A Triune Concept of the Brain and Behaviour: Hincks Memorial Lectures 9781487576752

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A TRIUNE CONCEPT OF THE BRAIN AND BEHAVIOUR

THE CLARENCE M. HINCKS MEMORIAL LECTURES, 1969

EDITED BY

T.J. BoagMo D. Campbell

PHO

A triune concept of the brain and behaviour BY

Paul D. MacLean

MD

Including PSYCHOLOGY OF MEMORY, and SLEEP AND DREAMING, papers presented at Queen's University, Kingston, Ontario, February 1969, by V.A.KRAL M. D. SUBOSKI A. MCGH1E J. INGLIS

R.BROUGHTON S.G. LAVERTY J.B. KNOWLES, E. J. BEAUMASTER, A. W. MACLEAN D. CAMPBELL, J. RAEBURN

Published for the Ontario Mental Health Foundation by University of Toronto Press

© University of Toronto Press 1973

Toronto and Buffalo Printed in Canada Reprinted in 2018 ISBN 0-8020-3299-0 ISBN 978-1-4875-7739-1 (paper) LC 72-90742

Contents

Foreword

vii

Clarence Meredith Hincks, 1885-1964

ix

Preface

xi

PART O"NE

Clarence M Hincks Memorial Lectures, 1969 DR PAUL D. MACLEAN , Hincks Memorial Lecturer, 1969

Introduction 1 Man's Reptilian and Limbic Inheritance 2 Man's Limbic Brain and the Psychoses 3 New Trends in Man's Evolution Bibliography PART TWO

Contributors 4 5 6 7

Psychology of Memory The Organic Amnesias/ v .A. KRAL Recent Developments in Memory Consolidation Theory/ M.D. SUBOSKI Input Dysfunction in Schizophren ia/ A. MCGHIE Similarities in the Side-Effects of ECT and Temporal Lobectomy in Man/ J . INGLIS

Sleep and Dreaming 8 Confusional Sleep Disorders: Interrelationship with Memory Consolidation and Retrieval in Sleep / R. BROUGHTON

2 4 6 23 42 61

68 69 81 88 99

115

9 Sleep Disorders and Delirium Associated with the Use of Ethanol/ s .G. LAVERTY 10 The Function of Rapid Eye Movement Sleep and of Dreaming in the Adult/ J.B. KNOWLES, E.J . BEAUMASTER, A.W. MACLEAN

11 Patterns of Sleep in the Newborn/

D. CAMPBELL, J. RAEBURN

128

146 156

Foreword

In 1965 the Ontario Mental Health Foundation established a lectureship, named in honour of the late Clarence Meredith Hincks, to stimulate professional workers in the field of mental health. It was the aim of the Foundation to make it possible for those engaged in training and research to hear, and more particularly to associate informally with, persons of outstanding professional stature from other centres. In furtherance of this purpose the locale of the lectures was not to be fixed but was to move among the faculties of medicine of the universities of Ontario. The Foundation is pleased to present in this volume the second Clarence Meredith Hincks Memorial Lectures, held at Queen's University in February of 1969. The Lectures 'The Brain and Behaviour' were delivered by Dr Paul D. Maclean, Chief, Laboratory of Brain Evolution and Behavior, the National Institute of Mental Health, Bethesda, Maryland, USA. Papers presented by various other experts in the mental health field have been included. A. POSLUNS, SR

Chairman, The Ontario Mental Health Foundation

Clarence Meredith Hincks BA, MD, DSC, LLD

1885-1964

The development of psychiatry as a major medical speciality and the growth of public interest in the mental health movement in Canada are clearly associated with the career of Dr Hincks. After graduating from the University of Toronto Medical School in 1907 he entered general practice in Toronto and became a part-time medical officer in Toronto schools. This led to the development of his interest in the mental hygiene of children and to a voluntary post in the juvenile court. In I 9 I 4 he joined the newly-organized psychiatric out-patient clinic at the Toronto General Hospital. Here he came under the influence of Dr C.K. Clarke, at that time Professor of Psychiatry, Dean of Medicine, and Superintendent of the Hospital. With his blessing and the assistance of Clifford Beers in New York, Dr Hincks organized the Canadian National Committee for Mental Hygiene in 1918 (now the Canadian Mental Health Association). As its first Secretary and later its Medical Director, he planned and carried out a varied programme of activities which included surveys of mental hospitals, the development of special classes in schools and better institutional facilities for retarded children, and the psychiatric screening of immigrants coming to Canada. He was very successful in soliciting financial support from the great American foundations to assist in the development of psychiatric and psychological teaching and research in Canadian universities, and in many other ways he stimulated the establishment of high professional standards in the mental health field. In 1930 he accepted the post of Medical Director of the National Committee in New York and for the next eight years, throughout the depression, he managed to keep both the Canadian and the American organizations solvent and usefully busy. During this time, he was successful in helping to launch the Schizophrenia Research Program of the Scottish Rite Masons, Northern Jurisdiction (I 935), the National Committee on Psychiatric Education (1930), and the American Board of Neurology and Psychiatry (1934). All of these organizations promoted improvements in undergraduate and graduate instruction in the field in both the United States and Canada.

X

Clarence Meredith Hincks

During the second world war, Hincks and his colleagues developed psychological and psychiatric services in the Canadian armed forces, and for children evacuated from bombed-out areas of Britain. Later he organized a Mental Health Consultation Service for Toronto which after his death became the Hincks Treatment Centre - a small but exemplary comprehensive psychiatric hospital for children and young people. Hincks was a public crusader in the interests of the mentally ill. As such, compassion, empathy, and sensitivity were essential. He had these qualities, and many more, including courage, conviction, aggressiveness, and an indignant impatience especially for obsolete government policies, professional irresponsibility, and public complacency. His greatest enemy was 'man's inhumanity to man.'

Preface

At the end of the last century Sigmund Freud abandoned his projected construction of a neurophysiologically based model of the mind and turned to the development of a psychological model, having recognized that the neurophysiology of his day was unequal to the task. Nonetheless, he predicted that a day would come when advances in knowledge of the functioning of the central nervous system would make possible the formulation of such a model. Over seventy years later we are still unable to propose a comprehensive theory, but there are many segments of our knowledge of the nervous system which can be related to behaviour, and now many investigators work at the interface between neurophysiology and the behavioural sciences. When Queen's University was invited to sponsor the second series of Hincks Memorial Lectures in 1969, the time seemed ripe to review some aspect of research and theory development in this frontier area between neurophysiology and behavioural science, preferably one of demonstrable relevance to the field of mental health. The choice of a Lecturer was easy. Dr Paul MacLean's investigations and development of the concept of the limbic system have been seminal in the field of psychiatry and in related disciplines, and he has combined rigour of investigation with a willingness to look, if necessary speculatively, at the broad implications of these findings. We were fortunate to be able to persuade him to accept the task of preparing and presenting these lectures, in spite of his many other commitments. The three lectures, which constitute the major part of this book, were delivered, and were the main theme, at a conference of the Faculty of Medicine on 'Brain and Behaviour' held on February 11-12, 1969. The conference was attended by representatives from the fields of mental health, medicine, and the behavioural sciences. To complement the lectures a number of panel discussions reviewing current work at the interface of neurophysiology and behavioural science were convened. Two panels dealt with work on 'Memory' and 'Sleep and Dreams.' The papers presented as a basis for these discussions are included in this volume.

xii

Preface

It is not possible to acknowledge individually all those whose work in organization and participation made the conference a success. Two people, however, worked behind the scenes and must be mentioned here. Mrs Jacqualine Norman, Administrative Assistant in the Department of Psychiatry, carried the administrative load throughout. Mrs Pamela Jones served as editorial assistant in the preparation of the manuscripts; without her help this book would never have come into being. Our thanks to both of them. T.J. BOAG D. CAMPBELL

DR PAUL D. MACLEAN Hincks Memorial Lecturer, 1969

Dr MacLean is a native of Phelps, New York. He prepared at the Taft School and received his BA degree from Yale College in 193 5. His original intention had been to study philosophy, but he turned to medicine as a more direct means of gaining an understanding of man. After a year of pre-medical work in Edinburgh he returned to Yale, where he graduated in medicine in 1940. Following an internship on the medical wards at Johns Hopkins, he continued his training at Yale. With the outbreak of the second world war he joined the Army of the United States as a medical officer, serving from 1942-1946. While in New Zealand as a member of the 39th General Hospital, he collaborated with Dr Averill Liebow in showing that the diphtheria bacillus was a cause of tropical ulcers, a finding that paved the way for prophylaxis and treatment. He was also in charge of medical and psychiatric wards. After separation from the Army in 1946, he practised medicine in Seattle and held a clinical appointment at the new medical school. In 1947 he was awarded a USPHS Fellowship for study with Dr Stanley Cobb at the Massachusetts General Hospital. He conducted research on psychomotor epilepsy and published his paper on the 'visceral brain,' for which he later introduced (in 1952) the term 'limbic system.' In 1949 he returned to Yale with a joint appointment in physiology and psychiatry, and in Dr John Fulton's laboratory investigated brain mechanisms of emotion. He became Associate Professor of Physiology in 1956 and was awarded a National Science Foundation Senior Postdoctoral Fellowship for study at the Institute of Physiology in Zurich. In 1957 he joined the Laboratory of Neurophysiology, National Institute of Mental Health, heading a new section on the limbic system. In addition to investigations on the anatomic and functional organization of the limbic system, his work dealt extensively with the cerebral representation of sexual functions. Dr MacLean has served as an editor of both physiological and neuropsychiatric journals. His writings and lectures have often bridged the two disciplines, as in his chapter on psychosomatics for the Handbook of

Dr Paul D. Maclean

3

Physiology. In 1964, he received the Distinguished Research Award of the

Association for Research in Nervous and Mental Disease. In 1966 he gave the Thomas William Salmon Lectures under the auspices of the New York Academy of Medicine and received the Salmon Medal for Distinguished Service to Psychiatry. He was recently (1972) the recipient of the Karl Spencer Lashley Award from the American Philosophical Society and the G. Burroughs Mider Lectureship Award from the NIH . In 1971, Dr MacLean became Chief of the Laboratory of Brain Evolution and Behavior, a new facility of the National Institute of Mental Health, designed for research on animals living under seminatural conditions.

Introduction*

The air Breathes invitation ; easy is the walk To the Lake's margin, where a boat lies moored Wordsworth, The Excursion Kingston , the home of Queen's University , enjoys an enviable location at the northeast end of Lake Ontario. The Indian name Ontario, according to some authorities, means 'beautiful lake .' Having summered most of my life among the Islands cooled by the waters of Lake Ontario, and having explored a number of its tributaries (including the incomparable canal system of the Rideau) I find it natural to favour this meaning of the name. Nurtured by such sentiments, I regarded it as a special honour to receive the invitation from Queen's University on behalf of the Ontario Mental Health Foundation to give the second series of the Clarence Hincks Memorial Lectures. In the letter of invitation, Dr Thomas J. Boag explained that the lectures are 'intended to provide an opportunity for a significant statement on a theme related to mental health.' In these words one could almost see the Lady of the Lake holding forth Excalibur for the hand of someone powerful enough to strike a blow against the nightmare of mental suffering. As would be true for anyone trying to understand the brain, the trouble in my case was that the child had not yet become the 'father of the man .' Full of curiosity to see the sword, but realizing my inability to grasp it, I requested that the lectures be scheduled in February when the Lake would be frozen over! Following the lectures I became aware of another lack of sophistication, and I will comment upon it in explaining the title of this published version. When I went to Kingston, I did not realize that if you speak publicly in Canada, there may be a period when the sun will never set on what you say! * Copyright does not apply to the introduction, which was contributed by an employee of the US Government

Introduction

5

Through the communication ties of the British Commonwealth, the underlying theme of my lectures - the three-brain concept - gained rather wide circulation. In the abbreviated reports it was easy to get the impression that I conceived of man as though he behaved under the direction of three autonomous brains. To hedge against this implication I have changed the original title of my lectures ('The Brain and Behaviour') to read 'A Triune Concept of the Brain and Behaviour.' In its evolution the human brain expands along the lines of three prototypes for which I have used the terms reptilian, paleomammalian, and neomammalian. If the three cerebrotypes are pictured as intermeshing and functioning together as a triune brain, it makes it evident that they cannot be completely autonomous but does not deny their capacity for operating somewhat independently. Moreover, the word triune has the advantage of implying that the 'whole' is greater than the sum of its parts, because the exchange of information among the three brain types means that each derives a greater amount of information than if it were operating alone. Some might argue that my underlying theme is simplistic, pointing out, for example, that one might also speak of prototypical brains in regard to each of the sensory systems. But what I have wished to emphasize in these lectures are the three major evolutionary developments, realizing that one cannot say anything about such a complicated structure as the brain without indulging in oversimplification. I wish to acknowledge my indebtedness to the late Wade Hampton Marshall, first Chief of the Laboratory of Neurophysiology of the National Institute of Mental Health (I 953-1970) for his unswerving support; and to the former members of the Section on Limbic Integration and Behavior (now the Section on Comparative Neurophysiology and Behavior, the Laboratory of Brain Evolution and Behavior) for their help and collaboration. Finally, in acknowledging my indebtedness to the Ontario Mental Health Foundation and Queen's University for the opportunity to present these lectures, I wish to express my personal appreciation to Professor T.J. Boag and Dean E.H. Botterell for their gracious letters of invitation and their warm hospitality to me while I was in Kingston. PAUL D. MACLEAN

1

Man's Reptilian and Limbic Inheritance*

The cursed crocodile became to me the object of more horror than all the rest. I was compelled to live with him; and (as was always the case in my dreams) for centuries. Thomas DeQuincey, The Confessions of an English Opium-Eater The population explosion is an alanning sign that the problems of modem man are soaring at an unprecedented rate. Calhoun (I 971) points out that the von Foerster curve for population growth since the time of Christ shows that each successive doubling of the population required only half the time of the previous doubling. At the present rate, von Foerster and his colleagues (1960) calculate that the human population will squeeze itself to death by the year 2026, a date which they term 'Doomsday.' In his recent book The Ghost in the Machine, Arthur Koestler, who was honoured last year by Queen's University, has a final chapter called 'The Age of Climax' (1967). In it he poignantly reminds us that the same 'brakes-off situation pertaining to the population explosion also applies to the power of weapons, the speed of missiles, communications, and scientific infonnation. He quotes, for example, Morris' figures that whereas there were only 10 scientific journals in 1700, there were l00 in 1800; 1000 in 1850; 10,000 in 1900; l00,000 after the first world war; with an expected total of one million by the year 2000. Apparently, as many scientists were produced in the last fifteen years as existed during the entire previous period of science. I have friends teaching in the humanities who find these figures on the growth of science almost as terrifying as the prospect of an atomic holocaust! One must certainly agree with them that we would not be in our present predicament if it were not for the spiralling achievements of science. But * Copyright does not apply to this chapter, which was contributed by an employee of the US Government

