Progress in Brain Research Volume 18 Sleep Mechanisms

PROGRESS I N B R A I N RESEARCH V O L U M E 18 SLEEP M E C H A N I S M S

PROGRESS I N BRAIN RESEARCH

A D V I S 0R Y B 0.4 R D

W. Bargmann H. T. Chang E . De Robertis j. C . Eccies

J. D. French

H. Xydtn J. Ariens Kappers

S. A. Sarkisov J. P. SchadC

F. 0. Schmitt

Kiei Shanghai

Suenos Aires Canberra Los Angeles Goteborg Amsteraam Moscow Amsterdam Cambridge (Mass.)

T. Tokizane

Tokyo

H. Waelsch

New York

J. Z . Young

London

PROGRESS I N B R A I N RESEARCH VOLUME 1 8

SLEEP MECHANISMS EDITED BY

K. A K E R T Institute for Brain Research, University of Zurich, Zurich (Switzerland)

C. BALLY F. Hoffmann-La Roche & Co. Ltd., Bade (Switzerland) AND

J . P. SCHADG Netherlands Central Institute for Brain Research, Amsterdam (The Netherlands)

ELSEVIER PUBLISHING COMPANY AMSTERDAM / L O N D O N / NEW YORK

1965

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J A N V A N G A L E N S T R A A T , P.O. B O X

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E L S E V I E R P U B L I S H I N G COX%P A N Y L I M I T E D R J P P L E S I D E C O M M E R C I A L E S T A T E , B A R K I N G , ESSEX

This volume contains the proceedings of a SYMPOSIUM O N THE PHYSIOLOGICAL, PHARMACOLOGICAL AND CLINICAL ASPECTS O F SLEEP

organized by the Brain Research Institute of the University of Zurich (Director: Prof. K . Akert) at the Department of Surgery of the Kantonsspifal, Zurich (Switzerland) from 18-19 September, 1964. The Symposium u~ossponsored by F. Hoffmann-La Roche & Co. Ltd., Bade (Switzerland)

F I R S T P U B L I S H E D : 1965

F I R S T R E P R I N T : 1966 LIBRARY OF CONGRESS CATALOG C A R D NUMBER

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ILLUSTRATIONS A N D

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65-20132

TABLES

ALL RIGHTS RESERVED T H I S BOOK OR A N Y P A R T THEREOF MAY N O T BE R E P R O D U C E D I N A N Y FORM I N C L U D l N C P H O T O S T A T I C O R M I C R O F I L M FORM, W I T H O U T WRITTEN PERMISSION FROM THE PUBLISHERS

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OTHER VOLUMES IN THE SERIES PROGRESS IN BRAIN RESEARCH

Volume 1 : Brain Mechanisms Specific and Unspecific Mechanisms of Sensory Motor Integration Edited by G. Moruzzi, A. Fessard and H. H. Jasper Volume 2: Nerve, Brain and Memory Models Edited by Norbert Wiener? and J. P. Schade Volume 3 : The Rhinencephalon and Refuted Structures Edited by W . Bargmann and J. P. Schade Volume 4: Growth and Maturation of the Brain Edited by D. P. Purpura and J. P. Schade Volume 5 : Lectures on the Diencephalon Edited by W . Bargmann and J. P. Schade Volume 6: Topics in Basic Neb-ology Edited by W . Bargmann and J. P. Schade Volume I: Slow Electrical Processes in the Brain by N . A. Aladjalova Volume 8: Biogenic Amines Edited by Harold E. Hirnwich and Williamina A. Himwich Volume 9: The Developing Brain Edited by Williamina A. Himwich and Harold E. Himwich Volume 10: The Structure and Function of the Epiphysis Cerebri Edited by J. Ariens Kappers and J. P. Schade Volume 11 : Organization of the Spinal Cord Edited by J . C. Eccles and J. P. Schade

Volume 12: Physiology of Spinal Neurons Edited by J . C. Eccles and J. P. Schade Volume 1 3 : Mechanisms of Neural Regeneration Edited by M. Singer and J. P. Schade Volume 14: Degeneration Patterns in the Nervous System Edited by M. Singer and J. P. Schade Volume 15: Biology of Neuroglia Edited by E. D. P. De Robertis and R. Carrea Volume 16 : Horizons in Neuropsychopharmacology Edited by Williamina A. Himwich and J. P. SchadC Volume 17: Cybernetics of the Nervous Systern Edited by Norbert Wiener? and J. P. Schade Volume 19: Experimental Epilepsy by A. Kreindler Volume 20: Pharmacology and Physiology of the Reticular Formation Edited by A. V. Valdman Volume 21 : Correlative Neurosciences Edited by T. Tokizane and J. P. SchadC Volume 22 : Brain Reflexes Edited by E. A. Asratyan Volume 23: Sensory Mechanisms Edited by Y . Zotterman and J. P. Schadb Volume 24: Carbon Monoxide Poisoning Edited by H . Bour, I. McA. Ledingham and J. P. Schade

List of Contributors

K. AKERT,Institute for Brain Research, University of Zurich, Zurich (Switzerland). J. ALANO,Psychophysiological Laboratory of the Faculty of Sciences and Centre for Experimental Therapeutics, PitiC Hospital, Paris (France). J. CAHN,Psychophysiological Laboratory of the Faculty of Sciences and Centre for Experimental Therapeutics, Pitic Hospital, Paris (France). M. A. CORNER, Netherlands Central Institute for Brain Research, Amsterdam (The Netherlands). H. E. DIEMATH, Neurosurgical Section and Department of Surgery, University Hospital, Graz (Austria). A. DOENICKE, Department of Neurology and Department of Policlinical Surgery, University of Munich, Munich (Germany). Laboratory of Clinical Science, National Institute of Mental Health, E. V. EVARTS, National Institutes of Health, Public Health Service, U.S. Department of Health, Education and Welfare, Bethesda 14, Md. (U.S.A.). J. GALEANO MuGoz, Clinic of Psychiatry, Medical Faculty, Montevideo (Uruguay). G. GOGOLAK, Pharmacological Institute of the University of Vienna, Vienna (Austria). C. GOTTESMANN, Psychophysiological Laboratory of the Faculty of Sciences and Centre for Experimental Therapeutics, PitiC Hospital, Paris (France). G. HARRER, State Neurological Clinic, Salzburg (Austria). R. HERNANDEZ P E ~ NInstituto , de Investigaciones Cerebrales, A.C., Moras 445, Mexico 12, D.F. (Mexico). A. HERZ,Department of Experimental Neurophysiology, German Research Institute for Psychiatry, (Max-Planck-Institute), Munich (Germany). R. HESSJR., EEG-Department, University Hospital, Zurich (Switzerland). W. R. HESS,Zurich (Switzerland). F. HOW,Medical Clinic of the University of Frankfort-on-Main, Frankfort-on-Main (Germany). L. HOSLI,Physiological Institute, Basle (Switzerland). H. HYDBN, Institute of Neurobiology, Medical Faculty, University of Goteborg, Goteborg (Sweden). M. SOUVET,Laboratoire de Pathologie GCnCrale et Exptrimentale, FacultC de Midecine, Lyon (France). R. JUNG,Department of Clinical Neurophysiology, University of Freiburg, Freiburg (Germany).

LIST OF CONTRIBUTORS

VII

H. KONZETT,Pharmacological Institute, University of Innsbruck, Innsbruck (Austria). A. KUEHN,Department of Pharmacology, Research Division Hoffmann-La Roche Inc., Nutley 10, N.J. (U.S.A.). J. KUGLER,Department of Neurology and Department of Policlinical Surgery, University of Munich, Munich (Germany). W. KUHLO,Department of Clinical Neurophysiology, University of Freiburg, Freiburg (Germany). P. W. LANGE,Institute of Neurobiology, Medical Faculty, University of Goteborg, Goteborg (Sweden). H. LECHNER, Psychiatric-Neurological Clinic, University of Graz, Graz (Austria). G. A. LIENERT, PsychologicalInstitute, University of Hamburg, Hamburg (Germany). M. MONNIER, Physiological Institute, Bade (Switzerland). G . MORUZZI, Physiological Institute of the University of Pisa, Pisa (Italy). I. OSWALD, Department of Psychological Medicine, University of Edinburgh, Edinburgh (Great Britain). E. OTHMER, Psychological Institute, University of Hamburg, Hamburg (Germany). K. PATEISKY, Psychiatric-Neurological Clinic of the University of Vienna, Vienna (Austria). J. J. PETERS,Netherlands Central Institute for Brain Research, Amsterdam (The Netherlands). B. PILLAT,Pharmacological Institute of the University of Vienna, Vienna (Austria). J. P. SCHADB,Netherlands Central Institute for Brain Research, Amsterdam (The Netherlands). W. SCHALLEK, Department of Pharmacology, Research Division Hoffmann-La Roche Inc., Nutley 10, N.J. (U.S.A.). A. SOULAIRAC, Psychophysiological Laboratory of the Faculty of Sciences and Centre for Experimental Therapeutics, Pitie Hospital, Paris (France). R. TISSOT,Department of Psychiatry, University Hospital, Geneva (Switzerland).

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The increasing part played by psychological factors in the genesis of disease is no doubt the price we pay for the rapid advance in our civilization and standards of living. Sleep disturbances frequently give the first warning that the organism is in danger, and in many cases they appear as the main symptom of a manifest psychosomatic disease. As such the sleep problem has become a matter of prime importance, not only for psychiatrists and internists, but also for doctors in other specialties and for the general practitioner. This urgent situation has led brain research to be directed with particular emphasis in recent years towards the nature and regulation of sleep, and the fruits of this work have already been seen in several international symposia. It was the desire of the organizers that this Symposium should concentrate less on the technical and methodological aspects of the problem but should, on the contrary, present more basic information in context and thus provide participants with an ordered, didactic sum of knowledge. In how far the numerous individual contributions have. succeeded in this endeavour must be left to the reader to judge. The organizers and editors wish to extend their special thanks to all those who came from so many countries for making this meeting and exchange of information possible. We should like to thank all those who have helped us, especially the two untiring secretaries, Miss. K. Findeisen and Miss V. Wegelin, as well as the translators Mr. J. Ward and Mr. B. Levin, for their great contribution to the realization of this project. To Professor W. R. Hess, pioneer of sleep research, in the name of all speakers and participants at the Symposium, this volume is dedicated. His presence and active contribution have conferred a special distinction upon this meeting of two generations of scientists. May it be a token of our high regard for him; the immense gratitude we owe him can never be fully expressed.

K. AKERT C . BALLY

J. P. SCHADE

Contents

List of contributors . Preface . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

VI

IX

I. Integral aspects of sleep Sleep as a phenomenon of the integral organism W. R. Hess (Zurich, Switzerland) . . . . . . The anatomical substrate of sleep K. Akert (Zurich, Switzerland) .

....................

3

. . . . . . . . . . . . . . . . . . . . . . . . . .

9

Paradoxical sleep - A study of its nature and mechanisms M. Jouvet (Lyon, France) . . . . . . . . . . . . . .

...............

20

Cortical and subcortical auditory evoked potentials during wakefulness and sleep in the cat A. Herz (Munich, Germany) . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63

Some aspects of the electro-ontogenesis of sleep patterns J. P. SchadC, M. A. Comer and J. J. Peters (Amsterdam, The Netherlands). . . . . . . . 70

II. Microelectrical and molecular aspects of sleep Relation of cell size to effects of sleep in pyramidal tract neurons E. V. Evarts (Bethesda 14, Md., U.S.A.) . . . . . . . . . . .

. . . . . . . . . . . .

81

Rhythmic enzyme changes in neurons and glia during sleep and wakefulness H. HydCn and P. W. Lange (Goteborg, Sweden) . . . . . . . . . . . . . . . . . . . 92 Central neuro-humoral transmission in sleep and wakefulness R. Hernandez Pe6n (Mexico 12, D.F., Mexico) . . . . . .

..............

96

Humoral regulation of sleep and wakefulness by hypnogenic and activating dialysable factors I18 M. Monnier and L. Hosli (Basle, Switzerland) . . . . . . . . . . . . . . . . . . . .

III. Clinical aspects of sleep Sleep and sleep disturbances in the electroencephalogram R. Hess, Jr. (Zurich, Switzerland). . . . . . . . . .

. . . . . . . . . . . . . . . .

Neurophysiological studies of abnormal night sleep and the Pickwickian syndrome R. Jung and W. Kuhlo (Freiburg, Germany) . . . . . . . . . . . . . . . . .

....

127 140

CONTENTS

Some psychophysiological features of human sleep I. Oswald (Edinburgh, Great Britain) . . . . .

XI

...................

160

Objective correlates of the refreshing effects of sleep G. A. Lienert and E. Othmer (Hamburg, Germany)

. . . . . . . . . . . . . . . . . .

170

The effects of certain drugs on the sleep cycle in man R. Tissot (Geneva, Switzerland). . . . . . . . . .

.................

175

Amplitudes and evoked responses in the EEG in humans during sleep and anesthesia J. Kugler and A. Doenicke (Munich, Germany). . . . . . . . . . . . . . . .

. . . .

178

IV. Therapeutic aspects of sleep Pharmacology of hypnotic agents H. Konzett (Innsbruck, Austria)

..........................

185

Neuropharmacc!ogical aspects of the action of hypnogenic substances on the central nervous system A. Soulairac, J. Cahn, C. Gottesmann and J. Alano (Paris, France) . . . . . . . . . . . 194 Effects of benzodiazepines on spontaneous EEG and arousal responses of cats W. Schallek and A. Kuehn (Nutley 10, N.J., U.S.A.) . . . . . . . . . .

. . . . . . . 231

V. Summary statements Summary statement G. Moruzzi (Pisa, Italy)

..............................

Summary and conchsion from the internal medical aspect F. Hoff (Frankfort-on-Main, Germany) . . . . . . . .

241

...............

244

Author Index.

...................................

249

Subject Index.

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254

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I . INTEGRAL ASPECTS O F SLEEP

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3

Sleep as a Phenomenon of the integral Organism W. R.HESS Zurich (Swifzerland)

Sleep may be characterized on the basis of many different criteria. First the eyes are voluntarily, or under certain circumstances involuntarily, closed, the pupils contract, the tonus of the orbicularis oculi, the velum palatinurn and the skeletal musculatzire decreases; and while the respiratory changes may be variable, the blood pressure falls, the heart rate is slowed, the metabolic rate reduced and various changes occur in the blood chemistry. No less characteristic is the reduction of awareness, culminating in ioss of consciousness. The physiologist today is thoroughly informed about these and other processes, and has some insight into the relative expression of the various symptoms and their dependency on external conditions. The book by Kleitman (1939) provides information on all these aspects, whilst the recent review by Jung (1963) adds to the picture. As for my own contribution, my main interest is to coordinate the isolated findings, i.e. to relate the various data to one another and characterize them as elements of an integral functionaI system. MAINTENANCE OF INDIVIDUAL EXISTENCE AS A VALID BIOLOGICAL AIM

To approach more closely the actual subject of this paper we must first discuss the conditions which, as 1 have saiu, enable us tc understand sleep as an integral physiological function. Since we are dealing here with an elementary phenomenon of life, it must be brought into relationship with the basic conditions of life in man and animals, especially those species for which sleep represenis an indispensable phase in the continuity of their existence. The waking state perinits a mode of behaviour that takes account of environmental circumstances and avoids or actively combats threatening dangers. Both of these functions are made possible by the activity of the sensory organs. A further, special skill also comes into play: consciousness of specific sensations translated into awareness. Our subjective interpretation of these sensations motivates our behaviour, whether it be the gathering of food, pouncing, defence, or flight. FACTS OR T H E O R I E S ?

It might be feared that my paper would be purely theoretical and thus superfluous, as giving facts can only advance our understanding. But there are two sides to this References p . 8

4

W. R. HESS

question. I have indeed for years been occupied with obtaining as many data as possible by experiments involving electrical stimulation and circumscribed lesions of specific brain-stem areas. Surely, such observations are indispensable in support of any comprehensive interpretation. Once individual experiments have been concluded, it is essential that the data are interrelated and woven into a theoretical fabric. In this process of general theoretical integration I have repeatedly gained new insight particularly in respect to the organization of the diencephalon. Coordination of the findings is also necessary, if the true significance of the data is to be ascertained; this is especially true in biology. The interpretation of my own experimental results has met with certain reservations, especially in those instances where I have imputed ‘meaning’ or ‘purpose’ to given functional relationships. But such scepticism towards a synthesizing approach to biology means neither more nor less than giving up hope ever to understand the integration of life functions-the alpha and omega of the unity of the individual organism. It is in this sense that my theme has a definite place in biological thought and is, indeed, of paramount theoretical importance. Admittedly, mistakes may be made in our efforts at theoretical integration. But this is also true of the interpretation of individual facts, seeing that all interpretation is ultimately dependent upon our immediate sensations (which may be misleading) and cognitive activities that are necessarily divorced from the immediately given. It is an illusion to suppose that simple facts have by themselves the power to constitute a theory. It is only the inference based upon them that will advance our viewpoints. PARADOXICAL ASPECTS

To return now to the main topic, you will remember that I referred earlier to the general conditions which assure constantly the preservation of life; this is a matter of taking advantage of environmental conditions and avoiding situations that endanger existence. But the situation of a sleeping man is in direct contradiction to these conditions. He can neither appropriate desirable objects, nor appreciate dangers. In animals, too, this suspension of perceptual powers and alertness is of the greatest importance. The question therefore arises why the waking state, organized as it is for safety, is interrupted by periods of sleep. The answer is best provided on the basis of personal experience. TWO PHASES IN THE INDIVIDUAL PATTERN OF LIVING

Let us say I have worked through the day from the early hours with a short break. Whether the effort was a physical or mental one, my capacities often decline in the late evening. My usual fervour for work may disappear and give way to a real disinclination. Yet next morning I feel quite different and am able to undertake my programme in a more positive mood and with better results. Now what happened to me between yesterday and today? Here it is important to realize that all the events of life occur at two different levels. When I see, hear or feel, I am an organized individual

PHENOMENON OF THE INTEGRAL ORGANISM

5

confronting the diversity of the environment, in my relationships with which I am an active agent. That is one level. It comes about by the use of certain sensory organs, built of specialized cells and connective tissues and the performance of which depends on the conditions reigning in the internal milieu of the tissues. It is the function of another group of organs, which provide materials and relieve the system of metabolic waste products, to create and maintain adequate conditions in these tissues. These processes at the lower level ensure the performance of the integral organism. Thus, there is mutual dependence between certain sensory and autonomic functions. Of particular interest here is the hierarchical organization of the autonomic nervous system (Hess, 1924) culminating in the diencephalon, where nervous and hormonal regulation meet and whence a contact with the higher systems of the central nervous system is mediated. The influences here are discernible in two directions, firstly that of an adaptation to better and maximum performance, and secondly that of a buffer against overtaxing the organs concerned, i.e. directed towards protection and restitution. Thus, the two regulatory mechanisms act in competition with one another, which may result in either a balance between them, or a preponderance of one, with the corresponding ergotropic or trophotropic orientation (Hess, 1924, 1925). SLEEP-A

TROPHOTROPIC AUTONOMIC FUNCTION

Like hunger and thirst, physical and mental fatigue automatically makes itself felt. This is the subjective signal that the performance of the individual is no longer up to the external demands made on it. There is a tendency of the integral organism to adjust itself to the situation with which it is confronted. At the height of maximal activity the vegetative functions cannot keep pace with the demands of the moment and a negative balance ensues in the required equilibrium between somatic and autonomic functions. With the onset of fatigue a re-establishment of that equilibrium is introduced. The effects of the involuntary rest during sleep are an unequivocal demonstration of this. In the somatic sphere nothing has happened, and the explanation can be no other than that restorative processes have been in play during the functional relaxation of the organs at the autonomic level. In this light the phenomenon of sleep, judged by its effect, is seen to be a positive function and the obligatory internal rest an indirect means to the end (Hess, 1949). If this whole process is brotight into rektionship with the polarity of the functional organization of the autonomic nervous system it will be seen that sleep is the expression of a predominance of the trophotropic component of the autonomic system and a preventive measure against exhaustion which can no longer be controlled by the flexible processes of adaptation. A question that still remains unanswered is by what means restitution of the tissues occurs. Further, more profound research will be necessary before this can be elucidated. Oxidative mechanisms can probably be excluded, since they are already regulated during the active phase and immediately afterwards. One is led all the more strongly to consider the compensation of defects in the structural organization, either of the cell membranes or conditions within the cell. Whilst here the help of the electron References p . 8

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W. R. HESS

microscopist, the biochemist and the physical chemist must be sought, the neurophysiologist has another aspect to study, namely that of coordinating the various psyahAogica1 and somatic manifestations of the process of falling asleep and of the state of sleep itself. THE SLEEP CENTRE

The well-known and acknowledged achievements of Pavlov in the field of neurophysiology justify the mention first of certain observations and their interpretation related to the mechanism of falling asleep. Pavlov refers to experiments with dogs in which a conditioned reflex had been established. If the feed which regularly followed the ringing of a bell was not forthcoming, some of the animals progressively lost contact with the outside world and fell asleep. Pavlov attributed this behaviour to an inhibition of the salivation released by the bell in the absence of the expected feed, this inhibition spreading to a wide area of the cerebral cortex. The observation described is doubtless correct, and 1 myself have been able to verify the same phenomenon later. Nevertheless, the interpretation of a cortico-central mechanism is open to doubt. In our opinion the explanation could well be hypnosis, in which following the stimulus of the bell the attention of the dog is increasingly focussed on the expectation of the feed, whilst other connections with the outside world are repressed. There are, indeed, parallel indications in experiments on hypnosis in animals. The application of delicately apportioned electrical impulses to certain areas of the diencephalon points to a different interpretation. Within a half to a few minutes signs of drowsiness are visible in cats. In well differentiated cases this gives way to typical sleep behaviour. On the basis of these observations we have come to regard this change as the manifestation of diencephalic organization and to connect it with a sleep centre which may be presumed for the most part to be located in the diencephalon. The effect produced is thus brought into line with the urge to eat, the affective defense reaction, the flight reaction, and other elementary patterns of vital behaviour, and the close relationship with the autonomic nervous system is emphasized. A point to be noted is also the contact between the nervous apparatus and the pituitary, acting as the ‘control centre’ of hormonal regulation, a fact that calls to mind the possibility of hormonal components being implicated in the function of sleep. Finally in view of recognized nervous connections the inclusion of higher cerebral systems into the picture becomes reasonable. The structures responsible for the induction of sleep still remain to be defined precisely, however. In our own experiments stimulation of the area close to the lower portion of the massa intermedia and the adjacent area towards the anterior nucleus produced a definite somnogenic effect. The latest reports indicate that other structures of the brain stem participate in regulating the waking-sleeping pattern (Moruzzi, 1963 ; Hassler, 1964; Parmeggiani, 1964). Further experimental observations will be necessary to show in how far theareas participating in sleep induction comprise an integrated system.

