precise course alteration occurs in mid-flight, so that the hand reaches the new target location, with a lengthening of transit time by about 100 msec, with no loss of accuracy (Fig. 14–4C). The movement is under continuous visual control from start to finish. In humans, there is visual guidance of the hand during the projection movement through the periphery of the visual field. This is a

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Fig. 14–4 Kinematics of reach and grasp movements. A: Four successive frames of a film of a reaching movement; frames at 200-msec intervals. The widening finger aperture has already begun at the 200-msec mark, D and E, and has closed to object size before frame 4, at 600 msec. B: Averaged two-dimensional recordings of spatial paths of thumb, forefinger, and wrist, shown left to right. C: Similar averaged spatial paths during reaches in which the object was moved quickly to the right at the onset of movement. Small bars indicate 1 SD from the mean trajectories during 10 movements. D and E plot wrist velocity and grip size during one of the trials in B and C, respectively. (From Jeannerod et al., 1995; data are from Paulignan et al., 1991.)

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movement analyzing system, for the guidance is not effective under stroboscopic illumination (Paillard et al., 1981; Paillard, 1991, Chapter 10). Visual guidance is linked to the movement generating mechanisms, for it acts only upon actively initiated, not passively imposed, projection movements. When the moving hand passes from the eccentric to the central portions of the visual field—as it nears the fixated target—the visual guidance passes from the movement to a positional control system operative under both steady and stroboscopic illumination. This double mode of visual guidance is an instance of preconscious processing in spatial vision, and in this way must have been invaluable for life in the trees, and for humans when using weapons or tools. The properties of the fovea-sparing parietal visual neurons are just those appropriate for the input to a movement analyzing and control system. Their receptive fields are large, frequently bilateral, and extend to the rims of the visual fields. They are especially sensitive to the movement and the direction of moving stimuli; their directional sensitivities are radially organized with respect to the center of the visual field (Motter and Mountcastle, 1981). Comparison of the graph of Fig. 14–4D with the patterns of impulse discharge of parietal reach and hand manipulation neurons (see Figs. 14–6 and 14–7) shows a remarkable sequence. The reach neuron reached peak discharge a bit earlier than the hand movement; its activity then declined during the slowing phase of arm reach and ceased well before hand contact with the target, a decline overlapped in time by the onset and increase in discharge frequency of the hand manipulation neuron that parallels the postural adjustment of the hand. The shaping of the postures of the hand and fingers to the object to be grasped is an example of the preconscious choice of a posture appropriate for the target. Further aspects of the grasp and reach have been defined in experiments in humans by Johansson and his colleagues, who showed that the fingers are applied appropriately to the object to facilitate lifting, with just sufficient force to allow lifting without slipping or crushing, described below. The grasping force is under primary afferent control via reflex actions that may involve both segmental and supraspinal circuits (Johansson, 2002). The precise grip and lift depends upon the subject’s visual interpretation of the surface structure and implied density of the object, and what information he can recall from memory about such objects.

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Electrophysiological Studies of the Parietal Frontal Systems A welcome innovation for neuroscientists is that the higher functions of the brain can be observed directly at the level of neuronal populations and the distributed systems in which they are embedded. Experiments of this kind are made in waking primates as they work in behavioral tasks designed to require for success activation of high-level brain systems; see Chapter 1 for a description of the method. They include studies of the intention to move; the formulation of action programs for movement; the perceptual operations of detection, rating, and discrimination; the role of the posterior parietal fields in visuospatial perception and visual attention; and, of interest in the present context, neural operations in the parietal frontal system dealing with the transitions from intention to action. A number of studies have been made of the parietal frontal systems as monkeys execute tasks known from lesion studies to require action in those systems. These include studies of reaching toward and hand manipulation of objects, the control of eye movements, the neural mechanisms of attention, and the function of the parietal systems in ambient vision. The physiological experiments have been paralleled by anatomical tracing studies of the connections linking the areas. A rudimentary knowledge of the structure and function of the parietal frontal systems controlling reaching and grasping has been achieved. For a sampling of many reviews, see Kalaska et al. (1997), Sakata et al. (1998), Colby and Goldberg (1999), Andersen and Buneo (2002), Battaglia-Mayer et al. (2003), Merchant et al. (2003), and Rizzolatti and Matelli (2003). The general result is that the parietal frontal system consists of a number of subsystems arising from defined areas in the parietal cortex linked reciprocally with defined areas of the premotor cortex (Fig. 14–2). There are three major components: (1) area LIP generates signals for the position and movement of the eyes and is linked to the frontal eye fields; (2) the parietal reach region generates signals for the initiation and regulation of reaching movements of the arm while in flight and is linked to premotor areas F2/F7; (3) area AIP generates commands for the postural adjustment of the hand to conform to the three-dimensional form and surface texture of the target and is linked to premotor area F5. The evidence supports the idea that these parietal frontal systems are to a certain degree independent. Some doubt remains, for the idea that these three

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subsystems are isolated does not take into account other classes of parietal neurons that have been identified in many experiments, notably the visual fixation neurons that are widely distributed in the inferior parietal lobule. Moreover, many of the neurons whose functional properties are used to identify the areas shown in Fig. 14–2 are not restricted to the areas they are said to define. They occur in significant numbers in other parietal areas assigned different functions. Many neurons in these areas have complex properties suggestive of convergence/integration, and receive afferent input from one or more sensory sources. There may exist a more complex functional organization in the posterior parietal cortex than is presently envisaged in terms of isolated parietal frontal subsystems.

The Visual Grasping of Objects: The Lateral Intraparietal Area Although primates can react quickly and reach accurately toward objects in remembered locations, the majority of reaching movements are initiated by visual capture of the target object by a rapid saccade. Neurons active before, during, and after visually evoked saccades are widely distributed in the inferior parietal lobule, but are densely concentrated in area LIP on the posterior bank of the intraparietal sulcus. This area was first identified in anatomical tracing experiments by its reciprocal connections with the frontal eye fields, and is now known to be interconnected with other nodes in the distributed system controlling eye movements, including the frontal eye fields (Andersen et al., 1985a, 1990; Baladier and Mauguiere, 1987; superior colliculus (Lynch et al., 1985), and the pulvinar (Asanuma et al., 1985; Hardy and Lynch, 1992). LIP is specialized for generating commands for saccadic movements, and many neurons in both its dorsal and ventral divisions discharge before, during, and after visually evoked saccadic movements of the eyes, but not in relation to the spontaneous saccades with which we scan the external environment. LIP saccade neurons have wide directional fields, c. 90 degrees, with a population weighting toward the contralateral side; the directional preferences are the same for all phases of the response (Barash et al., 1991a,b). Local microstimulation within LIP evokes saccadic movements, and local inactivation modifies but does not eliminate saccadic movements. An analogous area has been identified in the human parietal cortex (DeSouza et al., 2000). The response properties of many LIP saccade neurons are determined

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Fig. 14–5 Histograms show in millimeter slabs of cortical tissue the spatial distributions of neurons studied in areas 5 and 7 in waking monkeys relative to the depth of the intraparietal sulcus. Upper left: cross-hatched bars, total neural population, solid bars, distribution of sampling; that is, the total distance of microelectrode tracking in each millimeter slab. The distributions almost exactly equal the distribution of electrode tracking distances, and are essentially flat over the anterior-posterior distance examined. Upper right: Joint neurons are restricted to area 5. Lower right: Visual neurons (all classes) are restricted to area 7. Lower left: Reach and hand manipulation neurons, classed together as projection neurons, are found in both areas 5 and 7. (From Mountcastle et al., 1975.)

by the multiple sensory inputs to the system—visual, somatic sensory, auditory, vestibular—which contrasts with the more direct linkage to the saccade control system that characterizes neurons of the linked eye fields of the premotor cortex (Andersen and Buneo, 2003). Other investigators interpret the results of their studies of area LIP somewhat differently, emphasizing that LIP is an area containing a “salience map,” and in this way is more involved in the direction of attention and in updating a central representation of the visual world in the midst of eye movements (Goldberg et al., 2002; Bisley

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and Goldberg, 2003; Merriam et al., 2003). It is likely that each of these views of LIP function is partially correct, and that the full functional range of LIP function will be revealed by further study. The inferior lobule contains sets of neurons not taken into account in these formulations. Neurons of a large class distributed throughout the inferior parietal lobule (Fig. 14–5) are active during the steady fixation of gaze; some do but most do not have an associated visual receptive field. These visual fixation neurons are selectively active when a monkey fixates an object of interest, most powerfully when it inspects a parcel of food held in his hand, a typical monkey behavior, but also when it fixates a target light whose dimming or change in position he must detect for reward. Visual fixation neurons are most intensively active for objects fixated within immediate extrapersonal space, and seldom for objects in far space. Visual fixation neurons do not appear to be densely concentrated in local areas of the intraparietal cortex, but are distributed throughout area 7a, and perhaps in areas of the intraparietal sulcus (Lynch et al., 1977).

Reaching with the Arm: The Parietal Reach Region The patterns of activity of parietal reach neurons and in the reciprocally connected premotor areas of the frontal lobe appear as positive images of the defects in reaching produced by parietal lobe lesions. Reach neurons are active during the projection of the arm toward objects of rewarding natures, selectively so in parallel with the flight of the arm through space—a mirror of one of the defects in optic ataxia. The reach and hand manipulation neurons are widely distributed over the broad expanse of area 5 (PE) and area 7 (PE, PFG, PG) as shown by the spatial distribution plot of Fig. 14–5. Reach neurons are, in the midst of this wide distribution, concentrated in a “parietal reach region” in the most medial part of the superior parietal lobule, defined as including PEc, MIT, and V6A. The activity pattern of a typical reach neuron recorded in the midregion of area 5 is shown in Fig. 14–6. Reach neurons in this broad area have the following properties. 1. They are active only when the monkey projects its arm toward an object of interest, like food when it is hungry or the target light it must reach for reward. They are not active in any other arm movements; for example, those of defense or aggression.

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Fig. 14–6 Replicas of the nerve impulse discharges and histograms of that activity made during study of an active reach projection neuron of area 5 in a waking monkey working in a reach to target task. Each horizontal line represents a single trial, each upstroke the instant at which a nerve impulse occurred. Only a fraction of the trials averaged in the histograms is displayed. Histogram size, 20 msec. Upper: Records and histogram oriented by aligning trials at the instant of the go-light detection; bar = mean response time 1 SD. Lower: The same records and a histogram, now oriented at the instant of closure of the target switch by the projecting hand. Bar = mean detect time, 1 SD. Neural activity accelerated before key release, accelerated and then declined as the arm moved through the air, paralleling the time course of a human reach shown in Fig. 14–4, and was silent when the activity of the hand manipulation neurons increased (Fig. 14–7). (From Mountcastle et al., 1975.)

2. Individual parietal reach neurons are relatively insensitive to the directions of reaches along the horizontal meridian, but a vector analysis revealed a significant population signal for the direction of movement (Kalaska et al., 1983). 3. The discharge of a reach neuron leads and parallels the increase and decrease in the velocity of arm movement toward the target and ceases well before target contact, overlapping in time the simultaneously incrementing discharge of the hand manipulation neurons (Figs. 14–6 and 14–7).

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Fig. 14–7 Replicas of the original nerve impulse records and the histograms made during study of a hand manipulation neuron of area 5, in a monkey working in a task in which, upon dimming of a fixated light, he was required to reach forward and manipulate within a recess to close a switch for reward. Upper: Records are oriented at the moment of release and start of the reaching movement, lower at the moment of closure of the target switch. The neuron discharged only rarely except during periods of hand manipulation of any kind. Compare its time course with that of the reach neuron of Fig. 14–6. The neuron was not activated by any mechanical stimulation of the palmar skin, nor by stretch of intrinsic hand muscles. (From Mountcastle et al., 1975.)

4. Parietal reach neuron discharge continues its temporal course whether or not a subsequent movement occurs (Kalaska and Crammond, 1995). The activity in the connected area of the premotor cortex, by contrast, dwindled to background levels during the delay period in no-go signals.

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5. Parietal reach neurons generate command signals for the kinematics, not the dynamics of reaching movements. Loads placed on the arm during reaching movements produce continuously graded changes in muscle activity, but with reasonable loads do not alter the hand paths of movements, nor the patterns of parietal reach neurons (Kalaska et al., 1990). An area of cortex on the medial superior parietal lobule containing parts of PEc, MIP, and V6A and the adjacent cortex on the lateral bank of the intraparietal sulcus has been defined by Snyder et al. (2000) and by Andersen and Buneo (2002) as a special parietal reach region (PRR). The region contains a population of neurons that combine signals of the positions of the eyes with those of the hand to create global tuning fields, in which the optimal directions are superimposed for position holding or directional movement for eye and hand. These globally tuned neurons are thought to provide a framework for coordinate transformation, in a feed-forward model (Mascaro et al., 2003).

Grasping with the Hand: The Anterior Intraparietal Area Hand manipulation neurons are active during the preforming phase of the movement as the hand approaches the target, and continue to discharge during target grasp. They are also active during finger manipulation in skilled tasks; for example, in winkling a small piece of food from a small container (Mountcastle et al., 1975). These hand manipulation neurons are widely distributed in both areas 5 and 7 (Fig. 14–5) and are heavily concentrated in area AIP located on the most anteroventral extreme of the posterior wall of the intraparietal sulcus, an area identified also in the human brain by imaging studies of humans working in grasping tasks (Connolly et al., 2003). A typical pattern of discharge of such a neuron (Fig. 14–7) begins late in the reach movement, overlaps the decline in activity in the reach neurons, correlates in time with the preformation of the hand to match the three-dimensional structure of the target; and may be maximally active at the time of grasp. Both Sakata Jeannerod et al., 1995; Murata et al., 2000; (Sakata, 2003) and Gardner (Debowy et al., 2001; Gardner et al., 2002) have described several classes of parietal hand manipulation neurons. Each class is tuned preferentially to the hand posture appropriate for grasping the three-dimensional form of a particular one of several targets used in

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the reach-to-target experiment. The targets used were bars, squares, rings, and so forth, none of which monkeys ever encounter in normal life, but on which they had been trained for many months and thousands of trials before the final experiment. It seems likely that these investigators have discovered an example of plasticity in the parietal frontal cortical circuits, and in motor learning, if, as they conclude, classes of hand manipulation neurons are differentially tuned to the shapes of the target objects used in training. The advent of methods for recording from chronically implanted microelectrodes, during the prolonged training periods, opens the possibility for the direct study of plasticity in an operating cortical circuit.