Man's Reptilian and Limbic Inheritance

7

man's decisions as to how he will utilize his scientific knowledge and plot his future course are essentially a matter of politics. This emphasizes the urgency for a simultaneous effort on the part of all nations to work for world-wide enlightenment. I am referring now to the enlightenment of self-knowledge, and not to the much advertised kind of enlightenment of our western bulldozer culture. It has long been an abiding faith of psychiatry that selfknowledge, more than anything else, holds the promise of reducing those inner tensions of man that otherwise have the potentiality of exploding with catastrophic consequences. Such was the abiding faith of Clarence Hincks in whose memory these lectures are given. It is my own faith, based on the study of the brain, that a wide dissemination of available knowledge about basic brain mechanisms and behaviour would do much to help man live in greater contentment with himself and his society. I say this despite the emphasis I give in this first lecture to psychological difficulties emanating from lopsided differences between evolutionary old and new systems of man's brain, and for which I have only a few homely prescriptions. For the real tenet of my faith you will have to wait for the third and last lecture on 'New Trends in Man's Evolution .' Perhaps then you will see why I harbour some hope for Calhoun's optimistic prediction that just about the time of 'Doomsday' there will in fact be 'Dawnsday' (I 97 I). In order to appreciate where we are going, we must first look back in time to see where we have been. Rocketed by our imagination, which exceeds the speed of light, we will go back 200 million years to the age of reptiles, when animals which never learned to talk began to work their way into the brain of man (MacLean 1964a). Man puts so much emphasis on himself as a unique creature possessing a spoken and written language that, like the rich man denying his poor relatives, he is loath to acknowledge his animal ancestry. In the last century it almost killed him to admit his resemblance to apes, but t.he time is approaching when he must say 'uncle' and admit to having far poorer relatives! Intellectually he has been aware of this for a long time, but emotionally he cannot bring himself to recognize it. It is a little bit like the 'denial of illness' which is much more familiar to us. Perhaps the most revealing thing about the study of man's brain is that he has inherited the structure and organization of three basic types which, for simplification, I refer to as reptilian, old mammalian, and new mammalian (MacLean 1962, 1964a, 1967a, 1968a, 1968b, 1969b, forthcoming). It cannot be over-emphasized that these three basic brains show great differences in structure and chemistry. Yet all three must intermesh and function together as a triune brain. The wonder is that nature was able to hook them up and establish any kind of communication among them.

8

The Triune Concept of the Brain and Behaviour

In evolution one might imagine that the brain has developed like a building to which wings and superstructure have been added. The hierarchy of these three brains is shown in Figure 1. Man's oldest brain is basically reptilian, 1 forming the matrix of the upper brainstem and comprising much of the reticular system, midbrain, and basal ganglia. The reptilian forebrain is characterized by greatly enlarged basal ganglia which resemble the striatopallidal complex of mammals.2 But, in contrast to mammals, there is only a rudimentary cortex. The old mammalian (paleomammalian) brain is distinctive because of the marked development of primitive cortex which, as will be explained later, corresponds to the limbic cortex. Finally, there appears late in evolution a more complicated type of cortex called neocortex, which is the cerebral hallmark of higher mammals and which culminates in man to become the brain of reading, writing, and arithmetic. In the popular language of today, these three brains might be thought of as biological computers, each with its own peculiar form of subjectivity and its own intelligence, its own sense of time and space and its own memory, motor, and other functions (MacLean 1968a, 1968b, I 969b, forthcoming). On the basis of behavioural observations of ethologists, there are indications that the reptilian brain programmes stereotyped behaviours according to instructions based on ancestral learning and ancestral memories. At the new NIMH field laboratory, The Laboratory of Brain Evolution and Behavior, we· plan to test the hypothesis that the counterpart of the reptilian brain in mammals is fundamental for such genetically constituted forms of behaviour as selecting homesites, establishing territory, engaging in various types of

a

Here it is worth a reminder that there are only four surviving orders of reptiles, and none is considered representative of the forerunners of mammals. The four existing orders are: (1) Chelonia, comprising tortoises and turtles, and so named because of the box-like shell in which they are encased; (2) Squamata, or scaly reptiles, consisting of two suborders called Lacerti/ia (lizards) and Ophidia (snakes); (3) Crocodilia (crocodiles and alligators) which share with birds (Aves) an origin from the Archosauria (ruling reptiles); and, finally, (4) Rhynchocephalia (snout-head) represented by the single species Sphenodon Punctatum or so-called Tuatara of New Zealand. Some authorities believe that of the existing reptiles the turtle possesses the type of brain resembling most closely the one antecedent to that of mammals. Perhaps, however, the behaviour of lizards would be most similar to that of the mammal-like reptiles 2 Neuroanatomical inferences about the evolutionary homogeneity of the striatopallidal complex have recently been strengthened by comparative histochemical studies. With the Koelle stain for cholinesterase, the corpus striatum (caudate + putamen) acquires a vivid orange-brown color. What are regarded as comparable structures in reptiles and birds show a similar intense staining (Parent and Olivier 1970). Using the fluorescent technique of Falck and Hillarp, Juorio and Vogt (1967) have found in avian and lower mammalian forms that these same structures glow brightly because of the presence of dopamine. David Jacobowitz and I have observed a similar fluorescent picture in the monkey (unpublished). The presence of dopamine in the striatum is attributable to a projection of dopamine-containing cells in the substantia nigra (Anden et al, 1965)

9

Man's Reptilian and Limbic Inheritance

~~oMAMMAl/

~I\I

Figure I Diagram of hierarchic organization of three basic brain types, which, in the evolution of the mammalian forebrain, become part of man's inheritance. Each type has distinctive structural and chemical features. The triune brain, with its extensive interconnections, would, in Koestler's (1967) terminology, represent a 'holonarchy.' Man's counterpart of the paleomammalian brain comprises the so-called limbic system (Maclean 1952), which has been found to play an important role in emotional behaviour. (After Maclean 1967a)

IO

A Triune Concept of the Brain and Behaviour

display ,3 hunting, horning, mating, breeding, imprinting, forming social hierarchies, and selecting leaders. The cardinal importance of territory seems to have been emphasized first by Eliot Howard (1929), the English naturalist, who observed that the establishment of territory was a necessary preliminary to mating and breeding. The reptilian brain seems to be hidebound by precedent. Behaviourally, this is illustrated by the reptile's tendency to follow roundabout, but proven, pathways, or operating according to some rigid schedule. Customs of this kind appear to have some survival value and raise the question as to what extent the reptilian counterpart of man's brain may determine his obeisance to precedent in ceremonial rituals, religious convictions, legal actions, and political persuasions (Maclean 1968a, 1969b ). In his essay Beyond the Pleasure Principle, Freud (I 922) refers again and again to man's compulsion to repetition, or as he otherwise calls it, the repetition-compulsion. Obeisance to precedent is the first step to obsessivecompulsive behaviour, and this is well illustrated by the sea turtle's returning to the same place year after year to lay her eggs. It has been shown in recent studies on mammals that they are also like the reptile in their tendency to return to home grounds. This has been observed, for example, in the case of seals, sheep, and goats (Harper 1970). Man, too, may harbour a continuous yearning to return home after moving to a distant land. I remember a surgeon's widow in Auckland, New Zealand, who, during the second world war, was wonderfully hospitable to members of our 39th General Hospital. A native of England, she had lived in New Zealand many years and had reared her children there. Once she said to me, 'You know, I have lived here most of my life, but I have never settled here.' Most of us have experienced from time to time the compulsion to return to our childhood home. I remember once smelling hay in Switzerland and feeling overwhelmed by yearning to return home to our summer place not far from here. One might go so far as to generalize with Freud (1922, p. 47) that all repetition-compulsions represent a form of homing. Certainly there seems to be a recognized tendency among animals, after exploring and reaching out for food, for a mate, or whatever else, to return to a recognized frame of reference . Freud saw a biological model for this in the 'circuitous paths' of As described in a preliminary report (Mac Lean 197 2), I have since found that bilateral lesions of the striatopallidal complex abolish the innate display behaviour of squirrel monkeys described in the final lecture. Because of the traditional clinical view that the striatopallidal complex subserves purely motor functions, it should be emphasized that large lesions of the complex may result in no apparent motor incapacity if there is no injury to the internal capsule. These findings, as discussed in the above-mentioned report, suggest that the striatopallidal complex is fundamentally involved in species-specific and imitative forms of behaviour

Man's Reptilian and Limbic Inheritance

11

recapitulation in ontogenetic development, and in line with such thinking was led to the conclusion that 'the goal of all life is death,' with the animate returning to the inanimate. There are several other aspects of reptilian behaviour that invite speculation about the functions of man's counterpart of the reptilian brain. Obviously, it will take many lifetimes, if it is ever possible, to pin a number of these things down. But before leaving this subject, I will mention a few more examples. One is the capacity for an appropriate dummy, or even part of a dummy, to precipitate in reptilian forms a sequential acting out of genetically constituted forms of behaviour. Some of the best illustrations are provided by birds which, in the branching of the evolutionary tree, are closely related to reptiles. 4 In Tom turkeys on our farm, for example, I have many times seen the copulatory act triggered by a mere phantom, and performed in entirety without a partner. A similar tendency in mammals is illustrated by the use of partial dummies for collecting semen for artificial insemination. The mind readily associates to human fetishism. Other dummy-induced behaviours are aggressive display, fighting, and flight and following reactions. One wonders how often the caricature of a leader such as a Hitler is sufficient to deceive people into thinking that they are following a true leader! The question of imprinting also arises in connection with human behaviour. It is recognized that there are certain critical times in the brain's development when it is particularly receptive to forming attachments to things in the environment. Spalding (I 954 ), in the last century, was probably the first to describe what ethologists call imprinting (Lorenz 1937), when he reported his observation that, in the absence of a hen, baby chicks would follow the first moving object to which they were exposed. I am among those who speculate that in human society the age of adolescence may be a critical time for imprinting to occur with respect to the same or opposite sex. At this age boys and girls have many features in common, and there is the possibility that , in schools of one sex, imprinting at these times may be conducive to a life of continued homosexuality . This raises the question of the advisability of providing co-education whenever possible. It is doubtful, however, that such reasoning lies behind the co-educational trend in our country where, in some universities, as you know, boys and girls are now sharing the same dormitories. Reptilian behaviour raises other intriguing questions. How, for example, do ancestral memories detennine man's love of hunting and horse racing, his choice of spouse, and even perhaps his profession? Symbolically, in affairs of 4 See n. l above

12

A Triune Concept of the Brain and Behaviour

sexual attraction, I am reminded of DeQuincey's relentless search for Ann, whose face had become idealized and imprinted in his mind. 5 There is also the question as to how reptilian proneness to imitation is relevant, in human affairs, to mass hysteria, mob violence, and now, thanks to television, a world-wide adoption of fads and fashions. In summary, the reptilian brain behaves as though it were neurosis-bound by an ancestral superego (Macl..ean 1964a), lacking the adequate neural machinery for learning to cope with new situations. The evolutionary development, in lower mammals, of a respectable cortex appears to represent nature's attempt to provide the reptilian brain with a 'thinking cap' and to emancipate it from the ancestral superego (Maclean 1968a). The primitive cortex might be likened to a primitive television screen, giving the mammal a better picture for adapting to its internal and external environment. Evidence for its reception of signals from both internal and external sources will be given in the next two lectures. In all mammals, most of the primitive cortex is found in a large convolution which Broca (I 878) called the 'great limbic lobe' because it surrounds the brain stem. Limbic means 'forming a border around.' In dealing with the question of function, it deserves emphasis that this lobe, as illustrated in Figure 2, is found as a common denominator of the mammalian brain. Its relative stability throughout mammalian phylogeny contrasts with the mushrooming neocortex which culminates in man and gives him a large screen on which a picture can be portrayed by a written and spoken language. Because of its close relationship to olfactory structures, the old mammalian brain was formerly believed to subserve purely olfactory functions and was accordingly referred to in many texts as the rhinencephalon (Schafer 1900, p. 765, n. 1). Papez's famous paper of 1937 struck a mortal blow to this line of thinking. Since then, extensive investigation has revealed that in addition to olfactory functions, this brain plays an important role in elaborating emotional feelings that guide behaviour with respect to the two basic life principles of self-preservation and the preservation of the species (Maclean 1958b, 1959). In 1952 I suggested the term limbic system as a suitable descriptive designation for the limbic cortex and structures of the brain stem with which it has direct connections. It should be emphasized that the limbic cortex has similar features in all mammals and is structurally more simple than the new cortex. From this it can be inferred that it continues to function at an animalistic level in man as in animals. Also, in marked contrast to the new cortex, it has strong connections with the hypothalamus which plays a basic role in integrating emotional expression. 5 Thomas DeQuincey, Confessions of an English Opium Eater

13

Man's Reptilian and Limbic Inheritance

RAIUIT

CAT

MONKEY

Figure 2 Most of the cortex of the limbic system (old mammalian brain) is contained in the limbic lobe which surrounds the brain stem. This figure (depicting the relative sizes of the brains of the rabbit, cat, and monkey) illustrates that the limbic lobe is found as a common denominator in the brains of all mammals. The rapidly evolving neocortex, comparable to an expanding numerator, is tinted grey. Upper and lower drawings, respectively, show lateral and medial views of the cerebral hemispheres. (After MacLean, in Wittkower and Cleghorn (eds. ), Recent Developments in Psychosomatic Medicine, London: Pitman, 1954)

In proceeding now to consider some elementary functions of the limbic system, I shall refer to a simplified anatomical diagram, recognizing that it is impossible to say anything about such a complicated organ as the brain without being guilty of oversimplification. The diagram in Figure 3 focuses on three main subdivisions of the limbic system . The three main cortical subdivisions in the limbic ring are shaded by the small numerals l, 2, and 3, and their principle connecting links with the hypothalamus and other parts of the brain stem are correspondingly labelled by the large numerals. You will note that the two upper branches of the medial forebrain bundle (MFB) meet with the descending fibres from the olfactory bulb and feed into the lower and upper halves of the ring through the amygdala and the septum at the points marked no . l and no. 2. In the rest of this lecture we will focus attention on these two limbic subdivisions, but in anticipation of the third and final lec,ure, and to point out an important contrast, it should be emphasized that the third large pathway branching from the hypothalamus bypasses the olfactory apparatus. The third subdivision connected with this pathway reaches maximum development in man and will

14

A Triune Concept of the Brain and Behaviour

OLF.