PHENOMENON OF THE INTEGRAL ORGANISM

7

THE RELATIVITY OF THE CONDITIONS FOR SLEEP

Under normal conditions the transition from the waking to the sleeping state follows the rhythm of day and night. But this pattern may be affected by other external or internal factors such as noise, which acts both as an obstacle to sleep and a stimulus of arousal. Its efficacyin this respect is not related to its volume alone. The nature of the sound is of importance, too, and after continual repetition certain noises will be recognized as irrelevant and will no longer be a disturbing factor. This is dependent on a selective latent alertness in the individual, which may include judging the passage of time. An endogenous factor influencing sleep-apart from pathological states-is affective excitation, which interrupts the absolute rest. But neutral thought processes, too, can have a delaying effect on sleep, when intense mental activity before the moment of retiring continues to function, and no effort of will is made to counter it. Such an effort of will can, on the other hand, serve to delay sleep in the interest of a set task, for days and nights if necessary. But finally the endogenous need for sleep makes itself so forcefully felt that the readiness of the sensory organs to receive stimuli and the capacity for somatomotor activity both break down. In animal experiments, too, a certain differentiation of sleep can be recognized in that in some cases it is inhibition of sensory perception that dominates the picture, and in other cases relaxation of the skeletal musculature (Hess, 1954). Such a dissociation is demonstrated particularly clearly in individuals who walk in their sleep. A generalized phenomenon is the temporary manifestation during sleep of certain cerebral functions, namely in the dream phases. One or other, or sometimes several, of the sensory faculties can participate here and even, abortively, the somatomotor system. A synoptic study of the various characteristics of sleep leads to the conclusion that sleep is not tantamount to a passive loss of function but is the conditional action of a structural organization. In other words, the sleep centre is a functionally organized system. This I feel to be of the greatest importance, for the facts represented here are of profound significancefor the interpretation of existing and future results of research. SUMMARY

(1) In contrast to the prevalent tendency in physiological research to reduce functional

systems to their elementary components, stress is laid on striving to conceive them integrally. (2) On the basis of experimental results sleep is classified as a vegetative mode of behaviour essential to survival. (3) The activity of the autonomic organs determines in the somatic sphere the readiness of the organs to act. (4) The meaningful classification of symptoms is primarily a theoretical endeavour. Experimental control affords insight into reality. (5) Viewed superficially, sleep seems to have mainly negative aspects. However, in the light of its restorative functions, it should be viewed as a fundamentally positive phenomenon. References p . 8

8

W. R. HESS

(6) Waking and sleeping alternate under natural conditions in a rhythm specific to the species and the individual. Changes can be produced in the pattern by both exogenous and endogenous influences. (7) Considerable individual differences occur in the ‘structure’ of sleep, because given individual central systems may be inhibited to a varying degree, while others may be relatively activated. (8) Experimental findings point to the activity of a central nervous organization localized in the brain stem-especially the diencephalon-which may be regarded as a functional sleep centre. ACKNOWLEDGEMENT

The author wishes to express his gratitude to Dr. E. Lenneberg for translating his manuscript from German into English. The work was supported by the Swiss National Foundation for Scientific Research. REFERENCES HASSLER, R., (1964); Spezifische und unspezifische Systeme des menschlichen Zwischenhims. Progress in Brain Research, Vol. 5. Lectures on the Diencephalon. W. Bargmann and J. P. Schade, Editors. Amsterdam, Elsevier (p. 1-32). HESS,W. R., (1924, 1925); Uber die Wechselbeziehungen zwischen psychischen und vegetativen Funktionen. Schweiz. Arch. Neurol. Psychiat., 15, 260-277; 16, 36-55; 285-306. HESS,W. R., (1948); Die funktionelle Organisation des vegetativen Nervensystems. Benno Schwabe, Basel. HESS,W. R., (1949); Le somrneil comrne fonction physiologique. J. Physiol., 41, 61A-67A. HESS,W. R., (1954); Das Zwischenhirn. Benno Schwabe, Basel (p. 43). JUNG,R., (1963); Der Schlaf. Physiologie und Pathophysiologie des vegetutiven Nervensystems. II. Band, Pathophysiotogie. M. Monnier, Editor. Hippokrates Verlag, Stuttgart (p. 650-684). KLEITMAN, N., (1939); Sleep and Wakefulness. University of Chicago Press. MORUZZI,G., (1963); Technical (final) Report, Research on Relations of Brain Stem Reticular Formation to Animal Behavior. Arti grafiche Pacini Mariotti, 1-13. PARMEGGIANI, P. L., (1964); A study on the central representation of sleep behaviour. Progress in Brain Research, Vol. 6. Topics in Basic Neurology. W. Bargmann and J. P. SchadC, Editors. Amsterdam, Hsevier (p. 180-190).

9

The Anatomical Substrate of Sleep K. AKERT Institute for Brain Research, University of Zurich, Zurich (Switzerland)

The anatomist is primarily interested in the following two questions : (1) Where is the somnogenic substrate to be found? (2) What are its structural elements? Let me make it quite clear at the beginning that this paper will deal with only the first question; a clear answer to the second does not seem possible at present. In answering the first question, we shall make use of both clinical and experimental observations. CLINICAL OBSERVATIONS

One would expect useful information from the two contrasting sleep disturbances, insomnia and hypersomnia. Accordingly, a collection was made of all cases reported in the literature which comprised both sufficient clinical data and an anatomo-

Fig. 1. Location of waking (3) and sleep centres (S) according to Von Economo (1929). References p . 17-19

10

K. AKERT

pathological description of a circumscribed process. Astonishingly enough, there was not a single case of insomnia which qualified. Von Economo (1929) concluded from TABLE I OBSERVATIONS ON SOMNOLENCE I N ~-

NO.

17 CASES ~-~

Author

Symptom

Sex,age

Patliology

-

Localization

6 28 Chronic encephalitis Dorsal parts of ped. cer., thalamus, floor of I V ventr. and lat. grey of I11 ventr. 2 Fulton, J. F.. case 2 Drowsiness 9 28 Leptomeningial Tumour (2 x 1.5 cm) of Bailev, P., (1929) sarcoma infundibular region 3 case 4 Drowsiness 3 20 Astroblastoma Egg-shaped tumour (5 x 3 cm) freely movable in 111 ventr. fixed at left col. fornicis with temporary obstr. of aqueduct 4case 5 Drowsy 6 15 Pinealoma Gland. pin., 111 ventr. attacks 5 Marinesco, G. case 1 Sopor S 7 Tbc. meningoBase of brain, infiltr. nc. et a/.(I 929) encephalitis tub., nc. periventr., hypoth. 6 case 2 Sopor 3 40 Tbc. meningoBase of brain, sulcus Sylencephalitis vii, walls of 111ventr. 0 13 Tuberculoma Distension of I11 ventr. by 7 case 3 Sopor tumour, peduncular cap., aqueductal grey 8 Rowe, S. N. case 1 Sopor 6 47 Glioblastoma Rostra1 tip of mesenceph(1935) multiforme alon, aqueductal grey, dorsomedial nc., centre median, pulvinar, habenula Sopor 9 36 Small infarct Small lesion of right thala9 Schaltenbrand, G. (1 949) rnus, fasc. mamm.-thalam., anterior intralarninar and dorsomedial thal. nc. 10 Orthner, H. case 2 Sopor S 49 Craniopharyngeoma Small tumour invading (1957) tuber cin., anterior grey of thalamus, mama intermedia 11 Krayenbuhl, H. case 15 Sopor 0 46 Electro-coagulation Lesion (5 rnm) in left et al. (1965) (stereotaxic) in ventrolat. thalamus inParkinson’s disease vading centre median 12 Martin, J. P. Sopor 9 5 6 Hemorrhage Middle of pons, median (1949) and lateral fillets, 6th and 7th nerve nuclei 13 Davison, C., case 1 Sopor 36 Hernangioblastorna 1V ventr. and periventriDemuth, E. L. cular grey of med. (1 946) oblong. 14 case5 Sopor d 42 Spongioblastoma Periaqueductal grey, tegm. mesenc. 15 case 3 Sopor,coma 8 33 Hemangioblastoma Pons compressing tegm. mesenc. 16 Campbell, A.C.P., case 3 Lethargy ? 48 Polioenceph. hem. Paramedian nc. of thalaBiggart, J.H., sup. Wemicke mus, hypothal. and (1939) midbrain tegm., periaqueductal grey 17 case 11 Drowsiness ? 23 Polioenceph. hem. Corp. mamm. and other sup. Wernicke midline struct. of hypothal. and thal. 1 Gayet, M. f 1875)

Sopor

T H E ANATOMICAL SUBSTRATE OF SLEEP

11

observation of patients with striatal hyperkinesia and generalized agitation that a region in the anterior hypothalamus was responsible (Fig. 1). His idea was not far wrong. Akert and Hess (1962) recently described in detail a case of an agitated state caused by damage to the suprachiasmatic area, and suggested that disinhibition of the dynamogenic zone in the posterior hypothalamus, due to failure of the rostrally situated antagonistic system, played an important role. There are far more observations on somnolence. Seventeen cases were selected from the many available in the literature, and are summarized in Table I. Fig. 2 shows the localization of the lesions, in which five groups can be distinguished : hypothalamic, thalamic. mesencephalic, pontine, medullary. They are distributed throughout the brain stem. Greater differentiation is not really possible, although it is apparent for instance that medially situated thalamic lesions tend to cause somnolence while lateral lesions produce no disturbances in the sleepwaking rhythm (Krayenbuhl et al., 1965). Of particular interest are the cases of Wernicke’s polioencephalitis hemorrhagica superior involving the limbic midbrain and pontine nuclei, frequently associated with hypersomnia (Campbell and Biggart, 1939).

Fig. 2. Location of lesions in clinical cases of hypersomnia. Numbers correspond to cases in Table I.

If the balance is drawn up of these observations, the first important fact becomes clear: there is no single site of predilection for sleep, as Mauthner (1890) and Von Economo (1930) believed, but a widely dispersed substrate which is difficult to apprehend histologically and anatomically.

EXPERIMENTAL OBSERVATIONS

We shall =strict ourselves here to a few classic studies which are especially relevant to the problem of localization. We start from the widely accepted hypothesis that the Rrferences p. 17-19

12

K. AKERT

level of excitation in the brain cells, and especially the cortical neurons, which determines the sleeping and waking states, is under the influence of both an inhibiting and an activating system in the brain stem, each of which, by reciprocal inhibition of its antagonist can produce particdar nuances of behaviour. For this reason, we must briefly consider these two systems. ( I ) Localization of the arousal system By means of electrical stimulation, Moruzzi and Magoun (1949) demonstrated the arousal effect of the mesencephalic tegmental reticular formation on behaviour and EEG. Conversely, bilateral, circumscribed lesions in this area result in more or less severe impairment of attention and vigilance (Lindsley et al., 1950), although the more critical study of Sprague et al. (1963) indicates that some of these defects are shown by prolonged observation to be reversible. Although in the beginning the reticular elements of the upper part of the brain stem-and above all the meso-diencephalic border-were especially emphasized, Moruzzi and Magoun (1949) themselves stress the systemic nature of the arousal substrate, as a central reticular zone traversing the whole brain stern. Later Batini et al. (1959) and Cordeau and Mancia (1959) were able to show that particularly important elements of the arousal system were located in the area of the pons. By comparing unilateral and bilateral sections in the pons and midbrain, they were able to produce evidence of considerable differences in EEG and behaviour. Midbrain section (cerveau isole : Bremer, 1935) leads characteristically to somnolence with predominantly synchronized cortical activity, whereas after midpontine, pretrigeminal section, a waking state, with desynchronized rapid cortical activity predominates. It was concluded from this work that arousal stimuli which are significant for the cortex arise from the anterior third of the pons. Such investigations can, of course, only delineate the rough outlines of an active area. The question especially of how far back this activation area extends has not yet been satisfactorily settled, since according to Batini et al. (1959) pronounced activating effects on the cortex can still be elicited after transecting the pons at the posterior end, whereas Rossi et al. (1963) restrict the area to the anterior half of the pons on the basis of experience with unilateral transections (Fig. 3). When severe agitation occurs, one must also consider the possibility of the activating systems having been freed from the normal inhibitory effect of antagonistic areas. Such areas are to be found especially caudally in the dorsal part of the medulla oblongata and rostrally in the preoptic region. This would explain how lesions in the anterior hypothalamus and neighbouring structures can lead to severe excitation and sleeplessness, as the activating centers in the posterior hypothalamus are no longer inhibited. In the same way the marked agitation produced by section of the pons at B in Fig. 3 is probably at least partly due to the elimination of medullary centers which normally inhibit the midbrain-pontine activating areas. Another important point is that the reticular activating system depends on excitation by both nervous stimuli, transmitted by peripheral receptors, and humoral

THE ANATOMICAL SUBSTRATE OF SLEEP

13

factors. An example of the effect of peripheral stimulation is the observation, following section at A in Figure 3 on the meso-diencephalic border, that activation responses can only be elicited with difficulty, in spite of the persistent connection with the cerebrum of the dynamogenic zone in the posterior hypothalamus shown by Hess (1944) in central stimulation experiments to be so powerful. Apparently, impulses from the olfactory and optic nerves are not sufficient to maintain function in this part of the activating system, nor does it possess adequate autonomous activating potential.

desynchron.1

A

6

Fig. 3. Influence of prepontine and midpontine section of the brain stem on electrocortical activity (Rossi et al., 1963).

This strongly suggests that caudal reticular elements and their afferent supply play an essential role in maintaining the waking state. The role of humoral factors such as epinephrine, norepinephrine, sex hormones, and C 0 2 are sufficiently well known through the work of Bonvallet et al. (1956) and Rothballer (1956). It remained for Livingston (1957) with a group of his co-workers to show that the arousal system of the brain stem not only influences the cortex as just described but also receives back important arousal stimuli from certain areas of the cortex (especially association cortex). Finally, we should mention that the activating system exerts an effect on behaviour through the cerebral cortex on the one hand, via cortico-spinal and cortico-bulbar systems. On the other, however, there is the direct descending system of reticulo-spinal pathways (Magoun and Rhines, 1947) which controls not only effectors but also the reactivity of receptors (Granit and Kaada, 1952). Lastly there are also the impulses transmitted from the hypothalamus to the autonomic nervous system and the pituitary control of the endocrine system to be mentioned. It is not our task here to offer all the detailed evidence, but simply to show that the neuroanatomist is not so much concerned any more with a single focal area but rather with a complete system of peripheral and central elements which interrelate and interact in multiple circuits (Fig. 5, right). References p . 17-19

14

K. AKERT

( 2 ) Localization of the inhibitory or sleep system

Pavlov (1927) pointed out active inhibiting processes which, according to his idea were initiated by the cortex in the course of a conditioning experiment. A direct inhibitory process was obtained by Hess (1944) particularly by experimental stimulation of the thalamus. The location of Hess’ sleep centers are shown in Fig. 4. These experiments had long been denied their due recognition, but they have been confirmed in recent years by numerous workers in various species (Akimoto et al., 1956; Caspers and Winkel, 1954; Proctor et al., 19571, so that there can no longer be any doubt as to the correctness of the findings. Hess characterized the thalamic regions lateral to the massa intermedia as the most important hypnogenic area.

i

...... .........

Fig. 4. Location of points in the brain stem a: which stimulation (Hess, 1944) produced steep or sleeplike behaviour in freely moving cats. 1 = Jntralaminary thalamus; 2 = Caudatenucleus; 3 = Preoptic and supraoptic areas.

Investigations of Akert et al. (1952) indicate that the substrate is probably the intralaminar nuclei (Morison and Dempsey, 1942; Jasper, 1949) a view which is supported by Hassler (1964). Further, there is the caudate nucleus. We know today that this structure and the intralaminar thalamus are directly connected anatomically (Powell and Cowan, 1956). The inactivating effects from the caudate nucleus were studied in greater detail by Akert and Andersson( 1951)and Buchwald et al. (1961) have revealed the electro-physiologica1 reflections in the cortex and multisynaptic transmission of these processes. Another inhibitory area reported by Hess is in the supra- and prechiasmatic region, today regarded, especially by Sterman and Clemente (1962) and Hernandez Pe6n and Chavez Ibarra (1963) as one of the major EEG synchronizing substrates. This probably extends further rost&y. Observations of Nauta (1946) can also be included in this system, which in principle inhibits Hess’ dynamogenic area in the posterior hypothalamus and thus exerts a sleep-inducing or sleep-facilitating action basically by recirmcal inhibition.

THE ANATOMICAL SUBSTRATE OF SLEEP

15

A new development was initiated by Parmeggiani (1960) who was able to elicit sleep and sleep-like effects from the cortical and subcortical elements of the limbic system by electrical stimulation (Hess-Wyss method). This was foreshadowed in the earlier literature in that Waldvogel (1945) found in Hess’ preparations a concentration of points in the region below the anterior commissure from which yawning could be elicited, in some cases repeatedly, by electrical stimulation. It .seems as though there may be two sleep systems in the forebrain, a neo-sleep system and a paleo-sleep system, the ascending limbs of which in the lower brain stem are not so clearly distinguishable. Furthermore, we should mention the results obtained by Magnes et al. (1961) in stimulation experiments and by Bonvallet and Allen (1 963) by means of localized lesions in the region of the nucleus tractus solitarius, which appears to exert a strongly synchronizing effect on cortical activity and to compete with the bulbo-pontine activating system under normal circumstances (Fig. 4). Moruzzi (1963) recently described the synchronizing action of this medullary region in masterly fashion. All in all, multiple brain areas seem to contribute to the initiation and maintenance of sleep and it seems that these areas are either part of or in close association with the reticular formation of the brain stem. Consideration of the sleep system would be incomplete without reference to the peripheral afferents and the humoral factors which normally stimulate this system and keep it in action. While the role of certain receptors and specific modes of their stimulation were carefully worked out by Pompeiano and Swett (1963), the investigations of Cordeau et al. (1963) suggested that cholinergic transmitters are involved in the hypnogenic process. These latter findings have a worthy predecessor in the studies of Hess (1925) who already at this early date was able to induce sleep by intraventricular administration of ergotamine. Up to this point, ascending hypnogenic mechanisms have been considered. Mention must be made of descending components of the sleep system as well: first of all the inhibitory system descending directly from the brain stem, described by Magoun and Rhines (1946), which decreases reflex excitability of spinal motor neurons. And secondly, the descending inhibitory system for certain receptors, described by Desmedt and LaGrutta (1963) and Granit and Kaada (1952). As already indicated earlier, the reticular formation is not only the regulator of cortical activity, it also receives from the cortex important impulses and is thereby subject to cortical control. We mentioned at the beginning of this section the observation by Pavlov (1927) suggesting the likelihood of an inhibitory influence of cortical areas on the brain stem. Jouvet (1961) showed experimentally that frontal areas are of particular importance for maintaining the synchronizing activity of thalamocortical systems. Further research will be needed to define these regions more exactly. As stated at the end of the previous section, one comes to realize that the sleep system too comprises widespread areas of subcortical grey matter and related receptor and effector organs. Its functional and anatomical make-up bears close resemblance with that of the arousal system (Fig. 5). Considering the organization of the two, one is struck by its analogy with the dualistic structure of the autonomic nervous system. Rqferences p . 17-19

16

K. AKERT

To mention only the fine caliper nerve nets, their cholinergic and adrenergic sensitivity, and their balancing action on a given organ. Further research on the fine structure and ASLEEP

AWAKE

Fig. 5. Sleep and arousal systems. The emphasis is not on nuclear centers in the brain stem but on integrated control circuits in which the so-called centers are shown to be themselves end-organs for peripheral and cortical influences. (Modified from Hernandez Pe6n and Chavez Ibarra, 1963.)

the continuity of these networks will have to determine whether they form a truly integral system of fine control over cerebral as well as bodily functions. SUMMARY

(1) The anatomical substrate of sleep can no longer be regarded as a centre, but must be seen as an integrated system on which peripheral receptors, humoral factors, ascending and descending pathways of the reticular formation and the neocortex and paleocortex all impinge on one another i n multiple circuits. (2) There are specific regions in the brain stem which are particularly involved in the process of sleep. These include: (a) the intralaminary nuclei of the thalamus; (b) the caudate nucleus; (c) the preoptic area and (d) medullary areas around the nucleus solitarius. ( 3 ) The last two must probably be considered especially as inhibitors of the arousal system in the posterior hypothalamus and anterior third of the pons respectively. (4) Consideration of the sleep system by itself is not enough. In order to obtain certain sleeping states, the function of the reticular activating system must also be reciprocally inhibited. (5) Comparison of the structural elements of the sleep system with those of the arousal system shows them to be organized in the form of mirror images. In the brain

THE ANATOMICAL SUBSTRATE OF SLEEP

17

stem the two systems are so closely interwoven as to be in fact almost inseparable. The functional and anatomical organization of the two systems resembles closely the one of the autonomic nervous system. ACKNOWLEDGEMENTS

The author had the advantage of frequent discussion with Prof. W. R. Hess, Dr. R. B. Livingston and Dr. R. Hernandez Pe6n. My colleague, Dr. F. Wyss, assisted in the compilation of clinical observations and in the preparation of the illustrations. The work was supported by Grant USPH, NB-3705.

REFERENCES B., (1951); Experimenteller Beitrag zur Physiologie des Nucleus caudatus. AKERT,K., and ANDERSON, Acta physiol. scand., 22, 281-298. AKERT,K., and HESS,W. R., (1962); Uber die neurobiologischen Grundlagen akuter affektiver Erregungszustande. Schweiz. tned. Wschr., 92, 1524-1530. AKERT,K., KOELLA, W.P., and HESS,R., Jr., (1952); Sleep produced by electrical stimulation of the thalamus. Arner. J. Physiol., 168, 260-267. AKIMOTO, H., YAMAGUCHI, N., OKABE, K., NAKAGAWA, T., NAKAMLJRA, I., ABE,K., TORRJ, H., and. MASAHASHI, K., (1956); On the sleep induced through electrical stimulation of the dog thalamus. Folia psychiat. neurol. jap., 10, 117-146. BATINI,C., MORUZZI, G., PALESTINI, M., Rossr, G. F., and ZANCHEXTI, A., (1959); Effects of complete pontine transections on the sleep-wakefulness rhythm: the midpontine pretrigeminal preparation. Arch. ital. Biol., 97, 1-12. BONVALLET, M., and ALLEN,M. B., Jr., (1963); Prolonged spontaneous and evoked reticular activation following discrete bulbar lesions. Electroenceph. clin. Neurophysiol., 15, 969-988. BONVALLET, M., HUGELIN,A., and DELL,P., (1956); Milieu inttrieur et activite automatique des cellules reticulaires mesencephaliques. J. Physiol. Path. gin., 48, 403406. BREMER, F., (1935); Cerveau isole et physiologie du sommeil. C .R. SOC.Biol., 118, 1235-1242. BUCHWALD, N. A., WYERS,E. J., OKUMA, T., and HEUSER, G., (1961); The ‘caudate spindle’. I. Electrophysiological properties. Electroenceph. din. Neurophysiol., 13, 509-51 8. CAMPBELL, A. C. P., and BIGGART, J. H., (1939); Wernicke’s Encephalopathy (polioencephalitis hemorrhagica superior): Its alcoholic and non-alcoholic incidence. J . Path. Bact., 48, 245-262. CASPERS, H., and WINKEL, K., (1954); Die Beeinflussungder Grosshirnrindenrhythmik durch Reizung im Zwischen- und Mittelhirn bei der Ratte. Pjfiigers Arch. ges. Physiol., 259, 334-356. CORDEAU, J. P., and MANCIA, M., (1959); Evidence for the existence of an electroencephalographic synchronization mechanism originating in the lower brain stem. Electroenceph. clin. Neurophysiol., 11, 551-564. CORDEAU, J. P., MOREAU, A., BEAULNES, A., and LAURIN,O., (1963); EEG and behavioral changes following microinjection of acetylcholine and adrenaline in the brain stem of cats. Arch. ital. Biol., 101, 3047. DAVISON, C., and DEMUTH, E. L., (1946); Disturbances in sleep mechanism: a clinicopathological study. IV. Lesions at the mesencephalometencephalic level. Arch. Neurol. Psychiat., 55, 126-1 33. DESMEDT,J. E., and LAGRUTTA, V., (1 963); Function of the uncrossed efferent olivo-cochlear fibres in the cat. Nature, 200, 472474. FULTON, J. F., and BAILEY,P., (1929); Contribution to the study of tumors in the region of the third ventricle: their diagnosis and relation to pathological sleep. J. nerv. ment. Dis., 69, 1-25; 145-164; 261-277. GAMPER, E., (1926); Bau und Leistungen eines menschlichen Mittelhirnwesens (Arhinocephalie mit Encephalocele).Zugleich ein Beitrag zur Teratologie und Fasersystematik. Z. ges. Neurof.Psychiat., 102, 154-235 and 104,49-120. GAYET,M., (1 875); Affection enckphalique (endphalite diffuse probable) localis& aux Ctages superieurs des p&donculesdrebraux et aux couches optiques, ainsi qu’au plancher du quatrikme

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ventricule et aux parois laterales du troisihne. Observation recueillie. Arch. Physiol. Brown Siquard, 7, 341-351. GRANIT,R., and KAADA, B. R., (1952); Influence of stimulation of central nervous structures on muscle spindles in cat. Acta physiol. scand., 27, 13C160. HASSLER, R., (1964) ; Spezifischeund unspezifische Systeme des menschlichen Zwischenhirns. Progress in Brain Research, Vol. 5 . Lectures on the Diencephalon. W. Bargmann and J. P. SchadB, Editors. Elsevier, Amsterdam (p. 1-32). HERNANDEZ P E ~ NR., , and CHAVEZIBARRA, G., (1963); Sleep induced by electrical or chemical stimulation of the forebrain. Electroenceph. clin. Neurophysiol. Suppl., 24, 188-198. HES, W. R., (1925); Uber die Wechselbeziehungen zwischen psychischen und vegetativen Funktionen. 111. ‘Zentrale’ Wirkung vegetativer Reizstoffe. Schweiz. Arch. Neurol. Psychiat., 16, 285-306. HESS,W. R., (1944); Das Schlafsyndrom als Folge diencephaler Reizung. Helv. physiol. pharmacol. Acta, 2, 305-344. JASPER, H. H., (1949); Diffuse projection systems: the integrative function of the thalamic projection system. Electroenceph. clin. Neurophysiol., 1, 405-420. JOUVET, M., (1961); Telencephalicand rhombencephalic sleep in the cat. CIBA Foundation Symposium on The Nature of Sleep. G . E. W. Wolstenholme and M. O’Connor, Editors. Little Brown, Boston (p. 188-206). JOWET, M., (1962); Recherches sur les structures nerveuses et les mkcanismes responsables des differentes phases du sommeil physiologique. Arch. ital. Biol., 100, 125-206. K., and YASARGIL, M. G., (1965); Etude de corrdation KRAYENBUHL, H., AKERT,K., HARTMANN, anatomo-clinique de malades operes du Parkinsonisme. Neuro-chirurgie, (in the press). LINDSLEY, D. B., SCHREINER, L. H., KNOWLES, W. B., and MAGOUN, H. W., (1950); Behavioral and EEG changes following chronic brain stem lesions in the cat. Elecfroenceph. clin. Neurophysiol., 2 , 483498. LIVINGSTON, R. B., (1957) ; Neurophysiology of the reticular formation. Brain Mechanisms and Drug Action. W. S . Fields, Editor. Thomas, Springfield (p. 3-14), MAGNES, J., MORUZZI,G., and POMPEIANO, O., (1961); EEG-synchronizing structures in the lower brain stem. CIBA Foundation Symposium on The Nature of Sleep. G. E. W. Wolstenholme and M. O’Connor, Editors. Little Brown, Boston (p. 57-85). MAGOUN, H. W., and RHINES, R., (1946); An inhibitory mechanism in the bulbar reticular formation. J. Neurophysiol., 9, 165-171. MAGOUN, H. W., and RHINES,R., (1947); Spasticity: the stretch Reflex and extrapyramidal Systems. Thomas, Springfield. MARINESCO, G., DRAGANESCO, S., SAGER,O., and KREINDLER, A., (1929); Recherches.anatomocliniques sur la localisation de la fonction du sommeil. Rev. Neurol., 2, 481497. MARTIN,J. P., (1949); Consciousness and its disturbances considered from the neurological aspect. Lancet, ii, 1-6; 48-53. MAUTHNER, L., (1890); Uber die Pathologie und Physiologie des Schlafes. Wien. klin. Wschr., 3, 445446, MORISON, R. S., and DEMPSEY, E. W., (1942); A study of thalamo-cortical relations. Amer. J . Physiol., 135, 281-292. MORUZZI,G., (1963); Active processes in the brain stem during sleep. Harvey Lect., 58, 233-297. MORUZZI, G., and MAGOUN,H. W., (1949); Brain stem reticular formation and activation of the EEG. Electroenceph. clin. Neurophysiol., 1, 455473. NAUTA,W. J. H., (1946); Hypothalamic regulation of sleep in rats. An experimental study. J. Neurophysiol., 9, 285-316. ORTHNER, H., (1957); Pathologische Anatomie der vom Hypothalamus ausgelosten Bewusstseinsstorungen. First Internat. Congr. Neurol. Sci. Brussels. Acta med. belg., 2, 77-96. P. L., (1960); Reizeffekte aus Hippocampus und Corpus mammillare der Katze. PARMEGGIANI, Helv. physiol. pharmacol. Acta, 18, 523-536. I. P., (1927); Conditioned Reflexes. Oxford Univ. Press, London. PAVLOV, POMPEIANO, O., and SWETT,J. E., (1963); Actions of graded cutaneous and muscular afferent volleys on brain stem units in the decerebrate, cerebellectomized cat. Arch. iral. Biol., 101, 552-583. POWELL, T. P. S., and COWAN,W. M., (1956); A study of thalamo-striate relations in the monkey Brain, 79, 364-390. PROCTOR, L. D., KNIGHTON, R. S., and CHURCHILL, J. A,, (1957); Variations in consciousness produced by stimulating reticular formation of the monkey. Neurology, 7, 193-203.