The Premotor Areas of the Frontal Lobe Recent studies indicate that the “motor cortex” in the precentral gyrus is composed of a number of cortical areas, at least the seven shown in Fig. 14–2. Each of these areas has specific connections, several with defined areas in the posterior parietal cortex. Neurons in the reciprocally linked premotor and parietal areas have similar functional properties. The most intensely studied of these couplings is that between area AIP of the intraparietal sulcus, described above, and the portion of area F5 buried in the inferior bank of the arcuate sulcus. Like LIP neurons, those of F5 discharge during the pre-contact hand posture-forming phase of reaching, and they continue to discharge after the grasp. F5 is somewhat closer to the final cortical motor output to the hand muscles from the classical motor cortex (F1), for identified sets of F5 neurons are differentially active for different grasp postures, most commonly for the precision grip, others for finger prehension, and still fewer for whole hand prehension. Correlative evidence has come from a study of inactivation of small areas of the motor and premotor cortex by muscimol injections (Fogassi et al., 2001). Small injections into the critical portion of F5 in monkeys produced a transient incapacity for grasping postures, just as do similar local injections into LIP. Local lesions in these areas produce similar defects in grasping. These results support the proposition that the distal musculature active in hand grasping is controlled by a parietal frontal circuit distinct from that controlling projections for the arm. The F5 area projects directly into the hand area of F1, the motor cortex itself. For reviews see Luppino and Rizzolatti (2000), Rizzolatti and Luppino (2001), and Rizzolatti et al. (2002).

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Similar lines of evidence support the generality that the several other specialized areas of the posterior parietal and agranular precentral cortex are reciprocally linked, and are specialized for different aspects of the visuomotor transition to action: the parietal reach region and area F2 for arm movement; the lateral intraparietal areas and the frontal eye fields for control of eye position and movement; and, less certainly, the ventrolateral intraparietal area with F4 for more complex visual functions. These are extreme examples of specialization for function, and the recent results of Rizzolatti indicate that the areas of the agranular premotor cortex are involved in higher order cognitive functions.

Neural Signs of Cognitive Operations While the functional properties of neurons in each of the specialized areas of the posterior parietal cortex suggest that they may be linked in an obligatory way through specialized parietal frontal systems to particular phases of the upcoming reach to target movement, much evidence supports the idea that they operate also at a higher level that is neither purely motor or sensory but cognitive in nature. For example, study of neurons in LIP and PRR in monkeys working in delayed response tasks revealed that the ongoing activity in the time between trial onset and initiation of movement composes plans for the instructed movement (Mazzoni et al., 1996). This activity is interpreted as intentional in nature, a part of a neural mechanism for the planning of action. Moreover, if the instruction for action is changed in the midst of the delay period; for example, to change the direction of a reach or a saccade, there is a rapid change in the pattern of neural activity which indicates a shift to plans for the newly instructed movement (Bracewell et al., 1996; Snyder et al., 2000). These are remarkable observations, made with some difference in interpretation in different laboratories, but their importance is obvious. They are interpreted as neural correlates of intention (Andersen and Buneo, 2002, 2003; Bisley and Goldberg, 2003).

The Coordinate Frame Problem The different areas of the posterior parietal cortex are thought to generate different sensory representations in coordinate frames appropri-

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ate to the afferent sources, and that these are then transformed into coordinate frames appropriate for the particular actions. A major problem in understanding the function of the posterior parietal cortex is that of changes in coordinate frames. The question is, how is it that the neural signals of the location of a visually identified target, coded in eye-centered coordinates, are transformed into the patterns of neural activity coded in hand–object coordinates in a reaching task? Several candidate sequences are outlined in Fig. 14–8. It seems unlikely that there is a single ordered path of coordinate transformations, but that the parietal frontal distributed network transforms any

Fig. 14–8 Three different schemes for transforming a reach target position from eye-centered to hand-centered coordinates. A: The sequential scheme. B: Combination scheme. C: Direct scheme. D: Illustration of the task in reaching for a cup while fixating a newspaper, assuming the direct method. The position of the cup relative to the position of the hand (M) is, on the direct scheme, obtained by subtracting hand position (H) from the target (T), both in eye coordinates. (From Andersen and Buneo, 2003.)

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one of several sensory frames into various motor coordinate systems, and that these may vary with variation in the properties of the reachto-grasp task. Moreover, which particular pathway of coordinate transformation is predominant in any given task depends on several variables including the nature of the task and of the object and the level of attention (Stein, 1991). Studies of the inferior parietal lobule in waking monkeys revealed that the activity profiles of several identified classes of parietal neurons differ with the angle of gaze (Mountcastle et al., 1975; Lynch et al., 1977; Mountcastle, 1981; Andersen and Mountcastle, 1983). For example, the “gaze field” of a visual fixation neuron is sensitively affected by changes in the angle of gaze, and it appears that the activity of several classes of neurons in the inferior parietal lobule have gaze-dependent changes in activity. These effects have been observed throughout the posterior parietal cortex, and it is now clear that the eye-centered response or activation fields of many parietal neurons are influenced by head and limb position, as well as by the angle of gaze. These observations have led to the proposal by Andersen that gain fields may function in coordinate frame transformations (Buneo et al., 2002; Cohen and Andersen, 2002; Andersen and Buneo, 2003). How frame transformations are formulated in terms of neuronal activity remains to be determined. For a general review, see Salinas and Thier (2000).

Automatic Regulation of Reaching Movements in Mid-flight The parietal frontal system generates the neural correlates of directional motor commands and controls the movements as they evolve, correcting “on line” for errors and for changes in target position. These corrections are automatic and unconscious and occur at latencies much shorter that those of the usual visual reaction times, depend upon view of the target, but are independent of view of the moving arm. They are executed via rapid cortical reflexes, are interrupted by transcranial magnetic stimulation directed at the posterior parietal cortex, and are lost after lesions of the contralateral parietal cortex, even when such patients can make reasonably accurate arm projections to targets (Desmurget et al., 1999; Grea et al., 2002).

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Sensory–Motor Mechanisms of the Precision Grip The reach to grasp of a fixated object is followed on contact by a reflex adaptation of the hand to the surface contour and texture of the object grasped, and the adjustment of the gripping force to the lifting requirements. The adjustments are determined by visual inspection of the object, memory of object qualities, and by the direct reflex control evoked by activity in mechanoreceptive afferents innervating the glabrous skin of the gripping fingers; several grasps are shown in Fig. 14–9. The neural mechanisms of the grip and lift operation have been studied by Johansson and his colleagues (Johansson 1991, 1998, 2002; see also Westling and Johansson, 1984; Westling, 1986; Witney et al., 2004). The experimental arrangement used (Fig. 14–10) allows measures of the grip and load forces, the movement and position of the object gripped, and, in some experiments, simultaneous recording of the responses in large myelinated mechanoreceptive afferents inner-

Fig. 14–9 Postures of the hand in grasping objects, showing three of the many ways the hand can provide oppositions around objects; for example, at the end of a reach to grasp action. The solid lines show the opposition vectors relative the plane of the palm. A: Pad opposition. B: Palm opposition. C: Side opposition. (From MacKenzie and Iberall, 1994.)

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Fig. 14–10 Schematic drawing of the arm and test apparatus used for simultaneous study of the grip-lift-reset sequence, and microneuronographic recording from axons of the medial nerve, in waking humans. The touched surfaces are two interchangeable discs 30 mm in diameter mounted on each side of the object to be lifted, in two parallel vertical planes 30 mm apart. Object equipped with strain gauge transducers to measure grip and load forces; forces at thumb and forefinger recorded separately. Position indicator used to measure movement, and accelerometer to record vibrations of the object. (From Westling, 1986.)

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Fig. 14–11 A schematic diagram to illustrate the results of the lift and hold experiment, including typical discharge patterns of the four classes of mechanoreceptive afferents innervating the glabrous skin of the human hand: FAI, Meissners; SAI, Merkels; FAII. Pacinian; SAII, Ruffini receptors. a—initial contact; b—slip during the loading phase evoked tactile slip, followed by change in force ratio; c—FAII discharges at the start of the lift movement; d—FAI responses during periods of muscle tremor; e—activity in both FAI and SAI afferents produced by localized slips followed by upgrading of the force ration that maintains steady position; f—slip triggered responses in FAI, FAII, and SAI but not in SAII afferents, eliciting upgrading of force ratio; g—FAII response at the movement of table reset; h—release responses. (From Westling, 1986.)

vating the glabrous skin of the fingers of waking human subjects. Fig. 14–11 is a composite illustration of the results obtained, including records of force, force ratio, position of the object lifted, and the patterns of responses in the mechanoreceptive afferents during the lift, hold, and reset sequence. The force ratio is just sufficient for lifting, and adjusts rapidly to different surface textures and to mid-course perturbations such as the slips at e and f. The slip-evoked responses in the RA (Meissner) and SA-1 (Merkel) afferents evoke the necessary increments in the force ratio (Johansson and Westling, 1987; Westling and Johansson, 1987). The grip force is adjusted by reflex contractions of finger flexors evoked through both segmental and suprasegmental circuits at latencies of about 35 and 60 msec, respectively (Macefield and Johansson, 2003), and depends only on the glabrous skin afferents; the muscle afferents in the long or short muscles of

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the hand are not involved. Functional magnetic resonance imaging studies in normal humans working in the grip-force load task suggest the involvement of the right intraparietal cortex in the adjustment of grip and load forces in manipulation (Ehrsson et al., 2003).

Are Functions Localized in the Parietal Frontal Systems? No one of the studies of the posterior parietal areas has established a strict localization of function in them, in the sense of Gall or of those who followed him who used the clinical correlation method (Marshall and Fink, 2003). Contrarily, the functional properties of the areas outlined in Fig. 14–2 suggest that they are nodes in separate, largely parallel, distributed systems within which neural signals for different complex tasks are composed. Functions appear to be embedded in the dynamic activities in these distributed systems, rather than in single cortical areas. The execution of reaching and grasping, for example, begins with the projection into the posterior parietal cortex of visual afferent signals that define the location and salience of external objects. These signals are transformed and re-encoded in the posterior parietal areas, yielding signals for reaching toward and grasping the objects identified visually, and transferred via parallel parietal frontal systems to the premotor areas of the frontal lobe, and from them to the motor cortex, the major among several cortical sources in which descending neural signals controlling movements of the arm and hand are generated (Lemon et al., 2004). Separate parietal frontal systems dealing with reaching and grasping appear to converge only at the level of the motor cortex itself. The function is no more localized in any one of the nodes of such a system than in another, and each node makes a unique contribution to system function.

Concluding Remarks The posterior parietal cortex of the primate brain contains a neural apparatus that generates an internal image of the self, of the body and its parts and its position in immediate behavioral space and the gravitational field, of the spatial relationships between the body parts, of the direction of gaze and visual attention, and of dynamic changes in these postural and attitudinal sets. There exists also in the parietal lobe system a neural apparatus linked to this continually freshened image of the organism in its close-in surround, receives

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signals of the internal state in terms of needs and interests, and from time to time generates directions for action, for example, for reaching toward and grasping objects of interest. This system integrates visual with tactile and proprioceptive input, and generates in its population output signals for arm projection and hand manipulation through the trans-cortical parietal frontal system to the premotor cortex, and from thence to the motor cortex for detailed control of the relevant muscle sets. The visual receptive components of the parietal lobe system provide signals of the flow fields that guide forward locomotion and equilibrium. These generalities suggest the hypothesis that the parietal lobe system creates and maintains within the distributed neural systems of which it is a part an image of self and self in the world, which I infer to be essential parts of conscious self-awareness. In this sense, the neglect shown by patients with right parietal lobe lesion may be regarded as a spatially localized defect of consciousness; for the patient with such a lesion that part of the world does not exist. The withdrawn and self-isolation of a monkey after bilateral removals of the parietal lobes suggests a reduction in its level of conscious awareness, for he has lost that information-seeking behavior characteristic of attending primates. These speculations suggest that the neural mechanisms for consciousness are distributed throughout the cerebral cortex, and not localized to any one area or lobe. It is relevant to note that the dissolution of conscious unity in humans after callosal section occurs only when and if the connections linking the two parietal lobes are severed. N OTES 1. Brodmann was one of the first to recognize the general concept of the distributed cortical system, particularly as regards higher order functions, as witness this statement: “One must therefore assume a certain regional preference for higher activities, sometimes more in occipital and temporal areas, sometimes more in frontal. Such activities are, however, always the result (and not merely the sum) of the functions of suborgans distributed more or less widely over the cortical surface; they can never be the product of a morphologically or physiologically independent “centre.” The variety and the gradations of form and degree of higher intellectual activity are thus merely the expression of the infinite variability of functional combinations of individual

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cortical organs.” From Garey’s 1999 translation of Brodmann’s 1909 monograph, pp. 255–256 (London: Imperial College Press). 2. There is one exception. As a last therapeutic resort Penfield removed the right parietal cortex under direct vision in a number of patients with intractable right parietal lobe epilepsy. The lesions were followed by all the classical signs of the right parietal lobe syndrome; none of these had been present in the preoperative, epileptic state (Hecaen et al., 1956).