BULB

Figure 3 The functions of the limbic system are discussed with respect to three main subdivisions shown in this diagram. The three main cortical regions in the limbic lobe are indicated by the small numerals 1, 2, and 3. (The smaller numerals overlie archicortex and the larger, mesocortex [i.e., transitional cortex).) The principle pathways linking the three cortical regions with the brain stem are correspondingly labelled by the large numerals. Elementary functions of the two subdivisions (no. 1 and no. 2), closely related to the olfactory apparatus, are described in Lecture 1. Discussion of the third subdivision is deferred until Lecture 3. Abbreviations : AT, anterior thalamic nuclei; HYP, hypothalamus; MFB, medial forebrain bundle; OLF, olfactory. (Adapted from MacLean 1958a)

be discussed in the concluding lecture on new trends in the evolution of the brain. Clinical and experimental findings indicate that the lower part of the limbic ring fed by the amygdala is primarily concerned with emotional feelings and behaviour that insure self-preservation (MacLean I 958a, 1958b, I 959). In other words, there is evidence that its circuits are kept busy with the selfish demands of feeding, fighting, and self-protection. The most convincing evidence for this is derived from observations on patients with limbic epilepsy. At the beginning of an epileptic discharge in this part of the brain, patients experience feelings that come into play in the struggle for survival. These include elementary feelings of hunger, thirst, nausea, suffocation,

Man's Reptilian and Limbic Inheritance

15

choking, racing heart, or the urge to defecate and urinate, which may be conjoined with a variety of intense emotional feelings such as terror, fear, anger, sadness, foreboding, strangeness, and paranoid feelings. The automatic behaviour that follows these feelings often appears to be an acting out of the subjective states, as typified by eating, drinking , vomiting, showing anger, or running and screaming as if afraid. In stimulating the corresponding region in cats and monkeys, Delgado and I (1953) elicited similar forms of behaviour. Such findings, therefore, indicate that this subdivision of the limbic system is primarily concerned with selfpreservation both as it pertains to obtaining the requisites of life and avoiding the claws of injury and destruction. The classical studies of Kluver and Bucy revealed that if this part of the brain was surgically excised in wild monkeys, they (1) lost their sense of fear; (2) became tame; (3) would eat all manner of objects such as nuts, bolts, and faeces; and (4) developed bizarre sexual behaviour and other changes that would be prejudicial to their survival in a natural environment (Kluver and Bucy 1939). The changes in sexual behaviour were indicative of a release of other parts of the brain concerned with sexual functions. This turns our attention next to the second subdivision of the limbic system connected by the septum (no. 2). Several years ago we observed that following electrical or chemical stimulation of the septum and related hippocampus, male cats developed enhanced pleasure and grooming reactions and sometimes penile erection - aspects of behaviour seen in feline courtship (Maclean 1957a, 1957b ). These observations suggested that this part of the limbic system was involved in expressive and feeling states that are conducive to sociability and other preliminaries of copulation and reproduction. They were of heuristic value because, curiously enough, there had existed little but indirect evidence from ablation studies that the forebrain was concerned in sexual behaviour. Penfield, for example, who had stimulated the greater part of the cerebral cortex in man apparently never elicited penile erection or erotic sensations (Penfield and Jasper 1954). The sum total of negative findings seemed paradoxical in view of the highly organized behaviour required for procreation . The positive findings in the cat led me to undertake an exploration of the limbic system and other parts of the brain in the squirrel monkey in search for sexual responses to electrical stimulation. For these experiments a stereotaxic platform with electrode guides was chronically fixed above the scalp on four screws previously cemented in the skull (1967b ). This device avoids open surgery and provides a closed system for millimetre by millimetre exploration of the brain with stimulating and recording electrodes while the monkey sits in a special chair. Animals become readily adapted to this procedure and are

16

A Triune Concept of the Brain and Behaviour

provided with their favourite forms of fluid and nourishment. After each experiment the monkey is returned to its home cage. In the brain stem above the level of the hypothalamus there are two main locations where stimulation results in penile erection. One is the medial septopreoptic region and the other, as will be emphasized in the final lecture, is in the anterior and midline thalamic region (Maclean and Ploog 1962). Stimulation at positive loci in the medial septo-preoptic region commonly results in electrical discharges in the hippocampus, and during these discharges the erection may become throbbing in character and increase in size. Afterwards, the monkey may become placid and drowsy for prolonged periods. The general demeanour recalls one of Heath's patients, who, after stimulation in the septa! region said, 'I have a glowing feeling, I feel good' (1954). These observations were originally reported at meetings in 1952. Two years later Olds and Milner (I 954) described their remarkable finding that rats will repeatedly press a bar for the apparent satisfaction of receiving electrical stimulation of this part of the brain. Figure 4 utilizes the brain diagram in Figure 3 for presenting a graphic summary of the effects of stimulation at points within the two subdivisions of the limbic system related to the amygdala and septum. The shield of Mars (0) is used as a symbol for facial, oral, and alimentary responses, and his sword (1) for genital responses. The symbols for shield are seen to cluster in the amygdala region, while those for sword are concentrated in the medial septo-preoptic region . Followed downstream into the brain stem, sword and shield unite in the anterior hypothalamus, portraying a reconstitution of the warrior Mars in a region of converging nerve fibres involved in angry and defensive behaviour. Since fighting is frequently a preliminary to mating as well as feeding, these findings suggest that nature uses the same neural mechanisms for combat in both situations. In the dorsal hypothalamic area just above the focal region in the hypothalamus involved in agonistic behaviour, stimulation elicits full erection usually accompanied by vocalization. Then, as the electrode is lowered a little further, signs of angry or fearful behaviour begin to appear, as indicated by the quality of vocalization, struggling, biting, and showing of the fangs (Maclean, Denniston, and Dua 1963a, p. 280). Afterwards there is characteristically a rebound erection. At the point where the pallidohypothalamic tract loops over the medial aspect of the fornix, only agonistic signs are elicited. Finally, as the electrode leaves this focal area, stimulation primarily evokes biting or chewing. These findings would seem to throw some light on the neural basis for aggressive and violent expressions of sexual behaviour. In his three essays on sex, Freud (1948) noted that 'the sexually exciting influence of some painful

Man's Reptilian and Limbic Inheritance

17

Figure 4 Diagram summarizing effects of electrical stimulation at points within the two subdivisions of the limbic system interconnected respectively by amygdala and septum (compare with Figure 3). The shield of Mars (0) is used as a symbol for facial, oral, and alimentary responses and his sword (J') for genital responses. Symbols for shield cluster in amygdala region, and those for sword in septa! region. Followed along descending pathways, sword and shield unite in the anterior hypothalamus, portraying a reconstitution of the warrior Mars at a locus where electrical stimulation elicits angry and defensive behaviour. See text for implications. (Adapted from MacLean 1964a)

effects such as fear, shuddering, and horror is felt by a great many people throughout life and readily explains why so many seek opportunities to experience such sensations' (p. 62). He also remarked, ' ... a number of persons report that they experienced the first signs of excitement in their genitals during fighting or wrestling with playmates ... The infantile connection between fighting and sexual excitement acts in many persons as a determinant for the future preferred course of their sexual impulse' (p. 62). Returning upstream to the amygdala and septum, we find further implications of the physiological findings. Slow frequency stimulation in parts of the amygdala elicit movements of the face, chewing, salivation, and swallowing, followed several seconds later by the appearance of penile erection (Maclean I 962, p. 295). Such findings help to explain penile erection observed in

18

A Triune Concept of the Brain and Behaviour

animals and human infants when being fed . They also help to illuminate orogenital behaviour to which there have been so many allusions in the current literature and screenplays, such as James Joyce's Ulysses. An archetypal form of such behaviour is found in the lemur, a primitive primate which has a greeting display (see Lecture 3, Figure 5) in which the male and female mutually lick the anogenital region . The close connection of oral and genital functions is apparently due to the olfactory sense which, dating far back in evolution, plays a major role in both feeding and mating. In the neocortex the representation of the body is such that the head and tail stand at opposite poles like north and south. This is what one would expect of a structure with the nice discrimination of the neocortex. But in the limbic lobe head and tail are brought into proximity by the olfactory sense. Plate 1 shows a cat licking its erect penis following a hippocampal after-discharge. Civilized man long suspected that the world was round before Columbus sailed to America, but how could he have imagined that the limbic lobe was a closed ring and that in voyaging in one direction the head would be reached by way of the tail and vice versa (Maclean 1968). I have been told by some psychiatrists that these recent physiological findings have helped to relieve guilt feelings of a number of their patients about oral-sexual fantasies and related behaviour. But in other respects the physiology and anatomy that have been outlined in discussing the three-brain concept only serve to emphasize the special difficulties besetting the patient and therapist. In therapy the psychiatrist commonly proceeds on the assumption that since his patient is an articulate being, his psychological processes readily lend themselves to translation into words. The goals are to clear the way of resistances and through free association bring out unconscious and repressed material that will help to give insight and understanding and a relief of symptoms. One shortcoming of this approach may be that it fails to take into account those two ever-present animals which are conscious and wide awake, but hopelessly inarticulate. What it amounts to is that the neural machinery does not exist for the reptilian and limbic brains to communicate in verbal terms. Too often it seems the brain gets verbal insight, only to be more troubled by failing to see any improvement of the basic disturbance. Hopefully, future research will suggest other methods that will perhaps be more effective in communicating with our animal brains. But as implied in the introduction, the mounting problems of our times are such that psychiatry may be called upon to deal not only with the sickness of individuals, but also with a generalized world sickness. One present difficulty seems to be that our neocortex is all out of step with our animal

Man's Reptilian and Limbic Inheritance

19

Plate 1 Following electrically or chemically induced seizure discharges in the hippocampus, male cats may develop enhanced pleasure and grooming reactions and penile erection. This excerpt from a motion picture film shows a cat with penile erection grooming its genital region following an electrically induced hippocampal afterdischarge. (From Maclean 1957b)

brains. As opposed to the old cortex, the neocortex receives its information predominantly from the external environment through signals conducted from the eyes, ears, and somatic receptors. (Parenthetically, it is of interest that the energies giving rise to these signals, unlike those for smell and taste, lend themselves to electronic amplification and broadcasting.) It is evident, therefore, that the neocortex is externally oriented. Moreover, it seems to thrive on change, presumably because nature designed it to come up with new ideas and new solutions. So dramatic and all-engrossing have been the recent accomplishments of science, that our educational, political, and business leaders seem to be planning our existence as though we had to satisfy only our neocortex. With its imaamation that travels in excess of the speed of light, man's new brain may be able to keep up with the present accelerated tempo of life through speedreading, the help of computers, and otMJ conCrivaoces, but his

20

A Triune Concept of the Brain and Behaviour

two animal brains, which forever tag along , must be presumed to move at their own slow pace. They seem to have their own biological clocks and their own sequential, ritualistic way of doing things which cannot be hurried (MacLean 1967a). Nature , despite all her progressiveness, is also a staunch conservative and is more tenacious than the curator of a museum in holding on to her antiques. The reptilian and limbic brains have survived millions of years of evolution, and it is evident that we can expect no overnight permutation that will remove them from the brain of man. Indeed, it is questionable whether or not the human race could survive without limbic emotions because, whatever else they do, they assure conflict and argument which in tum insure the mixing of the gene pool of ideas! Although we are already anticipating public transportation at rocket speeds, we will still have to move at a horse and buggy pace with our animal brains. Once this is realized , it is possible that we can learn to live in greater contentment than at the present time . Perhaps one of the things we need to do is to spend more time cultivating those simple domestic pleasures for which the Europeans are famous and which in the last century were so colourfully prominent in the poetry and paintings of the pre-Raphaelites creating pictures and other things with our own hands , making bread, gardening, tending indoor plants and flowers, caring for pets, birdwatching, and keeping diaries . In symbolically trying to satisfy our hunting instinct, as well as our delight in newly laid eggs , let it be hoped that society will insist upon some alternative to the ugly, macadamized sprawl of our shopping centres. I myself have never recovered from the homesickness of leaving an idyllic country town at the age of five. It did a lot to relieve this feeling when we moved to a small farm in Potomac twelve years ago. I discovered that a little smell of horse manure once a week was more effective than a cocktail for quieting something deep down inside of me .· In reading about current trends one gains the impression that we are becoming a nomadic people, moving on the average of every three years. Under these disruptive conditions it will perhaps provide a comforting sense of home base for the reptilian brain if parents teach their children the stars and constellations. Most urgent at the present time is the need to devise some way of controlling our soaring population and thereby remove pressures that promote man's reptilian intolerance and reptilian struggle for territory. There is now an accumulation of evidence with respect to several animal species that aggressiveness increases with increasing density of population (e .g., Calhoun 1962; Ardrey 1966), often leading to mortal combat . There is no reason to

Man's Reptilian and Limbic Inheritance

21

assume that the animal represented in each one of us would not be similarly affected (MacLean 1967a). Already the world has become so small that there is almost no place to retreat except into the far reaches of our own minds. Some have looked to the 'mind-expanding' drugs as a means of extending the horizons for such retreat. I will touch on this subject in the next lecture, but only with respect to mind-distortion, not retreat. More than retreat, the undrugged, unfettered mind is capable of ascent, and it is the evolutionary direction of this ascent that I will consider in the last lecture.

SUMMARY

As evidenced by the population explosion, the problems of modern man are soaring at an unprecedented rate. There is hope that a solution to these problems can be helped through a better understanding of the brain. In its evolution, man's brain retains the hierarchical organization of three basic types, which for purposes of discussion, are referred to in ascending order as reptilian, paleomammalian, and neomammalian. Despite great differences in structure and chemistry, all three brains must intermesh and function together as a triune brain. In popular terminology, the three sub-brains might be regarded as biological computers, each with its own special form of subjectivity, intelligence, time measuring, memory, motor, and other functions. This lecture focuses attention on the reptilian and paleomammalian brains. There are indications that the reptilian brain 'programs' behaviour according to instructions based on ancestral memories and ancestral learning, playing a primary role in what are commonly referred to as instinctual forms of behaviour. The paleomammalian brain represents. an inheritance from lower mammals and corresponds to the so-called limbic system or limbic brain. It is of special psychiatric interest because of clinical and experimental evidence of its important role in emotional behaviour. A common denominator in the brains of all mammals, it stands in a Janus-like position between the reptilian and the new mammalian brains. The functions of the limbic brain are considered in reference to three main subdivisions, two of which are closely related to the olfactory apparatus and are respectively involved in oral and sexual functions

22

A Triune Concept of the Brain and Behaviour

required for self-preservation and the preservation of the species. Psychiatric implications of the close organization of the two subdivisions concerned with oral and genital functions are discussed. Finally, it is emphasized that no matter how fast man may eventually travel with his neomammalian brain, he will need to acquire self-knowledge that will allow him to accommodate to the horse and buggy pace of his reptilian and limbic brains.