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ROSSI,G. F., MINOBE, K., and CANDIA, O., (1963); An experimental study of the hypnogenic mechanisms of the brain stem. Arch. ital. Biol., 101, 470-492. A. B., (1956); Studies on the adrenaline-sensitive component of the reticular activating ROTHBALLER, system. Electroenceph. clin. Neurophysiol., 8, 603-621. ROWE,S. N., (1935); Localisation of the sleep mechanism. Brain, 58, 21-43. SCHALTENBRAND, G., (1949); Thalamus und Schlaf. Allg. Z. Psychiat., 125, 48-62. SPRAGUE, J. M., LEVIIT,M., ROBSON, K., LIN, C. N., STELLAR, E., and CHAMBERS, W. W., (1963); A neuroanatomical and behavioral analysis of syndromes resulting from midbrain lemniscal and reticular lesions in the cat. Arch. ifal. Biol., 101, 225-289. STERMAN, M. B., and CLEMENTE, C. D., (1962); Forebrain inhibitory mechanism: sleep patterns induced by basal forebrain stimulation in the behaving cat. Exp. Neurol., 6 , 103-117. VONECONOMO, C., (1929); Die Encephalitis lethargica, ihre Nachkrankheiten und ihre Behandlung. Urban and Schwarzenberg, Berlin and Vienna (p. 251). VONECONOMO, C., (1930); Sleep as a problem of localization. J. nerv. ment. Dis., 7,249-259. WALDVOGEL, W., (1 945); Gahnen als diencephal ausgelostes Reizsyrnptom. Helv. physiol. pharmaC O ~Acta, . 3, 329-334.

20

Paradoxical Sleep - A Study of its Nature and Mechanisms* M. JOUVET Laboratoire de Pathologie CPnPrale et Expirimentale, FacultC de Mkdecine, Lyon (France)

INTRODUCTION

It has recently been discovered that during behavioural sleep there periodically OCCUFS a state characterized by fast cortical activity similar to that of the waking state, accompanied by a complete disappearance of muscular tonus and of rapid eye movements (Dement, 1958; M. Jouvet et al., 1959). This gives rise to the following problem: Should we consider ‘classic’ sleep, with its slow cortical waves (slow sleep), and paradoxical sleep (P.S.) to be the expression of a single hypnogenic mechanism? On the basis of this hypothesis, P.S. would represent no more than the overstatement of an active hypnic process, since in adults P.S. almost always follows slow sleep and is the deepest state of sleep (M. Jouvet et al., 1959; Hubel, 1960; Rossi et al., 1961). Or, on the other hand, should we consider P.S. to be a specific state of central nervous activity which differs qualitatively from slow sleep? Such a dualistic hypothesis must be based on the experimental differentiation of P.S. and slow sleep. To this end, we shall present the EEG findings and behavioural, phylogenetic, ontogenetic, functional and structural criteria, which represent a number of concordant arguments in favour of the duality of the states of sleep and of the autonomy, at least relative, of P.S. with respect to slow sleep. In the second part we shall attempt to delimit certain mechanisms regulating the appearance of P.S. The results presented here have been obtained since 1958 in collaboration with J. F. Delorme, M. Jeannerod, D. Jouvet, M. Klein, F. Michel, J. Mouret, J. L. Valatx and P. Vimont. The term paradoxical sleep (P.S.) which we employ in this text for the sake of brevity signifies the paradoxical or rhombencephalic phase of sleep. EVIDENCE OF THE DUALITY OF THE STATES OF SLEEP

( a ) EEG and behavioural findings

It is believed at the present time that slow sleep is characterized (in the chronic adult cat) by two successive EEG stages. The first is made up of cortical spindles of 15-18 c/s, the second of slow high-voltage waves of 2-4c/s which invade the cortex and subcortical structures. These two stages are accompanied by tonic nuchal activity in ____

* This work was carried out with the help of the United States Air Force under grant 62/67, (European Office of Aerospace Research), the Fonds de Developpement de la Recherche Scientifique and the Direction Genkrale des Recherches et Moyens d’Essai.

21

PARADOXICAL SLEEP

the EMG and almost complete absence of eye movements. The appearance of spindles requires the integrity of the thalamus (Naquet et al., 1964), while that of slow cortical and subcortical waves necessitates the neocortex (M. Jouvet, 1962a). The mechanisms of the appareance of slow sleep have been discussed elsewhere (M. Jouvet, 1962a; Moruzzi, 1960). Paradoxical sleep differs entirely from slow sleep in EEG, behavioural, tonic and phasic aspects. (i) Tonic aspects (Fig.I ) ( I ) EEG. In normal adult cats not deprived of sleep, P.S. always occurs after a phase of slow sleep. Its average duration is 6 min, but periods of 15-20 min are often SMC

PLETH

A

0

C

Fig. 1. Polygraphic aspects of the two states of sleep. (A) Wakefulness: Fast cortical and subcortical activity. (B) Slow sleep: Cortical and subcortical spindles and slow waves. Persistence of nuchal EMG activity (EMG). No eye movements (EYES). (C) P.S.:Fast cortical activity similar to (A). Regular &activity in the ventral hippocampus (HIPP). Phasic activity in the pontine reticular formation (PRF). Complete disappearance of nuchal EMG activity and rapid eye movements. Changes in respiratory activity (RESP) and the plethysmographic index (PLETH). SMC = sensorimotor cortex; ESC = ectosylvian cortex. MRF = midbrain reticular formation. Scale: 1 sec; 50 pV. From Jouvet, 1962a.

recorded. It represents an average proportion of 20-25% of behavioural sleep (i.e. approximately 15% of the total time). It is characterized by fast, low-voltage neocortical, diencephalic and mesencephalic activity (2&30 c/s), similar to that of cortical activation which regularly accompanies a state of intense alertness or attention. But certain local electrical peculiarities make it possible to draw a formal distinction between the electrical cerebral activity of P.S. and that of behavioural alertness. The appearance of continuous 6-activity in the dorsal and ventral Rcfcrences p . SS-S7

22

M. JOUVET

hippocampus is highly characteristic: it is more regular, more rapid (5-7 c/s) and, above all, of a more extensive topography than that observed during intense alertness (4-4.5c/s) in the dorsal hippocampus-the presence of a 8-rhythm in the ventral hippocampus occurring only exceptionally in the waking state. A 8-rhythm has vis. cx.

II

Nuchal EMG .

-

-

Whiskers

Temporal EMC

-9-

Isec

/-&q

Facial EMG

Fig. 2. Phasic phenomena during P.S. Normal cat: 3 days after enucleation of both eyes. Monophasic peaks grouped in pseudo-spindles in the pontine reticular formation (PRF), the oculomotor nucleus (N. III), the lateral geniculate nucleus (Lat. gen.) and the visual cortex (Vis. Cx.). Note phasic twitching of the whiskers, the temporal muscles, and the minor muscles of the face, and absence of nuchal EMG activity. Scale: 1 sec; 5OpV.

also been registered in the peri-aqueductal grey matter, the anterior portion of the pons and the limbic midbrain area (M. Jouvet, 1962a). (2) Behavioural criteria. In contrast to slow sleep, which is not clearly defined behaviourally, the beginning and end of P.S. can be located to within a few seconds on the basis of behavioural criteria alone. The complete extinction of muscular activity, especially of the neck, is the most striking sign of the inhibition of muscular tonus that characterizes P.S. (M. Jouvet et al., 1959). Before, or some seconds after the cortical activity of P.S. begins, the lack of activity in the EMG is accompanied by

PARADOXICAL SLEEP

23

a sudden dropping of the animal's head if it has been in an unsupported position during slow sleep. The end of P.S. is marked by a renewal, usually sudden, of considerable activity in the EMG, the awakening of the animal or transition back to the state of slow sleep. (ii) Phasic aspects

Among the phasic phenomena characteristic of P.S. the eye movements are of such great importance that we shall consider them separately. But they are not in fact an isolated phenomenon and P.S. is punctuated in a strange and disordered manner by sudden movements of the ears, whiskers, limbs (flexion) and tail, and sometimes veritable clonic jerks of the muscles of the back (Fig. 2). These phasic phenomena are particularly developed in the young cat after birth and are characteristically increased after long privation of P.S. Phasic phenomena of the oculomotor system. One of the most remarkable characteristics of P.S. IS the appearance of rapid eye movements, accompanied by phasic ponto-geniculo-visual electrical activity. Rapid eye movements (Fig. 3 ) . Rapid eye movements occur from the beginning of cortical activation. With a frequency of 60-70 per min, they differ in speed, distribution, and pattern from ocular movements of observation during the waking state (Jeannerod and Mouret, 1963). They may be isolated or dccur in short bursts of less than 5 movements (as during observation), but most characteristic are bursts of a greater number of movements, up to 50 without a pause. The ratio between the number

Fig. 3. Electro-oculographic aspect of eye movements during P.S. (a) Normal cat; (b) Pontile cat; (c) After coagulation of the superior colliculi; (d) After occipital decortication; (e) After total decortication. The oculographic tracings were made one month after the lesions. Scale: 1 sec; 50pV. From Jeannerod el al., 1965. References p. 55-57

24

M. JOUVET

of movements during the bursts and the total number of movements remains constant for each animal (50%). During P.S., myosis is at a maximum most of the time while the nictitating membranes are relaxed. Nevertheless, sudden mydriasis with retraction of the nictitating membranes can on occasions accompany the bursts of eye movements (Berlucchi et al., 1964). Analysis of the structures responsible for the appearance of isolated movements and bursts gave the following results (Jeannerod et al., 1965): pontile cats in which the superior colliculi were destroyed showed only isolated lateral and external movements (dependent on N. VI). In the mesencephalic cat with superior colliculi intact the larger bursts persisted. In contrast, coagulation of a zone in the superior colliculus and the mesencephalic tegmentum in intact animals suppressed these bursts. The latter were, on the other hand, very much enhanced in the totally decorticated animal. The role of the cortex is not unequivocal, for ablation of the visual cortex will decrease the number of bursts and isolated movements, sometimes to a considerable degree, whilst frontal decortication increases the number of bursts. These observations can be summarized as follows: the rapid eye movements in P.S. are not identical with those of the waking state and persist, for example in decorticated, pontile cats, when eye movements in the waking state are completely impossible. They are also present during P.S. in kittens immediately after birth and still blind (Valatk 5 et al., 1964). The mechanisms responsible for the rapid eye movements of P.S. must thus be different from those regulating the eyes during observation. The results suggest that these eye movements are initiated in the pons and are rendered more complex in the superior colliculi and the midbrain, whilst the process of ‘cortical integration’ (facilitating visual cortex and inhibiting frontal cortex) would act on this latter region. Phasic ponto-geniculo-occipital activity (Fig. 4 ) . Owing to the difficulties encountered and the slow development of a broad and systematic study of the cortical and subcortical structures under chronic conditions several years were necessary before a common link was found between the ‘spontaneous’ potentials observed during eye movements in P.S. First observed in the pontine reticular formation, monophasic peaks of 200-3OOpV of 100 msec duration, often appearing in groups of five or si.x (whence their appearance as pseudo-spindles) (M. Jouvet et al., 1959), were then observed in the lateral geniwlate nucleus (Mikiten et al., 1961), the occipital cortex (Mouret et al., 1963), the superior colliculus and oculomotor nucleus (Brooks and Bizzi, 1963; Michel et ul., 1964a), and the pulvinar and parietal cortex (Hobson, 1964). The pontine and geniculate spikes are the earliest signs of incipient P.S. They can in fact precede rapid cortical activity and extinction of the nuchal EMG by several seconds. More rarely, this phasic activity can occur in fleeting bursts during slow sleep without the appearance of P.S. Lesions of the nucleus reticularis pontis caudalis or in front of the pons, in the dorsal or central part of the brain stem, may suppress the appearance of geniculate and visual spikes during P.S. (Hobson, 1964). On the other hand, monophasic spikes persist in the pontine reticular formation (PRF) in the pontile animal during P.S- It is thus probable that an ascending ponto-geniculo-occipital system, of which the topography has still to be clarified, reacts phasically during the rapid eye movements. But the relationship between this phasic activity and the eye movements is not a

25

PARADOXICAL SLEEP

simple one. Neither darkness, retinal coagulation, nor even total ablation of the eyeballs and the extrinsic muscles of the eye (Michel et al., 1964a) suppresses the pontovisual peaks, which therefore cannot be regarded as a possible feedback of retinal (on and off effect) or extrinsic muscular origin (Fig. 4). Moreover, this phasic activity 50 pV EMG rn.rect.0~. int.

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1 sec

I

Vis. c x .

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0

Fig. 4. Persistence of phasic electrical activity in the visual system after enucleation of the eyeballs. (A) Phasic spikes during P.S. in the pontine reticular formation (PRF), lateral geniculate (Lat. pen.) and visual cortex (Vis. cx), with concurrent eye movements (EOG) and EMG activity from the m. rectus oculi internus (EMG m. rect. oc. int.). (B) Four days after enucleation of the eyeballs. Persistence of phasic phenomena during P.S. From Michel et al., 1964.

precedes the eye movements by some 30-90 sec at the beginning of P.S., and the movement can occur without demonstrable spike activity, but in the majority of cases there is a relation in time between the monophasic ponto-geniculo-occipital spike and the activity of the extrinsic muscles of the eye. This activity appears above all as rapid phasic bursts, whilst in the waking state a tonic element occurs (Michel el al., 1964b). It would be premature to try to correlate this phasic activity and the rapid eye movements at the present time, and it is sufficient to note the essential difference between these phenomena and those occurring during the eye movements of observation (when such phasic activity is not recorded) and especially during slow sleep, during which phasic phenomena occur neither in the motor effectors nor in the EEG. These findings thus enable us to draw a clear distinction between P.S. and slow sleep on the basis of their EEG and tonic and phasic behavioural aspects. By these criteria P.S. appears as distinct from slow sleep as the latter is from the waking state. But we cannot affirm on the basis of EEG methods and polygraphy alone that slow sleep and P.S. are the result of different mechanisms and structures. In order, therefore, to obtain more evidence in favour of the dualist concept for the two states of sleep (M. Jouvet et ul., 1959) we studied the possibility of differentiating them, either References p . 55-57

26

M. JOUVET

in the course of their phylogenic or ontogenic evolution, by selective deprivation, or by central nervous lesions.

(b) Phylogenetic findings Polygraphic studies of sleep in vertebrates (Klein, 1963; Klein et al., 1964; Hermann et al., 1964) provide comparative physiological evidence on the basis of which the

EMG

2

3

Fig. 5. Slow sleep and paradoxical sleep in the hen. (1) Wakefulness: fast activity in the hyperstriatum (EEG). (2) Slow sleep: slow, high-voltage activity in the hyperstriatum. No true spindles. (3) Paradoxical sleep (lasting 8 sec) : considerable reduction, but not complete disappearance, of nuchal EMG activity; fast, low-voltage cerebral activity; note the burst of eye movements (EM). Bradycardia is also present. Scale: 1 sec; 50pV. From Klein et al., 1964.

phylogenetic evolution of the two states of sleep can be differentiated. Slow sleep has in fact been demonstrated in all the mammals studied so far (see bibliography, Jouvet and Jouvet, 1964).It is also veryreadily recognizable in birds and reptiles by the presence of slow waves in the hyperstriatum of hens or pigeons and the archipallium of tortoises in association with immobility, closing the eyes, slowing down the respiratory and

27

PARADOXICAL SLEEP

cardiac function, and the preservation of a certain muscular tonic activity in the neck. In contrast, during behavioural sleep in the tortoise no periods of rapid electrical archipallial activity associated with eye movements can be demonstrated. Paradoxical sleep thus apparently does not occur in chelonians. In birds (pigeon, hen, chick), on the other hand, very short periods of P.S. occur, lasting from 6-15 sec (Figs. 5 and 6). 1

-.

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Fig. 6. Periodicity of P.S. in the chick. Chick aged 36 h.Diagrammatic representation of recording lasting 83 min. The black rectangles represent periods of P.S., which never lasted for more than 15 sec and were accompanied by a considerable reduction in nuchal EMG activity and by eye movements (+). The proportion of P.S. is 0.3%. Sleeping: 82.4%; awake 17.3%. Time scale: 1 min. Below: Changes in pulse rate (bradycardia) during the same period. The crosses represent P.S. Time scale (abscissa): 1 min. Ordinate scale: pulse rate per min. From Klein, 1963.

They are characterized by the appearance, after a phase of slow sleep, of rapid activity in the hyperstriaturn, rapid eye movements, an appreciable-but not complete-reduction in nuchal EMG activity, considerable bradycardia and postural relaxation objectified by drooping of the wings. These phases of rudimentary P.S. thus constitute only 0.15-0.2% of the behavioural sleep. In mammals, on the other hand, P.S. is much more developed and accounts for 6 3 0 % of the behavioural sleep of adults, depending on the species (Fig. 25). ( c ) Ontogeneticfindings

Tnvestigations into the ontogenetic evolution of slow and paradoxical sleep have been described in detail elsewhere (Valatx et al., 1964; D. Jouvet et al., 1961). The results References p. 55-57

28

M. JOUVET

show three categories of facts supporting the theory of distinct mechanisms for P.S. and slow sleep: ( i ) During the first days after the birth of kittens, P.S., known as ‘sleep with jerks’ (Valatx et al., 1964) or ‘agitated sleep’ (Cadilhac et al., 1961), accounts for almost all (80-90%) the behavioural sleep. It is characterized by behavioural phenomena (global muscular jerks, rapid eye movements, extinction of nuchal muscular tonus) in which the phasic aspect is far more pronounced than in adult animals. The average duration of P.S. at one week o f age is similar to that o f the adult cat, while its frequency is higher (Fig. 7). Thus, the mechanism responsible for P.S. is present from the very start of life, whereas the state o f slow sleep is hardly recognizable at this stage.

30

30’

Fig. 7. Development of periodicity of P.S. in the kitten. Each circle represents 1 h; the black sectors show the average duration of phases of P.S., and the white sectors the intervals between. Key: (A) First week; (B) Second week; (C) First month; ( D ) Second month; (E) Third month; (F) Adult. From Valatx et a/., 1964.

(ii) P.S. can appear immediately after behavioural awakening during the first days of life, without any transitional phase of slow sleep. (iii) During maturation the two states of sleep develop differently: the periods of P.S., of which the average duration remains constant, become less and less frequent, and constitute only 25-30% of behavioural sleep in the adult; the duration of slow sleep, on the other hand, increases from 10% at birth to 70% of behavioural sleep in the adult (Fig. 8).

( d ) FunctionalJindings

A technique of instrumental and selective deprivation of P.S. (D. Jouvet et al., 1964) was employed in order to dissociate the two states composing behavioural sleep in the

29

PARADOXICAL SLEEP

adult cat. The animal is placed on a small support floating on water. It can stand or crouch, but the small surface of the support prevents it from lying down completely and relaxing its muscular tonus without falling into the water. The EEG and EMG activity is recorded continuously or integrated by means of an Oneirograph (M. Jouvet, 1962b). The animal’s behaviour is further recorded with the aid of photographs. %

Fig. 8. Diagram of the postnatal development of the states of sleep in the kitten. (Based on three-hour recordings daily.) Stippled : Wakefulness. Vertical hatching: Slow sleep with nuchal EMG activity. Crossed area: Slow sleep without tonic muscular activity. Diagonal hatching: P.S. The limit between the vertical white columns and the continuous marking represents the age at which cortical activity takes on the appearance seen in adulthood. Abscissa: Relative proportion (%) of each state. Ordinate: Age in days. From Valatx et al., 1964.