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Adaptive Reorganizations of Central Somatic Sensory Networks

A persisting theme in neurobiology in the century since Cajal is that synaptic relationships in the central nervous system can be changed by experience. The mechanisms include axonal growth and synaptogenesis in the ontogenetic development of the nervous system, a plasticity that persists into adult life. Understanding of the plasticity of synaptic junctions, of network operations, and of the molecular basis of neuronal action, has led to plausible mechanistic theories of learning and memory, and of the acquisition of motor skills. For a sample of reviews of the spectactular advances in these fields in recent decades, see Weinberger (1995), Edeline (1998), Kandel and Pittenger (1999), Martin et al. (2000), Kandel (2001), Blake et al. (2002), and Morris et al. (2003). Synaptic changes also contribute to the recovery of function after brain lesions, as witness the sometimes remarkable capacity of humans to regain significant motor control after vascular lesions of the motor cortex or capsular infarcts. The phrase synaptic plasticity is used to refer to many phenomena Jones (2000b). Here I use the term synaptic plasticity to designate the changes in synaptic connectivity, both structural and dynamic, produced in the central regions of the somatic afferent system by peripheral deafferentation or its reverse, increases in afferent input. These changes lead to modification of the representational maps at each level of the system. Changes that appear almost instantaneously are produced by operations in network dynamics; others involve changes in synaptic structure and function, and in network connectivity. They may persist and increase over many months and

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years. This temporal course is the result of a cascaded series of causes with different time courses. Many changes that follow nerve lesions or amputations are maladaptive and lead to the devastating syndromes of pain of central origin. Amputations of hand or foot are commonly followed—sometimes immediately—by the appearance of a phantom limb; these phantoms are frequently accompanied by a persistent syndrome of central pain. Increases in the spatial representation in the somatic afferent system are produced by intensive training and use of the fingers in repetitive tasks requiring skilled movements that depend upon precise sensory input, such as playing stringed instruments or reading Braille. Whether the enlargements of the representations of the trained fingers in the central maps are causally related to the increase in the skilled use of the fingers is a matter of much study and speculation. I describe here only parts of this field, including the variability of somatic afferent representational maps in individual primates of the same species, and how those maps may change with changes in peripheral input. I include summaries of the mechanisms thought to be responsible for synaptic plasticity in the somatic afferent system. Several earlier studies preceded the current explosion of research in this field. Nakahama et al. (1966), for example, observed a rapid change in the sizes and locations of the receptive fields of thalamic neurons in cat during local anesthesia of the initial peripheral receptive fields of those cells. Wall and his colleagues described the changes in synaptic connectivity and in the operation of central networks in the dorsal horn and cuneate nucleus produced in rats and cats by transection of dorsal roots (Wall and Egger, 1971; Basbaum and Wall, 1976; Millar et al., 1976; for review, see Wall, 1977). These were followed by the work of Merzenich, Kaas, and their colleagues who discovered more than two decades ago that the representational maps in the postcentral somatic sensory areas of monkeys can be changed in enduring ways by peripheral deafferentation, or by increased input from trained areas of the glabrous skin (Kaas, et al., 1983; Merzenich et al. 1983a,b; Merzenich et al. 1984, 1990; Kaas, 1991; Buonomano and Merzenich, 1998; Kaas, 2000, 2002; Kaas and Collins, 2003b). These experiments followed and paralleled others showing that the plasticity already known for the neonatal cortex persists into maturity, and that alterations in synaptic connectivity are produced at spinal, brain stem, and thalamic levels of the somatic system by peripheral deafferentation in

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rats, cats, raccoons, flying foxes, and humans (Nakahama et al., 1966; Wall and Egger, 1971; Basbaum and Wall, 1976; Dostrovsky et al., 1976; Millar et al., 1976; Wall, 1977; Devor and Wall, 1978; Kalaska and Pomeranz, 1979, 1982; Rasmusson, 1982, 1988; Calford, 2002a). A large literature has accumulated.1 Together with similar discoveries in the visual (Hubel et al., 1977) and auditory systems (Merzenich et al., 1984; Weinberger, 1995), these observations and the following studies of the phenomenon in monkeys were factors leading to our present understanding of the degree to which the brain is a dynamic and adaptive system. Adaptive changes in connectivity occur at each level of both the large- and small-fibered components of the somatic afferent system, in adult as well as in immature mammals, and in every other mammalian sensory and motor system studied, as well. Cortical plasticity can be induced by behavioral or experimental conditions that change the afferent input to the nervous system. The degree of change that may occur in the trans-postcentral somatic sensory areas of the cortex, or in other homotypical areas, is still uncertain, but the inference is that representations in those areas may be more labile than is the representational map in 3b, where most experiments have been made. An older speculation of many neuroscientists is that changes in behavior with any degree of permanence, including learning, long-term memory, and the acquisition of motor skills, are due to changes in synaptic microstructure in the brain, including changes in transmitter and receptor functions. Whether these mechanisms are identical to those operative in central plasticity and the modification of representational maps by peripheral deafferentation, described in this chapter, is presently uncertain. Adaptive plasticity is now generally recognized as a pervasive characteristic of neural tissue, and has been observed in virtually all central brain systems. It is induced under many conditions that change the pattern of activity reaching the cerebral cortex. For a group of reviews, see Huntley and Jones (2002).

The Microelectrode Mapping Method The discoveries of Merzenich and Kaas, and the results obtained in many following experiments, involved use of a complicated and difficult method, and tests of its validity. They reasoned that a

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single sample at any point in a cortical column, and especially for recordings made in layer IV, provides a measure of the place and modality properties of the column. They devised the method of microelectrode mapping, in which a large number of microelectrode penetrations are made to the level of layer IV, using lowimpedance microelectrodes for multineuronal sampling. The mapping item is the combined receptive field of the cluster of neurons recorded at the electrode tip. The penetrations are made at densities of 20–30/mm2 of the cortical surface, and repeated until all or a significant part of a representational map is completed. This method has been used to reveal the details of the map of the body surface on the postcentral gyrus in nonhuman primates (see Figs. 10–11, 10–12, and 10–13), and used successfully in many comparative studies of the somatic sensory cortex in a range of mammals (Kaas, 1987, 1989; Kaas and Collins, 2003b). If made with aseptic precautions, the experiment can be repeated in the same cortical area even weeks or months later. This allows a direct measure of the changes in representational maps produced by manipulations that either remove or increase peripheral afferent input. Figure 15–1 gives the results of such an experiment made in the normal, adult new world owl monkey (Merzenich et al., 1987). The map shows the outlines of the representations of digits two, three, and four of the contralateral hand; the drawings below show the finger parts. Three questions concerning the validity of the method were addressed by Merzenich and his colleagues: (1) Is there observer bias in such an experiment? (2) Do the maps vary with anesthetic state? and (3) How precisely can the boundaries be drawn between the representations of the fingers, or around the entire hand representation? The first was answered in experiments in which two or three groups of investigators mapped the same brain in succession, each group blind to the results obtained by others. The two or three maps obtained in these double- or triple-blind experiments on the same postcentral gyrus were nearly identical. In other experiments the maps made in the waking state were found to be similar to those obtained in monkeys anesthetized with ketamine, nitrous oxide, or sodium pentobarbital (Stryker et al., 1987). A statistical analysis of the results obtained indicated that the borders between areas could be placed with errors in the range of 25–150 µm.

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Fig. 15–1 The figure above shows the penetration grid of a micromapping experiment made in the hand area of the postcentral gyrus of a normal, anesthetized owl monkey. Each symbol marks a microelectrode penetration site: diamonds, stars, and large dots mark penetrations containing neurons with receptive fields limited to digits 2, 3, and 4, respectively. Clusters of penetrations enclosed by dashed lines show boundaries of the representations of the three digits. In the drawings of hands below, the locations of the centers of receptive fields on glabrous skin marked by filled circles, those on the hairy skin by open squares, those in deep tissues by filled squares. Each line marked by numbers above corresponds to a similarly marked line below. (From Merzenich et al., 1987.)

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Normal Variations of Representational Maps in the Somatic System No two individuals of the same primate species have identical representational maps in area 3b. Maps may differ in size, details, and magnification factors for different parts of the hand, but the overall topographic patterns are similar in all. Maps of the hand areas in postcentral area 3b for three adult owl monkeys and three adult squirrel monkeys are shown in Fig. 15–2, each studied with the microelectrode mapping method. The maps are idiosyncratic, and the variations in the overall map sizes and in the representations of individual fingers are several-fold greater than the error in determining map borders (Merzenich et al., 1987; Stryker et al., 1987). Despite these individual differences in the representational maps between individuals, they all preserve a similar topographical order. The maps vary several-fold in area 3b, and even greater differences occur in maps of area 1 (not shown), which is somewhat less strictly topographic than is area 3b. Variations in the representations of the hand in the human postcentral gyrus have been shown with magnetoencephalgraphic recording (Mogliner et al., 1993) and imaging methods; for reviews see Burton (2002). Several mechanisms may contribute to this variability. The first is that the genetic determination of the distribution of progenitor neurons in the germinal epithelium and their subsequent migration to the cortical plate may vary between individuals. There is an example of remarkable individual variations in another ectodermal derivative, the glabrous skin of the hand, where the life-long dermatoglyphic pattern unique for each individual is determined by the pattern of projection to the skin of the large mechanoreceptive afferents of the dorsal roots. It would be difficult to test whether individual variability is present at birth by executing the micromapping experiment in newborn primates, for many neurons in the postcentral gyrus are unresponsive to peripheral stimulation in the first month of postnatal life. Second, differences may occur in this early stage of postnatal brain maturation, but again there is no direct evidence for such differences. Third, imposed changes in manipulative experience in adult monkeys produce changes in representational maps. The inference is that the differences in the maps between individuals may have been produced by differences in the use of the hand, but there have been no descriptions of how different monkeys may use their hands differently in their natural state.

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Fig. 15–2 Representational maps of the hands in area 3b of the postcentral gyrus in three normal owl and three normal macaque monkeys, anesthetized. Open areas, glabrous skin; cross-hatched, dorsal hand surfaces. Experiment made as described the text. The maps show the normal variability between individuals of the same primate species. (From Merzenich et al., 1987.)

There is direct evidence that intensive use of the hands by humans produces adaptive changes in the postcentral gryus; for example, in musicians and in Braille readers (Chapter 16). However, in any single individual, absent such unusual events as amputation of a limb or other massive peripheral deafferentation, there is an inherent and

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lifelong stability in the sequential order of the representation of the body parts along the postcentral gyrus. Plastic changes in the proportion of cortex allotted to individual parts do not change the topographical sequence. A similar variation between the volumes of the precentral motor and premotor cortices has been demonstrated with quantitative cytoarchitectonic and myeloarchitectonic methods by Rademacher et al. (2001).

Adaptive Reorganization of Somatic Sensory Representational Maps in Monkeys After Peripheral Deafferentation The experiment in which transection of a peripheral nerve changes the representational map of the hand in the monkey postcentral area 3b has been elaborated in a number of ways. These include nerve transection with and without reinnervation; digit, hand, or arm amputation; lesions of the afferent pathways of the spinal cord; transection of all cervical and upper thoracic dorsal roots; experimental syndactyly; transection and cross-union of peripheral nerves, and skin transplant. For reviews see Buonomano and Merzenich (1998), Merzenich et al. (1990), Kaas (2000), and Blake et al. (2002). The results obtained have extended the original observations. Merzenich, Kaas, and their colleagues used the microelectrode method to map areas 3b and 1 in owl and squirrel monkeys at intervals ranging from hours to years after nerve transection (Merzenich et al., 1983a,b) or digit amputation (Merzenich et al., 1984). In one experiment they mapped these areas in an owl monkey before and after section of the median nerve. The map made within hours of median nerve section showed large unresponsive areas, but equally large areas, not seen in the pre-transection map, responded to stimulation of the dorsal hairy skin of the hand. By the 22nd day the unresponsive area had disappeared, and the map showed an early encroachment by afferent input from the still innervated glabrous skin adjacent to the median nerve field. Figure 15–3 shows maps made before and 62 days after amputation of the third finger in another owl monkey; the third finger has disappeared from the postcentral map (Jenkins and Merzenich, 1987). In one unusual series it was possible to map area 3b in a number of macaque monkeys many years after transection of dorsal roots C2–T4 that innervate the upper limb (Pons et al., 1991). Micromapping of the postcentral

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Fig. 15–3 A: Representation of the surface of the hand in area 3b and surround in the postcentral gyrus of an anesthetized owl monkey, derived with the micromapping method described in the text (244 microelectrode penetrations). F—penetrations with neurons with receptive fields on the face; X—penetrations in which neurons were activated by stimulation of deep tissues. Open area, glabrous skin representations; hatched areas, hairy skin of the dorsal hand. Numerals, digits, and their representations: d, m, p—distal, middle, and proximal phalanges; p—glabrous skin pads on the hand. B: result of remapping of the same areas (355 penetrations) made 62 days after amputation of the third digit. The representation of that digit has disappeared, and its area is now occupied by expanded representations of digits 2 and 4, particularly of their distal phalanges. (From Jenkins and Merzenich, 1987.)

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gyrus in these long surviving animals showed that the hand–upper arm area was occupied by afferent input from peripheral skin innervated by the mandibular branch of the trigeminal nerve, a transcortical lateral-to-medial shift of 10–14 mm, so that the representation of the lower face came to be adjacent to the representation of the trunk. This accounts for the referral of tactile sensations to the hand evoked by stimulation of the lower face and jaw in human amputees with phantom limbs, described below. The experiment also shows that the modification of the representation map at the level of postcentral area 3b was not propagated farther into the cortical somatic sensory system, for afferent activity from the face now directed to the hand area still evoked normal perceptions of hand stimulation, with preservation of mode and spatial pattern. Similar results were obtained by Florence et al. (2000) after long-term amputation of the hand in monkeys, and by Jain et al. (1997) after transection of the cuneate fasciculus at the cervical level.