2

Man's Limbic Brain and the Psychoses*

For this second lecture I thought it would be timely to take a sidetrip to explore some volcanic terrain in one of the frontier regions of the brain. The purpose in going there is to sound out the possibility that rumblings in the hippocampal portion of the limbic brain may cause certain types of upheaval in the endogenous and toxic psychoses. In particular we shall explore the possibility that eruptions in this part of the brain may give rise to (I) disturbances of emotion and mood;(2) feelings of depersonalization; (3) distortions of perception; and (4) paranoid symptoms. The timeliness of this expedition will be apparent when we stop by the way to examine some of the chemical properties of the limbic brain in the light of speculations about disorders of catechol (e.g., Bunney and Davis I 965; Schildkraut 1965) and serotonin (Gaddum 1953; Woolley and Shaw 1954) metabolism in the genesis of the psychoses. The timeliness is further brought home by the alarming, popular use of psychedelic drugs and the realization that the hallucinogenic agents may precipitate psychoses. These drugs, among their other possible actions, interfere with the metabolism of cerebral amines, and single doses of LSD have been said to result in recurring psychotic symptoms in individuals showing no evidence of a pre-psychotic personality. Our point of departure for this expedition is from ground covered in the preceding lecture. For the sake of continuity let us briefly retrace some of the steps taken up to this point. It was emphasized that man and higher mammals have inherited essentially three types of brains (see Lecture I, Figure I). The brain of oldest heritage is basically reptilian. This reptilian brain appears to be genetically constituted for guiding behaviour on the basis of ancestral learning and ancestral memories. In carrying out stereotyped instinctual functions it is neurosis-bound, as it were, by an ancestral superego. * Copyright does not apply to this chapter, which was contributed by an employee of the US Government. An earlier version of this lecture which was given June 14, 1968 on the occasion of the opening of the Maryland State Psychiatric Research Center, Spring Grove Hospital, Catonsville, Maryland, has since been published in P. Black (ed.), Physiological Correlates of Emotion, New York: Academic Press, 1970, pp. 129-46

24

A Triune Concept of the Brain and Behaviour

h2

\

fO. /

Plate 1 Two examples of distinctive chemical properties of the archicortex (hippocampus). Photomicrograph on left shows complete loss of neurons in area CA3 of mouse following intraperitoneal injection of 3-acetylpyridine, an antimetabolite of nicotinamide. (From Coggeshall and MacLean 1958) Picture of guinea pig hippocampus on right reveals that the mossy fibres innervating this same area (McLardy 1955; von Euler 1962) are stained by dithizone, a chelating agent which gives a red colour when combined with zinc. (From Fleischhauer and Horstmann 1957)

Superimposed on the reptilian brain is the primitive cortex of the old mammalian brain that presumably represents nature's attempt to provide a 'thinking cap' for the reptilian brain and emancipate it from the ancestral superego. The old mammalian brain, which is found as a common denominator in the cerebrum of all mammals (see Lecture 1, Figure 2), is otherwise known as the limbic system or limbic brain. Appearing late in evolution is a new type of brain which reaches its greatest development in man to become the brain of reading, writing, and arithmetic. In the present expedition we will find additional evidence for believing that intercommunication among these three brain types must present special difficulties because of their differences in chemistry and functional anatomy. As a framework for discussing elementary limbic functions I showed a simplified diagram of the anatomy of the limbic brain (Lecture 1, Figure 2) depicting three main subdivisions. I summarized evidence indicating that the subdivision in the lower part of the limbic ring connected with the amygdala is largely concerned with emotional feelings and behaviour that assure self-preservation, whereas, in contrast, the subdivision related to the septum is implicated in feeling states that are conducive to sociability, procreation, and the preservation of the species. In the final lecture I shall consider functions of the subdivision connected by the third pathway that undergoes a great expansion in man and becomes functionally associated with the frontal lobes.

Limbic Brain and Psychoses

25

Plate 2 Radioautogram on right illustrates high uptake of S 35 labelled L-methionine in hippocampus (white arrow) of rat. Comparable section on left shows failure of uptake in a rat that had received a convulsive dose of insulin. (From Flanigan, Gabrieli, and Maclean 1957)

That the limbic brain is a functionally, as well as an anatomically, integrated system is dramatically demonstrated by mapping the propagation of hippocampal seizure discharges. The hippocampus, perhaps, has the lowest seizure threshold of any structure in the brain (Green 1964). If a seizure discharge is induced in the hippocampus by electrical stimulation it has a tendency to spread throughout and be confined to the limbic system (e .g., Maclean 1957a). The impulses of the discharging neurons might be imagined as stampeding bulls which do not jump the fence and leave the corral of the limbic system (Maclean 1958a). Nothing drives home so convincingly the functional dichotomy - or schizophysiology as I have called it (1954, 1958a) - of the limbic and neocortical systems. As regards this dichotomy of function it is significant, as I will point out , that patients with smouldering limbic epilepsy may manifest the various symptoms of schizophrenia . Before moving on into the psychotic area, however, we will interrupt our metaphorical expedition to look at a number of chemical differences, which like anatomical and physiological distinctions already mentioned, serve to distinguish the limbic brain from the reptilian and new mammalian brains.

26

( \

A Triune Concept of the Brain and Behaviour

I \

78 A

9

D

I

"

,r)

---

0

)19 E

'-

Figure 1 Certain cortical and subcortical structures of limbic system contain relatively large amounts of 5-hydroxytryptamine (serotonin). B to I give values in micromilligrams for respective areas of superficial limbic cortex of dog. The high value of 408 was found in the periamygdaloid cortex (G). Other abbreviations : A, olfactory bulb ; P and Q, sensory-motor cortex; R, auditory cortex; S, visual cortex. (From Paasonen, Maclean, and Giarman 1957)

Many years ago the Vogts (I 953) in documenting their topistic theory, pointed out several conditions suggestive of a distinctive chemistry of different parts of the hippocampus. In the past fifteen years, several additional studies have served to emphasize the distinctive chemical properties of the hippocampal formation . As illustrated in Plate 1, dithizone , a chelating agent for zinc, strongly stains the mossy fibre system (von Euler 1962; McLardy

Limbic Brain and Psychoses

27

Plate 3 The pronounced fluorescence in the region labelled A indicates the presence of noradrenalin in the radiate layer of the hippocampus. C identifies the pyramidal layer and B the stratum oriens. (From Fuxe 1965a)

1962), giving a deep red colour to the part of the hippocampus corresponding to areas cA4 and CA3 (Maske 1955; Fleishhauer and Horstmann 1957). In the mouse (Plate l) 3-acetylpyridine, an antimetabolite of the antipellagra vitamin niacin, selectively destroys the neurons of this same egion (Coggeshall and Maclean 1958). These areas are also among those parts of the brain that are damaged by methoxypyridoxine (Purpura and Gonzalez-Monteagudo 1960), an antimetabolite of vitamin B6, which induces seizures possibly

28

A Triune Concept of the Brain and Behaviour

BEFORE RESERPINE L. POST HIPPOCAMPUS

7 HOURS

12 HOURS

21 HOURS

27 HOURS

33 HOURS

70 HOURS

Figure 2 Samples showing development of changes in bioelectrical activity of posterior hippocampus of cat following single dose of reserpine (lmg/kg). Records are characterized by persisting theta activity, but note also the slower potentials occurring at 27 and 33 hours. Horizontal scale, 1 sec; vertical scale, l00µV. (From Kim and Maclean, unpublished observations 1955)

because of interference with glutamic decarboxylase activity and the resulting reduction in the neural inhibitor, r-aminobutyric acid (Glaser and Pincus 1969; Tower 1958). Radioautographic studies (Flanigan, Gabrieli, and MacLean 1957) have revealed an unusually high uptake of methionine in the hippocampal formation and other limbic areas (Plate 2), suggesting that the limbic cortex has a greater turnover of protein than the neocortex. Radioautographic techniques have also indicated that testosterone has an affinity for several limbic structures, including the hippocampus (Altman and Das 1965; Pfaff 1968).

29

Limbic Brain and Psychoses

(1)

HOYr"7(CH1CH1NH1

v~N) H

( 2)

(3)

HN

OH

H0~6HCHaNHR

+ McaNCHaCHaOCOCHa

Figure 3 Three classes of drugs noted for their hallucinogenic action are ( 1) substituted indole alkylamines, and (2) phenylalkylamines and those affecting the acetylcholine (no. 3) mechanisms. (Adapted from Downing 1964)

There next crops up the interesting matter of the biogenic amines . Formerly, when pooled samples were used, it was believed that the cerebral cortex and other parts of the forebrain contained negligible amounts of 5-hydroxytryptamine (serotonin). When we assayed specific areas, however, relatively large amounts of this amine were found in the amygdala and overlying pyriform cortex, the septum, and cellular parts of the hippocampus (Paasonen, Maclean, and Giarman 1957). The amount in the amygdala region was comparable to that of the hypothalamus. Figure l shows the values found for the superficial limbic cortex and the neocortex. As regards catecholamines, radioautographic (Csillik and Erulkar 1964; Reivich and Glowinski 1967) and fluorescent (Fuxe 1965a) studies have detected a notable concentration of noradrenalin in the radiate layer of the hippocampus (see Plate 3). These findings are of special interest in view of evidence that tranquilizing and psychotropic drugs known to affect the metabolism of serotonin and catechols induce distinctive electroencephalographic changes in the hippocampus. Figure 2 illustrates the sequence of changes occurring in the cat following the administration of reserpine . Using the Koelle stain for acetylcholinesterase, Lewis and Shute (I 967) have provided an assortment of evidence that in the rat the main pathway to

30

A Triune Concept of the Brain and Behaviour

the hippocampus from the septum is 'cholinergic' in type. In the coypu rat Girgis (1967) has found a high content of cholinesterase material in both the hippocampus and amygdala. The combined presence of cholinergic and adrenergic systems in the limbic brain suggests a certain parallel with the peripheral autonomic nervous system . The above considerations recall that the three major classes of psychotomimetic drugs (Figure 3) are (I) indole alkylamines; (2) phenylalkylamines; and (3) agents interfering with cholinergic mechanisms (Cohen 1967). In LSD, DMT, bufotenine, psilocybin, and harmine, one sees the indole nucleus of serotonin. In mescaline, one sees the phenyl nucleus of catechols such as noradrenalin. Denckla has made the interesting observation that for every tranquilizer there is a compound with a similar structure that has a hallucinogenic action. 1 Recently Dewhurst (1968) has criticized the hypothesis (e.g., Bunney and Davis 1965 ; Schildkraut 1965) that the manic phase of manic-depressive psychoses is attributable to an excess of cerebral catecholamines and the depressive phase to a deficiency. He emphasizes that catecholamines invariably exert a depressant action if administered so as to circumvent the blood brain barrier. He offers a substitute hypothesis that the fault lies in tryptamine metabolism, pointing out among other evidence, that the antidepressant monamine oxidase inhibitors primarily induce an increase in intracerebral tryptamine and that this amine has an excitatory effect on the brain. Ernst, van Andel, and Charbon (I 961 ), however, have reported that the in tracistemal administration of tryptamine produces catatonia in cats and that this effect can be antagonized by 5hydroxytryptamine which never produces catatonia. Tryptemine readily crosses the blood brain barrier. Denckla and I found that when given intraperitoneally to squirrel monkeys, this amine rapidly produces an apparent state of drowsiness and catatonia which lasts for about thirty minutes ( unpublished observations 1969). 5-Hydroxytryptophan exerts a similar but more prolonged action, with the effects persisting for five to six hours (Gelhard,Perez-Cruet, and Gessa 1971 ). A highly purified form of tryptamine is now available , and we shall attempt to learn whether its intracerebral administration produces catatonia or excitement. 2 l W.D. Denckla, personal communication, 1968 2 It was found, as might have been expected, that the intracerebral administration of purified tryptamine in the squirrel monkey resulted in the same kind of symptoms (including pupillary dilatation) seen with intraperitoneal injections. Intracerebral noradrenalin, in doses ranging from 50-S00µg, failed to elicit signs of excitation; the larger doses appeared to produce a state of quietude. Saavedra and Axelrod have reported in a current issue of Science (1972) that tryptamine occurs normally in the rat brain, and that an enzyme that converts it to dimethyltryptamine (a potent psychedelic compound) is present in the rat and human brain

Limbic Brain and Psychoses

31

Van Andel and Ernst (1961) have observed that catatonia caused by tryptarnine can be prevented by eserine. They suggest tryptamine acts as a competitive inhibitor of 5-hydroxytryptarnine at certain receptor sites, eliminating a function which 'tends to strengthen certain acetylcholine activities in the CNS.' On the basis of my own experience with chemical stimulation of the brain, I would not be inclined to favour the hypothesis that noradrenalin acts as an excitant. In experiments on cats in which I deposited noradrenalin (in solid form) in the midbrain reticular formation and other structures, I never observed any notable electroencephalographic or behavioural changes (Maclean 1957b, unpublished observations 195 7). On the contrary, the deposit of cholinergic agents in the third ventricle or surrounding gray matter close to the aqueduct provoked a state of profound excitement and angry 'hallucinatory' behaviour (Maclean 1957b ). It is of interest that Fuxe (1965b) finds a high density of catecholamine terminals in the dorsomedial hypothalamus and medial preoptic region, structures in which electrical stimulation induces such parasympathetic effects as penile erection and cardiac slowing. Is it possible that noradrenalin in these structures may play a role in the regulation of cholinergic mechanisms? The symptoms of patients with psychomotor epilepsy provide the most convincing evidence that the limbic cortex is implicated in the generation of emotional states, as well as symptoms of a psychotic nature. Structures in the lower part of the ring are particularly susceptible to ischemia at the time of birth, as well as to infection and head injury. The herpes simplex virus, for example, has a predilection for the hippocampus and other limbic areas (Drachman and Adams 1962; Glaser, Solitare, and Manuelidis 1964), providing another kind of evidence that the limbic system has a distinctive chemistry. Irritative lesions in or near the limbic cortex in this part of the ring give rise to epileptic discharges accompanied by emotional feelings that under ordinary conditions are important for survival. As mentioned in the preceding lecture, these feelings include terror, fear, foreboding, familiarity, strangeness, unreality, sadness, and feelings of a paranoid nature. Discharges in or near the basal limbic cortex may also result in feelings of depersonalization or what Hughlings Jackson (Jackson and Stewart 1899) called mental diplopia, in which one feels as if one is viewing oneself and what is going on from a distance, a symptom so common in individuals taking psychedelic drugs. To paraphrase Penfield (I 952), the patient feels as if he were in the act of a familiar play in which he himself is both actor and audience . There may also be distortions of perception of the type reported by patients with endogenous or toxic psychoses. Knowledge about the correlation