Four cats were subjected to successive periods of privation of 10, 24, 36, 48, 72 and 96 h, and 9 and 17 days. A minimum of a week was left between any two sessions to permit complete recuperation. Results of deprivation: (i) At the beginning of deprivation, behavioural and EEG arousal was slightly increased (40-60%) as a result of agitation, but phases of slow sleep reappeared within about twelve h. Spindles and even slow waves appeared in the cortex and subcortical structures, while the neck of the animal flexed. These phases of slow sleep were always followed by a sudden arousal caused by loss of balance as the neck bent more and more. Behavioural or EEG P.S. is thus impossible. Whilst References p . 55-57

30

M. JOUVET

deprivation of P.S. is absolute, deprivation of slow sleep is minimal (10-200/, depending on the animal). Even during the longest of these periods of deprivation we never observed hallucinatory patterns like those occurring after lesions of the pontine reticular formation which suppress P.S. (M. Jocvet, 1962a). There was a marked increase in the pulse rate. (ii) Recuperative phases were identical in all the animals. On leaving the tank, even after deprivation for as long as 17 days, the animals always indulged in a stereotyped act of grooming for 30 min to 1 h, after which they fell into a very deep sleep. On awakening their behaviour was reminiscent of asthenia. They were unable to jump onto a chair to obtain food and fell heavily to the ground. The first 6 h of recuperative sleep are represented in Fig. 9: after a deprivation of 72 h a plateau of 60% P.S. (in

,

Ild

13d

Fig. 9. Recuperation of paradoxical sleep after selective instrumental deprivation. Ordinate: Black columns: paradoxical sleep in % of total sleep. Hatched columns: slow sleep. Based on the first 6 h of recuperative sleep after deprivation. Abscissa: Duration Df PS-depriwlbionfflh.
terms of behavioural sleep) was reached, and was not exceeded even when deprivation lasted for 17 days. This high percentage of P.S. is due to a slight increase in its average duration (8 min against 6 min 20 sec in controls) and especially to the shorter intervals between the phases of P.S. During the first episodes of recuperative P.S. the twitching of the animal's body, paws, tail, and whiskers, was so intense that the animal occasionally presented a pictiwe of epileptic seizures. At these times the arousal threshold is very high and nociceptive stimuli are necessary to awaken the animal, while acoustic stimuli have no effect. The explosive return of P.S. after deprivation thus suggests a phenomenon of rebound and elective recuperation. The relative increase in P.S. during

PARADOXICAL SLEEP

31

recuperative sleep is proportional to the duration of the deprivation period. It was 20, 60 and 200 h for periods of 2, 5 and 17 days of deprivation respectively. Another important finding was that after deprivation of more than 3 days P.S. can immediately follow the waking state without spindles or slow waves to characterize a transitory phase of slow sleep, as would be the case in the normal animal. Thus total deprivation of P.S. produces a large, lasting and selective increase in P.S. during recuperation. This also speaks in favour of the existence of specific mechanisms for P.S. distinct from those for slow sleep. ( e ) Structural findings ( i ) Lesions of the pontine reticular formation We have reported elsewhere the results of coagulation of the pontine reticular formation at the level of the dorsal and lateral part of the nucleus reticularis pontis oralis et caudalis (M. Jouvet, 1962a).There is no extinction of the nuchal EMG in these animals nor periods of rapid activity during behavioural sleep. On the other hand, typical EEG patterns of wakefulness and slow sleep persist. When deprived of P.S. these animals show periodical behavioural disturbances resembling hallucinations that occur most commonly after a phase of slow sleep. The percentage of slow sleep (60% of the total time) was usually normal in these animals (Fig. 10). These results speak in favour of a duality of the nervous structures responsible for triggering off the two states of sleep, Study of the waking-sleeping rhythm of chronic poiitile cats strengthens this theory.

Fig. 10. Differential effects of lesions of the lower brain stem on the two states of sleep. Lesions projected onto a sagittal section of the brain stem. Diagonal hatching: coagulation of the median three-quarters of the nucleus reticularis pontis oralis and interpeduncular nucleus. Persistence of P.S. (15%). Increase in slow activity to 90% during first week. Return to normal proportion of slow sleep (60%) after third week (mean of 3 cats). Black area: lesion causing complete suppression of P.S.for 15-97 days. Mean proportion of slow sleep in 4 animals: 40%. Dotted area: Lesion in the caudal part of the nucleus reticularis pontis caudalis and the anterior part of the nucleus giganto-cellularis (involving the median two-thirds of these nuclei). Suppression of P.S. for 3 days followed by reappearance with normal rhythm (18%). Mean proportion of slow sleep in 2 cats: 40%. The proportion of slow sleep was determined in all animals in an average of 6 h of recording daily. References p. 55-57

32

M. JOUVET

(ii) Sleep in the cl~ronicpontile cat The experimental evidence by which the periodic phases of atony in chronic mesencephalic or pontile aninials can be identified with the phase of fast cortical activity in intact animals during sleep, has already been reported (M. Jouvet, 1961, 1962a). It is on these results and the results of coagulation of the pontine reticular formation that the concept of rhombencephalic sleep is based. But the periodic atonic state of pontile animals cannot be unreservedly identified with P.S. (Moruzzi, 1964).

Fig. 1 1 . Medio-sagittal section of the brain of a pontile animal with hypothalamic island. Anteriorly the trace of the brain stern smion can be seen where the strip of acrylic resin was placed, and posteriorly the trace of an electrode in the caudal part of the nucleus reticularis pontis caudalis. Animal sacrified on 66th day. Lux01 staining.

Our initial results had been obtained in animals which did not survive more than 10 days, and we therefore felt it necessary to obtain new data from animals with a much longer period of survival. Better knowledge of their requirements enabled us to study some 20 posterior mesencephalic or pontile animals for over 2 months. For such periods it is much easier to observe the different states of wakefulness. In a number of animals it was further possible to study more extensively the electrical activity of the brain stem. Our technique was very similar to that developed by Bard and Macht (1958). After total section of the brain stem in front of the tentorium with a leukotomy knife, the cerebral hemispheres and the thalamus are removed by aspiration. A hypothalamic island is left in situ, the dorsal surface of which is flush with the Horsley-Clark plane zero. The brain stem section between the pons and the remaining hypothalamic island is then completed by aspiration and an acrylic strip 1-2 mm thick and 15 mrn wide,

33

PARADOXICAL SLEEP

fixed aorsally to the tentorium cerebelli, is wedged between the brain stem section surface and the remaining hypothalamic island in such a manner as to prevent any neurocrine connections between the hypothalamus and the brain stem (Fig. 11). These poikilothermic preparations are then placed in an incubator and observed through a perspex window. A thermo-electric probe in the rectum of the animal conveys its temperature to a regulator (Fig. 12, B). The animal’s teniperatur eis thus

I

H

Fig. 12. Apparatus for the study of sleep in chronic pontile animals. The animal is placed in an incubator and its temperature maintained at a constant level (see details in the text). To obtain automatic deprivation of paradoxical sleep a system of relays (G)activates a stimulator (J) which delivers electric shocks to the cat’s paw. The stimulation is interrupted on the resumption of nuchal EMG activity. From M. Jouvet et a/., 1963.

maintained constant at any desired level by altering the heating element of the incubator. The urine is collected (K). The EEG activity of the brain stem (pons and medulla oblongata) and the EMG activity of the neck, are registered by permanently implanted electrodes and transmitted by cable 1 to the amplifiers (C) of the EEG apparatus (D). After amplification the muscular activity is integrated in an Oneirograph (F). During P.S. the absence of EMG activity is conveyed to a system of relays ( G )so that either the EEG motor (E) is automatically set in operation to record P.S. during the night, or the periodicity of P.S. is registered by a signal on a slow-running apparatus (H). The sleeping-waking rhythm of the animals can thus be continuously recorded. More than 10 000 periods of P.S. have thus been observed in 20 chronic poiitile cats (Fig. 13).

(iii) Results Immediately following the postoperative phase (after 12-36 h) the animals alternately presented wakefulness and P.S. without slow sleep intervening. Wakefulness is characterized by muscular hypertonia with regular respiration-a References p . 55-57

34

M. JOUVET

complete absence of movements over the first few days. This state is thus difficult to identify since behaviourally it can resemble caIm sleep during the first week, After about 10 days, however, this state can be regarded as a state of wakefulness. Theanimal then responds to acoustic stimuli of high intensity by turning its head towards the stimulus. Furthermore, as observed by Bard and Macht (1958), the animals are able to remain in a crouching position, with the head raised, supporting themse'lves on 10h

1

n

22h

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Fig. 13. Periodicity of P.S. in the pontile animal. Continuous recording with an Oneirograph for 5 days. Each line represents alternately recording from 10 a.m. to 10 p.m. and 10 p.m. to 10 a.m. P.S. is represented by the vertical rectangles. The arrows show the times of forced feeding. Recording from 30th-35th day. Time scale: 1 h.

their forelegs (Sphinx pwition). In this state the EEG of the brain stem shows continuous, fast, microvoltage activity which is not affected by any sensory stimuli. The waking state is periodically and regularly interrupted (Fig. 13) by a state of which all the characteristics are similar with those of P.S. in intact cats. This state consists of complete muscular atony, during which the head falls abruptly and eye movements appear. These movements are lateral (ix.dependent on N. VI) externai, rapid, returning slowly to the median line with a frequency of 20-30 per min. Their oculographic appearance is monotonous, in contrast to those of intact cats where several types of bursts of varying complexity can be recognized. During this state respiration becomes more rapid and irregular, while the heart rate increases in most cases. At the same time a characteristic electrical activity appears in the pons (Fig. 14): either isolated monophasic spikes or groups of 'pseudo spindles', 3-5 per sec, repeated at a frequency of 10-15.per min, sometimes. rising in amplitude, seldom rising and falling. In the majority of cases these spikes accompany the rapid eye movements, but not infrequently, especially in the first few days, there are isolated spikes without eye movements. The topographical distribution of these elements, and their electrical

35

PARADOXICAL SLEEP

DOE

I

1

.

. , . .

Fig. 14.Pontine animal with hypothalamic island. EEG recorded 89 days after operation. The four tracings represent uninterrupted consecutive activity. Above: Arousal followed by paradoxical sleep with typical monophasic spikes at the pontine level (PRF), eye movements (EM) and total depression of muscular activity in the neck (EMG). The fourth tracing represents &e end of paradoxical sleep. Each line represents 2 min of recording. Calibration 6 sec, 50 pV.

appearance, is similar to that in the pontine reticular formation during P.S. (M. Jouvet, 1962a; Brooks and Bizzi, 1963). ( I ) P.S. occurs immediately after the waking state. It has, in fact never been possible to demonstrate EEG or behavioural criteria of slow sleep in pontile animals. Whereas in intact cats the electrodes located in the pontine reticular formation regularly receive spindle activity and/or slow waves during the slow sleep preceding the appearance of P.S., no slow activity or spindles have ever been recorded during the minutes preceding P.S. in pontile animals. Furthermore, no behavioural criteria have been observed for a stage intermediate between wakefulness and P.S. The state of the pupils and the nictitating membranes remains constant in these animals. In certain cases-mesencephalic animals with intact oculomotor nucleus-a tonic ocular sleep References p. 55-57

36

M. JOUVET

syndrome (in which the eyeballs rock in and down) can appear. This phenomenon immediately precedes, by a few seconds, the rapid eye movements of P.S. It has never been observed alone during long periods without P.S. Furthermore in 90% of such animals muscular activity remains constant during the waking phases and begins to diminish only 30-40 sec before the inception of P.S., when the first monophasic spikes appear in the pons. In the normal animal, on the other hand, the nuchal EMG activity diminishes considerably in about 60% of cases during the phase of slow sleep preceding P.S. Thus, the muscular criterion of slow sleep (which even in intact animals is not absolute and seems to depend on the animal’s posture and thus often on the environmental temperature) does not show the hypotonic phases which would precede P.S. and would provide evidence of an intermediary behavioural sleep between wakefulness and P.S. (2) Periodicity 0 f P . S . The mean duration of P.S. in pontile and intact cats is the same (6 min and 6 min 20 sec respectively). Thus the two phenomena, which are identical from the point of view of subcortical electrical activity and of behaviour, are also identical from the point of view of time and can be entirely equated one with the other. The only difference is found in their periodicity. In pontile cats it is very regular and P.S. accounts for 10% of the total time (there is no distinction between day and night). In normal animals, on the other hand, the innumerable environmental influences (to which the pontile cat is almost totally insensitive) make it difficult to establish a regular periodicity of P.S. Furthermore, P.S. occurs only after periods of slow sleep when it accounts for approximately 25% of behavioural sleep, or 15% of the total time (since intact cats slept for an average of 70% of the time under the conditions of our trial, i.e. in sound-proof cages to which they have become ‘accustomed’). Summarizing, no EEG or behavioural phenomenon indicates the existence of slow sleep in pontile animals. On the other hand, the periods of muscular atonia occurring in such animals immediately after awakening can be completely equated with the P.S. of intact animals. Their average duration is the same as the latter, while the percentage of the total time they represent is slightly lower. P.S. thus appears to be absolutely independent of slow sleep. After having discussed in this first section the autonomy of P.S. with respect to slow sleep we shall pass in the second to some experimental results which make it possible to define some of the mechanisms at work. Most of these results have been obtained in pontile animals, in which P.S. appears as a veritable ‘biological clock’, the periodicity of which is subject to fewer factors than in the intact animal. The possibility of triggering off P.S. as a reflex suggests that peripheral mechanisms may be involved, but not exclusively, as the results of different deafferentations have shown. Experiments with automatic deprivation of P.S. in pontile animals suggest the existence of an active mechanism in the lower brain stem. Finally, the effects of-temperature and certain drugs, and the relationship of P.S. with the internal milieu permit the hypothesis of a periodic function in which the neuroglia is perhaps implicated.

PARADOXICAL SLEEP

37

MECHANISMS OF PARADOXICAL SLEEP

( a ) Producing P.S. as a repex The immedie e triggering of P.S. has been obtained during slow sleep in intact animals by stimulation of the pontile reticular formation (M. Jouvet, 1961), mid-brain reticular formation (Rossi et al., 1961), and hippocampus (Cadilhac et al., 1961). The same phenomenon has been seen following stimulation of the pontine reticular formation in pontile and mesencephalic animals and the existence of refractory phases after phases of spontaneous or provoked P.S. was also noted (M. Jouvet, 1961). Furthermore, periods of slow sleep can be induced by low-frequency stimulation of the cutaneous or muscular nerves during wakefulness (Pompeiano and Swett, 1962a,b), whilst the same stimulation during slow sleep in intact cats only exceptionally produces P.S. (Pompeiano, 1964). In the pontile animal, on the other hand, the P.S. reflex can regularly be obtained by proprioceptive and nociceptive stimulation. This phenomenon occurs only when certain conditions are fulfilled. Anatomical coiiditions: Reflex P.S. occurs only when section of the brain stem is placed behind the origin of 111. If the section is at or in front of this point in the mesencephalic animal, nociceptive and proprioceptive stimuli increase tonus and rigidity. Fig. 15 shows the most posterior (A) section t o prevent the P.S. reflex;

vi I

C D

Fig. 15. Section of brain stem and reflex production of P.S. Sagittal section of brain stem and location of the different sections allowing or suppressing production of P.S. by proprioceptive or nociceptive stimulation. Black area: common lesion suppressing P.S. in intact animals. See text for details.

(B) and (C) indicate the anterior and posterior limits of sections compatible with the appearance of the P.S. reflex and (D) the level of the section in retropontile animals in which no P.S. reflex could be obtained. These sections thus delimit two zones: the first, anterior to (A), at the level of the mesencephalic tegmentum, the integrity of which prevents the appearance of the P.S. reflex; these cond, between (C) and (D), at the level of the pons, which is necessary for the reflex and which encompasses the References p. 55-57

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posterior part of the nucleus reticularis pontis oralis and the anterior part of the N.R.P. caudalis (based on the coordinates of the atlas of Snyder and Niemer, 1961). (It should be noted that the coordinates of the reticular formation nuclei of the pons vary from atlas to atlas. Thus, the anterior limits of the nucleus reticularis pontis caudalis are situated at P2 according to Snyder and Niemer, (1961) and at P5 according to Reinoso-S6arez (1961).) Stimuli: P.S. can be triggered off as a reflex by the following stimuli: opening the mouth, introducing a tube into the esophagus with or without fluid, pinching the ear or fore or hind paws, flexion, extension, passive rotation of the head, passive flexion or hyperextension of the limbs. Cutaneous stimuli (stroking the back, face, stomach, limbs), and auditive stimuli, on the other hand, had no effect. Nociceptive stimuli almost always produce an immediate extension reaction of very short duration (afew seconds) and very brief apnea, and it is possible that the common denominator of all these reactions is the involvement of proprioceptive afferents. The P.S. obtained by these stimuli appears either immediately (after 1-3 sec) or after a delay of 2%30 sec. It is accompanied by the same EEG, autonomic and behavioural (eye movements) phenomena as spontaneous P.S., and the duration of both is identical. A 'refractory period' of 10-20 min follows spontaneous or evoked P.S., during which the same stimuli either are totally ineffective or produce phasic suppression or, more rarely, tonic suppression of the EMG (cataplexy), which can last for 1 or 2 min. But then no monophasic spikes occur in the pons and there are no eye movements (Fig. 16). Such cataplexic periods cannot therefore be identified with P.S. The duration of the refractory phases following nociceptive and proprioceptive stimulation was identical. It was shorter than the mean interval occurring between two

2

Fig. 16. P.S. and reflex cataplexy in the pontile animal. (1) Nociceptive stimulation of the ear (horizontal line) produces P.S. characterized by extinction of nuchal EMG activity and the appearance of a characteristic rhythmic activity in the nucleus reticularis pontis caudalis (PRF). Duration of reflex P.S.: 6 min; (2) 3 min after cessation of P.S. the same nociceptive stimulation produces extinction of nuchal EMG activity for 3 min, but there is no change in activity in the pons. Scale: 3 sec; 50pV.

PARADOXICAL SLEEP

39

phases of spontaneous P.S. Finally intravenous injection of 1-5 ,ug/kg adrenalin never caused a P.S. reflex in these animals.

(b) Results of deffaerentations The possibility that a reflex mechanism with a peripheral point of departure is involved in the production of a P.S. reflex should not be excluded a priori, since P.S. can be obtained by proprioceptive stimulation in pontile animals. Furthermore, the part played by the carotid sinus has often been referred to since the work of Koch (1932). Finally, changes in blood pressure (Candia et al., 1962) and in cardiac and respiratory rates allow for the hypothesis that P.S. is induced during slow sleep by means of nervous afferents with a vascular point of departure. In order therefore to rule out the possibility of exclusive triggering of P.S. by some extracerebral nervous mechanism we systematically eliminated the majority of nervous afferents (Fig. 17).

Fig. 17. Diagram showing deafferentation procedures that do not affect P.S. (a) Ablation of the cerebellum, midbrain, hypothalamus, pituitary, diencephalon, and telencephalon. (b) Section of the posterior cervical roots from C1 to C6. (c) Section of the spinal cord at C6. (d) Section of the two vagus nerves and of the sino-aortic nerves. (e) Ablation of the two stellate ganglia. (f) Splanchnicectomy and medullo-adrenal curettage. From D. Jouvet, 1962.

The following operations were carried out alone or successively in 10 normal cats: total section in two stages of the sino-aortic nerve, bilateral stellectomy verified by the appearance of a bilateral Claude Bernard-Horner’s syndrome, bilateral vagotomy in the neck, and intradural section of the posterior nerve roots from C1 to C6. The results, which were in the main negative, need not be reported in detail. None of the operations carried out alone produced appreciable EEG or behavioural changes References p . 55-57

40

M. JOUVET

during slow sleep or P.S. The average proportion of P.S. was not significantly different postoperatively. In 2 animals, in addition, total section of the sino-aortic nerve was successively followed by bilateral stellectomy and bilateral vagotomy, carried out in several stages. No great differences in slow sleep or P.S. were observed here either. Finally, it is noteworthy that suppression of nuchal EMG activity during P.S. was absolute in the 2 animals that had undergone section of the posterior cervical roots. Six dogs exhibited completely normal slow sleep and P.S. on the criteria of EEG, behaviour, and the duration, after the following operations : total section of the spinal cord at C6, total medullary destruction from D5 to S2 together with bilateral section of the brachial plexus, abdominal sympathectomy, bilateral splamhnicectomy together with medullo-adrenal curettage, and total thyroidectomy. These results are represented diagrammatically in Fig. 17. As will be seen, exclusive involvement in the inception of P.S. can be ruled out for the spinal cord below C6, the cervical sympathetic chain, the sinus and aortic nerves, the vagus, and, lastly, the posterior roots from C1 to C6. Participation of medullo-adrenal and thyroid hormones can also be excluded.

( c ) Role of the hypothalamus and pituitary The role of the hypothalamus has often been mentioned in the induction of sleep (Von Economo, 1929; Nauta, 1946) and endocrine influences arising in the hypothalamus or pituitary cannot be excluded a priori. The hormonal dependence of P.S. has, furthermore, been reported in rabbits (Faure, 1962; Kawakami and Sawyer, 1962). We therefore undertook a study of the possible role of the hypothalamus and pituitary.

Fig. 18. Sagittal section of the brain stem of a pontile animal without hypothalamic island. Site of the electrode in the posterior part of the nucleus reticularis pontis caudalis. Loyez staining.

41

PARADOXICAL SLEEP

After total intercollicular section of the brain stem of 9 cats all the structures rostrd to the section were removed, including the hypothalamus and pituitary, by curettage of the sella turcica (Fig. 18). The first group of 6 animals received no substitution therapy. Urinalysis showed polyuria with low specific gravity, a considerable reduction in sodium and an increase in potassium content. These animals all died after 6 or 7 days, presenting polypnea, tachycardia, hyperexcitability (starting at the slightest sound). Nevertheless, typical and regular periods of P.S. appeared during the first 5 days (Fig. 20). Their incidence declined regularly after the first 3 days (Fig. 19), but

Fig. 19. Proportion of P.S. in pontile animals with and without hypothalamic island. Ordinate: Percentage of P.S. per 24 h (calculated from continuous Oneirograph recordings). Abscissa: Time in days. Continuous line: Pontile animals without hypothalamic island or substitutive therapy. Regular fall in P.S. and complete disappearance by 7th day (mean of 6 animals). Crosses: Pontile animal without hypothalamic island. The arrow shows the beginning of substitutive therapy (postpituitary extract and ACTH). Proportion of P.S. returns to normal by 15th day (mean of 3 animals). Dotted line: Pontile animal with hypothalamic island. A relative decrease in P.S. occurs about the 7th day. The average proportion of P.S. is 10%(mean of 15 animals). EMG

b

Fig. 20. Development of pontine and EMG activity during P.S. in the pontine animal without hypothalamus or pituitary. (a) 2nd day: monophasic pontine peaks during P.S. (b) 3rd day. (c) 6th day: muscular activity has not entirely disappeared and occurs phasically only during pontine rhythmic activity. Scale: 1 sec; 50 pV. References p. 55-57

42

M. JOUVET

periods of 5 min were still registered 120 h after the operation. Brief periods of atony lasting 2-3 sec, accompanied by a few pontine spikes still appeared periodically on the 6th or 7th day. The last sign of P.S. to disappear was thus the monophasic pontine spikes, which were then no longer accompanied by complete disappearance of muscu!ar tonus (Fig. 20). Substitution therapy (2 units total postpituitary extract daily, 1-2 units ACTH every second day) was started in 4 animals, either from the beginning or from the 4th day on. This therapy prolonged survival up to 1 month. P.S. reappeared regularly and periodically as in animals with an intact hypothalamic island. Thus, the appearance of P.S. more than 120 h after ablation of the hypothalamus and pituitary makes it possible to rule out the hypothalamic neurohormones and pituitary hormones as necessary criteria for the periodic incidence of P.S., for it can be presumed that 24 h after these ablations the hormones are no longer present in the blood.

(d) Deprivation of P.S. in the pontile animal Since P.S. is the only form of sleep in pontile animals we turned to a study of the effects of deprivation. Our technique was as follows : at the beginning of each phase of P.S. the fall in nuchal EMG activity, by the intermediary of an Oneirograph, switches on a stimulator which applies electric shocks to the animal's leg. The strength of these shocks is regulated to arouse the animal, in which case the reappearance of EMG activity automatically cuts out the stimulation. Results: Deprivation was maintained for a maximum of 8-9 h. It appeared that when P.S. is suppressed by a shock it tends to recur at ever shorter intervals. At first these intervals are similar to those between periods of P.S. in controls, but after some

,

' .

EM

Fig. 21. Automatic deprivation of P.S. in the pontile animal. Slow-speed recording. Disappearance of EMG activity in the neck on incipient P.S. produces an electric shock (artefact) which wakes the animal for some 10sec until P.S. inevitably sets in once again (5th h of deprivation). PRF: Activity of the pontine reticular formation. Note the appearance of eye movements (EM) as EMG activity falls. Scale: 3 sec; 50pV.

PARADOXICAL SLEEP

43

hours they become so short that 40-60 sec after being wakened by the shock the animal falls into 8 new phase of P.S. (Fig. 21). Thus the total number of incipient phases of P.S. was as much as 155 in sessions that lasted for 9 h, and P.S. can hardly be suppressed for longer periods than this in view of the very great number of shocks required. When the stimuli were stopped, P.S. returned immediately. Its average duration was then slightly more than that of controls (7 as against 6 min), and its periodicity remained at a higher level for 2-3 h and then returned to normal. A result such as this exemplifies the necessary nature of P.S. in pontile animals, it suggests an active process situated in the brain stem, the efficacy of which increases as its effect is suppressed. (e)

Effects of temperature on P.S. in the pontile animal

The poikilothermic pontile animal is subject to changes in the environmental temperature, so that the effects of hypothermia on P.S. can be readily studied. The fall in rectal temperature occurring when the animal is placed in a cold environment causes P.S. to disappear almost entirely. If, however, cooling is stopped and the rectal temperature remains stable, P.S. reappears periodically. Its duration is then in inverse proportion to the rectal temperature (Fig. 22). An increase in the duration of P.S.