Adaptive Reorganization in the Human Somatic System After Central Lesions or Peripheral Deafferentation Clinical neurologists frequently observe that for many brain lesions, particularly those of the cerebral cortex, the immediate defects of function seen on the day of lesion gradually regress, to degrees that vary between individuals and between lesion locations, and that improvements in function may continue for months or years after brain injury. A classic example is the initially rapid and then slower recovery of a degree of motor control after vascular lesions of the precentral motor cortex, or capsular infarction. Much of the early phase of recovery of partial function after a vascular lesion is attributed to the survival of brain tissue made ischemic, but not destroyed, within the penumbra of decreased oxygen supply surrounding the region of total vascular insufficiency. This recovery occurs quickly after the vascular accident with the recovery of that tissue as blood flow improves. Clinical therapeutic efforts now aim at increasing the degree and rate of that recovery and thus limit the extent of the permanent lesion. Vascular recovery does not explain the increase in functional capacity that continues beyond the immediate period of injury, and many attribute this delayed phase of recovery to a positive adaptive plasticity within the cortical circuits controlling movement, a process enhanced by training resembling that in motor learning

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(Nudo et al., 1997; Sanes and Donoghue, 2000; Hallett, 2001; Chen et al., 2002; Carmichael, 2003). How and where these postulated plastic changes occur is a matter of intense study, with the object of finding therapeutic agents to promote them. Severe pain of central origin frequently appears months or even years after a transection of the spinothalamic tract made in humans to relieve pain of peripheral origin. This reappearance of pain may be due to a maladaptive capture of denervated elements of the small-fibered afferent system by elements of the large-fibered (lemniscal) system at one of their convergent central targets. Such an abnormal convergence in the dorsal horn results in sensitization phenomena. Abnormal evoked responses and unusual spontaneous activity patterns in the ventral posterior lateral thalamic nucleus occur in humans with this central pain syndrome (Lenz et al., 1998). Similar abnormal activity patterns have been observed in the ventral posterior lateral nucleus in monkeys some months after transection of the spinothalamic tract, when the animals show exaggerated responses to previously innocuous stimuli, spike-burst patterns of spontaneous activity, and altered receptive fields, interpreted as a model of the human central pain syndrome (Weng et al., 2000). It may be that the matrix thalamic cells, ordinarily innervated by the spinothalamic input, are captured by the lemniscal inputs to the core thalamocortical neurons, for the two cell types are closely intermingled in the thalamic rods and in the close surround of the rods in the ventral posterior nucleus. There is no direct evidence for this hypothesis. It has been known for half a century that alterations in the body image occur during local or regional anesthetic blockade of afferent input, described by many observers, for example, Riddoch (1941). The perceptual illusions during regional anesthesia vary between individuals, but almost all include changes in the perceived size and shape of the anesthetized body region. Pacqueron et al. (2003) studied 36 patients during the course of a variety of anesthetic blockades, including spinal anesthesia. The perceptual illusions appeared in these patients in parallel with the loss of the detection of warm, coolness, and painful stimuli delivered to the anesthetized region, well before the loss of tactile or proprioceptive sensibilities, evidence that the fine-fibered afferent system plays a critical role in maintaining the normal body image. The perceptual illusions disappeared in parallel with the recovery of peripheral sensibility.

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Phantom Limbs Amputations of the arm or leg are frequently followed, in some cases almost immediately, by the appearance of a vivid perception that the limb is still present—a phantom limb. Many phantoms are painful, in some patients persistently and excruciatingly so. The phantom phenomenon after amputation must surely have been experienced by humans since antiquity, for skeletons with signs of long survival of limb amputations have been identified, and dated from prehistoric times. An early description of the phantom limb syndrome was published by Ambrose Pare in 1552; for historical review, see Finger and Hustwit (2003). Clinical descriptions of phantom phenomenology have appeared many times since the monograph of Mitchell (1872), including a large-scale survey of veteran amputees by Sherman et al. in 1984. Flor (2002) and Ramachandran and Hirstein (1998) described the phantom syndrome and reviewed the candidate mechanisms that produce phantoms after peripheral deafferentation. In most cases the phantom limb is perceived as an integral part of the body image. Those of the leg or arm are frequently foreshortened, terminating at their peripheral ends in a normally sized hand or foot, replicating to some degree the representation of the body form in the postcentral gyrus, modified as it is by differences in the magnification factors for different body parts. The appearance of phantoms indicates that the central representation of the limb survives amputation, and that activation of that representation and the projection of activity from it into the perceptual operations of the cortical somatic system produce the perceptual illusion. What maintains the ongoing activity in the peripherally denervated postcentral representation is uncertain. There is evidence, given below, that in some cases it depends on sustained peripheral input from tissues adjacent to the amputated region, but that in others it must depend upon re-entrant signals to the postcentral representation; the sources of this input are unknown. The appearance of a phantom appears to be linked to the rapid and dynamically maintained adaptive change in the postcentral representational map, but a causal link between these parallel events has not been established. One question is whether a phantom has ever been observed in the absence of adaptive changes in the postcentral map, or at subcortical levels of the somatic system. Phantom limbs occur in only 10–15 percent of individuals with congenital absence of limbs, and postcentral reorganizations do not occur in them (Flor et al., 1998; Montoya et al., 1998).

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The change in the postcentral map in amputees with phantom limbs may result in sensory reference to the face and/or to the shoulder. Ramachandran and Hirstein (1998) described 18 upper limb amputees, in 8 of whom stimulation of the face evoked both the expected experience of facial stimulation and also sensations referred to the phantom limb. The referral from face to limb was point to point, and preserved the specificity for place and modality characteristic of the normal hand area. The modalities represented on the face included touch, warmth, and coolness, each in appropriate sensory register. The pattern of representation of the fingers in the representation zone of the face is shown in Fig. 15–4A. The pattern was changed after 6 months, with an expansion of the

Fig. 15–4 A: Map of the sensory reference to the hand evoked by stimulation of the face, in a patient with a limb phantom. The map is contained within the mandibular portion of the trigeminal projection. Sensations evoked by light tactile stimulation, and by other specific modalities as well were mode and place specific. Patient had sustained a brachial plexus avulsion, followed a year later by amputation of his anesthetic arm, and the appearance of a phantom with extended arm without telescoping. B: A second map made 6 months later showed moderate changes in the topographical map. (From Ramachandran and Hirstein, 1998.)

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representation of the thumb, shown in Fig. 15–4B. The facial representation of the hand was confined to the mandibular nerve representation zone (Manger et al., 1998). A second referred map (not shown) was located on the ipsilateral shoulder. The mandibular face and the shoulder representations in the postcentral map border laterally and medially, respectively, the representation of the denervated hand area, and it appears that each has captured a portion of that representation. In amputees with face capture of the hand area magnetoencephalic and magnetic resonance imaging studies showed a lateral to medial shift of the face area of as much as 20 mm. In some humans with spinal cord injury the referred phantom sensations are not adjacent in the periphery, nor are their representations adjacent in the postcentral map, as shown by functiional magnetic resonance imaging (Moore et al., 2000). These results indicate that in some cases remapping at subcortical levels of the somatic system may generate perceptual illusions after deafferentation in humans.

Phantom Limb Pain Several surveys reveal that 60–80 percent of amputees have some post-amputation phantom limb pain (Sherman, 1997). The intensities, distributions, and durations of these pains vary among amputees, and for a significant number they are severe and permanent. Phantom limb pain is one of the most difficult of all pain syndromes to treat. More than 50 treatment methods ranging from central nervous lesions of the pain pathways to hypnosis have been tried, but only about 1 percent of treated amputees report permanent relief. Flor et al. (1995, 1998) have shown a high correlation between the degree of phantom limb pain after arm amputation and the extent of adaptive changes in the representational maps of hand and arm in the postcentral sensory and precentral motor maps. In a later series Birbaumer et al. (1997) found that the sources maintaining phantom limb pain after amputation differ among individuals in the amputee population. They induced brachial plexus blocks with local anesthetics in six amputees with phantom pain, and in four pain-free amputees. The pain disappeared in three of the six during the period of arm anesthesia. What is remarkable, the adaptive shifts in their postcentral maps, measured with the evoked

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potential method to be a 20-mm shift of the lip into the now denervated hand area, reversed to normal during the 2- to 3-hour period of anesthesia of the arm. This reversal provides an existence proof that at least in some cases even long-standing adaptive changes in the postcentral representational maps are maintained dynamically, and do not depend on structural changes in the system. Conversely, the other three amputees with painful phantoms experienced no pain relief during anesthesia of the arm, and their modified postcentral maps did not change. The conclusion is that the input maintaining the central painful phantom in some cases is derived from continuing peripheral input, while in others it depends on continuing re-entrant input to the postcentral gyrus from other parts of the somatic afferent system. The four subjects with nonpainful phantoms showed no changes in their modified postcentral maps during the period of peripheral blockade of both afferent and efferent innervation. The presence of an adapted and changed postcentral map may be a necessary but not a sufficient condition for the appearance of a painful phantom (Elbert et al., 1994). Some amputees describe the phantom as resting in a comfortable position, and that they can willfully move it; other phantoms, particularly painful ones, may be fixed in space, sometimes in bizarre and anatomically impossible positions, from which the amputee cannot dislodge them by willful effort. Amputees commonly report sensations referable to the phantom that cover a wide spectrum of somatic sensory modes, including in many some degree of pain. There are older descriptions of amputees with phantom limb pain in whom a subsequent large lesion in the hemisphere contralateral to the amputation removed the phantom, but attempts to duplicate this by surgical removal of the postcentral gyrus have rarely provided any long-term relief. Several studies of the effect of drugs that block N-methyl-D-aspartate (NMDA) receptors have produced equivocal success in relieving phantom limb pain (Schwenkries et al., 2003). Some amputees with preoperative pain and postoperative phantom pain describe the latter as similar in location and nature to the former. This led to a number of studies in which preoperative anesthesia of the limb was used in the attempt to block the “pain memory” following amputation. The results obtained are equivocal, and differ between studies, and in general the method is regarded as ineffective (Jensen and Nikolajsen, 2000).

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Experience-Dependent Modifications in Representational Maps in the Somatic Afferent System In humans intensive use of the receptor sheet on the glabrous skin of fingers in skilled tasks such as playing string instruments (Elbert et al., 1995) or Braille reading (Pascual-Leone and Torres, 1993), is paralleled by an increase in the representation of the trained fingers in the human postcentral sensory and precentral motor maps, with preservation of topographic order. Observations on the human somatic system resemble the results of a number of experiments in monkeys in which micromapping revealed an expansion of both the postcentral and precentral representations of the fingers in animals trained in sensory–motor tasks. Jenkins et al. (1990), for example, trained owl monkeys to maintain constant pressure on a rotating disc using only two or three finger tips, a task requiring precise pressure control. Mapping experiments made after training showed an expansion by several fold of the representation of those trained finger tips. The receptive fields of neurons in those expanded regions were correspondingly smaller than those on fingers of the untrained hand, thus providing a more detailed representation of the trained fingers. Other owl monkeys were trained to make discriminations between the frequencies of flutter stimuli delivered to their fingers. Micromaps revealed that the representation zones of the trained fingers enlarged 1.5 to 3 times, in different animals (Recanzone et al., 1992c). Frequency discrimination training also unveiled the emergence of an enlarged cutaneous representation of the fingers in area 3a, and a recession of the normal deep receptor input to this region (Recanzone et al., 1992b). In a related study of this series, owl monkeys were trained to retrieve pellets of food from increasingly smaller containers. After 23–30 days of training the monkeys adopted stereotyped retrieval movements using the distal pads of two or three fingers to retrieve food pellets from the smallest container. Micromapping experiments showed a doubling in the cortical representation of those finger pads, accompanied by a reduction in receptive fields to less than half their normal sizes (Xerri et al., 1996, 1999). The interpretation of these and similar findings is that the increased population of cortical neurons responding to the training stimuli equates in a causal way to the increased tactile skill, but there

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is no direct evidence that this is so. It may be, for example, that more subtle factors are important in the improved tactile performance, for example changes in the dynamic neuronal operations in both the enlarged postcentral area and in the trans-postcentral areas of the cortical somatic system to which it projects. In difficult tasks such as reading Braille the skill is restricted to the trained finger (Pascual-Leone and Torres, 1993). This is not always so for less difficult tasks. Monkeys trained in a tactile frequency discrimination task in the 20- to 40-Hz frequency range of flutter achieve discrimination limens of 2–3 Hz, equal to that of trained human subjects. The trained capacity in monkeys is immediately evident when tested on adjacent fingers, and is transferred to the contralateral, untrained hand in one day of training (Chapter 12). The implications for function of enlarged representations differ between those produced by peripheral deafferentation and those associated with tactile training. In the first, the capture of the denervated hand area by face or shoulder is frequently accompanied by phantom limb pain, and leads to the paradoxical activation of the projected hand representation by stimulation of face or shoulder, surely a maladaptive change of no utility for somatic sensory perception. What is known about the increased representation of skin areas trained in skilled tactile tasks provides candidate explanations for the neural mechanisms of the increased sensory–perceptual skills attained by training.

Synaptic Modifications Occur at Each Level of the Somatic System Observations of synaptic plasticity and network reorganization in the somatic system were made by Patrick Wall and his colleagues in rats and cats, in the dorsal horn (Wall and Egger, 1971; Basbaum and Wall, 1976; Millar et al., 1976; Devor and Wall, 1978) and in the cuneate nucleus (Dostrovsky et al., 1976), and, independently, by Chambers et al. (1973). These observations have been confirmed and extended in studies in monkeys at cuneate and thalamic levels (Xu and Wall, 1997, 1999a,b; Weng et al., 2000; Churchill et al., 2001), and in the ventral posterior nucleus in humans (Davis et al., 1998; Dostrovsky, 1976). The changes observed include the rapid appearance of new and shifted receptive fields, the reorganization of representation maps, and the appearance of new patterns of neuronal

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activity. All the mechanisms of synaptic reorganization observed at the level of the postcentral cortex, described below, occur also at brain stem and thalamic levels. There is direct evidence in rats obtained with many microelectrodes implanted at each of the three levels, that after peripheral deafferentation produced by local anesthesia of cutaneous receptive fields there is a immediate and simultaneously sensory reorganization at all levels (Faggin et al., 1997). For reviews see Kaas et al. (1999), Jones (2000a), and Wall et al. (2002).