32

A Triune Concept of the Brain and Behaviour

of the site of the lesion and the symptomatology has been gained particularly from the operative studies of Penfield and Jasper (l 954). They have observed that electrical stimulation in the involved region may elicit the same kind of symptoms as those occurring in a spontaneous seizure. Objects may appear large or small, near or far; sounds may seem loud or faint; one's tongue, lips, and extremities may seem swollen to large proportions. Time may appear to speed up or slow down. Persons intoxicated by psychedelic drugs or suffering from 'return trips' after LSD may experience such disorders of perception. The interseizure symptomatology of some patients with limbic epilepsy may be indistinguishable from that of paranoid schizophrenia. I remember one patient, for example, who was continually obsessed by the feeling that God was punishing her for overeating. While we were recording her electroencephalogram during the expression of these thoughts, random spiking was prominent in the lead from the tympanic electrode underneath her left temporal lobe. Malamud (I 966) has emphasized the high incidence of medial temporal sclerosis in cases of psychomotor epilepsy, and has stated that sclerosis of the hippocampus is a common denominator of this condition. On the basis of clinical and experimental findings, it is probable that in limbic epilepsy the hippocampus is nearly always involved in the seizure discharge, with the discharge either originating within the hippocampus or spreading to it secondarily from related structures. Before taking up some experimental observations I want to emphasize that I am not implying that schizophrenia or other types of psychosis represent a form of epilepsy. Rather, I am placing emphasis on the study of limbic epilepsy as a means of learning what parts of the brain may be responsible for some of the symptomatology seen in the psychoses. No other clinical entity promises to shed more light on mechanisms underlying psychic functions. It is obvious that in dealing with such questions as depersonalization, one must depend solely on subjective reports of patients, but there are some psychotic manifestations concerning which animal experimentation can be helpful in clarifying the underlying neural mechanisms. First, let us consider the question of disturbances of emotion and mood. Sometimes in the wake of after-discharges induced by stimulation of the amygdalo-hippocampal region, a cat may be in an agitated state for several minutes, meowing, running around the room, and trying to climb the walls (Maclean I 959, p. 47). In contrast to this agitated behaviour, after-discharges induced by stimulating a few millimetres further caudally in the hippocampus may be followed by grooming, pleasure, and sexual reactions that persist for several minutes (Maclean I 9 57b ). After stimulations of limbic nuclei that induce penile erection and hippocampal after-discharges, aggressive monkeys

Medial view of squirrel monkey's brain showing approximate location of limbic cortical areas in which single nerve cells were Plate 4 activated by visual stimuli-namely, the posterior hippocampal gyrus (H), and the parahippocampal portion of the lingual gyrus (L), and the retrosplenial cortex (R). The responsive area in the fusiform gyrus (F) falls outside the limbic cortex. The curved black lines schematize the circuitous path of part of the optic radiations traced anatomically to these areas. This component of the radiations would correspond to part of Meyer's loop in man. Arrow points to caudal extremity of rhinal fissure. (From MacLean and Creswell, 1970)

34

A Triune Concept of the Brain and Behaviour

may become placid and tame, and these apparent changes in mood sometimes seem to linger for several hours (Maclean and Ploog 1962). The septum is one of the main sources of afferent connections to the hippocampus (Daitz and Powell 1954; McLardy 1955). As mentioned in the preceding lecture, Heath and his group (I 954) reported that patients experienced pleasurable feelings and persisting changes in mood following stimulation through electrodes presumably in the region of the septum. We turn next to the alterations of perception occurring in the psychoses. As classical anatomy provides no evidence of inputs to the limbic cortex from the auditory, somatic, and visual systems, it has always been puzzling that, with epileptic discharges arising in or near the limbic cortex of the insula and hippocampal formation, patients may experience alterations of perception and hallucinations involving any one of these sensory systems (Penfield and Jasper 1954). Malamud (1966) recently reported a case of a 26-year-old man with a small ganglioma in the uncus-amygdaloidhippocampal region, who, during the epileptic aura variously experienced gustatory, olfactory, auditory, visual, and somatic illusions or hallucinations without loss of consciousness. As not uncommon, this patient subsequently developed mental symptoms diagnostic of a schizophrenic reaction . In the 'visceral brain' paper of 1949, I showed a diagram depicting the convergence of all the sensory systems in the hippocampal gyrus which lies next to and projects to the hippocampus. It was then known that the olfactory system had indirect connections with the hippocampal formation, but there was no experimental evidence of a representation of the other senses. It has since been shown that the septum relays visceral information from the hypothalamus to the hippocampus (Green and Adey 1956). Because of the fundamental role of vision in man and higher primates, I have been particularly interested in the question of a visual input to the limbic cortex {MacLean 1966 ). In order to be certain about the location of neural responses, we have used microelectrodes for recording the activity of single nerve cells. The stereotaxic technique described in the preceding lecture provides a closed system for intracerebral exploration with microelectrodes in chronically prepared, awake, sitting monkeys . The letters H, L, and R in Plate 4 overlie limbic areas in which single nerve cells were activated by photic stimulation (MacLean, Yokota, and Kinnard 1968). A large percentage of responsive cells in the posterior hippocampal gyrus (H) were distinctive from those in all other areas because they gave a sustained onresponse during ocular illumination. The responses of three such cells are illustrated in Figure 4, and their cortical location is shown in Plate 5. It is possible that 'tonic' units of this kind may signal changes in background

35

Limbic Brain and Psychoses

A

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illumination and thereby play some role in wakefulness, alerting, and/or lightdependent neuroendocrine changes. How do visual impulses reach this cortex? Using modification of the Nauta stain for showing fine degenerating cortical fibres, Creswell and I (1970) have examined the brains of twenty-four squirrel monkeys with lesions in the various parts of the geniculopulvinar complex. As illustrated in Plate 6 it was found that a lesion in the ventrolateral part of the lateral geniculate body (the main nucleus for transmitting visual impulses) results in a continuous band of degeneration into the core of the hippocampal gyrus (Plate 5), and that some fibres enter the cortex here and in neighbouring areas. The inferior part of this band corresponds to Meyer's temporal loop in man . It has always been a mystery why this part of the optic radiations takes this temporal detour, but it now appears, on the basis of the anatomic and microelectrode findings, that

! I

Plate 5 Arrows point to the loci of the tips of the microelectrodes recording the unit responses shown in previous figure. The recording sites appear to have been within or just undernearth the granular layer. In the case illustrated on the far left the electrode was fixed in place; in the two other cases a small electrolytic mark was made. (From Maclean, Yokota, and Kinnard 1968)

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broken occasionally when the intoxicated subjects wished to stay up later. After the control period a test-drink was given in the evening (approximately 3.5 oz ethanol in orange juice) to determine individual reactions to the proposed drinking schedule. Each subject showed a definite suppression of REM sleep on that night. Only subject A showed a definite rebound on the following night. The period of morning drinking was curtailed to five days in the case of the alcoholic subject (subj. c) because at the end of this period he said that he could not continue without drinking or obtaining medication outside the schedule. On a morning and evening schedule he continued to drink for a further I 8 days. During withdrawal he twice drank covertly to relieve withdrawal effects.

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140

A Triune Concept of the Brain and Behaviour

TABLE4 Sleep variables in relation to ethanol Subject A

Subject B

Subject C

conditions

conditions

conditions

2

REM%

N X

p Direction REM latency

N

X

p Direction SWS%

N

X

p Direction

4

2

3

4

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7 5 17 4 2 0 0.031 0.025 0.227

13

16 10 8 5 0 3 0.105 0.001 0.363

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7

6

4

8

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+

10

7

12 9 7 5 1 1 0.337 0.020 0.062

N

3

16 10 8 2 6 0 0.227 0.055 0.044

N

p Direction

2

13 10 7 6 4 0 0.500 0.377 0.008

6

X

Total sleep

4

X

p Direction SWS latency

3

•

4

2

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+

3

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1 0.109

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N = nights of observation. X = smaller of observed frequencies. P = probabilities given by the binomial test (small samples). (Siegel, 1956, p. 250) Conditions: 2, morning drinking; 3, morning and evening drinking; 4, withdrawal period

Results (Study 3) The main findings are summarized in Table 4 and discussed individually for each subject. Changes from control night observation are shown for REM and sws under conditions 2, 3, and 4. x represents the number of observations either above or below the median value obtained on the control nights; the smaller of these two frequencies is shown as x and the sign below (entered

Sleep Disorders and Delirium

141

wherever p < 0.10) gives the direction of the change, e.g. 3, -, means that 3 observations are less than the median obtained for control nights. Subject A . In spite of an initial suppression of REM this subject showed very little continuing disturbance of the pattern of REM sleep. In the heavy drinking period (3) values for REM tended to crowd around 15 per cent for several days. Alternation between high values of REM and sws characterize this very stable sleep record despite an over-all shortening of total sleep time. The alternation of these variables has the balance of a passage of Mozartian counterpoint, and in the withdrawal period (4) REM rebound alternates with the redistribution of sws. This subject withstood the effects of drinking well except for a brief depressive reaction following the first exposure to alcohol. Withdrawal symptoms were minimal. Subject B. REM increase with reduced latency was present in the later stages of drinking and during withdrawal. More pronounced was the absence of slow-wave sleep during the heavy drinking period (3). Reduction of total sleep time occurred during withdrawal. This subject was more disturbed during the period of prolonged drinking; irritability, depressive symptoms, awakening with dreaming, and severe morning hangover symptoms were noted, including tremulousness and anorexia. No perceptual symptoms were described. Subject C. The subject with an alcoholic history was older than the other subjects, 54 years. Pronounced suppression of both REM and slow-wave sleep developed during the drinking periods (2 and 3). REM recovery did not include obvious 'rebound' scores. Slow-wave sleep following a brief increase tended to remain low during withdrawal. Two episodes of drinking after a full week of withdrawal demonstrated that suppression effects could still be produced.

Effects on Variables state. In the non-alcoholic subjects REM suppression was only remarkable at the onset of drinking, and REM 'rebound' was associated with the withdrawal period. The alcoholic subject, despite REM suppression, showed no rebound on withdrawal. REM latency. Decreases in REM latency (during withdrawal) were predictably associated with REM increase but occurred only in the non-alcoholic subjects. REM suppression in the alcoholic was associated with postponement of REM. Slow-wave sleep. In one non-alcoholic (the more stable), no effects were noted; the other two subjects showed suppression during heavy drinking; this continued in the alcoholic subject during the withdrawal period.

REM

142

A Triune Concept of the Brain and Behaviour

sws latency. Decreased latencies for sws in subject A (phases 2 and 3) were associated with a strong need for sleep which subject described as 'needing to flake out.' Longer latencies occurred for subject c when sws suppression was observed (2). Total sleep. Total sleeping time was reduced in all periods of drinking and withdrawal, except that the alcoholic subject slept slightly longer during the period of heavy drinking. Most of this sleep was stage I (NREM) and stage 2 sleep, and the subject was characteristically easily woken during this period. Shortening of sleep time in the non-alcoholic subjects was contributed to by their delaying the time of sleep onset. Shock threshold. Figure 4 shows the shock-recognition threshold (derived from small amperage shock given to the hand) for the morning drinking periods throughout study 3. Decreased thresholds develop during heavy drinking, continue in withdrawal, and gradually return to normal values. Discussion

From the small samples represented by these sleep studies only tentative conclusions can be drawn. An attempt will be made to piece together the evidence concerning the effects of ethanol on sleep at the beginning, middle, and end of a period of heavy drinking. The initial effect of ethanol in suppressing REM described by Gresham, Webb , and Williams (1963), Yules, Freedman, and Chandler (1966), Knowles, Laverty, and Kuechler (I 968), is confirmed in study 3. Continued drinking in the evening sufficient to produce definite intoxication (0.08 mgm per cent or more) was followed by continued REM suppression only in the alcoholic subject c. A similar suppression occurred with subject o in a separate study. Both these subjects drank more heavily than the non-alcoholic subjects. Knowles, Laverty, and Keuchler (I 968) have shown that REM suppression and rebound are dependent on dosage. Continued REM suppression during steady drinking might be expected to follow the large quantities and has been described (Greenberg and Pearlman 1967) with occasional nights of high percentage REM consumed by addicted drinkers. That REM suppression is in evidence at the end of the drinking bout is supported by the low percentages of REM in the first night of study 2 on the last day of drinking. However this was also the first night in the sleep laboratory when low values may be expected (Dement 1965). Values such as 0, 0, 7, 9, however, are unusually low. Evidence concerning continued REM suppression from ethanol is therefore conflicting; wide individual differences appear in these samples; definite continued suppression does occur, but so does adaptation.