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Fig. 22. Effect of temp‘rature on the rhythmicity of P.S. Ordinate: Time in min. Abscissa: Rectal temperature. Dashed line: Average duration of P.S. at different temperatures. Continuous line: Average interval between episodes of P.S. Mean of 3 animals.

during hypotherrnia goes hand in hand with an increase in the length of the intervals between each episode of P.S., the proportion of the latter always remaining in the Refcrwces

.T. 59-57

44

M. JOUVET

region of 10%. We have observed periods of P.S. lasting 25 min at a rectal temperature of 29". At this temperature the animals exhibit generalized clonism of the head and limbs, even when they are returned to a warm environment. There is no real shivering, however. During phases of P.S. clonism disappears almost completely. If the animal is rewarmed so that the rectal temperature increases P.S. occurs more frequently and in animals whose temperature rises from 30" to 37" in 4 h the amount of sleep can increase to up to 35% of the total time. In contrast, we have never observed P.S. at temperatures above 40.5". (This was the maximum temperature attempted, as hyperthermia has serious effects in pontile animals.)

(f) Action of y-butyrolactone (G.B.L.) The induction of P.S. by G.B.L. in intact or decorticated animals has already been reported (M. Jouvet, et al., 1961). It is impossible, on the other hand, to produce P.S. by means of G.B.L. in animals bearing lesions of the pontine reticular formation, and this led us to suggest that the drug might act at the level of the pons. This hypothesis was confirmed by the observation of the action of G.B.L. in pontile animals possessing the hypothalamic island. Intraperitoneal injection of 50 mg/kg G.B.L. produced, after a latent period of 5-10 min the appearance of P.S. of which the behavioural and EEG aspects were identical with spontaneous P.S. The frequency of periods of P.S. is enhanced for 60-80 min, the proportion of P.S. rising to 30% during the hour following the injection. Higher doses of G.B.L. (100-200 mg/kg) produce a state of anesthesia, with effacement of EMG activity and no monophasic spikes or eye movements. ( g ) Osmolarity of the blood and paradoxical sleep Two observations led us to investigate the relationship between the periodicity of P.S. and changes in the osmolarity of the blood. Firstly it appears that copious forcing of fluids (120-160ml) causes P.S. to disappear for several hours; we therefore administered 60ml twice daily. Secondly, we had observed that certain states of dehydration (in the transitory diabetes insipidus following transection of the brain stem leaving a hypothalamic island) are accompanied by a marked, transitory increase in P.S., up to 20-30% of the total time. Fig. 23 shows the results of our investigations on the relationship between the osmolarity of the blood and P.S. in pontile cats with hypothalamic island. (i) Hypo-osmolarity of the tdood was obtained by drip infusion of a quantity of tepid water equalling 10% of the body weight, via a stomach tube over 30-60 min, together with injection of 1-2 units of an antidiuretic hormone. This treatment completely suppressed P.S. for 6-10 h. P.S. then returned in short (1-2min), infrequent episodes. It was found that dilatation of the stomach by the same quantity of air did not affect the rhythm or duration of P.S. (ii) Hyper-osmolarity was obtained either by complete withdrawal of liquid for 24 h and forcing an equivalent quantity of dehydrated food, or by intravenous in-

PARADOXICAL SLEEP

45

re

Ac

20

- - - .+--x-d-x/'D

10-

a

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0

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b

x---x---x---x*'*

160'2dO' 360' ' 5h

660' ' 10 h

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Fig. 23. Relationship between P.S. and osmolarity of the blood. Pontile animal with hypothalamic island. Ordinate: Proportion of P.S. during recording period (calculated per period of 100 min). Abscissa: Time in minutes and hours. The normal proportion of P.S. (control determined over 10 days) is 8% (& 2%). Continuous line: After intravenous injection (arrow) of 20 ml of 20% hypertonic saline, high levels of P.S. for 5 h. Broken line: After forcing of a quantity of water 10%of the body weight, following injection of 2 units ADH, complete disappearance of P.S. for 5 h followed by slow return to normal. Blood Na and K levels were determined at A, B, C and D (in mequiv/l): before and after injection of saline: Na: 142-152-168-157; K: 6.4-5.2-6.3-6.2. a-6-c-d: after forcing of water: Na: 157-146-138-136-138; K: 6.2-6.6-6.2-5.6-7.2. In this animal injection of ADH had no effect on the proportion of P.S.

jection of 20ml of 20% hypertonic saline. In the latter instance the duration and frequency of P.S. increased almost immediately and remained high for 5-6 h. When liquids were withheld the increase in P.S. was maintained for 24 h, but as the state of the animal deteriorated with continued dehydration (polypnea) the phases of P.S. diminished in duration and frequency and finally disappeared. Resumption of normal hydration after 24 h was accompanied by an immediate return to normal of the P.S. rhythm. A curious phenomenon was observed in all cases during the first phases of P.S. following resumption of a liquid diet: the appearance of a very regular rhythmic activity of 3-4 c/s in the pontine reticular formation (Fig. 24), first in bursts of several

2

Fig. 24. Relationship between pontine electrical activity during P.S. and the osmolarity of the blood. Chronic pontile animal with hypothalamic island. (1) P.S. during dehydration. Monophasic spikes grouped in pseudospindles, accompanied by lateral eye movements (EM). The pontine electrode is situated in the nucleus reticularis pontis caudalis. (2) P.S. after rehydration (60rnl liquid). Very regular theta rhythm of 4.5 c/s associated with spikes and eye movements. This activity was observed only during the first two phases of P.S. after rehydration. It was never observed in the waking state. Identical pontine activity has been observed in 4 animals under the same conditions. References p . SS-57

46

M. J O U V E T

seconds associated with the pontine spikes, and then continuously until the reappearance of EMG activity. Such a pattern has never been observed in the waking state. DISCUSSION

(a) Duality of the siates of sleep

The first section will be limited to positive evidence of the duality of the states of sleep and thus of the specificity and autonomy of paradoxical sleep in relation to slow sleep. (i) Structural duality of the two states of sleep It is difficult to explain the totality of the results we have just described on the basis of a ‘unitary’ theory of behavioural sleep, according to which similar mechanisms and identical structures are responsible for the two states of sleep. To explain the desynchronization of P.S. following synchronization of slow sleep in accordance with this theory, it has been necessary to presume the existence of a single progressively ascending inhibitory process, which attacks first the ascending activating reticular system and secondarily the thalamic synchronizing structures (Hernandez Pehn, 1963). I n point of fact, the structural details we have described necessarily imply different nervous structures responsible for the two states of sleep. The results of experiments with section and coagulation all make it possible to localize the structures triggering off P.S. in the pons (M. Jouvet, 1961; Cadilhac and Passouant-Fontaine, 1962; Rossi et a;., 1963).We have discussed elsewhere (M. Jouvet, 1962a)the different arguments in favour of a descending origin of slow sleep from the telencephalon. But the initiation of this slow activity has not been finally cleared up. Some results indicate that synchronizing structures which could be responsible for slow sleep are to be found in the medulia oblongata (Moruzzi, 1960; Magnes et al., 1961). It has been suggested (Rossi et al., 1963) that these structures are situated immediately behind those responsible for P.S. (in the caudal part of the pontine reticular formation). This hypothesis does not however take into account the fact that coagulation directly behind the nucleus reticularis pontis caudalis at the level of the anterior part of the nucleus gigantocellularis does not suppress slow sleep. Also there is no intermediary phase of sleep between wakefulness and P.S. in pontile animals as shown by either EEG or behaviour. If the synchronizing structures were situated in the lower portion of the brain stem, at the level of the pons and the medulla oblongata, we would have to assume that they could produce no EEG or behavioural manifestations in pontile animals. Moreover, the ascending synchronizing influences would have to act on structures rostra1 to the pons to produce behavioural sleep of an intermediary type between wakefulness and P.S. without slow activity, as occurs in decorticate animals (M. Jouvet, 1962a), whilst the cortex would be necessary to produce slow subcortical activity in intact animals. (ii) Duality of the mechanisms of the states of sleep (Fig. 25) Like the structural findings, the EEG, phylogenetic and ontogenetic data speak for a duality of mechanisms. The results of cortical and subcortical recordings which show

PARADOXICAL SLEEP

47

the fundamental difference between P.S. and slow sleep are in fact confirmed by other methods. Thus, the cortical D.C. potential (Dement, 1964; Wurtz, 1964) in cats shows a sudden negative shift at the beginning of P.S., following the positive shift of slow sleep. The variations in cerebral impedance (Birzis and Tachibana, 1964) and cerebral blood flow (Kanzow et a/., 1962) are similar to those observed during wakefulness and contrary to those observed during slow sleep. Lastly, studies with elecr

1

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Fig. 25. Duality of the two states of sleep. Ordinates, for each diagram: percentage of P.S. (in black) with respect to behavioural sleep. (A) Phylogenetic aspect: hatched : newborn; in black: adult animz.1. (1) Tortoise: no P.S.; (2) Hen (0.2%); (3) Lamb (17%);sheep (6.6%); (4) Young rat (55%); rat (15%); ( 5 ) Kitten (80%);cat (30%); (6) Infant (50%); man (20%). From Klein, 1963. (B) Ontogenetic aspect (in kittens). Abscissa: Age in days. From Valatx, 1963. (C)After selective deprivation of P.S. during recuperative sleep. Abscissa: Duration of deprivation in days. (0) After destruction of the pontine reticular formation (posterior part of the nucIeus reticularis pontis oralis and anterior part of N.R.P. caudalii. No P.S. ( E ) Chronic pontile animal. No slow sleep.

trodes have shown a sudden increase in cortical (Evarts, 1962) or reticular activity (Huttenlocher, 1961) compared with that of slow sleep. Variations in both the autonomic and somatic spheres show that P.S. is indeed a state qualitatively different from slow sleep, for blood pressure drops suddenly at the beginning of the former, while there is little change in the course of the latter (Candia et al., 1962). Finally, the monosynaptic spinal reflexes change little during slow sleep, and disappear entirely in P.S. (Giaquinto et a/.,1964). All the results reviewed here cannot be explained on the basis of a ‘unitary’ theory of sleep. References p . 55-57

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M. JOUVET

Such a theory also necessarily implies that slow sleep (considered as a phase of light sleep) precedes P.S. (deep sleep). If the hypothesis is to be accepted, there ought to be a parallelism between the phylogeilic and ontogenic evolution of the two states of sleep. But this is not in fact the case. Whereas slow sleep appears to be a characteristic of all vertebrate species studied polygraphically up to the present time (from reptiles to mammals), P.S. does not appear to be related to slow sleep in their phylogenic evolution. What is more, the absence of P.S. in chelonians, and its very rudimentary form in birds, contrast with its constancy and relative importance in all mammals. The number of species so far studied is too small to permit definite conclusions to be drawn, but it does appear that P.S. occurs from birds upwards on the evolutionary scale. It may therefore be presumed that with its appearance a new function came into being which is not necessarily related to sleep, since it does not appear in reptiles. Ontogenic aspects also make a differentiation between the two states of sleep possible. At birth, in fact, P.S. occurs relatively more often and is less dependent on slow sleep than in later life. Periods of sleep with rapid eye movements have also been observed in newborns (Roffwarg et al., 1963; Delange et al., 1961). These phases of sleep similar to P.S. can also follow immediately on wakefulness. Thus in the newborn mammal, slow sleep is not a prerequisite of P.S. Until now, sleep states have been investigated primarily in animals that are very immature at birth and it is therefore difficult when analysing the greater amounts and autonomy of P.S. compared with slow sleep to know what to attribute to the immaturity of the nervous system and what to the conditions of early life-milk diet, etc. Nevertheless, one fact stands out: in the cat the average duration of P.S. is almost from the first identical with that in the adult animals. It is only by a reduction in frequency that the proportion of P.S. versus total sleep diminishes. It must therefore be assumed that the P.S. mechanism is already at birth what it will be later in the adult, whereas slow sleep requires further development. In other words, P.S. depends on an ‘innate’ mechanism, whereas the mechanism of slow sleep is acquired after birth. Whilst in adulthood a behavioural distinction can be made polygraphically between the two states of sleep, the fact that slow sleep habitually precedes P.S. would permit the conclusion that the former is a prerequisite of the latter. But our technique of selective deprivation makes it very easy to separate them. Our results confirm those of Dement (1960) in humans and show that a need for P.S. appears as soon as an attempt is made to suppress it. This suggests that a particular function is connected with the appearance of P.S. It is interesting to note in this context that a cat deprived of P.S. for more than 72 h resembles a newborn kitten in its recuperative sleep. In both cases P.S. constitutes the greater part of behavioural sleep (up to 80% of the first hour of recuperative sleep), phasic phenomena and periodicity are very much increased and, especially, P.S. can follow immediately on wakefulness, without being preceded by a phase of slow sleep. P.S. following directly on a state of wakefulness has also been observed in adult man during narcoleptic attacks (Rechtschaffen et al., 1963). Thus under particular conditions-selective deprivation of P.S., narcolepsy-not yet fully understood, it is possible to distinguish between the mechanisms of P.S. and slow sleep in adults.

PARADOXICAL SLEEP

49

( b ) Mechanisms underlying the appearance of P.S. We shall discuss here the question of reflex production of P.S., the effect of deprivation of P.S. in pontile animals and humoral factors. ( i ) Reflex production of P.S.

Inhibition of nuchal tonus during P.S. is not dependent on the gamma system alone, since it persists after section of the posterior cervical roots of the intact animal. Since, furthermore, the cerebellum is intact in pontile animals, it would appear that production of P.S. as a reflex depends on the integrity of the pontine reticular formation (posterior part of the nucleus reticularis pontis oralis and anterior part of the N.R.P. caudalis). There is thus no direct inhibitory effect emanating from the bulbar reticular formation (situated at the level of the nucleus giganto-cellularis and nucleus reticularis ventralis (Magoun and Rhines, 1946; Brodal, 1957), since P.S. can no longer be triggered by mechanisms distal to the mediopontine or retropontine areas. Participation of adrenalin secretion can also be ruled out, as P.S. can appear immediately after nociceptive stimulation and, furthermore, injection of adrenalin does not produce P.S. It also appears that the integrity of the mesencephalic tegmentum prcvents reflex P.S. in mesencephalic animals, although P.S. still occurs spontaneously. Activation of the descending facilitatory system (Magoun, 1950) would thus preclude descending inhibition in mesencephalic animals. We did not analyse the nervous effects of the natural stimuli used in our experimentation, so that it is difficult to isolate the particular type of afferents responsible for triggering P.S. But we do know that the majority of afferents of group I11 project principally on to the mesencephalic tegmentum, while those of groups I and I1 project for the most part on to the pontine reticular formation (Pompeiano and Swett, 1963), so that the latter may be responsible for producing reflex P.S. Thus, under certain conditions, P.S. can be produced by a reflex mechanism. A distinction must however be drawn between generalized atony, a veritable reflex cataplexy, without pontine spikes or ‘spindles’ and eye movements, and true P.S. The former state presents no refractory phase and can follow any proprioceptive, or nociceptive, stimulus when the pons has been transected at the nucleus reticularis pontis oralis level. Such cataplexy resembles the ‘sudden postural collapse’ described by Bard and Macht (1958). It has never been possible, on the other hand, to obtain an iterative form of P.S. Thus, the data invite the conclusion that there exist two different systems at the level of the pons. The first, which is not endowed with refractory period, is responsible for inhibition of muscular tonus (probably via the inhibitory bulbar reticular formation), and the second, which controls the first and presents a refractory period, is responsible for pontine spikes and ‘spindles’ (and probably the EEG phenomena in intact animals) and for the eye movements. This second system can be identified with the ‘centre diclenchant’ of P.S. (M. Jouvet, 1962a)for this is the level at which the refractory phase producing the periodicity of P.S. appears. Such a system may explain the different aspects of certain reflex cataplectic attacks in humans. The one type-cataplexy-narcolepsy-presents EEG, polygraphic and electromyographic References p . 55-57

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tracings identical with those in sleep with eye movements (personal observation), and the other-cataplexy-is characterized by intact consciousness. If, therefore, P.S. can be induced as a reflex under certain conditions, this does not appear to be the sole mechanism. Nevertheless, this hypothesis has been maintained by Lissak et al. (1962). These authors contend that inhibition of muscular tonus is the cause, and not the effect, 0f P.S. But several facts make it possible t o preclude the exclusive activation of P.S. by peripheral muscular afferents. ( I ) Cortical activation of P.S. often precedes the disappearance of muscular tonus in intact animals. (2) In pontile animals (without hypothalamic island) long periods of total atony are not infrequently observed. No EMG activity.in the neck or other muscles is then present. In spite of this complete atony, P.S. can regularly appear, recognizable by pontine EEG criteria, rapid eye movements and autonomic changes. Total muscular at ony is thus not per se an inhibitory or facilitatory factor of P.S. (3) Lastly, total section of the spinal cord at C6 with section of the brachial plexus, whereby a large number of afferents of muscular origin are suppressed, does not affect the appearance of P.S. Thus, the result of nervous deafferentation experiments is negative. Furthermore, the periodic and regular appearance of P.S. 4-5 days after ablation of the hypothalamus and pituitary rules out a direct and indispensable participation of ACTH and the post-pituitary hormones and the different hypothalamic neurohormones. The decrease in P.S.seen from about the fourth day and before death must be ascribed to delayed ionic and metabolic disturbances resulting from the prolonged absence of pituitary (especially antidiuretic) hormones. The periodic appearance of P.S. thus cannot be explained by peripheral nervous or hypothalamo-pituitary factors, so that investigation can be restricted to pontine phenomena (neuronal or glial), although peripheral humoral factors cannot be excluded a priori.

(ii) It is difficult with the methods of study employed to specify the mechanisms of P.S. precisely. But several indirect findings all point to this state of sleep being endowed with a certain ‘autorhythmicity’ and situated in the pons. The presence of P.S.under conditions of hypothermia at 29” indicates the resistance to cold of its underlying mechanisms. The findings are similar to those in anesthesia: P.S. in fact continues to appear periodically in decorticated animals after doses of 20-30 mg/kg pentobarbitone (M. Jouvet, 1962a). Furthermore, the greater duration of P.S. (and of the intervals between the phases) during hypothermia is reminiscent of enzymatic processes and suggests a metabolic phenomenon. The action of y-butyrolactone (G.B.L.) is difficult to interpret, in spite of the fact that its structure is simple. Bessman and Skolnik (1964) see G.B.L. as a normal constituent of the brain, an increase in the intracerebral concentration coinciding with anesthesia induced by G.B.L. or y-hydroxybutyrate (G.H.B.). Giarman and Roth (1964), on the other hand, found no G.B.L. in the blood or brain and attribute the anesthetic role to y-hydroxybutyrate. G.B.L. does not appear to be a precursor of

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cerebral GABA, for the level of the latter does not increase after injection of G.B.L. (Giarman and Schmidt, 1963). It has also been shown that injection of G.B.L. can raise the level of acetylcholine in the brain (Giarman and Schmidt, 1963), and specifically in the area of the corpora quadrigemina. Whilst the mechanism behind this increase in cerebral acetylcholine is not known the data suggest a cholinergic-type link within the P.S. process. Certain peripheral manifestations of P.S. in intact animals (myosis, bradycardia, increased and irregular respiration, arterial hypotension (Candia el al., 1962) inhibitory role of atropine(M. Jouvet, 1962a), support this view. But while such observations suggest the intervention of cholinergic neurons during P.S., they cannot explain the periodicity. (iii) Deprivation of P.S.

The progressive diminution of the intervals between each incipient phase of P.S. in pontile cats caused by the increasingly frequent repetition of the disturbing shock, suggests a biochemical process whereby the accumulation during wakefulness of an unknown factor among the metabolites of neuronal activity provokes the increasingly rapid induction of a recuperative process. The inescapable nature of this reappearance of P.S. meant that with our technique prolonged deprivation was impossible. It nevertheless appears that a minimal increase in the recuperative process is adequate to restore the earlier conditions and normal rhythm of P.S. In the intact animal, on the other hand, in which prolonged periods of deprivation are possible, P.S. increases considerably but does not exceed a certain ceiling (60%). during the first 6 h of recuperative sleep. This plateau thus appears to represent the upper limit of the cyclic metabolic processes of P.S. In this connection, it is interesting to note that recuperation does not occur in one long phase of P.S., but the periodicity remains, as though it were impossible for P.S. to last for more than 20-25 min at a stretch. Thus, the P.S. deficit which is accumulated over a long period of deprivation can only be partially and slowly compensated by a phenomenon which remains periodical and is of limited duration. This suggests the existence of a self-regulating cyclic metabolic process which requires several days before it can ‘neutralize’ the unknown factor accumulated during deprivation. (iv) It is a difficult task to interpret the relationships between osmolarity of the blood and P.S., for the amounts of ions normally present in the cerebrospinal fluid and the brain are not known. The post-pituitary hormone could be cited as an indirect factor in the increase of P.S. during withdrawal of liquids and following injection of hypertonic saline solution. But injection of ADH does not promote P.S., which can occur in transitory diabetes insipidus (i.e. in the absence of post-pituitary hormones). There must therefore be another mechanism at work, which could be none other than a direct influence of the osmolarity of the blood. In the case of pontile animals with an intact hypothalamic island, the relationship between the blood and the brain must always be considered in particular at the level of the barrier between the capillaries and the neuroglial cells, to which an important and active role is accredited in what is termed the blood-brain barrier (Edstrom, 1964). According to recent findings (De Robertis References p . 55-57

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and Gerschenfeld, 1961), the neuroglia appears to be the tissue that plays the greatest part in the mechanisms of ion and water exchange between the internal milieu and the neurons. It constitutes a water ion pool (Gerschenfeld et al., 1959) between the blood and the neurons, playing a part in the transportation of metabolites and the storage or elimination of K and Na at the neuronal level. An active barrier, which has been likened to the renal glomeruli (Tschirgi, 1958; Edstrom, 1964), would thus keep the whole neuronal complex relatively independent of variations in the ion content of the extracellular fluid. Furthermore, the osmolarity of the brain is closely related to that of the blood and quickly adjusts itself to variations in the latter (Stern and Coxon, 1964). There are thus grounds for supposing that variations in the osmolarity of the blood above all affect the glial cells. It is therefore possible that an electrolyte concentration exceeding that of these cells facilitates the enzymatic mechanisms responsible for P.S., whereas a lower concentration would inhibit them. Lastly, the appearance of regular rhythmic activity during rehydration (after fluid deprivation) only during P.S. would appear to signify a close relationship between the electrical activity of the pons in P.S. and the osmolarity of the blood. One might therefore presume that at this moment, and only at this moment, the glial structures participate in the recurrence of a certain type of cerebral homeostasis. This hypothetical periodic glial mechanism, with its purpose either of maintaining cerebral homeostasis (cerebrostasis) or as an active process for the elimination of certain metabolites, would protect the brain so that P.S would appear as a periodic phenomenon interrupting waking activity in the pontile animal and slow sleep in the intact animal, to restore equilibrium at the neuronal level. It must be admitted that if such a mechanism exists its location in the pons would be ideal. For, at that level, the nervous and glial cells could receive biochemical information on the activity of the neurons from the whole nervous system, since the afferents from the rostra1 and caudal regions of the nervous system converge at that point (Brodal, 1957), whilst efferent ascending and descending pathways lead out from the pons to the cortex and spinal cow (Scheibel and Scheibel, 1957). (v) The nature of P . S . Finally, we must gather the facts together and attempt to draw up some hypotheses on the nature of P.S. It would appear to be established that P.S. is dependent on a periodic mechanism of an unknown nature situated in the pons. This mechanism triggers an ascending tonic neuronal activity similar to (or perhaps identical with) that of the waking state and a phasic activity which is specific to it. However intense the cortical, reticular or pyramidal neuronal activity during P.S., it is prevented from expressing itself (except for the rapid eye movements) in appropriate tonic motor phenomena by the inhibitory reticular formation set in action by the pons. The findings we have discussed also show P.S. to be a state differing qualitatively from slow sleep. The relation between the two is nonetheless a close one, however, for slow sleep is normally a precondition for P.S. Finally, numerous observations in humans show that dreaming is the subjective equivalent of P.S. (Dement and Kleitman, 1957; M. Jouvet and D. Jouvet, 1964). Passing from the facts to hypothetical considerations, a number of points can be