Mechanisms of Adaptive Reorganizations in the Somatic Afferent System Synaptic Divergence at Each Level of the System The divergences between pre- and postsynaptic neural populations successively cascaded at each level of the somatic system contribute to the large adaptive shifts in cortical representational maps after peripheral deafferentation. Small changes at lower levels, for example, in the dorsal column nuclei, are magnified through spatially related elements in higher levels of the system. That normal divergence is seen in the early maps made at thalamic and cortical levels with gross electrode recording methods (Chapters 9 and 10). It is emphasized by the observation of Jones et al. (1997) that a large lesion of the VPL nucleus (45 percent) is required to produce a zone of complete denervation in the postcentral gyrus. This degree of divergence accounts for the fact that the adaptive shift in the representational pattern exceeds the shift that would be expected if it were limited by the divergence in the thalamocortical projection alone (Rausell et al., 1998). The divergence in the system is thought to account for the minimal changes in the molecular components of the glutamic and GABA transmitter systems in the reorganized postcentral gyrus, which contrasts with the marked changes in those elements in the visual cortex after removal of one eye (Rausell et al., 1998; Jones et al., 2002).

Dynamic Changes in Network Operations Receptive fields of neurons of the lemniscal system are dynamic constructs, at times determined by the balance between several controlling factors, first by its dominating thalamocortical input, then by acetylcholine (ACh) excitation and γ-aminobutyric acid (GABA)

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disinhibition from the nucleus basalis of the forebrain (Dykes, 1997), then by the tonic influences of the converging fine-fiber afferent system and by the modulatory systems of brain stem origin (Gu, 2002). In the absence of long-term adaptive changes the response centers of the receptive fields determined by the balance between these factors remain remarkably stable. Each field determined by evoked action potentials is surrounded by a subliminal fringe of synaptic inputs into which the active field may expand or from which it may contract, in a labile manner. The subliminal fringe is well known in classical neurophysiology,2 and has been shown to exist to varying degrees in every synaptic transfer region of the brain, with the exception of the calyx of Held in the trapezoid body, where there is a one-to-one relationship between input axon and target neuron. The subliminal fringes of cortical neurons are large and widely overlapping, so that target neurons, for example those in layer IV, are within the fringe of the axonal distributions of adjacent thalamocortical afferents, and of horizontally directed intracortical axons of pyramidal cells that may be 4–5 mm distant. The overlapping subliminal fringes account in part for the rapid adaptive changes in the postcentral map following peripheral deafferentation. A number of studies have shown that these adaptive changes begin in the monkey postcentral somatic areas within minutes after peripheral deafferentation (Kolarik et al., 1994; Silva et al., 1996; Calford, 2002a,b). Figure 15–5 shows the expansion of the receptive field of a neuron in area 3b of an anesthetized macaque monkey during a transient anesthetic blockade of a finger (Calford, 2002a), a confirmation of Nakahama’s original observation in 1966. After deafferentation these previously subliminal synapses quickly became suprathreshold, so that the target cell was activated by impulses in thalamocortical axons or in those of horizontal cells 4–5 mm away, and thus the target cell acquires a new and in this case greatly expanded receptive field. An initial deafferentation leads almost immediately to a change in dynamic operations in the cortical network. The thalamocortical input to both the target cell and to the inhibitory circuit in which it is embedded is removed, so that the balance in the circuit shifts toward excitation. The target neuron lies within the subliminal fringe of other elements. The synapses from these sources normally have only subliminal capacity to excite the target cell, or may be completely “silent synapses” without a complete transmitter molecular apparatus. The transition of synapses from subliminal fringe to suprathreshold driving is sometimes referred to as

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Fig. 15–5 Drawings of the receptive field of a neuron in area 3b of an anesthetized monkey before and at intervals after local anesthesia of the skin containing the field. The field of the neuron rapidly expanded to cover almost the entire hand by 2 min, and the expanded field persisted for several minutes after return of drivability from the original field at 14 minutes after anesthesia began. (From Calford, 2002b.)

the “unmasking of ineffective synapses.” The rapidity and reversibility of these changes are attributed to the dynamic property of the synaptic networks of the system to change the balance between excitation and inhibition, without structural change (Calford, 2002a,b). In another series of experiments using reversible anesthetic deafferentation of fingers, Calford and Tweedle (1991a) observed that receptive fields for fingers on the unanesthetized hand, recorded in the cortex ipsilateral to the anesthetized fingers, enlarged and regressed in unison with receptive fields of the anesthetized fingers. Whether this marks a progression of acute plastic changes into interhemispheric circuits is uncertain, for anatomical tracer studies indicate that the finger regions of the two hemispheres are not directly connected. The excitatory capture of denervated cortical neurons by input in adjacent thalamocortical axons, or in horizontally directed axons of intracortical pyramidal cells, is thought to account for the rapid, adaptive modification of postcentral representational maps produced by deafferentation. Those horizontal projections in area 3b may transit from the representation of a single digit over two adjacent digits. Dynamic mechanisms such as these may maintain map modifications for long periods of time without structural changes, as evidenced by the experiment of Birbaumer et al. (1997), described above.

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It is sometimes suggested that the processes of changes in synaptic excitability caused by different frequencies of synaptic input, called long-term potentiation and long-term depression, may play a role in the rapid adaptive changes in the cortex following deafferentation. Other mechanisms suggested to account for these rapid adaptive changes include that proposed by Ariens-Kappers et al. (1936) to explain the changing synaptic connectivities in the comparative development of the nervous system; see quotations from Ariens-Kappers. The idea is that when pre- and postsynaptic elements are (nearly) simultaneously active, the synaptic linkage between them will be strengthened and stabilized, but that if the two activities are asynchronous, the relation will be progressively weakened, and the two eventually retracted. This hypothesis was later elaborated by Hebb (1949). Such a mechanism might contribute to the capture of a denervated cortical neuron by impulses in a fringe input, if the frequency of action potentials in the two were sufficiently high to allow a statistical likelihood of coincidence. Contrarily, asynchronicity would lead to a decreased probability of capture of the denervated neuron. Evidence that this mechanism is operative in some forms of cortical plasticity has come from studies of the creation and release of syndactyly, in both humans and monkeys, in which cases the afferent input from the two fused fingers is often synchronous. Presurgical magnetoencephalographic maps of humans born with fusion of two fingers showed fusion of their postcentral representations; after surgical separation cortical reorganization occurred with separate representations of the two fingers (Mogliner et al., 1993). The creation of a syndactyly in monkeys resulted in a fusion of the cortical representations of the two fingers, later resolved to separate representations by surgical separation of the two (Clark et al., 1988; Allard et al., 1991). It is surmised that the synchronized afferent input from the fused fingers led to the fused representations by what is called by some the Hebbian mechanism. It is not clear how this mechanism could produce the acute changes in the representational maps such as that described above, for it requires maintenance of spontaneous rate of discharge in both pre- and postsynaptic elements.

Synaptogenesis and the Formation of New Connections Connections in nervous systems are generated by axonal growth and synaptogenesis, subjects of continuing study in developmental

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neurobiology. Connectivity and system organization in the developing brain can be altered by central lesions or peripheral denervation. The capacity for axonal growth and synapse formation, known by the colloquial term “sprouting,” persists in the adult brain, and is considered to be an essential cellular mechanism in learning, memory, the acquisition of motor skills, and so forth. These changes can appear very rapidly in the mammalian cortex, certainly within hours and perhaps within minutes, in response to sensory activity (Zito and Svoboda, 2002); perhaps they do so just as quickly after peripheral deafferentation. The relevance in the present context is that sprouting occurs at each level of the somatic afferent system after peripheral denervation, or transection of the dorsal columns (Florence and Kaas, 1995; Florence et al., 1998; Kaas et al., 1999; Xu and Wall, 1999a; Wall et al., 2002; Wu and Kaas, 2002). It has been proposed that this mechanism contributes to the large-scale modifications of the postcentral representational maps, which in humans varies from 12–20 mm in lateral shift of the face area into the hand area after, for example, arm–hand amputation. This shift is thought to be too great to be accounted for by dynamic changes in local circuit operations in the denervated area of cortex. Even the local capture of a denervated cortical cell by closely adjacent, still-innervated, thalamocortical axons requires axonal sprouting and either new synapse formation or capture of old synapses on the denervated cell. This local capture could be explained by the competition model suggested by Hubel et al. (1977) to account for the ontogenetic development of ocular dominance columns in layer IVc of the striate cortex. Alternatively, that developmental event in the visual system and the adaptive modifications discussed here might be explained on the axonal process of sprouting and retraction in the framework model of Elliott et al. (1996). Behavioral evidence that face to hand transfer occurs is given above in the descriptions of phantom limbs, but this observation reveals only that a connection has been made, nothing of its mechanism. The argument has been made from anatomical study of the brains of monkeys surviving many years after peripheral deafferentation, that even the minimal amount of axonal sprouting observed linking the spinal trigeminal nucleus and the cuneate nucleus, located close alongside, will be amplified at ventral posterior and cortical levels, and could account for the massive shifts observed there (Jain et al., 2000). However, stimulation of the face that evokes

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sensory reference to the hand in humans with hand–arm amputations is modality specific, and requires only the gentlest tactile stimulation. Yet the spinal trigeminal nucleus receives mainly if not entirely small myelinated and unmyelinated axons of the trigeminal nerve. There appears to be a misfit between the source of the sprouting, suggested to account for the sensory reference, and the stimulus quality required to evoke it. A second unanswered question is whether the axonal sprouts observed make effective synaptic connection with their targets, which requires either electronmicroscopic reconstructions of labeled sprouting axons, or intracellular recording in their target cells, or both; apparently neither has been done. Nevertheless, the sprouting hypothesis remains as a candidate explanation of large-scale modifications of representational maps in the somatic system. Imbal et al. (1987) and C. Darian-Smith and Brown (2000) have confirmed the observation of Head and Rivers (1908) that some weeks after section of a peripheral nerve a zone of sensation reappears on the fringe of the denervated zone, and Imbal et al. (1987) found that this reappearance of sensation was the result of invasion of the fringes by axons in adjacent, intact nerves: the fringe of reappeared sensation disappeared with anesthetic block of the adjacent nerve. How this fringe produced by axonal sprouting contributes to the modification of central maps after peripheral deafferentation is unknown.

Transneuronal Atrophy The results of an anatomical study of the somatic sensory thalamus of a monkey 20 years after transections of dorsal roots C2–T8 is shown in Fig. 15–6 (Jones and Pons, 1998). The still-innervated representation of the face in the ventral posterior medial nucleus has extended to occupy the region formerly occupied by the representation of the arm and hand. Notably, the extended representation of the face is largely that region innervated by the mandibular branch of the trigeminal nerve. The mandibular nerve and the upper cervical segments are adjacent both in peripheral innervation zones and central representations. This expansion at the level of the ventrolateral posterior nucleus may have contributed significantly to the changes in the representational map in area 3b. Anatomical studies of monkeys who survived for 13–21 years after cervical and upper thoracic dorsal root

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Fig. 15–6 Left: Representational map of head and body in a frontal plane through the ventral posterior lateral and medial thalamic nuclei in a macaque monkey, obtained in several mapping studies. Italic type in VPM indicates ipsilateral representations of peri—and intraoral structures. Right: Result of a similar mapping study in the thalamus of a macaque 20 years after section of dorsal roots C2–T4. The normally innervated arm–hand area of VPL has disappeared after severe secondary transneuronal atrophy, with expansion of the lower face area into the previous hand area. VPL—ventral posterior lateral nucleus; VPM—ventral posterior medial nucleus. VPI—ventral posterior inferior nucleus; VMb—basal ventral medial nucleus; (From Jones, 2000a.)

sections central to the dorsal root ganglion revealed a severe atrophy of the dorsal column projections of those roots, a trans-neuronal atrophy of the neurons of the cuneate nucleus, and a secondary transneuronal atrophy of neurons in the former hand–arm area of the ventral posterior nucleus. It was surmised by the authors that this latter must have led to an atrophy or withdrawal of thalamocortical axons in the postcentral gyrus and a powerful deafferentation effect on cortical neurons (Woods et al., 2000).

Concluding Remarks The general conclusion from what has gone before is that peripheral de-afferentations of any type, or lesions of afferent somatic sensory pathways, lead to adaptive plastic changes through the somatic

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afferent system from the level of the dorsal horn to the postcentral gyrus, and, it is surmised, beyond. These changes are global and occur simultaneously at every level. They include dynamic changes in the excitatory–inhibitory interactions in somatic sensory synaptic networks, changes in the molecular and transmitter systems in every location, degeneration and trans-neuronal atrophies, and axonal sprouting with new synapse formation. These changes are cascaded in time, some appearing immediately after peripheral deafferentation; others are of slower onset but may progress for years. Changes in the central somatic afferent systems following peripheral de-afferentations or nerve injuries lead to devastating syndromes of pain of central origin, including both those produced by plastic alterations in the function of dorsal horn synaptic circuits, and the severe phantom pains, which may occur immediately or years after amputation, and appear to be related directly in severity to the degree of postcentral adaptive changes that follow many cases of limb amputation. Maladaptive changes are thought to contribute to some of the severe signs and symptoms of epilepsy, and other disorders of brain function. In contrast to these dire results of maladaptive plastic changes, some are thought to be of value; for example, in facilitating brain mechanisms compensating for injury, particularly in the recovery from vascular disorders that destroy local brain tissue. Major therapeutic efforts are directed at ways to channel and enhance this inherent recovery process. N OTES 1. As of July 18, 2004, PubMed lists 13,249 papers under the call “brain plasticity.” Of these, 4,023 refer to human brain plasticity, and 372 to monkey brain plasticity. Of the total, 1086 refer to visual cortex plasticity, 270 to auditory cortex plasticity, and 103 to tactile cortex plasticity. 2. In much of the literature on synaptic plasticity the presence of the subliminal surround is described by the term “hidden synapses.” Such a surround has been known and studied since Sherringtonian times, and in electrophysiological studies of the spinal cord; for example, in David Lloyd’s studies of synaptic actions in spinal cord reflexes.