Sleep Disorders and Delirium

143

Increase in REM on withdrawal after ethanol administration is reported (Knowles, Laverty, and Kuechler 1968; Gross et al. 1966; Greenberg and Pearlman 1967) and confirmed in the non-alcoholic subjects (subjs. A and B) in study 3. The subjects in withdrawal (study 2) also showed an increase in REM during the first four nights, and although this period might be explained as a result of adaptation to the first nights in the sleep laboratory, the pattern follows that seen in REM deprivation studies (Dement 1965) where REM is made up over a period of several nights. Only two subjects in this study (subjs. 6 and 8) showed levels (50 per cent, 46 per cent, 48 per cent) high enough to be described as 'rebound' effects. REM rebound is therefore not a necessary or conspicuous result of the alcohol withdrawal state, even after days of heavy drinking, and its relative absence in alcoholics may be an adaptation to repeated bouts of drinking. Subjects in withdrawal delirium , on the other hand, do show, at least for short periods, very high proportions of REM sleep (Gross et al. 1966; Greenberg and Pearlman 1967). That hallucinations in delirium are a direct result of, or a continuation of, REM-sleep increase appears open to doubt, for the following reasons. (1) Hallucinations may continue during periods when the REM component of sleep is in the normal range, as was observed in subject 3 (study 1). (2) REM sleep in delirious states may be misidentified. In particular, the persistence of muscular activity, generalized restlessness in sleep, and the presence of a variety of eye-movements complicates such records. Vogel (1968) raised this objection in relation to other studies. However, in the current study two good examples of continuous REM sleep were seen in association with waking into a hallucinatory state. (3) REM deprivation as a cause of hallucinatory psychosis has not been confirmed. An exhaustive discussion of REM deprivation studies by Vogel (1968) suggests that total sleep deprivation might be a more important contributing factor in cases cited. REM deprivation is conceded to increase general drive and irritability (Vogel 1968; Agnew, Webb, and Williams 1964), changes commonly seen in alcoholic subjects during drinking and in withdrawal. (4) The disturbances seen in delirious alcoholics, and in the severe withdrawal syndrome , are much more general than those attributable to REM deprivation and rebound, and include the general reduction to sensory thresholds illustrated in Figure 4, increased motor activity, and even major convulsive seizures. It would seem appropriate at this point to include the sleep disorders and perceptual disturbances as symptoms of the unstable state of the central nervous system rather than to explain one symptom (hallucinations) in terms of the other (REM rebound) . The most striking observation common to the sleep records in the alcoholic subjects studied here, has been the low proportion of slow-wave sleep,

144

A Triune Concept of the Brain and Behaviour

and particularly the absence of stage 4. Slow-wave sleep was significantly reduced in experimental subjects B and c (study 3) during the period of evening drinking, while subject A showed a persistent periodic rebound. Records from alcoholics with persisting insomnia have also shown low levels of slow-wave sleep, after abstinence for as long as three months. Smith, Johnson, and Burdick (in press) report a near-absence of slow-wave sleep in 14 alcoholics studied for 12 days of withdrawal, and low values for stage 3. Deprivation of stage 4 sleep (Agnew, Webb, and Williams 1964) has been related to depressive symptoms, and these are common in alcoholics after periods of drinking. A possible synergism appears to link REM and stage 4 sleep. Agnew, Webb , and Williams (1964), for example, report that stage 4 sleep rebound (following stage 4 deprivation) occurs in the succeeding night and may be followed by increases in REM over the next two nights, although no REM deprivation has occurred. Deprivation of stage 4 during drinking may precede (or provoke) additional REM rebound, such as may occur in delirium tremens. Certainly, the finding of changes in both these components of sleep related to ethanol use deserve further investigation. Many other drugs produce REM suppression but few of these are associated with an acute withdrawal psychosis. An exception are the short and medium acting barbiturates (Kales 1969; Oswald, Berger, Jaramillo, Olley, and Plunkett 1963; Oswald and Priest 1965; Kales and Jacobson 1967). Like alcohol, their action and elimination is relatively rapid, and the action of both is associated with the development of tolerance and changes in sleep pattern. Drugs with a slower withdrawal effect appear to be less potent and return to a normal sleep pattern less disruptive.

REFERENCES

Agnew, H.W., W.B. Webb, and R.L. Williams, The effects of stage four sleep deprivation. Electroencephalog. Clin. Neurophysiol., 1964, 17 :68-70 Aschan, G., M. Bergstedt, L. Goldberg, and L. Laureti, Positional nystagmus in man during and after alcohol intoxication. Quart. J. Studies Ale., 1956, 17:381-405 Dement, W.C., An essay on dreams: the role of physiology in understanding their nature. In New Directions in Psychology, 2. New York: Holt, Rinehart & Winston, 1965 Dement, W.C. and N. Kleitman, The relation of eye-movements during sleep to dream activity : an objective method for study of dreaming. J. Exp. Psycho/., 1957, 53 :339-46 Dynes, J.B., Survey of alcoholic patients admitted to Boston Psychopathic Hospital in 193 7. New Engl. J. Med., 1939, 220: 195-8 Engel, G.L., Delirium . In A.M. Freedman and HJ. Kaplan (eds.), Comprehensive Textbook of Psychiatry. Baltimore: Williams and Wilkins, 1967

Sleep Disorders and Delirium

145

Eysenck, H.J. and S.B.G. Eysenck Manual of the Eysenck Personality Inventory. San Diego, Calif.: Educational and Industrial Testing Service, 1963 Goldberg. L., Behavioral and physiological effects of alcohol on man. Psychosomat. Med., 1966, 28 :570-95 Greenberg, R. and C. Pearlman, Delirium tremens and dreaming. Amer. J. Psychiat., 196 7, 124 : 133-42 Gresham, S.C., W.B. Webb, and R.L. Williams, Alcohol and caffeine: effect on inferred visual dreaming.Science, 1963, 140: 1226-7 Gross, M.M., K. Goodenough, M. Tobin, E. Halpert, D. Leport, A. Pearlstein, M. Sirota, J. Dibianco, R. Fuller, and I. Kishner, Sleep disturbances and hallucinations in the !'cute alcoholic psychoses. J. Nervous Mental Disease, 1966, 142:493-514 Isbell, H., H.F. Fraser, A. Wikler, R.E. Belleville, and A.J. Eisenman, An experimental study of the etiology of 'rum fits' and delirium tremens. Quart, J. Studies Ale., 1955, 16: 1-33 Kales, A. Sedatives and sleep-dream alterations. In A. Kales (ed.), Psychology and Pathology of Sleep. Philadelphia: J .B. Lippincott, 1969 Kales, A. and A. Jacobson, Mental activity during sleep: recall studies, somnambulism, and effects of rapid eye movement deprivation and drugs. Exp. Neurol., 1967, Suppl. 4 :81-91 Kat, W. and J.G. Prick, Uber Pathogenese und Klinik des Delirium tremens. Schweiz. Arch. Neurol. Psychiat., 1940, 45: 303-40 Knowles, J .B., S.G. Laverty, and H.A. Kuechler, Effects of alcohol on REM sleep. Quart. J. Studies Ale., 1968, 29 : 34 2-9 Kraepelin, E., CTinical Psychiatry. Adapted from the 7th Gennan ed. and translated by A.R. Defendorf. New York: Macmillan, 1907 Kraines, S.H., Mental Depressions and their Treatment. New York: Macmillan, 195 7 Mendelson, J.H. and J. LaDou, Experimentally induced chronic intoxication and withdrawal in alcoholics. Quart. J. Studies Ale., 1964, Suppl. no. 2: 1-126 Moore, M. and M.G. Gray, Delirium tremens: study of cases at Boston City Hospital, 1915-1936. New Engl. J. Med., 1939, 220:953-6 Oswald, I., R.J . Berger, R.A . Jaramillo, K.M .G. Keddie, P.C. Olley, and G.B. Plunkett, Melancholia and barbiturates: a controlled EEG, body and eye movement study of sleep. Brit. J. Psychiat. , 1963, 109:66-78 Oswald, I. and R.G. Priest, Five weeks to escape the sleeping-pill habit. Brit. Med. J., 1965, v.2 (5470) : 1093-5 Rosenbaum, M., M. Lewis, P. Piker, and D. Goldman, Convulsive seizures in delirium tremens. Arch. Neurol. Psychiat., l 93 8, 40: 922-7 Siegel, S., Nonparametric statistics. New York: McGraw-Hill, 1956 Smith, J.W., L.C. Johnson, and J .A. Burdick, Sleep ; psychological and clinical changes during alcohol withdrawal in NAO-treated chronic alcoholics. (In press) Thompson, G.N., Acute and chronic alcoholic conditions. In S. Arieti (ed.), American Handbook of Psychiatry. New York: Basic Books, 1959 Vogel, G., REM deprivation : Ill. Dreaming and psychosis. Arch. Gen. Psychiat., 1968, 18: 320-8 Yules, R.B., D.X. Freedman, and K .A . Chandler, The effect of ethyl alcohol on man's electroencephalographic sleep cycle. Electroencephalog. Clin. Neurophysiol., 1966, 20: 109-11 Yules, R.B., J.A. Ogden, F.P. Gault, and D.X. Freedman, The effect of ethyl alcohol on electroencephalographic sleep cycles in cats. Psychonom. Sci., 1966, 5:97-8

JOHN B. KNOWLES, EUGENE J. BEAUMASTER, ALISTAIR W. MACLEAN

10

The Function of Rapid Eye Movement Sleep and of Dreaming in the Adult'

Although REM sleep never regains the prominence it enjoys during neonatal life, changes in sleep that occur with age suggest that REM sleep in the adult may be more than a vestige of its neonatal self. Studies conducted in a number of laboratories agree in showing that with increasing age the total period of sleep declines, but that within this span of time the proportion spent in REM sleep remains remarkably constant - approximately 20 to 25 per cent. In contrast, as Table I shows, with increasing years the proportion of stage 4 sleep declines precipitously from approximately 15 per cent in the twenties and thirties to about I to 5 per cent in subjects sixty and over. In other words, while some sleep characteristics change quite dramatically with increasing age, this is not true of the REM state; it persists, and its persistence demands some explanation. What function then does REM sleep perform in the adult? Presumably its function can derive either from the physiological changes that serve to define REM sleep or from the psychological events - namely dreaming - that typically occur during REM sleep. In other words we can distinguish hypotheses about REM sleep from those that refer more specifically to dreaming. One view that clearly falls within the first category is that the cerebral activation characteristically associated with REM sleep serves to maintain cortical tonus or arousal (Ephron and Carrington 1966). From this point of view periods of REM sleep act homeostatically to offset the decline in arousal which occurs during non-REM sleep . We examined this hypothesis by arguing that if it were true then we would expect that the prolongation of non-REM sleep prior to the first REM period would lead to an augmentation of REM activity in the sleep period remaining to the individual; in a sense the late starter would have to make up for lost time. Accordingly, we calculated the regression of REM time on latency to the first REM period in two sets of data Some of the data cited are derived from studies supported by grant # 14 7 from the Ontario Mental Health Foundation and by a grant from Merck, Sharpe, and Dohm

Rapid Eye Movement Sleep

147

TABLE 1 Duration of sleep stages {as percentage of total sleep) in persons of differing age Author

Age

Awake 2 1

16 M

21-31

0.9

5.4 48.7

7.7 13.2 24.l

16 F

19-28

1.1

5.9 48.0

6.9 16.2 21.9

20-29

-

4.9 49.6 10.3 11.2 24.0

19-36

-

9.6 13.0 22.7

30-39 50-60

2.4 4.1

7.5 53.0 10.9 51.1

5.5

8.4

9.6 21.9 2.7 22.8

60-69

9.9

11.9 50.6

4.5

2.7 20.4

64-87

-

6.5 56 .9 14.0

71-95 65-96

-

53.9 17.2 16.5

N Williams, Agnew, and Webb (1964) Williams, Agnew, and Webb (1966) Kales et al. {1967a) 1

% stages after sleep onset

Subjects Sex

10 SM SF Feinberg, Koresko, and 15 9M Heller (1967) 6F Agnew and Webb {1968a) 12 M Agnew, Webb, and 16 M Williams (196 7a) Agnew and Webb {1968b) 16 llM SF Kales et al. (196 7b ) 3 10 SM SF Kahn and Fisher (1969) 16 16M Feinberg, Koresko and 15 9M Heller (1967) 6F

-

2

3

4

1 REM

1.3

22.3

4.5 20.1 7.3 21.1

1 Data for third of three nights of recording 2 In five studies periods ~f wakefulness subtracted from total sleep time 3 Data for fourth of four nights of recording

collected in our laboratory. One refers to a group of 40 subjects for whom REM sleep was calculated from records obtained on the second of two nights. The second set of data refers to a single subject seen for 31 virtually consecutive nights. Within the sample of 40 subjects we found that though the slope of the regression line did differ significantly from zero (see Figure 1), only 17 per cent of the variance in REM time was accounted for by variation in REM latency. The findings on the single subject are even more striking. As Figure 2 shows, the regression line does not differ significantly from zero; if anything, the correlation is negative. Essentially similar results were obtained when we calculated the regression of REM time on latency to the second REM period. Therefore we conclude that our data do not support the homeostatic hypothesis. The behavioural effects of experimentally induced REM deprivation are also relevant to a discussion of REM sleep and the function it might perform. As is well known, Dement (I 960) selectively deprived subjects of REM sleep for four or more consecutive nights by waking them at the onset of each REM period. He reported that 'psychological disturbances such as anxiety, irritability, and difficulty in concentrating developed during the period of

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dream deprivation ...' (p. 1707) though these disturbances were not 'catastrophic.' However, of the seven similar investigations published since that time (Snyder 1963; Kales, Hoedemaker, Jacobson, and Lichtenstein 1964; Sampson 1966; Clemes and Dement 1967; Agnew, Webb, and Williams 1967b; Vogel and Traub 1968; Vogel, Traub, Ben-Horin, and Meyers 1968), only two (Sampson 1966; Agnew, Webb, and Williams 1967) have found adverse mood or personality changes in the REM deprived subjects, and in one of these (Sampson 1966) the clinical observations were not substantiated by psychological test data . In a particularly striking study, Vogel and others (1968) were even able to demonstrate that in a small series of depressed

200

Rapid Eye Movement Sleep

149

patients, deprived of REM sleep for between 7 and 14 nights, those who reacted by showing progressively diminishing inter-REM latencies and by showing the characteristic 'rebound' of REM sleep during the subsequent recovery period were sufficiently improved clinically to be discharged from hospital without further treatment. On the other hand, patients who did not respond to the REM deprivation in these two ways failed to improve clinically. With respect to mood and personality changes it seems reasonable to conclude, as does Vogel (1968), that the early findings 'were probably a result of uncontrolled factors such as the expectations of the experimenters and the subjects' (p. 319). However, it remains possible that REM sleep plays a more critical role in maintaining what we may broadly refer to as cognitive functions. Dement and Fisher (I 963) noted impairment of memory and concentration in their subjects, as did Sampson (I 966), but, in common with most other investigators, Sampson was unable to demonstrate any significant change in scores on objective psychological tests. The fact that test performance has not been adversely influenced by REM deprivation procedures might be taken as lending additional support to the contention that experimenter and subject expectations contributed to the earlier clinical findings, but we have also to consider the possibility that the negative findings are attributable to limitations in the psychological tests employed. Studies of the psychological effects of total sleep loss are highly informative in this connection. From the results of these studies it is apparent that to be sensitive to total sleep loss - and, thus, presumably to loss of REM sleep - performance tests should be long, at least thirty minutes in duration, lack incentive value, and be of moderate complexity. The duration of the test is particularly important (Wilkinson 1968). However, performance tests used in studies of REM deprivation have rarely, if ever, met these criteria. Particularly striking is the fact that for the most part the tests have been relatively brief in duration. Thus, it may be premature to conclude that REM deprivation has no detrimental effects on behaviour. Even so, cognitive and memory impairment is more likely to result from stage 4 deprivation than from REM deprivation, if only because such impairment is most obvious in the elderly in whom, as we have seen, there is a relative absence of stage 4, but not of REM sleep. 2 The existence of reliable individual differences in REM sleep has permitted an alternative approach to the problem of REM function. In a relatively early 2 Subsequent to the presentation of this paper, we were able to analyse the results of a study (Maclean 1969) in which reaction time, dichotic listening, and signal detection tasks were given to subjects during the day following a night in which REM sleep was significantly reduced by the administration of Amitriptyline (Elavil) prior to sleep. None of the tasks were adversely influenced by this experience