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53

made. Recollection of recent or past events during P.S. suggests that certain memory processes occur during this phase. The relatively high incidence of P.S. in the neonatal period, when the ‘plastic’ processes of learning are at their most active, is also indicative of a probable relationship between P.S. and the process of memory. A further sign is the presence of a particular rhythmic &activity in the limbic system. The relationship of such activity during wakefulness to storage of information in the CNS has been discussed by Adey (1964). Finally the parallelism between variations in P.S. and the osmolarity of the blood suggests the intervention of the neuroglia, perhaps as regulator of certain processes of protein synthesis essential to storage in the neurons; this is in keeping with the findings of Hydtn and Pigon (1960). Is it possible that the biological clock in the pons which activates P.S. may be the mechanism responsible for the complex biological processes by which we retain (or lose) the memory of past events during dreaming? It must certainly be admitted that if molecular changes are to occur at the level of the sensory and motor neurons it would be logical for them to occur during sleep and at a moment when a safety mechanism prevents peripheral motor expression of the discharges due to protein synthesis within the neurons, for otherwise the dreamer would run the risk of behaviourally reacting to dangerous hallucinations. Paradoxical sleep, the physiological substratum of dreaming, would thus appear as the expression of a periodic function of storing information at the molecular level. Why this mechanism expresses a need, as objectified by deprivation experiments, remains to be explained. Are we to imagine a threshold in the functional information storage processes occurring in the waking state which initiates slow sleep? A large quantity of information (external stimuli, prolonged low-frequency stimuli) does in fact quickly produce slow sleep in the intact animal (supraliminal inhibition of the Pavlovian type, hypnogenic stimulation). It is possible that, in the pons, where the majority of neurons of the central nervous system converge, certain cells are subject to a biochemical mechanism which represents a certain threshold of functional storage of information. Once this threshold has been passed, a pontine mechanism would initiate the storage process at the molecular level. It is not unreasonable to presume that such processes are cyclic and autoregulatory and that they cannot exceed a certain limit of activity of 60%, as is the case during recuperation following deprivation of paradoxical sleep. SUMMARY A N D CONCLUSIONS

In the first part of this study, the arguments supporting the theory of the duality of sleep (slow sleep-paradoxical sleep) are set forth. (1) Both tonic and phasic EEG or peripheral index of P.S. are totally different from EEG and behavioural slow sleep. The pontine origin of rapid eye movements and of the phasic ponto-geniculo-occipitalactivity occurring during P.S. is emphasized. (2) Phylogenetic study shows that slow sleep may be observed in reptiles, birds and mammals. In contrast, P.S. is not found at all in the tortoise, and is of very short duration in birds (its ratio to the total sleep being only 0.2%). In mammals this ratio is about 630%). References p . 55-57

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(3) Ontogenetic studies in the kitten show that P.S. may appear immediately after wakefulness and constitutes 90% of total sleep during the first days. During maturation, the relative percentage of P.S. decreases to 30% while the percentage of slow sleep increases to 70% of the total sleep. (4) The results of selective deprivation of P.S. in the adult animal are summarized. They show that after deprivation for more than 72 h, a maximum of 60% of P.S. is reached during recuperative sleep. This percentage is not exceeded even after 17 days of deprivation. On the other hand, during recuperation P.S. may be observed immediately after waking. After prolonged deprivation several days are required before the animal recovers the control level of P.S. ( 5 ) Coagulation of the pons may suppress P.S. electively without producing any change in slow sleep. (6) In chronic pontile animals, with hypothalamic islands, the rhombencephalic phase of sleep, showing all the pontine electrical and behavioural criteria of P.S. in the intact animal, can be completely identified with the latter. Its mean duration (6 min) is analogous to that of the intact animal while its duration per 24 h is somewhat less (10%). No behavioural or EEG index of slow sleep was observed in pontile animals. All these results cannot be explained by a unitary theory of sleep. On the contrary, they allow us to differentiate P.S. from slow sleep in its structural bases and mechanisms. The second part of the paper outlines some mechanisms of triggering P.S. in pontile animals. It is possible to trigger reflex P.S. by proprioceptive or nociceptive stimulation in pontile animals, provided that the section is made caudally to the mesencephalic tegmentum. Various nervous deafferentations (afferents going through the spinal cord below C6, the vagus, buffer nerves) do not prevent P.S. from occurring in intact cats, and it does not therefore seem possible that P.S. is only triggered by reflex nervous pathways. Ablation of the pituitary and hypothalamus does not suppress P.S. during the first 5 days of survival. A hormonal hypothalamo-pituitary mechanism is thus ruled out. Deprivation of P.S. by electric shocks in pontile animals involves the reappearance, with increasing rapidity, of P.S., so that after a few hours P.S. can recommence several times per minute. This fact speaks for an active mechanism at the level of the pons. The action of hypothermia on P.S. is considered and the resistance of this phenomenon to hypothermia shown. The facilitatory effect of y-butyrolactone is emphasized. It was also found that P.S. is suppressed by hypo-osmolarity and facilitated by hyper-osmolarity of the blood. All these results speak in favour of a self-regulating metabolic process, located in the pons, and the possibility of a neuroglial mechanism is considered.

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55

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HOBSON, J. A., (1964); L’activitk Clectrique phasique du cortex et du thalamus au cours du sommeil desynchronisk chez le chat, C.R. SOC.Biol. (Paris), in the press. HUBEL,D. H,, (1960); Electrocorticograms in cats during natural ?leep, Arch. ital. Biol., 98. 171-181. HUTTENLOCHER, P. R., (1961); Evoked and spontaneous activity in single units of medial brain stem during natural sleep and waking, J. Neurophysiol., 24, 451468. HYDEN,H., and PIGON,A., (1960); A cytophysiological study of the functional relationship between Oligodendroglial Cells and nerve cells of Deiters’ nucleus, J . Neurochem., 6, 57-72. JEANNEROD,M., and MOURET, J., (1963); Etude comparative des mouvements oculaires observes chez le chat au cours de la veille et du sommeil. J. Physiol. (Paris), 55, 268. JEANNEROD, M., MOURET,J., and JOUVET,M., (1965); Etude de la motricitk oculaire au cours de la phase paradoxale du sommeil chez le chat. Electroenceph. clin. Neurophysiol., in the press. JOUVET, D., (1962); La phase rhombenckphalique du sommeil. Ses rapports avec I’activitk onirique. Thesis, Lyons. JOUVET,D., VALATX, J. L., and JOUVET, M., (1961); Etude polygraphique du sommeil du chaton, C.R. Sac. Biol. (Paris), 155, 166&1664. JOUVET,D., VIMONT,P., DELORME, J. F., and JOUVET, M., (1964); Etude de la privation de phase paradoxale du sommeil chez le chat. C.R. SOC.Biol. (Paris), 158, 756-759. JOUVET, M., (1961); Telencephalic and rhombencephalic sleep in the cat, The Nature of Sleep, G . E. W. Wolstenholme and M. O’Connor, Editors, London (p. 188-208). JOUVET,M., (1962a); Recherches sur les structures nerveuses et les m h n i s m e s responsables des diffkrentes phases du sommeil physiologique, Arch. ital. Biol., 100, 125-206. JOUVET, M., (1962b); Un appareil enregistreur automatique des phases rhombenckphaliques du sommeil chez I’animal : l’onirographe, Rev. Neurol., 107, 269-271. JOUVET, M., CIER, A., MOUNIER,D., and VALATX,J. L., (1961); Effets du 4 butyrolactone et du 4 hydroxybutyrate de sodium sur l’E.E.G. et le comportement du chat, C. R. Soc. Biol. (Paris), 155, 131 3-1 316. JOWET,M., and JOWET,D., (1964); Le sommeil et les rEves chez les animaux. Psychiatrie animule. H. Ey, Editor. DesclQ de Brovwe. JOUVET,M., JOWET,D., and VALATX, J. L., (1963); Etude du sommeil chez le chat pontique chronique: sa suppression automatique. C.R. SOC.Biol. (Paris), 157, 845-849. JOUVET, M., MICHEL,F., and C O ~ O NJ.,, (1959); Sur un stade d‘activite Clectrique drkbrale rapide au cours du sommeil physiologique. C.R. SOC.Biol. (Paris), 153, 1024-1028. KANZOW,E., KRAUSE, D., and KUEHNEL, H., (1962); The vasomotor system of the cerebral cortex in the phases of desynchronized E.E.G. activity during natural sleep in cats. Pfliigers Arch. ges. Physiol., 274, 593-607. KAWAKAMI, M., and SAWYER, C. H., (1962); Effects of hormones on ‘paradoxical’ sleep in the rabbit. Fed. Proc., 21, 354-359. KLEIN,M., (1 963); Etude polygraphique et phylog6nirique des difirents Etafs de Sommeil. Thesis. Lyon, Bosc Edit. KLEIN,M., MICHEL, F., and JOUVET, M., (1964); Etude polygraphique du sommeil chez les oiseaux. C.R. SOC.Biol. (Paris), 158, 99-103. KOCH,E., (1 932); Die Irradiation der pressoreceptorischen Kreislaufreflexe. Klin. Wschr., 2, 225227. LISSAK,K., KARMOS, G., and GRASTYAN, E., (1962); The importance of muscular afferentation in the organization of the ‘paradoxical phase’ of sleep. Abstract XXZZ Znt. Physiol. Congr., Excerpta Medica, No. 932. Leiden. MAGNES,J., MORUZZI,G., and POMPEIANO, O., (1961); Synchronization of the E.E.G. produced by low-frequency electrical stimulation of the region of the solitary tract. Arch. ital. Biol., 99, 33-67. MAGOUN,H. W., (1950); Caudal and cephalic influences of the brain stem reticular formation. Physiol. Rev., 30,459414. MAGOUN,H. W., and RHINES,R., (1946); An inhibitory mechanism in the bulbar reticular formation. J. NeurophysioZ., 9, 165-171. MICHEL,F., JEANNEROD, M., MOURET,J., RECHTSCHAFFEN, A., and JOUVET,M., (1964a); Sur les mkanismes de l’activitC de pointes au niveau du systeme visuel au cours de la phase paradoxale du sommeil. C.R. SOC.Biol. (Paris), 158, 103-106. MICHEL, F., RECHTSCHAFFEN, A., and VIMONT, P., (1964b); Activitk tlectrique des muscles oculaires extrinskques au cours du cycle veille-sommeil. C.R. SOC.Biol. (Paris), 158, 106-109.

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M I K I ~ NT., , NIEBYL, P., and HENDLEY, C., (1961); E.E.G. desynchronization during behavioural sleep associated with spike discharge from the thalamus of the cat. Fed. Proc., 20, 327. MORUZZI, G., (1960); Synchronizing influences of the brain stem and the inhibitory mechanisms underlying the production of sleep by sensory stimulation. Electroenceph. clin. Neurophysiol., 13 SUPPI., 231-253. MORUZZI, G., (1964); Reticular influences on the E.E.G. Electroenceph. clin. Neurophysiol., 16, 2-17. MORUZZI, G., and MAGOUN,H. W., (1949); Brain stem reticular formation and activation of the E.E.G. Electroenceph. clin. Neurophlisiol., 1, 455473. MOURET, J., JEANNEROD,M., and JOUVET, M., (1963); L'activitC Bectrique du systeme visuel au cours de la phase paradoxale du sommeil chez le chat. J. Physiol. (Paris), 55, 305-306. NAQ~ET, R., DENAVIT, M., LANOIR,J., and ALBE-FESSARD, D.; Alterations transitoires ou definitives de zones diendphaliques chez le chat. Leurs effets sur I'activit6 electrique corticale et le sommeil. Znternat. Symp. on the Anatomo-Functional Aspects of Sleep. Lyons 9-1 1 Sept. 1963. Edition C.N.R.S., in the press. NAUTA,W. J. H., (1946); Hypothalamic regulation of sleep in rats. An experimental study. J. NeurPphysiol., 9, 285-316. POMPEIANO, O., Ascending and descending influences of somatic afferent volleys in unrestrained cats: supraspinal inhibitory control of spinal reflexes during natural and reflexly induced sleep. Znternat. Symp. on the Anatomo-Functional Aspects of Sleep. Lyons 9-11 Sept. 1963. Edition C.N.R.S., in the press. POMPEIANO, O., and SWETT,J. E., (1962a); E.E.G. and behavioral manifestations of sleep induced by cutaneous nerve stimulation in normal cats. Arch. itul. Biol.,100, 311-342. POMPEIANO, O., and S w ~ r r J. , E., (1962b); Identification of cutaneous and muscular afferent fibers producing E.E.G. synchronization or arousal in normal cats. Arch. ital. Biol., 100, 343-380. POMPEIANO, O., and SWETT,J. E., (1963); Actions of graded cutaneous and muscular afferent volleys on brain stem units in the decerebrate cerebellectomized cat. Arch. ital. Biol., 101, 552-583. RECHTSCHAFFEN, A., WOLPERT, E. A., DEMENT, W. C., MITCHELL, S. A., and FISHER,^., (1963); Nocturnal Sleep of Narcoleptics. Electroenceph. clin. Neurophysiol,, 15, 599-609. REINOSO-SUAREZ, F.,(1961); Topographischer Hirnatlas der Katze. Darmstadt, Merck. ROFFWARG, H. P., DEMENT, W. C ., and FISHSR, C., (1963); A sleep E.E.G. rapid eye movement cycle h new born infants associated with specificphysiological variations. Report of Curr. Res. Assoc. for the Psychophysiol. Study of Sleep. Ross[, G . F., FAVALE, E., HARA,T., GIIJSSANI, A., and SACCO,G., (1 961) ;Researches on the nervous mechanisms underlying deep sleep in the cat. Arch. ital. Biol., 99, 270-292. Rossr, G. F., MINOBE,K., and CANDIA,O., (1963); An experimental study of the hypnogenic mechanisms of the brain stem. Arch. ital. Biol.,101, 470-492. SCHEIBEL, M. E., and SCHEIBEL, A. B., (1957); Structural substrates for integrative patterns in the brain stem reticular core. Reticular Formation of the Brain. Henry Ford Hospital Symposium. Boston, Little Brown and Co., (p. 31-55). SNYDER, R. S., and NIEMER, W. T., (1961); A Stereotaxic Atlas of the Cut Brain. Univ. of Chic. Press. STERN,E. W., and COXON, R. V., (1964); Osmolarity of brain tissues and its relation to brain bulk. Amer. J. Physiol., 206, 1-7. TSCHIRGI, R. D., (1958); The blood brain barrier. Biology of Neuroglia. W. F. Windle, Editor. Springfield, C. Thomas, (p. 130-138). VALATX, J. L., (1963); Ontogendse des diflirents Etats de Sommeil. Etude comportementale E.E.G. et polygraphique chez le Charon. Thesis. Lyons, Annequin Edit. VALATX, J. L., JOLTYET, D., and JOLJVET, M., (1964); Evolution 6lectroen&phdographique des diff6rents ttats de sommeil chez le chaton. Electroenceph. elin. Neurophysiol., 17, 218-233. VONECONOMO, C., (1929) ;Schlaftheorie. Ergebn. Physiol., 28, 312-339. WURTZ,R. H.; Steady potential shifts during arousal and deep sleep in the cat. Submitted to J. Neurophysiol. DISCUSSION

TISSOT:One form of sleep or several? The discussion brings to mind the classic quarrel between the neoticians and the associationists. The problem must be put differently. Although there are different structures, mechanisms and functions, often

58

DISCUSSION

,even opposed to one another, normal sleep has the characteristic quality of integrating them into a harmonious activity.

JOUVET: I agree with you, but if I adopt this way of trying to show the duality of the states of sleep it is because there is often a tendency to consider sleep as a single state with only quantitative changes-light or deep sleep. I think these terms are very misleading because they might give the impression that paradoxical sleep is only due to an intensification of the hypnic process whereas the occurrence of something else is in fact involved. SOULAIRAC : The phylogenetic study of sleep ought to provide information about the physiological significance of the two types of sleep. The fact that only the higher vertebrates (mammals and to a very slight extent birds) manifest paradoxical sleep prompts the question whether it is not connected with the presence of the neocortical system. One might suggest that just as development of the neocortex involves the appearance of a second vigilance system, superimposed on the fundamental mesencephalic system, paradoxical sleep would in the same way represent the manifestation of a second system of sleep regulation. This would then represent not a true duality but the coordination on the phylogenic plane of two chronologically different mechanisms controlling the unitary biological function of sleep in the higher vertebrates.

JOUVET:It would nevertheless seem that the cortex is not necessary for the occurrence of paradoxical sleep since the latter persists in decorticated or pontile animals. We also found to our surprise that, contrary to the classic theory, ontogenetic development does not simply repeat on a smaller scale the pattern of phylogeny since paradoxical sleep is particularly developed at birth, in both the kitten and the newborn human infant, whereas it is practically abserlt in birds. In this sense paradoxical sleep does not appear to be archisleep as we first thought. HERNANDEZ-PE~N : 1share Prof. Hess' opinion supporting a unitary concept of sleep. Sleep and wakefulness are physiological states subserved by the dominance of antagonistic neural systems which must have a complex but integrated organization. I also agree with Prof. Jouvet that the region of the nucleus reticularis pontis caudalis plays a n important role in the muscular hypotonia of the desynchronized phase of sleep. However, there is no need to postulate two different independent neural systems in order to explain the two groups of epiphenomena of sleep. Their habitualchronological relationship can be easily explained by different degrees of activation within a single sleep system which produces different degrees and extents of inhibition within the vigilance system.

JOUVET: I am afraid I do not agree with you at all. The fact that first slow then paradoxical sleep can be produced by injecting acetylcholine in situ is no proof that the same mechanism is responsible for both. Paradoxical sleep occurs spontaneously

PARADOXICAL SLEEP

59

during slow sleep and it would be very nalve to imagine that it had been specifically produced when it occurs more than a minute after an injection. (The same applies, by the way, to slow sleep.) On the contrary we have demonstrated that slow sleep was not necessary for the occurrence of the paradoxical phase (ontogenesis, deprivation, pontile animals). TISSOT: Dementia in advanced age has been shown to produce a longer duration of paradoxical sleep (as in the child) than that of the adult. T h s is another argument in favour of Jouvet's concept of archisleep. JOUVET: I do not think we should generalize yet on the data concerning insanity. We have made tracings of psychotic subjects with Korsakoff's syndrome and have been surprised to see a significant decrease of paradoxical sleep in them.

MORUZZI: Prof. Jouvet has just given us new and very important facts on the phylogenic and ontogenic aspects of desynchronized or paradoxical sleep. I should like to ask his opinion of the relationship of classic or synchronized sleep to these bursts of desynchronized sleep which are of fairly short duration and characterized by essentially phasic phenomena. What is the reason for the sudden disappearance of a phase of desynchronized sleep? An answer to this question might help us understand the functional significance of the phenomenon. Are we dealing with something new, which only interrupts synchronized sleep but which is not related to it and which disappears immediately and spontaneously, as any convulsive or subconvulsive manifestation? Or does synchronized sleep inevitably lead to paradoxical sleep and suppress it again as soon as it can deal with the situation? It would be interesting to try to prolong the phases of paradoxical sleep in cases where it is very short, such as in the pigeon. A study of the postural and ocular effects in the thalamic pigeon would provide an answer to this question. JOUVET: I think we are not yet in a position to solve this important problem. There seems to be no connection between the duration of slow sleep and that of the paradoxical sleep that follows. On the other hand, in about 70% of cases paradoxical sleep terminates in waking, however brief, and not in a return to slow sleep. We must regard paradoxical sleep as a self-regulated process of metabolic or enzymatic nature. Even after very long deprivation (22 days), such as we have recently carried out, the mean duration of recuperative paradoxical sleep falls to 6 min after 24 h. On the other hand, the intervals between each phase are shortened for some 12 days. We have the impression that if paradoxical sleep represents either the synthesis or the elimination (or both) of some substance, this synthesis can only take place according to a process comprising a mechanism for its own autoregulation. The only way to increase the duration of paradoxical sleep (in the pontile animal) is hypothermia foIlowed by rewarming. It would of course be interesting to study thalamic pigeons, but I am afraid the phases of paradoxical sleep in birds are very short indeed.

60

DISCUSSION

KUGLER: Jouvet has demonstrated that in the case of the cat, the EEG patterns of certain phases of sleep accompanied by muscular atony are difficult to distinguish from the waking EEG. Hence he has coined the term ‘paradoxical sleep’ for these phases. In man, sleep accompanied by muscular atony and eye movements produces lowvoltage, fast EEG patterns instead of the high-amplitude slow activity of classic sleep. But they are not identical with the waking rhythm in humans. The frequencies are generally slower than those of the normal a-rhythm and present superimposed flat &waves. The patterns can more easily be compared with those of stage B of classic sleep. When a-like activity occurs it has a different topographical distribution and a different reactivity from the occipital a-rhythm. A characteristic of these phases, moreover, is the moment of occurrence : they occur only after classic sleep phases and not immediately after waking periods.

MINKOWSKI : I am wondering whether paradoxical sleep, accompanied by eye movements beneath closed eye-lids, as described so admirably by Prof. Jouvet, does not represent a recurrence-mutatis mutandis, of course-of the fetal form of sleep in the adult. Eye movements are very probably produced in the fetus long before the palpebra1 slits are formed, either as movements accompanying the first fetal head movements or as movements of proprioceptive origin in the strict sense of the word, i.e. produced by proprioceptive stimulation in the eyeballs. From the anatomical aspect there is good reason to stress that the posterior longitudinal bundle in the protuberantial and mesencephalic tegmentum, one part of which unites and coordinates the oculomotor nuclei, is one of the formations that undergo myelinization earliest in the fetus-in the 4th month of intrauterine development-and that part of the fibres df the reticular formation and the nuclei and intracerebral parts of the oculomotor nerves undergo the same process shortly after. These formations thus constitute an anatomical fetal substrate for early eye movements which occur well before their postnatal reactions to visual stimulation. As a result of my research into the successive development of nervous function in the early stages of the fetus, the newborn, the infant, the child and the adult, I formed the idea that each different phase of development does not completely disappear when the next one begins but continues to exist, at least potentially, at deep functional levels, and to interact according to the circumstances with the superimposed more highly differentiated adult components. It would be extremely interesting if this sleep could be demonstrated as manifesting the coexistence of elements of different genetic levels, the paradoxical phase of sleep appearing as a relic of fetal sleep in the general and complex sleep of the animal and adult human. JOUVET:I fully agree with this interpretation. I think that experiments on apes will soon have reached the stage where we can study fetal sleep. The only facts we have so far refer to birds. Klein in my laboratory studied the chick embryo (from the 17th to the 20th day of incubation) and noted periods of rapid eye movements accompanied by bradycardia, but the cerebral electrical activity did not vary and no muscular activity could be recorded. These embryonic states possibly represent something connected with paradoxical sleep.

PARADOXICAL SLEEP

61

MONNIER : What differences in autonomic function have you observed during the two phases of sleep? How do the pupils react during paradoxical sleep?

JOUVET: The pupil is generally in a state of extreme miosis during paradoxical sleep (more contracted than during slow sleep). But short periods of mydriasis often accompany the sudden eye movements and even persist after cervical sympathectomy. KONZETT:What is the effect of minimum doses of hypnotic substances on paradoxical sleep?

JOUVET: This question is very interesting. We have particularly studied the action of ‘Nembutal’. This drug, even in anesthetic doses (30-35 mg/kg body weight), does not appear to suppress the occurrence of the paradoxical phase during anesthesia. Paradoxical sleep is certainly much more difficult to recognize than in the normal animal, but if the monophasic peaks in the pons or the lateral geniculate are taken as a criterion they will be seen to persist for regular periods of about 6 min during anesthesia and that their incidence is increased after selective deprivation. The process responsible for paradoxical sleep seems to be particularly active since it is not suppressed by anesthetic doses of ‘Nembutal’. PLErsCHER :

What is the physiological significance of paradoxical sleep?

JOUVET: I wish I could answer your question! This is certainly one of the most fascinating problems of the physiology of sleep. It would seem that paradoxical sleep may represent the expression of a ‘dreaming function’ and that it might possibly also have some connection with the phenomena of memory formation. A very speculative hypothesis would be that paradoxical sleep might represent the molecular synthesis of the proteins responsible for memory storage. This would explain the particular importance. of paradoxical sleep at an early age when the learning processes are very much to the fore. We have equally been struck, as I mentioned just now, by the decrease of paradoxical sleep in subjects suffering from Korsakoff‘s syndrome (unpublished observations). However, I must confess that such observations are much too limited to enable us to establish a connection between paradoxical sleep and memory.