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16

Haptic Sense as Substitute for Vision

I consider here the special function of the somatic afferent system as a set of channels over which the chronically blind can detect and recognize objects and events in the world around them. Many substitution systems have been devised for this purpose; in some the link of external signals to the skin is made directly without recoding and with no intervening stimulating device. These direct methods are among the most successful, particularly for skilled and long-trained users; for example, Tadoma, finger-spelling, and the haptic-tactile transmission of the manual postures and gestures of American Sign Language (ASL). Other methods make the linkage through mechanical devices such as vibratory stimulators, often with abstract re-coding. These modes of communication are of special interest in the present context, for highly skilled, blind individuals who achieve unusual capacities to process distributed and temporally dynamic, mechanical stimuli delivered to or haptically grasped by their hands illustrate the capacity for textural and form perception achieved by training of the somatic afferent system. The most widely used and successful of these is the Braille system.

Direct Haptic-Tactile Substitution Systems Tadoma Tadoma is a method based on the transfer of tactile and haptic signals directly from the face of a speaker to the hand of a reader. It was

developed in Sweden in the 1880s, mainly for deaf-blind individuals, and introduced to the United States in the 1930s (see Norton et al., 1977). The reader places his hand on the face of the speaker, his thumb across the lips and his fingers fanned out over the cheek or to the side of the neck. The hand is thus positioned to detect tactile, vibrational, and movement signals generated from the face, larynx, lips, and chin of the speaker—a set of multidimensional parallel signals. Exceptional deaf-blind individuals with many years of training in using Tadoma can comprehend continuous speech in the conversational mode, with significant but acceptable error rates. The method is quite similar to that developed independently by Helen Keller. Such cases demonstrate that it is possible to apprehend speech through the tactile-haptic sense alone, but the majority of deaf-blind subjects never reach that level, even after extensive training. Several schools for the blind adopted this method in the 1930s, but its use has since declined, and presently there are only a few dozen skilled Tadomists in the United States. Tadoma carries a social handicap, for few other than close friends will tolerate a hand to the face, and the method can scarcely be used in ordinary social intercourse. Tadoma is of theoretical interest, since its successful use shows that the mechanoreceptive afferents innervating the hand can transduce a useful fraction of speech signals and transmit them to central perceptive mechanisms over the somatic afferent system. For this reason a group of investigators at the MIT Research Laboratory of Electronics first identified the candidate information-carrying components of the signals generated by speaking that are transduced in Tadoma: lip movements, air movement through the mouth, jaw movements, and laryngeal vibrations, and then showed that specific features relate to particular physical properties. They showed that the tactile perception of the laryngeal vibrations of the neck is important for voicing perception, but that changes in tension in the neck muscles and airflow through the nose are redundant (Reed et al., 1982, 1985; Tan et al., 1989). The nine unexceptional, yet experienced, deaf-blind Tadomists in the study achieved reading rates of about 2.5 syllables/sec, half that of normal speech, with correct recognition of key words that varied from 48 percent to 85 percent for different subjects. Normal persons transiently deafened and blind-folded did as well after 100–300 hours of training. Tadoma transmission rates were significantly increased by adding secondary channels signaling tongue position or other speech cues delivered over tactile arrays to the non-reading hand.

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Direct Tactile-to-Tactile Transmission of American Sign Language An example of the level to which somatic sensory skills can be trained is given by the haptic-tactile transmission of ASL by some of those congenitally deaf who later in life became blind (Usher’s syndrome), after having learned ASL before they lost their vision. Transmission of ASL is direct, as it is in Tadoma, but differs in that words are coded abstractly as manual gestures and postures emitted by sending hands and received by direct contact with intertwining receiving hands. Oliver Sachs illustrated this form of communication between these individuals in his dramatic film of 1998. This mode of transmission is rapid and accurate for skilled readers. Reed et al. (1995) found an average of 87 percent correct recognition of isolated signs in a group of deaf-blind users of direct contact ASL. Bellugi and her colleagues described the phonetic, syntactic, and lexical-semantic structures of ASL and, confirming previous work of others, established that ASL is a formal language comparable in complexity and logical organization to spoken languages (Poizner et al., 1987). Bellugi et al. (1989) examined the emission and transmission deficiencies in 13 signers with large vascular lesions of the left hemisphere, inclusive of the speech areas, and in 10 signers with comparable lesions of the right hemisphere; all were right-handed. Those with left hemisphere lesions were aphasic for both signing and reception, comparable to the aphasia such lesions produce in previously normal subjects, and to the deep alexia for Braille that occurs in the blind after similar lesions. Subjects with right hemisphere lesions showed the expected disorders in spatial perception, but retained near-normal capacity for ASL transmission (Hickok et al., 1996, 1998a,b). The essential role of the classical language areas for ASL processing was shown by positron emission studies of differential cerebral blood flow during signing (Soderfeldt et al., 1994, 1997), and by the obliteration of signing by left but not right carotid artery Amytyl injection (Damasio et al., 1986). These observations are of general importance, for when combined with Braille alexia, and the alexia of otherwise normal individuals with left-sided lesions, they support the growing consensus that the distributed language systems of the left hemisphere are modality independent, and are accessible over visual, auditory, or somatic sensory afferent channels carrying activity leading to the construction of language (Grossi et al., 1996).

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Functional magnetic resonant imaging of the brains of naive ASL signers working in ASL, in both hearing and deaf subjects, shows an invariant activation of the language systems of the left hemisphere during signing (Bavelier et al., 1998; Neville et al., 1998). A more variable activation of the comparable areas of the right hemisphere suggests that it may play an important role in ASL, as well as in its spatial perceptive functions. The role of the right hemisphere in ASL processing is not an essential one, for vascular lesions there do not disrupt ASL operations.

Direct Tactile-to-Tactile Transmission in Finger-Spelling Finger-spelling is a mode of tactile communication used by the deafblind in which the hand of the reader is placed within or upon the hand of the sender to monitor, by direct palpation, the successive shapes of the sender’s handshapes, which are abstract codes for letters. Each letter of the alphabet is associated with a unique, generally static, nonisomorphic, handshape. The rates of transmission and the levels of accuracy achieved by deaf-blind finger-spellers are comparable to those of average users of Tadoma or by tactile-to-tactile readers of ASL (Reed et al., 1995). The average rates of reading achieved in these three methods of direct transmission are from one third to one half that of slow, consecutive speech. Some exceptionally skilled subjects in each group do much better. Transmission rates in ASL and finger-spelling are limited on the output side, for the motor system can generate successively different output patterns in movements and postures of the hand at no more than about 5/sec.

Indirect Haptic-Tactile Substitutions: The Braille System Braille is the most successful and widely used of sensory substitution systems. The physical parameters of the Braille dot-pattern are well suited to the response characteristics of the slowly adapting mechanoreceptive afferents innervating the glabrous skin of the finger tips. There is some evidence that prolonged training in reading Braille produces plastic changes in the neuronal microstructure at central levels of the somatic afferent system, including increments in the areas of the precentral and postcentral gyri devoted to the motor and sensory representations of the trained fingers. This enlargement observed in some but not all studies is attributed to

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plasticity in the cortical microstructure, and to account for the increased tactile capacity of trained Braille readers (Chapter 15). Skilled, blind Braillists have only a small or no greater tactile capacity than do the sighted, when that capacity is measured by standard tests of threshold (Grant et al., 2000). Thresholds for discrimination of the orientations of grids of different groove widths are a bit lower in trained Braillists than in sighted individuals: 0.80 mm versus 1.46 mm. Threshold on the reading finger was similarly lower than that on adjacent fingers of the reading hand (Van Boven et al., 2000). Braille reading requires the conversion of textural mechanical stimuli into neural transforms of those images; it is a pattern recognition task in which small scale, two-dimensional patterns must be identified and discriminated from each other. The method involves the generation by coded, embossed dot patterns, each standing for a letter or number, of distributed afferent signals in the population of slowly adapting SA1 afferent nerve fibers innervating the glabrous skin of the finger tip, the Merkel afferents, described in Chapter 11 (Johnson and Lamb, 1981; Phillips et al., 1990, 1992). A nearly isomorphic replication of those first-order afferent patterns appears in the evoked activity of neurons at the first synaptic transfer in the postcentral gyrus, from which the lexical and semantic properties are extracted (Phillips et al., 1988). The system was devised by Louis Braille at the age of 15 years (he was blinded at the age of 3); and a description was published by him in 1829, when he was only 20. A recent historical study revealed a much earlier method of which Braille could not have known, a system of reading embossed letters carved in wood used by the blind Alexandrine philosopher, Didymus (313–398 A.D.) (Lascartos and Marketos, 1994). Undoubtedly many such systems were tried before and after Didymus, and such a system of embossed letters was used in the blind school of Paris when Braille entered there at the age of 10. Braille learned that a former military officer, Charles Barbier, had devised a method for night communication in battle by a code of 12 dots embossed on cardboard and had suggested that this method might benefit blind students. Braille reduced the 12 dot code to 6 and quickly developed this system into his own.

Braille Type Each Braille cell contains up to 6 bosses (dots) which yield the factorial limit of 64 different patterns; the empty set is used to separate

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words. The dots are arranged in two vertical rows of three each, 1–3 on the left and 4–6 on the right (Fig. 16–1). The standard specifications for Braille type are these: interdot distance, 2.28 mm, well above the human threshold of 0.7–0.9 mm on the finger tip; dot-todot between adjacent cells, 6.35 mm; dot-to-dot interline distance, 10.16 mm. The heights of the dots vary between 0.38 mm and 0.51 mm in different printing materials. These values are close to those originally proposed by Braille, and have been shown in a number of studies to be nearly optimal in terms of dot spacing and height. Like printed text, the Braille cells are arranged in lines to be read from left to right, and lines are sequenced from top to bottom on the page. The first 10 letters of the alphabet are formed with spatial arrangements of dots 1, 2, 4, and 5. When preceded by the Braille code for number, these cells have numerical values from 0 through 9. Other configurations signal the remaining letters of the alphabet, five common short words, a number of common letter combinations, punctuation marks, and some special modifiers, for

Fig. 16–1 Illustration of the Braille alphabet, followed by several single character constructions, each of which stands for more than one letter in English Braille. Each Braille cell is derived from a six (2 × 3) dot matrix; the dots are about 1 mm in diameter and spaced at 1.5-mm intervals. A Braille cell is 6.3 mm high. The Braille pattern is near the limit of human tactile acuity on the fingertips—which Braille could only have known by empirical test when he devised the type that goes by his name. (From S Millar, 1997.)

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example, the capital sign, the italic sign, and so forth. The Braille cell is also used in other codes with other meanings; a Braille code for mathematical and scientific notation is widely used, and there is another with notations for music. Later versions of Braille (Braille II and III) use contracted forms in which single cells represent frequently used words or letter sequences, yielding 256 combinations of Braille cell meanings. Most fluent Braille readers use these contracted forms of Braille.

Manual Operations in Reading Braille Skilled Braillists commonly read with two hands, and do so more rapidly with two than with either hand alone. The pattern of twohanded reading varies over a wide range between subjects, tasks, and reading skills. The photographic studies of Millar (1997) show that for many two-handed readers, when one reading finger is passing through the reading zone over an embossed letter the second finger is most often over an inter-letter or inter-word space, obtaining spatial rather than textural information; for example, in identifying word spaces, maintaining type alignment, or identifying the start of the next line. Although two hands are used in this mode, only one transposes textural information. At the other extreme are highly skilled Braillists who do read with two hands, each reading different zones of the type line; for at least a portion of each line the two fingers are reading simultaneously, and the two hemispheres are processing different textural information simultaneously (Bertelson et al., 1985). The essential feature of Braille reading is movement; palpation with a stationary finger of each succeeding cell yields a very slow rate of reading. Normally the reading finger moves swiftly and smoothly along a line of type with occasional pauses and recursions to resolve uncertainties (Fig. 16–2). This smooth movement of the reading finger converts the static spatial forms of the Braille cells into a spatiotemporal, dynamically changing pattern, evoking a similarly dynamic, spatiotemporal pattern of afferent nerve impulses in the cutaneous mechanoreceptive afferents. Blind children frequently read with the left hand when training begins, but hand preference varies greatly between trained adults and in different reading tasks. Earlier supposition that a left hand, right hemisphere superiority might be prevalent is apparently not true (Bradshaw et al., 1982). There is modest superiority of the right

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Fig. 16–2 Horizontal and vertical hand positions recording during reading of embossed Braille, constrained to use of one hand. The records were made during the reading of four successive lines. Reading of each line is followed by an abrupt rightto-left movement changing the line. These regressions were accompanied by smaller deflections. (From Hislop et al., 1985.)

hand-left hemisphere channel when the task undertaken requires linguistic in comparison to perceptual without linguistic identifications (Semenza et al., 1996), as would be predicted from the linguistic functions of the left hemisphere. Learning to read Braille is a difficult task that, for some individuals, requires several years of training. It is especially difficult for the elderly blind, perhaps because of the decrease in the mechanoreceptive innervation density of their distal finger pads (Stevens and Cruz, 1996). Reading ability decreases rapidly as one moves from finger to finger away from the preferred reading finger, and reading ability is not readily transferred to a contralateral, untrained hand. This emphasizes the difficulty of Braille; simpler tasks such as vibration frequency discrimination are transferred quickly from finger to finger and hemisphere to hemisphere in humans, and with a single days’ transfer training in monkeys working in similar tasks.