150

A Triune Concept of the Brain and Behaviour

study Rechtschaffen and Verdone (1964) reported that within a sample of individuals, distinguished only by their willingness to participate and by stable sleep habits, the proportion of REM sleep was associated with MMPI indices of introversion and anxiety. Working with a similar group of 40 subjects in our own laboratory, Beaumaster (I 968) found little or no difference between introverts and extraverts in this respect, but he was able to confirm that REM sleep was significantly associated with neuroticism as measured by the Eysenck Personality Inventory (Eysenck and Eysenck 1963). These data , which refer to the amount of REM sleep recorded during the first six hours of sleep on the second of two nights of recording, are shown in Figure 3. During this period the 'neurotic' and 'stable' 3 subjects spent respectively 23 per cent and 18 per cent of their time in REM sleep (F = 6.67, p < 0.05). Further analysis of these data showed that this difference was associated with significant differences between the mean latencies of the first REM period (I 36 mins and 89 mins for the stable and neurotic subjects respectively, F = 4.38, p < 0.05). The differences in REM latency, shown in Figure 4, probably account for the differing amounts of total REM sleep in that Beaumaster also found that the neurotic subjects experienced more, rather than longer, REM periods during the remainder of the six-hour sleep period, and that latencies between the remaining REM periods did not distinguish the neurotic from the stable subjects. One other difference between the two groups is noteworthy. The neurotic subjects fell asleep significantly later than did the stable. This was due to the fact that the neurotic subjects went to bed later than did the stable ; both groups took similar times to fall asleep once in bed. Since subjects were asked to come to the laboratory one hour before their normal bed time, it is reasonable to infer that these subjects characteristically retire at a relatively late hour. Though it is probable that personality types differ in their preferred scheduling of diurnal activity, occupational demands are likely to place constraints upon their freedom of choice. Consequently, it is possible that those who retire late suffer some curtailment of their sleep, particularly of the latter part of their sleep period, in which REM sleep predominates. This partial sleep deprivation, if continued for some time, could have two effects. First there may be an adjustment within the sleep cycle such that REM sleep occurs earlier (Webb 1969), secondly there could be periodic REM ' rebounds' occasioning a transitory elevation in REM time. 3 'Neurotic' and 'stable' refer to subjects selected because their N scores were respectively above and below the mean score of 10.08 for a sample of 233 male undergraduates at Queen's University. Stable subjects had scores ranging from I through 8 (mean= 4.90); the neurotic had scores ranging from 11 through 20 (mean= 14.35). There were twenty subjects in each group

Rapid Eye Movement Sleep

151

11 10 9 8

7

f

6

5

'STABLE' (N=20)

4 3 2 1

5 4

f

3

'NEUROTIC' (N=20)

2 1

-10 -20-30 -40 -50 -60 -70 -80 -90-100 101+

Minutes Figure 3 subjects

Total REM time (mins) in first six hours of sleep for 'neurotic' and 'stable '

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A Triune Concept of the Brain and Behaviour

Either or both processes described above could account for the diminished REM latency and increased REM times in the neurotic subjects, but the shorter REM latencies in the neurotic subjects appear to parallel the clinical observation of Hartmann, Verdone, and Snyder (1966) that in one of their cases, a male depressive continuously observed for three months, there was a significant inverse relationship between severity of depression and REM latency. Moreover, in a study of individual differences in response to REM deprivation, Cartwright, Monroe, and Palmer (1967) found that when deprived of REM sleep by being awakened at the onset of each REM period, subjects with high levels of anxiety (as measured by the Taylor Manifest Anxiety Scale) showed the shortest latencies between successive REM periods. In other words, it was the more anxious subjects who had to be awakened the most frequently to prevent the onset of REM sleep. Taken together, these data on personality differences suggest an alternative view that REM sleep derives significance from its psychological concomitants - namely dreaming. In particular, on the basis of their findings, Hartmann, Verdone, and Snyder (1966) speculated that REM sleep may not be related to psychopathology in a general sense, but to be sensitive to periods of what they term psychic disequilibrium or psychic pain. Stated alternatively, it may be that dreaming permits the expression of material that is avoided during the waking state, because this avoidance facilitates coping with stress. If so, we would expect to find increased REM time during periods of stress and, in addition, to find that REM sleep is particularly evident in individuals with relatively high levels of neuroticism. Moreover, if this were true, then one might also expect that dreaming would be particularly prominent in individuals who characteristically cope with stress by repression or denial. Pivik and Foulkes' (1966) findings, that 'repressors' as judged by Byrne's Repression-Sensitization Scale have significantly longer REM periods than do 'sensitizers,' and that when deprived of REM early in the night they react by intensifying the content of subsequent dreams to a greater extent than do sensitizers, are, we believe, consistent with this idea. However, whether this is a defensible proposition rests not only upon the validity of this particular hypothesis about dream function, but also upon the association between REM sleep and dreaming. This remains a contentious issue. Foulkes (1966), in particular, argues that dream-like mentation occurs in non-REM sleep, and we have also to consider the possibility that under unusual conditions, such as repeated awakenings required to deprive someone of REM sleep, or in some individuals, dreaming may be displaced into or occur during sleep stages other than stage 1 REM. The results of a recent experiment by Cartwright and Monroe (1968) suggest that this might be so. In their study subjects were awakened at the onset of each REM period that occurred during

153

Rapid Eye Movement Sleep

7 6 5

'STABLE' (N=20)

-

4

-

3 ~

I

I

9 8

7 6

f 5

'NEUROTIC' (N=20)

4

3 2 1

0

-20 -40 -60 -80 -100-120 -140-160-180-200 201+ Minutes Figure 4

Latency of first REM period (mins) for 'neurotic' and 'stable' subjects

154

A Triune Concept of the Brain and Behaviour

the first 200 minutes of sleep. On awakening, subjects were asked either to recall and elaborate upon the dream material briefly experienced before waking or they were asked to carry out a digit span task which occupied the same length of time and required a similar degree of arousal from sleep. They found that if the subjects were permitted to recount their dream material, to have, as it were, a waking dream, there was no elevation of REM time in the remaining 200 minutes of sleep during which they were allowed to sleep undisturbed, but if they had previously carried out the digit span task, a task designed to block the expression of dream content, there was a significant increase in REM time during the following period of uninterrupted sleep. Also there are a number of reports that dreaming may take place at sleep onset even though laboratory recording of sleep indicates that in normal subjects, at least, REM sleep does not occur until the subject has been asleep some sixty to ninety minutes. For the most part these observations are anecdotal, but Singer (I 966) has reported that he himself experienced a vivid dream shortly after sleep onset, but that rapid eye movements were not evident in the recording made concurrently. Thus, although dreaming usually occurs during REM sleep, there is reason to believe that dreaming is not inevitably linked with the occurrence of REM sleep. This would seem to be a crucial point when evaluating the results of the REM deprivation studies - for if dreaming is, as it were, a moveable feast, the fact that the majority of REM deprivation studies have failed to demonstrate that REM deprivation eventuates in psychological disturbance need not denude dreaming of psychological significance.

REFERENCES

Agnew, H.W. and W.B. Webb, Sleep patterns of 30-39 year-old male subjects. Psychophysiology, 1968a, 5:228 Agnew, H.W. and W.B. Webb, Sleep patterns of the healthy elderly. /bid., 1968b, 5:229 Agnew, H.W., W.B . Webb, and R.L. Williams, Sleep patterns in late middle age males: an EEG study. Electroencephalog. Clin. Neurophysiol., 1967a, 23: 168-71 Agnew, H.W., W.B. Webb, and R.L. Williams, Comparison of stage four and 1-REM sleep deprivation. Percept. Motor Skills, 1967b, 24:851-8 Beaumaster, E.J.B ., Individual differences in rapid eye movement (REM) sleep. Unpublished MA thesis, Queen's University, 1968 Cartwright, R.D. and L.J . Monroe, Relation of dreaming and REM sleep : the effects of REM deprivation under two conditions. J. Personality Soc. Psycho/., 1968, 10: 69-74 Cartwright, R.D., L.J. Monroe, and C. Palmer, Individual differences in response to REM deprivation.Arch. Gen. Psychiat., 1967, 16: 297-303 Clemes, S.R. and W.C. Dement, Effect of REM sleep deprivation on psychological functioning. J. Nervous Mental Disease, 1967, 144:485-91

Rapid Eye Movement Sleep

155

Dement, W.C. , The effect of dream deprivation. Science, 1960, 131 : 1705-7 Dement, W.C. and C. Fisher, Experimental interference with the sleep cycle. Can. Psychiat. Assoc. J., 1963, 8:400-5 Ephron, H.S. and P. Carrington, Rapid eye movement sleep and cortical homeostasis. Psycho[. Rev., 1966, 73 :500-26 Eysenck, H.J. and S.B.G. Eysenck, Manual for the Eysenck Personality Inventory, San Diego, Calif: Educational and Industrial Testing Service, 1963 Feinberg, I., R.L. Koresko, and N. Heller, EEG sleep patterns as a function of normal and pathological aging in man. J. Psychiat. Res., 1967, 5: 107-44 Foulkes, W.D., The Psychology of Sleep. New York: Scribners, 1966 Hartmann, E., P. Verdone, and F. Snyder, Longitudinal studies of sleep and dreaming patterns in psychiatric patients. J. Nervous Mental Disease, 1966, 142: 117-26 Kahn, E. and C. Fisher, The sleep characteristics of the normal aged male. J. Nervous Mental Disease, 1969, 148:477-94 Kales, A., F.S . Hoedemaker, A. Jacobson, and E.L. Lichtenstein, Dream deprivation: an experimental reappraisal. Nature, 1964, 204: 1337-8 Kales, A. , A. Jacobson, J.D . Kales, T. Kun, and R. Weissbuch, All-night EEG sleep measurements in young adults. Psychonom. Sci., 1967a, 7:67-8 Kales, A., T. Wilson, J.D. Kales, A. Jacobson, M.J . Paulson, E. Kollar, and R.D. Walters, Measurements of all-night sleep in normal elderly persons: effects of aging. J. Am. Geriat. Soc., 1967b, 15:405-14 MacLean, A.W., The behavioural effects of Elavil induced deprivation of the rapid eye movement phase of sleep. Unpublished PhD thesis, Queen 's University, 1969 Pivik, T . and D. Foulkes, Dream deprivation: effects on dream content. Science, 1966 , 153 : 1282-4 Rechtschaffen, A. and P. Verdone, Amount of dreaming: effect of incentive, adaptation to laboratory, and individual differences, Percept. Motor Skills, 1964, 19:94 7-5 8 Sampson, H., Psychological effects of deprivation of dreaming sleep. J. Nervous Mental Disease, 1966, 143 :305-17 Singer, J.L., Daydreaming: an Introduction to the Experimental Study of Inner Experience. New York : Random House, 1966 Snyder, F., The new biology of dreaming. Arch. Gen. Psychiat., 1963, 8:381-91 Vogel, G.W., REM deprivation : III. Dreaming and psychosis. Ibid., 1968, 18 :312-29 Vogel, G.W. and A.C. Traub, REM deprivation: I. The effect on schizophrenic patients. Ibid., I 968, 18: 287-300 Vogel, G.W ., A.C. Traub, P. Ben-Horin, and G.M. Meyers, REM deprivation : II . The effects on depressed patients. Ibid., 1968, 18:301-11 Webb, W.B., Partial and differential sleep deprivation. In A . Kales (ed.), Sleep, Physiology and Pathology; a Symposium. Philadelphia: Lippincott, 1969 Wilkinson, R.T., Sleep deprivation : performance tests for partial and selective sleep deprivation. In Progress in CTinical Psychology, vol. 8. New York : Grune and Stratton, 1968 Williams, R.L., H.W. Agnew, and W.B. Webb, Sleep patterns in young adults: an EEG study. Electroencepha/og. Clin. Neurophysiol., 1964, 17:376-81 Williams, R.L., H.W. Agnew, and W.B. Webb, Sleep patterns in the young adult female: an EEG study.Ibid., 1966, 20: 264-6

DUGAL CAMPBELL, JOHN RAEBURN

11

Patterns of Sleep in the Newborn'

In 1955 two papers on sleep appeared side by side in the Journal of Applied Physiology (Aserinsky and Kleitman 1955a, 1955b). Both papers described sleep in terms of a cyclical alternation of two phases. The first of the two papers described sleep in adults and drew attention to the fact that during the periods in which low voltage and fast EEG waves were to be seen, there were also rapid eye movements. The second paper described sleep in infants in whom periods marked by body movements coincided with the rapid eye movements. The two reports included estimates of the duration of the two major phases of the sleep cycle in both adults and infants; in infants the rapid eye movement period apparently lasted for about an hour and the companion quiet phase about 23 minutes; in adults the two phases apparently lasted about the same time : 20 minutes active sleep and 24 minutes quiet sleep. This last result suggested that REM sleep in children differed quantitatively from REM sleep in adults but this aspect of the subject did not at first attract a great deal of investigation. Perhaps because the REM period was described as 'an objective method for the study of dreaming' it attracted a great deal of work (Dement and Kleitman 1957). Dreams and the effects of REM deprivation were the major topics examined in the first few years of the new rush of sleep studies. More recently three kinds of finding have changed the emphasis of interest in sleep studies: studies of sleep in animals, neurophysiological studies of sleep, and studies of sleep made at a variety of times during the human life span. Sleep of a cyclical nature with two phases resembling those in man has been found in all mammals so far examined including species with a long evolutionary history such as the opossum (Snyder 1966). Neurophysiological studies with animals have shown that control of the active phase is due to an area in the brain stem (Jouvet 1967) which again suggests that active sleep may have a considerable history in evolution. This work was supported by the Ontario Mental Health Foundation (grant no. 150)

Sleep in the Newborn

157

TABLE I

Estimates of total sleep time and proportion of REM sleep in children (Hartmann 1967)

Prematures Term infants 0-2 years 2-5 years 5-13 years

Total sleep time (hours)