ARNOLD : Phylogenetically, sleep is a very old behavioural pattern. For this reason we are justified in discussing briefly the phenomenon of human sleep from the phylogenetic point of view. An important fact is that the development of man has been characterized by two absolutely opposed sleeping patterns. The earlier stage of3ylogenetic development is represented by vegetarian tree-dwellers who also slept in trees. For this purpose the extremities must be kept in a cramped position (clinging function), which is only possible through a more or less upright position of the body produced by the corresponding tonus systems of the brain stem and spinal cord. In this sleeping position the distance between each member of the group is larger and the mutual protection smaller; defence or flight in the event of attack is only possible when signals

62

DISCUSSION

(e.g. noise or vibration), perceived in spite of sleep, lead to immediate defence reactions. At a later period, during the transition to prairie dwellers, quite different sleeping positions emerged with the development of a hunting community. While some kept watch the others huddled close together and lay in positions where the exposed surface of the body was reduced to a minimum as protection against loss of warmth and getting wet (fetal position). This demanded complete relaxation of the whole muscular apparatus, a horizontal position and a corresponding functional modification in postural reflexes. These two phylogenically pre-formed and contrasting sleeping positions are still the extremes of a range of behavioural possibilities. Between these two extremes is a middle zone, which we might call the intermediary position. This perhaps includes paradoxical sleep with its numerous levels of activity expressed as frequent change of positions, muscular twitching and even sudden starts, attentive listening, getting up and sleep-walking. It appears necessary not only to consider the complex pattern of sleep in man from the aspect of organization and function of neurophysiological substrates and their elements but also to bear in mind that the overall and detailed function of these elements is subordinate to the very old pattern of sleep and has undergone the same phylogenic modifications.

63

Cortical and Subcortical Auditory Evoked Potentials during Wakefulness and Sleep in the Cat A. HERZ Department of Experimental Neurophysiology, German Research Institute for Psychiatry, (Max-Planck-Institute) , Munich (Germany)

While investigating the influence of neuropharmacologic agents on auditory evoked potentials it seemed appropriate to study these potentials at different waking stages. It was found that auditory responses after administration of stimulants and EEGactivating substances were not only very similar to those seen during drug-free wakefulness but could hardly be distinguished from the potentials during paradoxical (activated, rhombencephalic) sleep (Dement, 1958; Jouvet, 1962). Since the nature and significance of this peculiar phase of sleep is not yet completely understood, the evoked response during wakefulness and the various stages of sleep as found in these experiments are presented. METHOD

Recordings were taken by means of implanted electrodes in the auditory and visual cortex, the hippocampus and the medial thalamus of cats. The stimulus was a 800 c/s tone of approximately 250 msec duration and supramaximal intensity. The response t o 50 such tones at intervals of 10-15 sec was electronically analysed by a CAT computer and recorded by means of an X-Y-plotter. The analysis-time was relatively long (0.5 sec) so that long lateccy changes in potential could also be recorded. The following figures are unipolar tracings; upward deflection indicates a negative charge in the active electrode. RESULTS

Fig. 1 shows both the evoked potentials recorded from the cortex during wakefulness and various stages of sleep, and the corresponding EEG tracings. The tracings from auditory cortex showed marked changes. During sleep associated with spindle bursts the evoked response increased. During paradoxical sleep the evoked potentials were small and very similar to those during wakefulness. These changes were even more pronounced when the response to the auditory stimulus was recorded from structures outside the auditory system. Evoked potentials could not only be observed in the association cortex (Buser and Borenstein, 1959), but also in other structures, such as the visual cortex, except that the primary positive response is absent. Again, evoked References p . 69

64

a

X

u 0

c

0

u) ._ >

X

0

*

A. HERZ

0,

0

% E

C“

CORTICAL AND SUBCORTICAL AUDITORY EVOKED POTENTIALS

65

potentials in these areas were only slightly developed in the fully awake animal. During sleep associated with spindle bursts the amplitude considerably increased and returned to its previous size during paradoxical sleep. A similar relationship of evoked responses to the waking state could be observed in the hippocampus and medial thalamus. On account of the &activity during paradoxical sleep the hippocampus is particularly interesting in this respect. This activity suggests a particular significance of the limbic system for the occurrence of paradoxical sleep (Jouvet, 1962; Kawakami and Sawyer, 1959). During wakefulness in the experiment illustrated in Fig. 2, only an indistinct evoked potential was recorded in

-

100 msec

Fig. 2. Evoked potentials from hippocampus with the corresponding EEG tracings on auditory stimulation during wakefulness, spindle sleep and paradoxical sleep.

the hippocampus. During sleep accompanied by spindle bursts in the isocortex it was very pronounced and during paradoxical sleep it became small again and similar to Medial thalamus

Fig. 3. Evoked potentials from the medial thalamus on auditory stimulation of the animal during wakefulness, sleep with spindle activity and paradoxical sleep. References p . 69

66

A. H E R 2

that during wakefulness. Regarding the relation between EEG and evoked response it is interesting to note that in contrast to the isocortex, in the hippocampus evoked potentials were large during its desynchronisation and vice versa. Depression of evoked responses during wakefulness was similarly pronounced in the medial thalamus (Fig. 3). During wakefulness and paradoxical sleep the responses were rather flat, but during spindle sleep they showed high voltage. Relations between evoked potentials and spindling are illustrated in Fig. 4. An inAuditory cortex

visual

cortex

Awake

during

between spindles

W Medial thalamus

H@pocampus

foornsec

Fig. 4. Evoked potentials from the auditory and visual cortex, hippocampus and medial thalamus on auditory stimulation during, respectively between spindle phases.

.

CORTICAL AND SUBCORTICAL AUDITORY EVOKED POTENTIALS

References p . 69

67

68

A. HERZ

creased response during spindle bursts in the EEG has already been demonstrated by Moruzzi et al. (1950), but the computer method now reveals more details. If a stimulus was applied during the spindle phase, rhythmic potentials with a frequency corresponding to that of the spindles, were particularly clear (third session). On stimulation between the spindle phases (fourth session) a late positive wave was pronounced. The enhancement of evoked potentials during spindle activity was absent during barbiturate anesthesia (Fig. 5). The same animal which was asleep initially (first session) was aroused by confrontation with a mouse (second session). Again, the changes were similar to those obtained in the above mentioned experiments. After a subanesthetic dose of 25 mg pentobarbital per kg, the potentials remained relatively small (third session); rhythmic waves, however, were more pronounced than during wakefulness. During general anesthesia (adding 10mg pentobarbital per kg), the responses got even flatter, although the EEG was dominated by spindles (fourth session). This renders it probable that the non-specific pathways by which the structures outside the auditory system receive their impulses are for the most part blocked under the influence of the drug. This concerns also the late waves in the (specific) auditory cortex (Abrahamian et al., 1963). We shall, however, not go into further details of the various changes of evoked potentials by barbiturates, as they have already been the subject of many investigations. DISCUSSION

The experiments show the great similarity of responses evoked during wakefulness and paradoxical sleep. In other experiments (Herz, 1964) the cortical potentials following administration of stimulants such as amphetamine, DOPA and caffeine could hardly be distinguished from those during spontaneous arousal or arousal induced by natural stimuli-and were thus similar to the responses obtained during paradoxical sleep. Also applying other methods the potentials in this phase of sleep were similar to those in the waking state (Jouvet, 1962; Palestini et al., 1964). Recordings of discharges from single neurons in the cortex have likewise revealed surprisingly similar findings during wakefulness and paradoxical sleep (Evarts, 1962; Arduini, 1962). Whilst this certainly does not permit the assumption of a completely identical functional state of the cortex during these two behaviourally opposed states, there is nonetheless much evidence of increased cortical and subcortical activity during paradoxical sleep compared with ‘spindle sleep’. The differentiation between ‘brain sleep’ and ‘body sleep’ adopted by Von Economo (1929) and taken up again by Moruzzi (1962) should help to dispel many of these apparent contradictions. SUMMARY

Auditory evoked potentials were recorded in cats by means of permanently implanted electrodes during wakefulness and different stages of sleep. A clear relationship was observed between the amplitude of these evoked responses and the waking state. Fully awake animals showed potentials of small amplitude which grew during spindle sleep and became small again during paradoxical sleep. These changes, though clearly

CORTICAL AND SUBCORTICAL AUDITORY EVOKED POTENTIALS

69

displayed at the auditory cortex, were especially marked in the visual cortex, hippocampus and medial thalamus, i.e. non-auditory areas. A relationship was also observed between EEG sleep spindles and certain components of the evoked potential. Such a relationship does not hold, however, for barbiturate-induced spindling. These results are discussed in relation to the mechanism of paradoxical sleep. It is suggested that during this stage of sleep cortical and subcortical structures show increased activity in comparison with spindle sleep.

REFERENCES ABRAHAMIAN, H. A., ALLISON,T., GOFP,W. R., and ROSNER, B., (1963); Effects Of thiopental on human cerebral evoked responses. Anesthesiohgy, 24, 650-657. h o r n , A., (1962); Differences in cortical activity during desynchronized sleep and arousal. Proc. Int. Union Physiol. Sci.XXIZ. C0n-v. Leiden, 1, 464-466. BUSER,P., and BORENSTEIN, P., (1959); Rkponses somesthksiques, visuelles et auditives receuillies au niveau du cortex 'associatif' suprasylvien chez le chat curark6 non anesthkib. Electroenceph. clin. Newophysiol., 11,285-304. DEMENT, W. C., (1958); The occurrence of low voltage, fast electroencephalogram patterns during behavioural sleep in the cat. Electroenceph. clin. Neurophysiol., 10, 291-296. EVARTS, E. V., (1962); Activity in neurons in visual cortex of the cat during sleep with low voltage fast EEG activity. J. Neurophysiol., 25, 812-816. HERZ,A., (1964); Auditive evoked potentials during different stages of wakefulness and following administration of stimulating drugs. 4th Congr. Colleg. Int. NeuropsychopharmacologicumBirmingham. JOUVET, M., (1962); Recherches sur les structures nerveuses et les mkanismes responsables des diffbrentes phases du sommeil physiologique. Arch. itul. Biol., 100, 125-206. KAWAKAMI, M., and SAWYER,C. H., (1959); Induction of behavioural and electroencephalographic changes in the rabbit by hormone administration of brain stimulation. Endocrinology, 65,631643. MORUZZI,G., (1962); Contribution to discussion. Proc. Int. Union physiol. Sci. XXII. Congr. Leiden, 1,467469. MORUZZI,G., BROOKHARDT, J. M., NIEMER, W. T., and MAGOUN, H. W., (1950); Augmentation of evoked electrocortical activity during spindle bursts. EEG clin. Neurophysiol., 2, 29-31. PAL-, M., PISANO. M., ROSADIM, G., and ROSSI,G. F., (1964); Visual cortical responses evoked by stimulating lateral geniculate body and optic radiations in awake and sleeping cab. Exp. Neurol., 9, 17-30. VON ECONOMO, C., (1929); Schlaftheorie. Ergebn. Physiol., 28, 312-339.

70

Some Aspects of the Electro-ontogenesis of Sleep Patterns J. P. SCHADE, M. A. CORNER AND J. J. PETERS Netherlands Central Institute for Brain Research, Amsterdam (The Netherlands)

INTRODUCTION

The relationship between structural organization and physiological events during development and maturation of the cerebral cortex has been enormously aided by results of electron microscopic investigations, biochemical studies and refined electrical measurements during the last decade (cf. the comprehensive surveys by Purpura and SchadC, 1964, and Himwich and Himwich, 1964). To these another, more unifying factor should now be added, that of psychological events. An ideal application of these three factors would seem to be the study of sleep mechanisms since the electrical and behavioral concomitants of sleep occur in established sequence and chronology during postnatal maturation of the brain. Studies of the spontaneous electrical activity in the cerebral lobes of several types of animals during development have revealed that sleep patterns characterized by both synchronized slow rhythms and desynchronized, high frequency waves appear only at a relatively advanced stage of maturation (Jouvet, this volume p. 27). The electroencephalogram goes through a number of phases before these two patterns are seen. The first activity consists characteristically of irregular slow waves which then increase progressively in amplitude and frequency with development. A low amplitude rapid component appears next. At a still later stage, successions of high amplitude slow waves are seen at intervals, and shortly after these brief periods almost complete disappearance of the slow rhythms occur. With further development, the slow wave sequences tend to last longer and prolonged desynchronization can occur both spontaneously and in response to sensory stimulation. In the same way as the behavioral development at the time of birth varies greatly from one species to another, so dces the event of birth or hatching bear no fixed relationship to the electroencephalographic maturation just described. The generalization which so far seems to hold is that there is at first little correlation between behavioral and EEG states. In animals which are relatively immature at the time of birth (viz. rat, rabbit), changes from behavioral wakefulness to sleep occur with no specific changes in the cerebral electrical activity pattern. On the other hand, where the EEG reaches a high level of maturity prior to birth (viz. chick) changes from synchronized slow waves to irregular higher frequency activity occur without observable effects upon the movement patterns, reactivity, heartbeat, or respiration of the embryo. Only after birth, when the embryonic behavior patterns are largely superseded

ELECTRO-ONTOGENESIS OF SLEEP PATTERNS

71

or submerged by responses to the postnatal environment do the synchronized and desynchronized electrical patterns become associated with wakeful and sleeping states respectively. Even then behavioral sleep is accompanied by a variety of patterns which includes partially or completely desynchronized activity (‘paradoxical phase’). In general this latter type of activity occupies progressively less of the total time spent sleeping as the animal matures (Valatx et al., 1964). The foregoing considerations suggestqhat the characteristic slow sleep rhythms appear only when a certain level of bighemgal and histological maturation of the cerebral cortex or other parts of the hemispheres has been achieved. Connections with other brain regions and the interplay of excitatory and inhibitory synaptic drives are probably both involved in the genesis of the electroencephalogram, but its precise character must be largely determined by the amount and types of neuronal interconnections within the cerebral tissue itself. The present paper is a preliminary report on the maturation of embryonic and sleeping electrical patterns in the chick brain. In addition, data on certain correlations in the rabbit brain between the postnatal development of some electrophysiological events (EEG, sleep patterns, spreading depression) and histological data (the extent of the dendritic organization) will be presented. METHODS

(a) In the chick the spontaneous electrical activity was recorded from several points on the surface of the cerebral hemispheres, in embryonic stages by means of silversilver chloride electrodes and in post-hatched stages by insulated steel wires. In both cases the electrodes were 100 p in diameter. Embryos were prepared by removing the head from the cranium and immobilizing it in a plaster encasement. A large piece of the skull was then removed and the electrodes lowered and placed on the brain. Only preparations which showed normal spontaneous and evoked movements during the recording period were considered. Hatched chicks were placed in a special harness to minimize movements, a hole made in the skull with a fine jeweler’s chisel, and the electrode brought into contact with the dura and cemented in place. The bird was then released and allowed to move freely throughout the recording session.

(b) For recordings in the rabbit the method of Monnier and Gangloff (1960) was employed. For recording of spreading depression and spreading convulsion, a row of 5 silver-silver chloride electrodes, spaced about 5 mm apart, were gently placed on the surface of the cortex in a fronto-occipital direction. The most frontal electrode was used for stimulation while from two other pairs bipolar electrocorticograms were recorded. The requirements for optimal recording of spreading depression were fulfilled in all txperiments (Schadt, 1959).

References p . 77/78

72

I. P. S C H A D ~et

al.

RESULTS

( a ) Development of sleep patterns in chick brain Slow waves reminiscent of a deep sleep pattern have been seen several days prior to hatching, but they typically occurred only in short sequences(Fig. 1,A). The characteristic pattern at this stage was a more rapid and irregular rhythm of lower amplitude (Fig. 1,B). By 1-2 days before hatching, longer trains of slow waves were often seen, but their period showed a wide variation (Fig. 1,C). Shortly before or after hatching, on the other hand, prolonged sequences of regular slow waves were encountered A

B

Y

1 Fig. 1. Embryonic EEG patterns recorded from the frontal lobes of the chick brain. For discussion see text. Calibration: horizontal bars: 1 sec; vertical bars: lOOpV.

(Fig. 1,D). After hatching these waves were always associated with a behavioral state of closed eyes and a relaxed or dropping head and body posture (‘sleep’). Behavioral wakefulnesswas associated with the disappearance of the slow waves. The first signs of ‘drowsiness’(dropping head and body, eyes closing) were accompanied by intermittent

Fig. 2. Awake and drowsy patterns in the 1-day-old chick with sequences of alerting (a and b). Calibration: horizontal bars: 1 sec; vertical bars: 1OOpV.

ELECTRO-ONTOGENESIS OF SLEEP PATTERNS

73

slow waves superimposed upon the record (Fig. 2). Short periods of disappearance of the slow waves also occurred during behavioral sleep without any apparent movements of the eyes or other parts of the body (Fig. 3). Such periods occurred regularly and were also at times observed to be accompanied by brief, stereotyped ‘struggling’ movements without opening of the eyes. Prolonged and apparently constant states of behavioral sleep were in fact associated, even 2 weeks after hatching, with several different EEG patterns, which tended to occur in a regular sequence (Fig. 3).

Fig. 3. Al, 2,3, and B1,2: prolonged EEG sequencesduring behavioral sleep in the chick. Calibration: horizontal bars: 1 sec; vertical bars: 100pV.

It is interesting to note that in the chick the EEG becomes mature between the 12th and 15th day of incubation while only about 5 to 6 days later EEG patterns appear that are characteristic of specific states of sleep and arousal. In order to investigate whether the event of birth and the development of the EEG bear a fixed relationship to the maturation of sleep patterns, a quantitative study was performed on rabbits. (6) Spreading phenomena and sleep patterns in rabbit brain Caspers (1964) reported on the shifts of the cortical steady potential (DC component) during various stages of sleep in freely moving rats with implanted electrodes. He suggests that the positive DC displacement during sleep reflects a preferential polarization of neuronal structures in the outer cortical layers. Spreading phenomena (depressions and convulsions) are always accompanied by shifts of the cortical potential (Schade, 1959). The relationship between the occurrence of these phenomena and the transition from a desynchronized into a synchronized sleep pattern was studied simultaneously. Spreading depression is characterized by a decrease of the spontaneous cortical References p. 77/78

74

J. P. SCHADE et a/.

activity which spreads concentrically from the stimulated area with a velocity of 2-5 mm/min (Fig. 4). It is accompanied by a drop in cortical activity which in most of the experiments is of the order of about 10% (Van Harreveld and Schadt, 1959).

In young rabbits the reaction to a stimulus which in adults tends to produce

Fig.4. Spreading depression recorded in a 30-day-old rabbit. The arrow indicates cortical stimulation 10 V d.c. duration 3 sec. B1-4:recording from electrodes closest to stimulus. AI-4: recording from electrodes 3 rnm from B. Stimuli are recognizable by stimulus artefact.

spreading depression often was a spreading convulsion (Fig. 5, Table I). The slow potential changes which accompany both phenomena are of the same magnitude and shape (Schadt and Pascoe, 1964), therefore there is no reason to assume that the mechanisms underlying these phenomena have a different origin. Only during a very short period of postnatal development are spreading convulsions predominant.

ELECTRO-ONTOGENESIS OF SLEEP PATTERNS

75

For the study of the development of sleep patterns 6 periods of 15 min recordings were analysed during behavioral sleep. (An extensive report of this technique will be published in the near future.) A distinction was made between desynchronized and synchronized sleep patterns. The 6 periods of sleep cycles were analysed for a pre-

83

Fig. 5. Spreading convulsion recorded in a 20-day-old rabbit. The arrow indicates cortical stimulation 10 V d.c., duration 3 sec. B1-4: recording from electrodes closest to stimulus, A l - 4 : recording from electrodes 3 mm from B. Stimuli are recognizable by stimulus artefact.

dominance of one of these patterns. As is shown in Table I the period from 15-25 days of age is characterized by a predominance of desycchronized sleep while a transition t o a synchronized sleep pattern occurs at about 30 days of age. Refereerencesp. 77/78

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J. P. SCHADh

et a/.

TABLE I DEVELOPMENT OF SPREADING PHENOMENA AND SLEEP MECHANISMS

Age (days)

Number .for each series

15

10 10 10

-

10

7

10 10 10

9 10 10

20 25 30 45 60 adult

depression

spreading convulsion

I

Predominancy desynchronized synchronized sleep

sleep

1 2 1

9 8 8

I 2 2

1

4

6

2

8 10 10

-

-

DISCUSSION

The available data suggest a parallelism between the occurrence of spreading depression and the transition from a desynchronized into a synchronized sleep pattern. The relationship of such information to the structural organization of the cerebral cortex is not so easily deduced because of the lack of exact information about the excitatory and inhibitory synaptic contact sites. Quantitative data on the receptive surface of the neurons and the dendritic organization may serve as a basis for a working hypothesis (Baxter et al., 1960). The dendrogenesis of the neocortical neuron in the rabbit brain occurs almost exclusively postnatally. At birth the pyramidal cells in the deeper layers have apical dendrites extending to layers I1 and 111, but basilar dendrites and branches of apical dendrites are hardly distinguishable. The volume and surface area of the apical and basal dendrites increases markedly from 5 to 30 days after birth, as measured with a modified random hit method (SchadC and Baxter, 1960a, b; SchadC et al., 1963). Studies on Golgi-Cox preparations have revealed that the major development of the receptive surface of the neurons in the rabbit cerebral cortex occurs in the first 20-30 days postnatally. Morpho-physiological studies have shown that this latter period is characterized by an establishment of mature excitatory and inhibitory synaptic drives in the cerebral cortex (SchadC and Pascoe, 1964). The transient period in which spreading convulsions are more prominent than spreading depression, is also characterized by a transition from desynchronized into synchronized sleep. When spreading depressions are repeatedly activated in adult rabbits, there is a tendency for spreading convulsions to develop in the cortex (Van Harreveld and Stamm, 1953). Concentrations at 7 to 15%carbon dioxide were also effective in changing spreading depressions into spreading convulsions. This effect may be due to a selective increase in the excitability of groups of cells in the cerebral cortex (cf. Ochs, 1962). It seems reasonable to assume that various mechanisms of inhibitions are present in the cortex to prevent the cells from developing convulsoid patterns. During maturation of the cerebral cortex the inhibiting mechanisms are lagging behind in development for a

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short period and then spreading convulsions are found more often than spreading depressions (SchadC and Pascoe, 1964). The development of the differentiated inhibitory mechanisms also marks the transition from desynchronized into synchronized sleep patterns. The reticular activating system of the young brain may have little or no feedback from the immature cortex, and this may account for the inability to show a sustained synchronized sleep pattern. The development of spreading depression in the cerebral cortex seems to be closely related to the occurrence of an adult sleep pattern. Both phenomena may have as a common underlying mechanism the establishment of an inhibitory cortico-reticular feedback. SUMMARY

A preliminary report is given of the ontogenesis of the electrical concomitants of sleep in the chick and rabbit brain. (a) Already before hatching EEG waves resembling sleep can be recorded from the chick brain. A clear differentiation occurs within the first week after hatching. (b) In the rabbit brain a transitional phase was observed in which desynchronized sleep patterns changed into synchronized sleep patterns. This phase coincides with the period in which spreading convulsions shift to spreading depressions in the cerebral cortex. (c) A working hypothesis is discussed attributing the establishment of synchronized sleep patterns to the maturation of inhibitory cortico-reticular feedback mechanisms. ACKNOWLEDGEMENT

This research was supported in part by research grants from the National Institute of Neurological Diseases and Blindness (B. 3048) and the National Institute of Mental Health (MH. 6825), Bethesda, Md., U.S.A. REFERENCES BAXTER, C. F., SCHADE, J. P., and ROBERTS, E., (1960); Maturational changes in cerebral cortex 11. Levels of glutamic acid decarboxylase, y-aminobutyric acid and some related amino acids. Inhibition on the Nervous System and GABA. E. Roberts, Editor. New York, London, Pergamon Press (p. 21 3-220). H., (1964); Shifts of the cortical steady potential duringvarious stages of sleep. Electroenceph. CASPERS, clin. Neurophysiol., 17, 442. HIMWICH, W. A., and HIMWICH, H. E., Editors, (1964); Progress in Brain Resesrch, Vol. 9. The Developing Brain. Amsterdam, Elsevier. MONNIER, M., and GANGLOFP, H., (1960); Atlas for stereotaxic brain research on the conscious rabbit. Rabbit Brain Research, Vol. 1. Amsterdam, Elsevier. OCHS,S., (1962); The nature of spreading depression in neural networks. Int. Rev. Neurobiol., 4 , 1 4 9 . PURPURA, D. P., and SCHADB,J. P., Editors, (1964); Progress in Brain Research, Vol. 4. Growth and Maturation of the Brain. Amsterdam, Elsevier. S w E , J. P., (1959); Maturational aspects of EEG and of spreading depression in rabbit. J . Neurophysiol., 22, 245-257. SCHADB,J. P., and BAXTER, C. F., (1960a); Maturational changes in cerebral cortex. I. Volume and surface determinations of nerve cell components. Inhibition in the Nervous System and GABA. E. Roberts, Editor. Pergamon Press, New York-London (p. 207-213).