Speed of Reading Braille Reading rates vary between different Braillists, in terms of the duration of their training and practice, the difficulty of the text read, and

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the level of education and cognitive capacity of the reader (Nolan and Kederis, 1969). Trained Braillists read uncontracted Braille at rates in the range of 60–100 words per minute (Millar, 1997). Skilled Braillists may double this rate when reading contracted Braille II or III. Observations of the rapid, smooth hand traces of skilled Braillists indicate that they are extracting complex, discontinuous signals from a rapid but intermittent stream of separate and different tactile stimuli. The rapid pass of the reading finger over the Braille type, occasionally interrupted by corrective recursions, evokes a different spatial pattern of afferent discharge for each cell, most likely in the Merkel class of slowly adapting afferents innervating the skin (Chapters 5 and 11), and, in turn, a cortical neuronal image reflecting the spatial distribution of the bosses in each Braille cell. Even given the different sequential probabilities of letters, and of word predictability in English, this leaves approximately 75–100 msec for each central perceptual operation for skilled braillists (Davidson et al., 1992). The inferences are several. First, the nodes of the distributed somatic cortical system must be activated nearly simultaneously by each brief burst of impulses relayed from skin to cortex. Second, the time allows only a few impulses for each intracortical operation. Third, that processing must be carried out in the distributed population activity, not in a serial order from place to place. Fourth, the sustained discharge of the first order mechanoreceptive afferents to sustained mechanical stimuli is irrelevant for this operation: only the onset transient counts. A limiting factor in reading Braille rapidly is that the successive textural patterns are not related to one another in any coherent manner, so that the spatiotemporal patterns of neural activity evoked by successive cells cannot be integrated in time; each must be read independently.

Global Pattern or Textural Processing? Two hypotheses have been proposed to explain the perceptual mechanisms in fluent Braille reading: (1) that each successive cell is read in sequence for its texture, the spatial distribution of its embossed dots (Millar, 1997) or (2) that Braillists perceive the global outline shape of the embossed points, not the textural dot pattern itself (Loomis, 1981; but see Loomis, 1993). The idea that Braille is read in terms of spatial contours may derive from the monograph of Burklen (1932), perhaps based on gestaltist ideas. The question

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concerns the higher order perceptual mechanisms, for there is little doubt that Braille dot patterns delivered to the glabrous skin of the finger pads of humans and monkeys at Braille-reading speeds evoke in the slowly adapting type I (SA-I) mechanoreceptive afferent fibers veridical neural images of the dot distributions themselves. These isomorphic images are transmitted into the discharge patterns of neurons in the primary somatic sensory cortex of the monkey postcentral gyrus. These hypotheses have been tested in a number of experiments (Heller, 1987; Millar, 1997). The results indicate that rapid Braille reading depends on lateral dot-density scanning for texture. Both rapid and slow readers of Braille were faster and more accurate in judging identical pairs in the dot-pattern format than in global outlines (Millar, 1985). In another experiment, Millar rotated the Braille type 90 degrees, and asked braillists to read from near to far. This caused a slowing in reading rate, interpreted as a disruption of serial textural reading, and not compatible with the global reading hypothesis. Braillists were then allowed to rotate their reading hands 90 degrees, so that the type was read in the usual normal spatial relation of the finger to the line of type. There was no reduction in speed or accuracy of reading, in spite of the changed global spatial arrangement of arm and hand. Millar then degraded a few randomly chosen bosses in the braille type, and this too resulted in slowing and errors of reading, thought not predictable on the global outline hypothesis (Millar, 1987). The evidence from these experiments, and from those of Heller and his associates (Heller, 1989), tend to support the serial texture reading hypothesis. Reading styles and methods vary greatly between individuals, and it may be that global outline reading is used under some task and reading circumstances, perhaps when identifying single letters. However, Nolan and Kederis (1969) observed that a tendency of some Braille students to perceive the Braille cells as contours rather than as textures was the single greatest source of errors in character recognition, perhaps because the texture of a Braille cell may be interpreted as more than one contour, and a single contour may fit more than one Braille cell.

Peripheral Neural Mechanisms in Braille Reading Humans resolve the spatial structure of the discharge patterns of impulses evoked by each successive Braille cell while reading at rates up to 100 words per minute. The primary afferent population responsible

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for conveying the relevant information must resolve the spatial patterns of impulses evoked by individual dots separated by 2.3 mm as the Braille cells are scanned by the finger tip at rates of about 60 mm/sec. A reconstructed population response based on the study of a typical SA-I afferent fiber innervating the glabrous skin of a human finger tip to Braille characters scanned at 60 mm/sec is shown in Fig. 11–19. It can be seen there that the individual dots are resolved very well. The spatial distribution of impulses evoked by single Braille dots are ovoids in neural space measuring 1.6 × 3.5 mm in skin space (4.4 mm2 area; the average for SA-I afferents is 4.5 mm2; Johnson and Lamb, 1981). The “response area” reflects the afferent fiber’s spatial, not its temporal, response properties. That spatial response profile is unaffected over the scanning speed range from 20 up to at least 120 mm/sec, for both the SA-I afferents and their postcentral targets. During Braille reading, the cortical processing mechanisms beyond the postcentral gyrus operate on discrete bursts of impulses in distributed spatial arrays of neurons, evoked by each successive Braille cell. Even at the most rapid moving finger speed of skilled braillists, there is no interference between the neural activities evoked by consecutive Braille cells (Johnson and Lamb, 1981; Phillips et al., 1992; DiCarlo et al., 1998; DiCarlo and Johnson, 1999). One factor that might contribute to the limit on reading speed is dispersion in the conduction times between different fibers in the responding population over the path from the fingertip to the dorsal column nuclei. If the conduction delays in the activated population are dispersed over 10 msec, the spatial images of neural activity ranging over that 10 msec period could be partially superimposed, and thus blur, the spatial neural image of individual Braille cells. A best estimate of the SA-I conduction dispersion from skin to dorsal column nuclei is about 8 msec. Thus the SA-I population provides a robust neural image of the individual dots over the range of human Braille reading rates.

Cortical Operations in Reading Braille I described in Chapter 11 the isomorphic replication of the pattern of embossed dots of Braille cells in the discharge patterns of the first order afferent fibers innervating the hand in both monkeys and humans, when Braille type is used to stimulate the glabrous skin. Those

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patterns of neural activity are projected to and evoke complex representations of the patterns of Braille dots in the activity of neurons of area 3b of the postcentral gyrus in monkeys. Similar patterns of activity are assumed to occur in the postcentral neurons of humans when they read Braille. The results of the electrophysiological experiments suggest that the central processing networks beyond the postcentral gyrus operate upon discrete bursts of impulses in a distributed population of neurons, and that at the usual reading speeds of skilled Braillists there is no interference by the activity evoked by successive Braille cells. However, there is no direct evidence that such patterns, if they occur in the responses of somatic sensory cortical neurons, are necessary and sufficient for Braille reading. No case has been described in which the effects upon reading by a lesion limited to the postcentral gyrus has been studied in a skilled Braillist. It remains open whether areas outside the postcentral gyrus, such as the second somatic area or in posterior parietal cortex, might receive this same input in parallel and be sufficient for the function of Braille reading independently of area 3b of the postcentral gyrus, although this seems unlikely. Dense Braille alexia produced by vascular lesions of the left hemisphere suggest that the semantic and lexical operations of Braille reading engage the cortical systems essential for reading and understanding language by the sighted. Signoret et al. (1987) studied a 77-years old musician blinded at 2 years, who presented with a Wernicke’s aphasia and alexia for Braille following a vascular accident involving the left middle cerebral artery. This accomplished musician and composer continued to perform on the organ and to compose music in the midst of his dense Braille alexia. The symbols of Braille type for music are similar to those for language; only jargon results when read as if for language without the preceding cue for music. This man retained the capacity to encode and process neural signals evoked by Braille type, and to interpret them rapidly and correctly in the context of music, not that of language. Birchmeir (1985) studied a congenitally blind, skilled Braillist who, after a left middle cerebral artery accident, presented with a dense Wernicke’s aphasia and alexia for Braille. This man was more defective in reading standard than in reading contracted Braille. He retained all his pre-lesion motor skills for Braille reading. Although the lesioned areas of the cortex of the left hemispheres in these two cases were not defined precisely, there is little doubt that they included the

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classical areas of the temporal and parietal lobes essential for language comprehension. These observations combine with many others to suggest that these areas are engaged by the afferent input from any one of the three major afferent channels that can transmit information for language: the visual, auditory, the somatic sensory system. It has been shown with a number of methods that the area of representation of the contralateral reading finger in the sensory–motor cortex of skilled Braillists is enlarged by a significant amount (PascualLeone and Torres, 1993), and sometimes disordered (Sterr et al., 1998). A similar enlargement occurs in the postcentral finger area, contralateral to the fingering hand, in players of stringed instruments (Elbert et al., 1995). These changes have been interpreted as use-dependent reorganizations, in the style described in Chapter 15. Transcranial electromagnetic stimulation of the precentral motor cortex revealed an increased representation of the first dorsal interosseus muscle of the Braille reading hand, which controls many of the movements of the forefinger in reading Braille, and a decrease in the representation of a muscle active at the far side of the hand, the abductor digiti quinti, perhaps a victim of expansion pressure from the forefinger muscles. The change in motor representation subsides slowly over hours or days after an intensive reading session (Pascual-Leone et al., 1993, 1995, 1999). How these changes enable the use of previously learned skills, using the restricted sensory–motor loop from and to the Braille reading finger, remains as mysterious as do the mechanisms of any other use/disuse-dependent instance of cortical reorganization. Braille reading involves the interpretation of the quasi-isomorphic representations of the textural properties of the Braille cell in the postcentral sensory cortex, and then the projection-transformation of that pattern of activity into others within the distributed systems that construct lexical and semantic information. It is not surprising, then, that the cortical areas of the posterior parietal lobe are activated by the spatial perceptual requirements of Braille reading, as well as the cortical areas essential for the reception of language in the Wernicke and nearWernicke areas in the superior temporal gyrus. This activation is reciprocal to the Braille alexia produced by lesions in these areas, described above. The language areas essential for visual and auditory, and it is presumed also the somatic sensory, avenues to lexical and semantic processing are located in the left superior temporal gyrus, where they may be closely adjacent (Howard et al., 1992).

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Measurements of increments in cerebral blood flow (interpreted as “activations”) in early blind subjects reading Braille with their right forefingers revealed an unexpectedly large number and wide distribution of activated areas, as follows: bilaterally, the primary sensory and motor areas, ventral premotor areas, inferior and superior parietal lobules, primary visual cortices, superior orbital gyri, and the fusiform gyri; ipsilaterally, the dorsal premotor area, middle occipital gyrus, and the premotor area (Sadato et al., 1996, 1998). What was unexpected was the activation of the visual areas of the occipital lobe, an observation documented in a number of experiments with both blood flow (Buchel et al., 1998; Burton et al., 2002, 2003; Burton, 2003) and electrophysiological methods (Uhl et al., 1991; Roder et al., 1996). The occipital regions are also activated in the blind working in auditory discrimination tasks, but to a more restricted extent than when they work in tactile tasks (Kujala et al., 1995; Buchel et al., 1998). There is a robust activation of the occipital cortex, including V1, in the congenitally blind when they work in a verbal memory task, at which they are superior to the sighted (Burton et al., 2002; Amedi et al., 2003). These activations of occipital areas do not occur in the sighted when they work in somatic sensory or auditory discrimination tasks, although Sathian et al. (1997) observed that adjacent parts of the superior occipital gyri and parietal cortex are activated in sighted individuals working in a tactile orientation task. The macrostructure of the visual cortical areas appears to be normal in the long-term blind (Kujala et al., 1995), which fits with the findings of Rakic (1991) and Dehay et al. (1991) that a decrease in size of the visual cortex follows eye removal only if the enucleation is made early in the monkey’s embryonic life; eye removal even in the newborn leaves unchanged the development of a normal visual cortex. Further, glucose metabolism in the visual cortical areas in the longblinded is normal or elevated, but decreased in those with blindness of late onset (Wanet-Defalque, et al., 1988; Veraart et al., 1990; De Volder et al., 1997). The primary visual cortex V1 is activated in the late blind when they execute tactile tasks. Burton et al. (2002) compared the adaptive changes in the cerebral cortex in nine congenitally blind and seven late-onset blind subjects reading Braille, measured with fMRI. They observed robust activations of virtually all visual areas previously identified in sighted humans, and that these activations were greater in the congenitally blind than in the lateonset blind. Contrary to earlier descriptions, Burton et al. (2002) did

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not observe any expansion in the representation of the reading fingers in either sensory or motor cortex.

Does the Visual Cortical System Play an Essential Role in Reading Braille? How are we to interpret these wholly unpredictable findings? Activation of the visual cortical areas in the late-blinded, who have had several years of visual experience before losing sight, might be explained as a sign of the persisting capacity for visual imagery. These areas are activated when the sighted image visually, in the dark (Le Bihan et al., 1993; Kosslyn et al., 1995). Several of the late-blinded subjects studied by Buchel et al. (1998) reported that they imaged visually when reading Braille, and one subject stated that she first imaged the texture of the Braille cell tactually, and then superimposed upon it a visual image of the related letter of the alphabet! It is unlikely that visual imagery can explain the activation of the visual cortical areas in the congenitally blind when they read Braille, for they have no previous visual experience and thus may not image visually. It has been suggested that activation of the occipital visual areas in the blind when they engage in haptic tasks is evidence of the participation of those areas directly in somatosensory neuronal processing. This idea is supported by the finding of Cohen et al. (1997) that electromagnetic trans-cranial stimulation of these areas disrupts Braille reading. However, stimulation of the visual cortical areas slows Braille reading only minimally, a drop from about 72 to 60 words per minute in the experiments of Pascual-Leone et al. (1999), who also observed that more rapid stimulation of the visual areas, at 10/sec, facilitated Braille reading, with an increase from about 72 to 90 words per minute. These observations suggest that the prestriate cortical areas are actively engaged in the cortical mechanisms of Braille reading. How and over what pathways this might be effected is unknown. One candidate is that somatosensory systems capture the pulvinar–cortical projections to the prestriate areas that are known to function in some aspects of spatial perception. An alternative hypothesis has been suggested by Roder et al. (1997), based on studies of the slow electrical events recorded from the surfaces of the heads in sighted and congenitally blinded subjects as they worked in a haptic rotation task, and in a somatic sensory discrimination task (Roder et al., 1996). That is, that the occipital

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extension of the electrical events accompanying the task in the blind, as compared with the lack of that extension in the sighted, may represent the spread of a nonspecific activation accompanying modality specific processing in other regions, for example, the parietal lobe, initiated by thalamocortical activation of visual cortical areas in which inhibitory mechanisms are depressed by long-term visual deprivation. The question remains unsettled.