%REM

? 16 12

50-80 45-65 25-40 20-30 15-20

11

10

The studies of sleep at different ages in human subjects have shown that the pattern of total sleep and active sleep changes during life : the total time spent in sleep falls as individuals get older and the proportion of sleeping time spent in REM sleep also falls (e.g., Feinberg and Carlson 1968). This last result has led to a renewal of interest in sleep in the newborn. Further studies (e .g., Delange, Cadilhac, and Passouant 1962; Monod and Pajot 1965; Parmelee, Wenner, Akiyama, Stern, and Flescher 1967) have confirmed Aserinsky's original observation that infants have a greater proportion of REM sleep than adults. It also appears that the rate of change in the sleep pattern is greater during early infancy than at any other time during life. Similar results have been found in kittens and newborn rats in both of whom quiet sleep is seldom to be found (Jouvet 1967). The results for children are illustrated in the first table which shows estimates of total sleep time and estimates of the proportion of REM sleep during the first decade of life . It can be seen that the decline in the proportion of REM sleep is greater in the first months of life than it is later. Moreover, if one extends the tendency to the period before birth one must assume that the foetus in utero spends a substantial portion of time in active sleep and the few observations available confirm this extrapolation (e.g., Parmelee et al. 1967). You will notice that not only is the estimated proportion of REM sleep greatest about term but also that the variation between the upper and lower estimates is greatest. A starting point of the investigations to be described in this paper was the discrepancies in the proportion of REM sleep said to be typical of newborn infants. An analysis of the original reports showed that a wide variety of criteria have been used in the classification of infants' sleep: some studies have relied upon measures which were made by an observer; others depended upon additional measures for which a permanent record and subsequent analysis were necessary. Both of the techniques provide data which confirm the idea that

158

A Triune Concept of the Brain and Behaviour

sleep in infants can be divided into phases recurring in cycles but the time spent in the two phases can be estimated very differently . It is difficult to compare reports from different laboratories when the criteria upon which the estimates are based differ. One may suppose that the question of criteria to define sleep phases is a question of relatively minor importance. There are two reasons for supposing the point deserves some attention. First of all, if it is assumed that changes in the proportion of the various sleep phases during the early life of the organism can tell us something about the function of sleep and the development of the central nervous system, then it becomes important to measure these changes in a precise way. It has been argued, for example, that active sleep in utero has the function of 'exercising' the CNS (Roffwarg, Muzio, and Dement 1966) by providing inputs which are the equivalent of the stimulation delivered via the external senses after delivery. On this argument one might expect to see a drop in the proportion of active sleep at term when the internally generated stimulation would no longer be necessary. To establish such a proposition exact estimates of REM time are required . A second reason for treating the description of the differing phases of sleep as a point of importance is that studies of some abnormal groups have been made, for example mongol infants, with the idea of demonstrating that their pattern of sleep differs from normal (Goldie, Curtis, Svendsen, and Robertson 1968). Evidently in such studies it is necessary to have a clear description of what is normal in order to demonstrate what is abnormal. The study which I shall report was undertaken with two aims in view. The first was to compare estimates of infants' sleep phases based upon polygraphic measures used both singly and jointly; the second aim was to compare the polygraphic measures with the results obtained by a human observer. Our object was to prepare a scheme for scoring sleep states suitable to be used by a human observer working alone in the infant's home. We therefore required a scheme which had been validated by systematic comparison with measures obtained by the objective polygraphic method of recording and scoring. A group of 17 newborn, term infants was examined . Each child was selected from a full-term nursery in the Kingston General Hospital after an examination of the history of pregnancy and delivery showed an uneventful clinical career. Each baby was taken to the sleep laboratory before a feed and the electrodes necessary to make a polygraphic recording of sleep were applied before and during the feed. The following recordings were made : EEG ; EKG ; EMG; bodily activity; respiration ; horizontal and vertical eye movements. The record began as soon as the baby was put down after the feed and lasted for 120-180 min. While the baby slept he was watched by three observers. Each of the observers was required to make a record of the child's

Sleep in the Newborn Horizontal EM

Vertical EM EMG Respiration

Heart rate

Figure l

Record of a quiet sleep period in a newborn infant

Horizontal E-M

Vertical E-M EMG

EEG (F3-F4)

~ ---Heart rate

Figure 2

Record of an active sleep period in a newborn infant

159

A Triune Concept of the Brain and Behaviour

160

Active

Transitional active

Transitional quiet

Figure 3

Exemplary passages from infant's EEG records

overt behaviour. One observer, who controlled the polygraph, made a note of the number and kind of body movements; another made use of a sleep rating scale which had been used in other similar studies; and the third made a record of the occurrence of visible eye movements. Scoring of the records began with an examination of EEG and respiration. In the records one can see the infant pass through a series of graded changes which describe a continuum ranging between quiet sleep and active sleep. Figures I and 2 show typical examples of quiet and active sleep records. A substantial proportion of most records contained passages of sleep which could not readily be classified as either of the quiet or active sleep patterns shown in these figures. Rather, they were an admixture of both types. Nevertheless, it was possible, by using definite criteria, to classify sleep of this nature as being either predominantly quiet or predominantly active. To such sleep we have given the names Transitional Quiet and Transitional Active, respectively. The two varieties of transitional sleep are of key importance. First, it is a form .of sleep which is peculiar to the infant - although the phases may later be subsumed into the four-stage classification of NREM sleep in the adult. Second, the estimation of the proportion of REM sleep, and the description of the whole active/quiet cycle must be affected by the treatment given this

161

Sleep in the Newborn CLASSIFICATION OF EEG DURING SLEEP

10min

Cycle 1

Periods 1-I____ A_c_ti_ve_________~,-Q_u_ie_t----1l1--1I Cycle2

Periods t-----Ac....;..:_ct-'-'iv_e.;...__ _ _ _ _ _ _ _-+-~---Q..;;.;.;;.u_ie_t_ _ _-H

l■~-■1111

Cycle3

Cycle4 Figure 4

t:JTransitional quiet

fl

Oauiet

■ Active

Transitional active

Sleep cycles in terms of four categories of sleep

stage. If the transitional phases are assimilated to active sleep then one increases the proportion of REM sleep; if they are assimilated to quiet sleep then one diminishes the proportion of REM sleep. The differences can be considerable; for example, in one subject the proportion of the sleep cycle spent in transitional phases was 25 per cent. If this is said to be active sleep then 85 per cent of the sleep time is REM sleep but, if it is said to be quiet sleep, then 60 per cent is REM sleep. The four categories of sleep we have defined - active, transitional active, transitional quiet, and quiet - form the basis of the scoring system devised for EEG and respiration. Eye movements inevitably accompany active sleep, but may also be observed in all other stages - even occasionally in quiet sleep. Every minute of the EEG and respiration records was allotted to one of the four categories: quiet, active, transitional quiet, and transitional active. The results of this division applied to one EEG record will serve as an example. Figure 3 shows exemplary passages from an EEG record. The top line shows an active sleep EEG pattern, the

162

A Triune Concept of the Brain and Behaviour

SLEEP CLASSIFIED FOR EEG RESPIRATION AND EYE MOVEMENTS EEG~ RESP~ EM~ 10min L....----l

~Active

Dauiet

Figure 5 Sleep cycles as defined by independent analyses of EEG, respiration, and eye movements

bottom line shows a quiet sleep EEG pattern, and the two lines in between show transitional sleep. Using these four categories one can analyse an infant's EEG record in the manner shown in Figure 4 . As may be seen, successive minutes which can be scored as one category tended to occur in clusters. A passage which is of one predominant type can be called a period, and such periods correspond to the usual way of describing phases of infant sleep. However, while rules may be laid down for defining a period, in practice they are not always easy to apply, especially where there are frequent minute to minute changes of sleep type. Moreover, periods often contain passages of sleep which are not of the predominant type. An alternative way of describing the proportions of record occupied by different sleep stages is simply to use minute by minute scores, regardless of the general character of the period in which they occur. We have calculated sleep stages by both methods but the results cited here are estimates based upon minute by minute tallies. One period which can be unambiguously delineated by our criteria is the active or REM period. We have made use of this fact to determine the length of the sleep cycle. The cycle is defined as a passage of sleep extending from the beginning of one active period, through the other sleep stages, to the beginning of the next active period. This definition is illustrated by cycles 2 and 3 in the fourth figure. The cycle, rather than the whole sleep record, provides a denominator for statements regarding proportions of sleep occupied by different stages. It also permits an analysis of the changes in these proportions as sleep progresses because two or three cycles are usually obtained in a recording session.

163

Sleep in the Newborn TABLE 2

Quantitative analyses of sleep cycles 2nd cycle

1st cycle

x

SD

%

x

SD

%

EEG

Q A TA TQ Total

11.37 30.87 5.50 5.87 53.61

8.56 7.38 3.82 5.44

21.39 57.63 10.22 10.76

14.25 32.00 4.25 7.37 57.87

7.64 12.23 2.91 4.78

23.60 53.23 7.57 15.60

Respiration

Q A TA TQ Total

9.91 28.33 7.67 5.58 51.49

6.85 13.30 4. 12 3. 17

20.99 52.91 15.34 10.76

7.92 31.17 10.17 7.58 56.84

4.68 15.95 5.95 4.34

13.98 51.15 20.60 14.27

Eye movements

Q A

19.41 35.50

5.71 9.87

35.89 64.11

19.50 36.75

4.94 14.72

37.54 62.46

Observer scale

Q

20.58 34.75

5.21 9.84

37.85 62.15

21.17 34.83

4.80 13.95

40.30 59.69

A

In our experience the first passage of sleep may fall into any one of the four defined categories. It has been said (Roffwarg et al. 1966) that infants pass through an initial REM period but we did not see this in every case. There follows a relatively unpatterned interchange between different categories until the emergence of the first substantial active period, usually around the fortieth minute. Regular cycles then begin. Figure 5 shows, for one baby, the cyclical pattern arrived at independently for EEG, respiration, and eye movements . It can be seen that there is agreement, but not a perfect agreement, between these independent measures, and this is the case for many but not all babies. In the group of 17 babies, the mean length of the first cycle, using the EEG as the criterion measure, was 53 minutes, of which 58 per cent was spent in active sleep, 21 per cent in quiet sleep, and 21 per cent in transitional sleep (equally divided between transitional quiet and transitional active). Table 2 shows means and standard deviations of the time spent in the four sleep categories for EEG and respiration, of the time with eye movements present or absent, and of the time spent in the two major classifications used by the observers. It may be seen that second cycles tend to be longer than first and to have a lower proportion of active sleep. However, we may also say that, in the second cycle, respiration has a tendency to move toward the active end of the continuum, and EEG has a tendency to move toward the

164

A Triune Concept of the Brain and Behaviour

quiet end of the continuum. Eye movements, it may be seen, are present for almost exactly the same time as the sum of EEG active and transitional active minutes in both cycles. From these results one may deduce that there are at least two reasons why estimates of the proportion of REM sleep have varied so much: different criteria provide different figures, and different cycles provide different figures . But one should note that the different estimates provided by the different measures used in this experiment are not large enough to account for the differing estimates found in the literature. Another source of the variance of these estimates may lie in the clinical history of the infant. We have observed sleep, using an observer equipped with a rating scale in another group of 20 infants. Of these 20, seven were subsequently found to have had at least one feature in their history which one can regard as a clinically adverse factor (without any necessary long-term implications) such as a low Apgar score at 5 minutes after birth. In these seven infants the amount of R EM sleep was significantly greater than it was in the other 13 infants. When their sleep records were examined in detail it was found that this increase was due to a change in the pattern of sleep. The suspect group had an earlier onset of REM sleep so that, by the time the period of observation had ended, they had completed their second cycle when the non-suspect group had yet to do so. Taken together, these results suggest that, in the newborn, a feature of sleep to which interest must be directed is the amount of transitional sleep in relation to the criteria used to define transitional sleep and the form of the sleep pattern. Parmelee (Parmelee et al. 196 7) has recently shown that as the infant matures the amount of transitional sleep declines, and this decline can be thought of as a reflexion of the increasing maturity of the brain. The amount of transitional sleep, and changes in the amount of transitional sleep, can be interpreted as a result of differential rates of maturation in the brain stem reticular centres which control the phases of sleep. One can also ask what light these results throw on the function of active sleep. The most attractive hypothesis in our view is that the REM phase has a combined alerting and exercising function which, in the immature system, provides one element necessary for proper development and growth. In the mature system other functions may be acquired , and dreaming is perhaps one of these . But in the infant, as in the many small mammals who spend the greater part of their time asleep, it seems reasonable to suppose that active mechanisms are necessary to do for the brain what manoeuvres do for a standing army in peace time.

Sleep in the Newborn

165

REFERENCES Aserinsky, E. and N. Kleitman, Two types of ocular motility occurring in sleep. J. Appl. Physiol., 1955a, 8: 1-10 Aserinsky, E. and N. Kleitman, A motility cycle in sleeping infants as manifested by ocular and gross bodily activity. /bid., 1955b, 8: 11-18 Delange, P ., J. Cadilhac, and P. Passouant, Les divers stades du sommeil chez le nouveaune et le nourisson. Rev. Neurol., 1962, 107: 271-6 Dement, W. and N. Kleitman, The relation of eye movement during sleep to dream activity: an objective method for the study of dreaming. J. Exp. Psycho/., 1957, 53: 339-46 Feinberg, I. and V.R . Carlson, Sleep variables as a function of age in man Arch. Gen. Psychiat., 1968, 18:239-50 Goldie, L., J.A.H . Curtis, U. Svendsen, and N.R.C. Robertson, Abnormal sleep rhythms in mongol babies. lancet, 1968, 1: 229-30 Hartmann, E., The Biology of Dreaming. Springfield, Ill.: C.C. Thomas, 196 7 Jouvet, M., Neurophysiology of the states of sleep. Physiol. Rev., 1967, 47: 117-77 Monod, N. and N. Pajot, Le sommeil du nouveau-ne et du premature. I. Analyse des etudes polygraphiques (mouvements oculaires, respiration et EEG) chez le nouveaune terme. Biol. Neonatale, 1965, 8:281-307 Parmelee, A.H., W.H . Wenner, Y.Akiyama, E. Stern, and J . Flesch er, Electroencephalography and brain maturation. In A. Minkowski (ed.), Regional Development of the Brain in Early Life. Oxford: Blackwell, 1967 Roffwarg, H.P., J.N. Muzio, and W. Dement, Ontogenetic development of the human sleep-dream cycle. Science, 1966, 152 :604-19 Snyder, F ., The new biology of dreaming. Arch. Gen. Psychiat., 1963, 8: 381-91

a