Indirect Systems Accessing the Vibratory Afferent Channels Many efforts have been made to create substitutions for vision by translating the relevant information signals into patterns of vibratory stimuli delivered over distributed arrays of small mechanical stimulators placed against the skin. There are two classes of these devices: those in which the external objects are translated pictorially into the pattern of vibratory stimulation, and those in which the text or the surround is presented abstractly, coded in combinations of the locations, intensities, frequencies, and spatial temporal orders of the vibratory stimuli.

A Pictorial System: The Optacon The most intensively studied of the pictorial class is the Optacon. This direct reading aid for the blind converts printed text to spatially distributed vibrotactile images that are applied to the finger pad (Linvill and Bliss, 1966; Bliss et al., 1970; Craig and Sherrick, 1982). The Optacon consists of a hand-held camera unit containing a 6 × 24 array of photosensitive devices, each linked to one of an array of 6 × 24 mechanical stimulators arranged in a 1.1 × 2 .7 cm space. The spatial intervals between the rows of stimulator probes are only slightly above the spatial difference limen for touch on the human finger tip. Each of the small tactile probes is activated by darkness beneath its related photodetector, and then vibrates at 230 Hz. Observers seek a comfortable finger pressure upon the tactile array, well above the force thresholds. Although a few exceptional subjects reach high reading rates (Craig, 1977), those achieved by blind readers after 50 hours of practice are low (20–30 words/min), compared with those of Braillists. Nevertheless, the advantage of reading printed type is obvious. From a promising beginning in which several thousand instruments were delivered to blind users, the Optacon has

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fallen into disuse, perhaps because of the slow rate of reading. The reading speed is limited by powerful metacontrast effects, particularly backward masking. A major factor limiting the speed of reading, however, may be its mismatch to the functional properties of the sets of primary afferents innervating the glabrous skin. The Optacon optimally activates the quickly adapting Meisser and/or Pacinian afferents, while it is clear that it is the slowly adapting Merkel afferents that are the optimal channels for textural perception (see Chapter 11). The Optacon has been of value in psychophysical studies of masking, response competition, and attention in studies of vibrotactile sensibility (Craig, 1983, 1995; Craig and Rollman, 1999).

Dynamic Spectral Displays with Abstract Coding The direct methods described above for substituting the cutaneous afferents for the visual system show that the somatic system can function adequately in this way, even if slowly. However, each of the methods described requires direct physical contact between sender and receiver which limits usefulness in social intercourse and in the workplace; for a review of earlier work, see Kirman (1973). It has long been the objective of those working in this field to access the cutaneous afferent system from a distance by direct recording of visual signals by instruments carried by the receiver, thus freeing both sender and receiver. The recent development of vocorders as tactual aids for the deaf suggests this may soon be possible for the blind. Vocorders receive speech and other auditory signals from the environment, transform their spectral ranges to the low-frequency range of cutaneous afferents (10–300 HZ), divide the result into separate bands and deliver each to an independent mechanical stimulator placed on the skin. This is of considerable aid to the deaf in speech reading (see Summers, 1992 for reviews); and efforts are underway to achieve a visual to tactile translation (Way and Barner, 1997a,b). A significant advance has been made in delivering spatial arrays of mechanical stimuli to the hand, taking advantage of its dense innervation and highly developed somatic sensory capacity, Tan et al. (1999) tested a mechanical device for delivering both kinesthetic and cutaneous vibratory stimuli to three fingers of the hand. They measured an information flow rate of about 12 bits/sec when subjects were tested in a simple identification task. What remains to be done

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is to link such a device to local receivers of telemetered transforms of speech or the visual scene to achieve the goal of transmission to the untethered deaf and blind.

The Spatial Perception of the Blind I summarized in the Chapter 14 the evidence that the haptic sense contributes to the generation of internal schemata of the body image and of immediately surrounding space. Many congenitally blind individuals can perceive though the haptic sense the forms and spatial relations between objects within the space defined by reach of arm and hand, including the forms of their own bodies (Hollins and Kelly, 1988; Millar, 1994). Their performances are, in many cases, only marginally inferior to those of the late-blinded, who have visual experience before losing sight, or of blind-folded, sighted subjects (Thinus-Blanc and Gaunet, 1997). (1) They replicate from memory the spatial layout of several objects placed before them (Gaunet et al., 1997); and do so even after the object array is rotated with respect to the subject, or the subject moved around the array (Ungar et al., 1995). (2) The congenitally blind can generate spatial images of tasks laid out in both two- and three-dimensional space, and solve the tasks of position remembrance and pathway following within them, although they perform less well than do the sighted (Vecchi, 1998). (3) They identify from memory the shapes of objects small enough to be explored by the hand, and recognize raised outline pictures by haptic exploration as well as or better than do the blindfolded sighted (D’Angiulli et al., 1998). (4) They discriminate between objects of different sizes and shapes. (5) they can explore and then replicate with drawings raised edge images of objects, animals, or geographical maps, and spontaneously create recognizable drawings (Heller, 1989; Heller and Kennedy, 1990; Kennedy, 1993; Shimizu et al., 1993; Heller et al., 1996). For an historical review of the use of raised edge drawings, relief pictures, and topographical maps in the education of the blind, see Erikson (1998). Many blind become adept in the perception of a wider spatial surround by tools grasped by the hand, for example, in discriminating between the heights of objects by long cane exploration the congenitally blind surpass the performance of blind-folded sighted subjects (Sunanto and Nakata, 1998). Some of the congenitally blind achieve an appreciation of even larger zones of space, and make their way in

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houses, streets, and pathways. However the congenitally blinded do less well than do the late-blind or the sighted after brief exposure to a landmarked area in locomotor space (Veraart and Wanet-Defalque, 1987; Gaunet and Thinus-Blanc, 1996). It is conjectured that the congenitally blind construct through their haptic and auditory senses central neural images of various surrounding spaces, just as we imagine the sighted do through a combination of haptic, auditory, and— predominantly—visual senses. These images are called schemata (“the body schema”), or models, by which is meant functional models embedded in the microstructure and dynamic activity of central neural systems (Arbib, 1989). The central schemata of surrounding space generated through the haptic and visual senses are not identical, differing in neural location and perhaps in mechanism. Marks and Armstrong (1994) showed that the non-isomorphic relationship between verticals and horizontals within the central images of haptic and spatial illusions can be modified (in their term, “recalibrated”) by independent training; one could be changed without affecting the other. This suggests that these two neuronal schemata are to some degree separate in neural location, and perhaps in mechanisms as well.

“Facial Vision” in the Blind: The Use of Reflected Sound The adaptive training of sensory systems in the blind includes what is called “facial vision,” used by some blind to identify the presence of structures in their environment—walls, furniture, and so forth. Villey (1930) described the case of a blind subject who could detect accurately the place where books on a shelf stopped and the empty shelf continued, as he walked close by the shelf. It is now certain that the blind use sound reflection to construct their view of the objects surrounding them, for they lose this capacity in a sound-free environment. They use the ambient noise, and not a reflection of any sound created by themselves. Many blind report that they rely heavily on this auditory sensing when moving out of doors.

The Art of the Blind Opinion is divided over whether the chronically blind achieve an esthetic sense of their surrounding space and the structures within it, and can represent them at an artistic level. Revesz (1950) concluded

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that is true only in exceptional cases like that of the blind sculptor, Masuelli. Figure 16–3 shows the successive stages as Masuelli modeled the head of a young girl on four successive days, in Revesc’s presence. Figure 16–4 shows one of Masuelli’s statues, surely an enchanting work of art. This blind artist’s mode of working is an elegant example of the combined capacities of haptic memory and imagination, and the sensory–motor functions of the hands. Masuelli was trained as a sculptor before loss of sight, yet it took many years of effort to achieve results like those illustrated. He asserted that he had no visual conception of a work either before or after its

Fig. 16–3 Photographs of a sculpture made in successive stages by the blind sculptor Masuelli over a period of three days, Upper left, 90 minutes after start; upper right, 15 minutes after start on the second day; and, lower left, during the second day; lower right, after three hours intensive work on the third day. Masuelli had been blind for 14 years before beginning work as a sculptor. These figures were made in the presence of the Belgian psychologist, Revesz. (From Revesz, 1950.)

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Fig. 16–4 Photograph of one of Masuelli’s sculptures. (From Revesz, 1950.)

execution, but the pervasive influence of his previous visual world seems apparent in the excellence and symmetry of his work, executed only with somesthetic input from and motor output to the shaping hands.

What Do the Long-Blinded See When Sight Is Restored? The question of how the blind achieve internal images of surrounding space and objects within it initiated a crescendo of interest at the turn of the eighteenth century when it first became possible to remove cataracts from the eyes of those blinded by them from birth or early childhood, and thus, it was thought, to “restore” vision. This was seized as an opportunity to test the opposing views of empiricism and rationalism that preoccupied the intellectual world at the time, specifically, whether the internal constructs of surrounding space are given innately by the structure and function of the brain, or whether they are developed through experience of the external world. Although this question was not ignored in ancient times, interest was galvanized in the early eighteenth century as much as anything else by a question put to the philosopher John Locke by Mr. Molyneaux of Dublin: Would a man blinded from birth be able, with restored vision, to discriminate between threedimensional objects; e.g., between a sphere and a cube, with which he was familiar from his tactile experience when blind (see, Morgan, 1977, Molyneaux’s Question)? Both Molyneaux and Locke answered no, as did other leading philosophers of the enlightenment (for Locke’s answer, see Locke, 1690; 1959, Vol. 2, pp. 186–187). The question became one of intense debate between the empiricists and the rationalists; see Diderot (1749) A Letter on the Blind for Those Who Can See. Cataract displacements were carried out in England and France, sometimes before assembled audiences! The results obtained in these and many other cases since then are considered to provide evidence in favor of the empiricist hypothesis, for the newly “sighted” individuals can see very little at first, and cannot make spatial identifications and discriminations. The cases described up until 1930 were collected by von Senden (1932, 1960). In the majority of these individuals, “restoration of vision” after long-term blindness did not result in useful vision. Observations made in the eighteenth century have been confirmed in principle in these and several later studies, but many are compromised by the fact that no

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descriptions of the states of the newly exposed retinae are available. The perfect case for such a study has not been described, and probably will never occur: the restoration of vision in a congenitally blind person proven to have an intact and normally functioning visual system. It appears unlikely, for this reason, that the philosophical question can be settled by study of these patients. It is common, however, for individuals blinded by cataracts late in life, after many years of visual experience, to display virtually normal visual competence when their cataracts are replaced by implanted artificial lenses. It is assumed that their visual systems were fully “trained” during their years of normal sight, and to have remained functionally intact during the period of blindness. They lend little weight one way or the other to the empirical–rationalism debate. Perhaps this old controversy should now be put aside. We know from a century of study of the development and mature state of the primate brain that its gross structure, the arrangement of its pathways, nuclei, and areas, and the detailed microstructure within them, sets limits on the range of brain operational modes. These limits are set innately. Studies of plasticity, like those described for the somesthetic system in Chapter 15, suggest that the changes in microconnectivity occurring in development or induced by life experience or intensive training, occur within certain limits. For the primary motor and sensory areas, these occur within the connectivity range of relatively small sets of neurons. There are exceptions in which a drastic change in the input to the nervous system has induced grosser changes. However, we know virtually nothing about the degree of change in microconnectivity or in processing mode that may be induced by experience in the distributed systems of the homotypical cortex. Many neuroscientists conjecture that plastic alterations in these systems may be much greater, or of a different nature, than those observed in sensory and motor cortices, but there is presently no direct experimental evidence that this is so. Millar (1994) put the case forcibly that there is truth in both the empirical and rational positions, that further argument over the matter is futile, and that it is often not possible to make a clear, empirically based, decision about whether a given brain competence is innate or acquired, or indeed— as frequently seems to be the case—is partly both. Immediately after the restoration of vision, long-blinded individuals—with rare exceptions—cannot recognize objects or the spatial relations between them. This imperception for space and distance

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may last for months or even years. What is of special interest in the context of haptic sensibility is that the cases of Gregory and Wallace (1963), of Sachs (1995), and of Valvo (1971) provide evidence for a transfer of knowledge from the haptic to the visual domain. Each subject had been trained when blind to recognize by palpation capital letters carved on raised blocks. Immediately after the restoration of what was otherwise a low level of visual competence, each of these subjects recognized by vision capital letters carved on raised blocks, but not lower case letters, which were learned only after further training. This is taken to indicate that the haptically generated central schemata of objects had access to or overlapped the newly developing visual schema. Although the evidence from these and other cases supports the empiricist hypothesis, it is important to note that each of these subjects sensed and delighted in color immediately after the restoration of vision. Is it possible that the perception of color, but not other aspects of vision, is given innately by the structure and function of the visual brain? Many of the persons described by Senden (1932, 1960), Gregory and Wallace (1963), Valvo (1971), and Sachs (1995) suffered a sometimes devastating psychological and social stress attending the sudden transition from a familiar haptic world, in which they had learned to operate with confidence, to a visual world with which they were hitherto unfamiliar, and in which the essential, but newly exposed, afferent pathway functioned inadequately. Some of these individuals suffered severe depression, and some reverted to their former and more comfortable blinded life, as did the man described by Oliver Sachs.

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