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SCHADE, J. P., and BAXTER, C. F., (1960b); Changes during growth in the volume and surface area of cortical neurons in the rabbit. Exp. Neurol., 2, 158-178. SCHADE, J. P., and PASCOE, E. G., (1964); Maturational changes in cerebral cortex 111. Effects of methionine sulfoximine on some electrical parameters and dendritic organisation of cortical neurons. Progress in Brain Research, Vol. 9. The Developing Brain. W. A. Himwich and H. E. Himwich, Editors. Amsterdam, Elsevier, (p. 132-1 54). SCHAD~, J. P., VANBACKER, H., and COLON, E., (1963); Quantitative analysis of neuronal parameters in the maturing cerebral cortex. Progress in Brain Research, Vol. 4. Growth and Maturation ofthe Brain. D. P. Purpura and J. P. Schade, Editors. Amsterdam, Elsevier, (p. 150-175). VALATX, J. L., JOUVET, D., and JOUVET, M., (1964); Evolution electroendphalographiquedes differents Btats de sommeil chez le chaton. Electroenceph. elin. Neurophysiol., 17, 21 8-233. VAN HARREVELD, A., and OCHS,S., (1956); Cerebral impedance changes after circulatory arrest. Amer. J. Physiol., 187, 180-192. VANHARREVELD, A., and SCHADE,J. P., (1959); Chloride movements in cerebral cortex after circulatory arrest and during spreading depression. J. cell. Physiol., 54, 65-11. VAN HARREVELD, A., and STAMM,3. S., (1953); Cerebral asphyxiation and spreading cortical depression. Amer. J. Physiol., 173, 171-175.

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11. MICROELECTRICAL A N D MOLECULAR ASPECTS OF SLEEP

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Relation of Cell Size to Effects of Sleep in Pyramidal Tract Neurons EDWARD V. EVARTS Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Public Health Service, US.Department of Health, Education and Wegare, Bethesda 14, Md. (U.S.A.)

INTRODUCTION

It is now clear that sleep is not a state in which there is a generalized reduction of discharge of cerebral neurons. Recordings of single unit activity in a number of regions of the brain have shown that natural sleep (in contrast to anesthesia) is associated with increased discharge frequency in certain neurons and decreased discharge frequency in others(Evarts, 1964;Evartsetal., 1962;Hubel, 1959;Huttenlocher, 1961;Jasper, 1958). Given this fact, the question arises as to what functional or structural properties differentiate neurons which are more active during sleep from neurons which are less active. An attempt to provide a partial answer to this question for pyramidal tract neurons has been made in the present study. The report deals with the relation between effects of sleep and cell size (as inferred from antidromic response latency). For pyramidal tract neurons it is possible to estimate axonal conduction velocity from the latency of the antidromic response to stimulation of the medullary pyramid. Conduction velocity is closely related to axonal diameter and axonal diameter is closely related to cell size. As a result of these relations, it is possible to infer relative neuronal size from relative antidromic response latency : the smallest pyramidal tract neurons have the longest antidromic response latencies, and the largest pyramidal tract neurons (the Betz cells) have the shortest antidromic response latencies. METHODS

The techniques employed in identifying and recording from single pyramidal tract (PT) neurons in intact, unanesthetized monkeys have been described in detail elsewhere (Evarts, 1964). In brief, a remotely controlled hydraulic microdrive was used to insert a glass-insulated platinum-iridium microelectrode into the precentral gyrus of a monkey seated in a primate chair. Sleep and waking were identified by observations of the monkey and by recordings of eye movements, EEG, and nuchal electromyogram. Recordings were obtained from two regions of the precentral gyrus. One set of units was picked up from a 5 mm diameter circular zone of cortex centered at HorsleyClarke coordinates A-8, L-10. This region corresponds approximately to the tranReferences p . 88/89

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sition between the trunk and arm areas of the motor cortex. A second set of recordings was obtained from a 5 mm diameter circular zone of cortex centered at A-10, L-15. This is approximately the center of the arm-hand area. Data on sleep with low voltage fast EEG activity (S-LVF) will not be given in this report because too few of the 38 neurons recorded from the more lateral cortical region were recorded during S-LVF. Effects of S-LVF on the 13 neurons from the more medial region have been described in a previous report (Evarts, 1964). RESULTS

Table I lists the discharge frequencies of 51 PT neurons during sleep with EEG slow waves ( S ) and waking in the absence of movement (W). Each of the neurons was observed during both S and W. It may be seen in Table I that the neurons with short antidromic response latencies tended to be inactive during W and to show increased discharge frequencies with S. Thus, 15 of the 19 units with antidromic response TABLE I ANTIDROMIC RESPONSE LATENCIES A N D DISCHARGE FREQUENCIES OF 51 PT NEURONS DURING WAKING I N THE ABSENCE OF MOVEMENT A N D SLEEP WITH EEG SLOW WAVES

(s)

(w)

(The 13 units marked with an asterisk (*) were recorded in the more medial region of the precentral gyrus. The remaining 38 neurons were recorded from the more lateral region.)

Latency (nisec) 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.9 0.9 0.9 0.9 0.9* 1.o 1.o

1.2 1.2 1.2* 1.3 I .3

Discharge frequency

w

s

.I .2 .8 1.9 15.3 .O .6 .5 21.3 .7 .8 .2 14.9 .6 1.9 .4 1.6 .2 10.9 10.9 22.5 20.0 .7 12.4 6.4 24.5

5.1 7.1 11.6 4.8 6.3 8.2 8.2 4.2 8.5 9.2 5.1 3.4 11.8 3.8 4.2 3.7 3.7 12.1 3.7 8.0 11.7 10.0 8.3 6.6 16.3 17.9

Latency (msec) 1.4* 1.5 1.5* 1.5

1.5 1.5 1.7* 1.8*

1.8 1 .9* 1.9* 2.0 2.1 2.1* 2.1* 2.2 2.2 2.2* 2.7 2.8 3.0 3.8 4.2* 4.9 5.2*

Discharge frequency W S 5.6 18.6 18.1 29.3 28.0 15.0 16.2 12.8 9.6 23.8 26.8 6.0 20.7 12.2 14.7 24.8 29.1 11.7 21.9 11.8 11.6 15.0 9.8 20.1 8.3

4.0 19.2 3.9 17.2 11.2 12.1 6.8 5.5 13.8 10.0 12.5 5.0

6.6 9.9 6.8 11.1 11.3 10.0 12.7 6.0 9.0 12.8 6.2 2.7 5.7

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latencies less than 1 msec had discharge frequencies less than 2 spikes/sec during W, whereas none of the 13units with latencies longer than 2 msec had discharge frequencies less than 8 spikes/sec during W. All of the 13 units with latencies greater than 2 msec became less active with S, whereas 15 of the 19 units with latencies less than 1 msec became more active with S. Fig. 1 shows the distribution of discharge frequencies of the 51 PT units during W and S. During W some units have very low and others have very high discharge WAKING WITHOUT MOVEMENT

0

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9 12 15 DISCHARGE FREQUENCY

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Fig. 1. Distribution of discharge frequencies in the sample of 51 PT neurons during wakinb in the absence of movement (W) and sleep with EEG slow waves (S). During W, 16 of 51 units had discharge frequencies less than 3/sec, whereas only 1 of the 51 units had such a low discharge frequency in S. During W there were also many very active units, 15 of 51 units having discharge frequencies over 18jsec. With S only 1 of the 51 units had a discharge frequency above 18/sec. The data upon which this chart is based are in Table I.

frequencies. With S the extreme values disappear: the least active units of W speed u p with S and the most active units of W slow down with S . Fig. 2 shows the relation between antidromic response latency and change in discharge frequency from W to S. In Fig. 2 units have been divided into three groups according to latency of antidromic response. It may be seen that all of the units in the longest latency group and most of the units in the intermediate latency group became less active with S, whereas most of the units in the shortest latency group became more active with S. As mentioned in the section on Methods, the units listed in Table I were recorded from two different areas of the precentral gyrus. Only 1 of the 13 units recorded from the more medial region of the precentral gyrus (centered at A-8, G10) had a latency less than 1 msec, whereas 18 of the 38 units recorded more laterally (A-10, L-15) had latencies less than 1 msec. All of the 13 units recorded from the more medial region were tonically active during W. Among the units in the lateral region those with longer References p. 88/89

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am 0

0

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Fig. 2. Relation of antidromic response latency and change of discharge frequency from W to S. Units have been divided into three groups according to antidromic response latency; each solid circle represents a unit. Change in discharge frequency with S (W minus S) is plotted on the ordinate. For the shortest (< 1 msec) latency group, most units became more active with S,whereas all units in the longest latency (> 2 msec) group became less active with S.The data upon which this chart is based are in Table I.

latencies had tonic, regular discharge during W, but those with shorter latencies were relatively inactive during W though they showed intense phasic discharge during movement. With S the marked differences in discharge properties between units with high and low conduction velocities disappeared, both groups discharging in bursts. Thus, as previously reported (Evarts, 1964), PT units with regular tonic activity during W have sporadic bursts during S. The short-latency units which are inactive during W also have sporadic bursts during S. Fig. 3 illustrates this change in discharge pattern of two units (one with short and one with long latency), from W to S . The long latency unit had regular discharge during W and irregular high frequency bursts during S. The short latency unit was inactive during W, but during S it too discharged in high frequency bursts. DISCUSSION

Previous studies of single unit discharge in several cortical areas and in the brain stem tegmentum (Evarts et al., 1962) have shown that during W (quiet waking with minimal afferent input and without movement) a given sample of neurons tends to include some units with very high and other units with very low discharge frequencies, whereas the same sample of units observed during S (sleep with EEG slow waves) tends to lack units with extreme values of discharge frequency. This same finding appeared in the present sample of PT neurons. For PT neurons there is a clear relation between axonal

RELATION OF CELL SIZE TO EFFECTS OF SLEEP

85

E EG L=0.8 L=1.5 EMG

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L=1.5 EMG Fig. 3. Activity of a pair of PT neurons recorded simultaneously with the same microelectrode during alertnab, drowsiness, and sleep. The unit with antidromic response latency of 0.8 msec (second line from top) was quite inactive when the monkey was alert but not moving, showed occasional spikes when the monkey became drowsy, and had high frequency bursts with sleep. The unit with latency of 1.5 msec (third line from top) discharged regu!arly during alertness, showed a slight reduction in dkcharge frequency with drowsiness, and had irregular bursts with sleep. This figure was made by separating the two simultaneously recorded spikes with an 'electronic window' and using the separated spikes to trigger pulses which in turn deflected the pens of an inkwriting oscillograph. The deflections on the lines marked L = 0.8 indicate discharges of the unit with antidromic response latency of 0.8 msec, and the deflections on the lines marked L = 1.5 indicate discharges of the unit with antidromic response latency of 1.5 msec. The electromyograms (marked EMG) were recorded from the muscles of the arm contralateral to the hemisphere from which the unit was recorded.

conduction velocity and both discharge frequency during W andwange in discharge frequency with sleep. One may assume that the neurons with the highest axonal conduction velocities have the largest axons and cell bodies, and that a similar relation holds for units with low conduction velocities. Thus, the largest PT neurons are relatively inactive during W and speed up from W to S , and the smallest PT neurons are relatively active during W and slow down from W to S. This relation between cell size and effects of sleep will be discussed from two points of view. On the one hand, the relation may be viewed as a reflection of the differing functional properties of the large and small neurons during waking. Alternatively, it may be of heuristic value to speculate upon the possible teleological significance of the observed relationship between neuronal size and change in activity from waking to sleep. In discussing the present results from the teleological standpoint, one may begin by considering findings of previous investigators concerning the relation of axonal References p. 88/89

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diameter to the electrochemical consequences of the action potential. Ritchie and Straub (1957) have calculated that a short period of repetitive discharge (150 impulses in 10 sec) would cause practically no increase in the concentration of sodium ions inside the giant squid axon, whereas a similar train of impulses would increase the sodium concentration of a 1 ,u diameter C fiber by 24 mM, and of a 0.2 p diameter fiber by 120 mM. As nerve fibers become smaller and the ratio of their membrane surface area to axoplasmic volume increases, there is a corresponding change in the metabolic and electrochemical consequences of their activity. The presence of a myelin sheath (greatly limiting the surface area through which ion movements take place) r a c e s the extent of sodium influx and potassium e a u x during activity. Hodgkin (1951) has calculated that for a given number of impulses, a myelinated fiber needs to exchange only 11300 as much sodium as an unmyelinated fiber of equal diameter. Even for myelinated fibers, however, a given amount of activity will cause a relatively greater increase of sodium concentration in the small than in the large neuron. The reduction of ionic movement resulting from the myelin sheath does not extend to the neuronal soma, and for the membrane of the cell body, movement of ions and consequent requirement for Na-K exchange may approximate that of the unmyelinated C fiber. Coupled with this relationship between ionic movements and neuronal size is the fact that during W the smaller neurons tend to engage in relatively continuous tonic activity, whereas the large neurons have less over-all discharge, though they are very active during movement. It is impossible to say whether discharge frequencies of the order of 20/sec (a value seen in a number of tonic PT neurons) maintained over a number of days and nights of waking might build up a significant metabolic andior ionic debt. However, it does not seem unreasonable to suppose that if any PT neurons might benefit from a period of reduced discharge frequency it should be the small ones, both because of their tonic discharge during W and because their structure makes them inherently less capable of long-sustained, continuous discharge. The teleological analysis which has just been presented took as its point of departure the relation between cell size and the electrochemical consequences of the action potential. An alternative and non-teleological explanation for the relation of cell size to changes with sleep may be proposed if one considers the relation between cell size and the cell’s role in the over-all neural system. It is commonly the case that large neurons are phasically active and small neurons are tonically active. Eccles et al. (1957) have found that the average conduction velocity of soleus motoneuron axons is 72% of that for gastrocnemius motoneurons. The a-motoneuron fibers to gastrocnemius (a pale, phasically active muscle) have correspondingly larger diameter (Eccles and Sherrington, 1930) than the fibers to soleus (a red, tonically active muscle). Granit et ul. (1 957) have emphasized the relationship between structural and functional properties in a-motoneurons, and have presented several lines of evidence that tonically active a-motoneurons are smaller than phasically active a-motoneurons. To cite another example, the large Ia afferents of the nuclear bag intrafusal muscle fibers of the muscle spindle carry information which is particularly related to transients, whereas the smaller group I1 afferents of the nuclear chain intrafusal muscle fibers tend to carry steady-state information (cf. Matthews, 1964).The efferent supply

RELATION OF CELL SIZE TO EFFECTS OF SLEEP

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to the intrafusal fibers likewise shows a relation between function and structure, the larger y1 fibers innervating the phasically active nuclear bag intrafusal fibers, and the smaller y2 fibers innervating the more slowly contracting nuclear chain fibers (Boyd, 1962; Jansen and Matthews, 1962). Often, then, large fibers with high conduction velocities carry transient information and are phasically active, whereas small fibers with low conduction velocity carry steady-state information and are tonically active. Differences in discharge pattern as a function of cell size, seen so clearly for PT neurons during W, disappear with sleep, during which sporadic bursts of impulses occur in small and large cells alike. Large PT neurons become more active with S and small ones become less active, but in spite of this, the mean discharge frequency of the small cells during S is actually somewhat greater than that of the large cells. During S the group of 13 relatively small PT neurons (latencies greater than 2 msec) had a mean discharge frequency of 9.0/sec. For the 19 relatively large PT neurons (latencies less than 1 msec) the mean discharge frequency during S was 6.5/sec. Another point against the teleological argument is the behavior of PT neurons during sleep with low voltage fast EEG activity (S-LVF). A previous report (Evarts, 1964) has described the effects of S-LVF on the PT neurons recorded in the more medial region of the precentral gyrus. During S-LVF these neurons had discharge frequencies which approximated the values of W, and which were on the average twice as great as those of S. From S to S-LVF, discharge frequency increases regardless of antidromic response latency, both large and small PT neurons discharging in intense bursts. The fact that the smaller PT neurons discharge almost as rapidly during S-LVF as during W thus provides additional grounds for questioning the teleological explanation for the reduction of discharge frequency of small PT neurons from W to S. In this report the antidromic response latencies of PT neurons have been used to relate cell size to change in discharge frequency with sleep. Data on antidromic response latency are of additional value for an entirely different reason: they allow an estimate of the sampling bias resulting from the tendency of microelectrodes to record more effectively from large cells than from small ones. The pyramidal tract of the monkey contains fibers ranging from 1 to 20 p in diameter (Haggqvist, 1937). The corresponding conduction velocities for these fibers probably range from about 6-120 m/sec. In the present investigation, the straight line distance (as given by the Pythagorean theorem) between the lateral region of unit recording in the motor cortex (A = 10, L = 15, D = 28) and the point of electrical stimulation of the pyramidal tract in the medullary pyramid (A = -2, L = 2, D == -17) was 48 mm. It is difficult to estimate the actual length of the pyramidal tract between these two points, but if this distance were of the order of 50% greater than the straight line path, then the actual tract length would be about 70 mm and the conduction velocities of the most rapidly conducting units would be about 100m/sec. For the present sample of 51 units, the median antidromic response latency was 1.3 msec, which corresponds to a median conduction velocity of about 55 m/sec and a median axonal diameter of about lop. Thus, approximately 50% of the pyramidal tract neurons recorded in this study had axonal diameters greater than lop. By contrast, anatomical studies have shown that only References p. 88/89

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about 2% of PT axons in the monkey have diameters greater than lop (Haggqvist, 1937). The great proportion of large cells is only in part a function of selectivity by the microelectrode, since the pyramidal tract neurons of the precentral gyrus (from which units were picked up) include a much higher proportion of large neurons than does the pyramidal tract as a whole. Finally, PT neurons of the present study could be identified only if their axons were excited in the medullary pyramid, and the higher thresholds of the smaller fibers makes it likely that the medullary stimulus excited a greater proportion of large than of small fibers. These recording biases in favor of large neurons come as no surprise, but they should serve to emphasize the caution which must be exercized in generalizing from the results of observations on samples of neurons subject to such biases. Thus, 37% of the PT neurons i n the present sample were more active during S than during W, but it would clearly be unwarranted to conclude that 37% of the neurons in the pyramidal tract as a whole are more active during S than during W. SUMMARY

The relation between cell size and change of discharge frequency with sleep may be viewed either teleologically or as a consequence of the differing discharge patterns and functional roles of large and small cells during wakefulness. It is to be hoped that techniques will soon be available for determining the relation of sleep and waking to the metabolic and ionic status of individual neurons whose size and function are known. Such techniques may make it possible to test these alternative hypotheses. REFERENCES BOYD,I. A., (1962); The structure and innervation of the nuclear-bag muscle fibre system and the nuclear-chain muscle fibre system in mammalian muscle spindles. Phil. Truns. B., 245, 81-1 36. ECCLES,J. C., ECCLES,R. M., and LUNDBERG, A., (1957); Duration of after-hyperpolarization of motoneurones supplying fast and slow muscles. Nature, 179, 866-868. ECCLES,J. C., and SHERRINGTON, C. S., (1930); Numbers and contraction-values of individual motorunits examined in some muscles of the limb. Proc. roy. SOC.B., 106, 326-357. EVARTS, E. V., (1964); Temporal patterns of discharge of pyramidal tract neurons during sleep and waking in the monkey. J. Neurophysiol., 27, 152-171. EVARTS, E. V., BENTAL, E., BIHARI,B., and HUTTENLOCHER, P. R., (1962); Spontaneous discharge of single neurons during sleep and waking. Science, 135, 726728. GRANIT, R., PHILLIPS, C. G., SKOGLUND, S., and STEG,G., (1957); Differentiation of tonic from phasic alpha ventral horn cells by stretch, pinna and crossed extensor reflexes. J. Neurophysio/., 20, 470.4. HAGGQVIST, G., (1937); Faseranalytische Studien uber die Pyramidenbahn. Acta. psychiur., 12, 457466. HODGKIN, A. L., (1951); The ionic basis of electrical activity in nerve and muscle. Biol. Rev., 26, 339-409. HUBEL,D. H., (1959); Single unit activity in the striate cortex of unrestrained cats. J. Physiol., 147, 226-238. HUTTENLOCHER, P. R., (1961); Evoked and spontaneous activity in single units of medial brain stem during natural sleep and waking. J. Neurophysiol., 24, 451-468. JANSEN, I. K. S., and M A ~ H E WP. S , B. C., (1962); The central control of the dynamic response of muscle spindle receptors. J. Physiol., 61, 357-378. JASPER, H. H., (1958); Recent advances in our understanding of ascending activities of the reticular system. Reticular Formation ofrhe Brain, H. H. Jasper, L. D. Proctor, R. S. Knighton, W. C. Noshay, and R. T. Costello, Editors. Boston, Little, Brown (p. 423-434).

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MAITHEWS, P. B. C., (1964); Muscle spindles and their control. Physiol. Rev., 44, 219-288. Rrrcm, J. M., and Smm, R. W., (1957); The hyperpolarization which follows activity in mammalian non-medullated fibres. J. Physiol., 136, 8@-97. DISCUSSION

MORUZZI : This is an attempt to contribute to the discussion oftheimportant problem raised by Prof. Hess, concerning the functional significance of sleep as a recovery process. I have delayed my intervention after Dr. Evarts’ report, since I am convinced that his results may bring a fundamental contribution to the problem. The microelectrode findings on the cerebral cortex of the intact, free moving, unanesthetized mammal are important in two respects: (a) They compel us to give up the hope of exploring sleep as a period of rest-hence of inactivity or of decreased activity-for the cerebral cortex as a whole. We know that the neurons of the vagal cardio-inhibitory centre or of the cerebellar anterior lobe do not ‘sleep’. Comparison of the firing rate of the large cells of the visual cortex during synchronized sleep and during relaxed wakefulness (when the neurons are bombarded by visual impulses) shows that also some neocortical neurons do not ‘sleep’. (b) There is undoubtedly during sleep a decrease in the firing rate of the small pyramidal cells of the motor cortex and the problem arises whether we spend one third of our life unconscious in order to permit the recovery of the small neurons of the brain. But what kind of recovery? The fast recovery processes relate (1) to the membrane changes that occur when all-or-none impulses arise or are conducted away or (2) to synaptic transmission (cholinacetylase,etc.) are unlikely to be basically different in the large and in the small cortical neurons. What are the slow recovery processes which need hours of rest? I have made elsewhere the hypothesis that they might be related to the plastic activities which go on during wakefulness in connection with the so-called higher nervous activities (learning, elaboration of conditioned responses). It has been suggested by Eccles that the special synapses which electron microscopy has demonstrated on the spines of the dendrites may be the seat of these plastic changes. Plastic activity might be simply more important in the small nerve cells. EVARTS: Prof. Moruzzi has raised the important possibility that changes in the amount and pattern of activity of small as compared to large cells are related to functional differences between these cells rather than to differences in their metabolism or membrane properties. The more I consider Prof. Moruzzi’s view of the matter, the more I am inclined to agree with him. Thus, the differences in neuronal discharge patterns between sleep and waking may reflect functional changes without indicating that the neurons themselves have become in any way fatigued. As Prof. Moruzzi has said, sleep may be needed to allow recovery not of the capacity for all-or-none discharge, but may be required in order to restore the capacity for certain slower plastic processes of the type which may underlie memory. It is certainly to be noted that the vivid experiences of dreams do not set up permanent memory traces unless the subject is awakened during or very soon after the dream. Thus, the neuronal discharges re-

90

DISCUSSION

quired for the occurrence of immediate perception persist during sleep, but the processes underlying consolidation of the memory trace cease. Perhaps our understanding of sleep and memory mechanisms will come together, and it will depend on the development of techniques which allow us to better estimate the status of these slow, plastic processes.

HERNANDEZ P E ~ N :I would like to add a few words to Prof. Moruzzi’s comment on the teleological recovery represented by the state of sleep. The beautiful experiments which Dr. Evarts has presented to us this morning clearly show that a good number of cortical neurons are more active during the desynchronized stage of sleep than during the synchronized stage, or during wakefulness. Therefore, contrary to the classical view assuming that sleep is the result of inactivity in the brain, it is becoming more and more evident that a great amount of brain activity prevails during sleep. Since sleep seems to result from active inhibition of the vigilance neurons produced by a specific hypnogenic system, I wonder whether the increase of cortical activity and possibly of other subcortical structures observed during deep sleep is not related to a process of disinhibition. According to this view, many neurons tonically inhibited during wakefulness would be released during sleep while the vigilance inhibitory neurons are being inhibited by the hypnogenic neurons. If this interpretation is correct, the so-called recovery function of sleep is rather directed to allow recovery of the neuronal system involved in wakefulness. Extensive reticulofugal inhibitory connections permit recovery of a great deal of neurons during wakefulness.

EVARTS:Dr. Herniindez-Pe6n has pointed out that during waking the reticular system exerts important inhibitory effects on a number of centers, both of the cortex and of other structures. I would merely add that in all likelihood this inhibitory effect isnut exerted directly, but probably requires the mediation of short-axon interneurons, as shown by Eccles for the spinal cord. It seems possible that sleep involves a withdrawal of tonic facilitation of small, short-axon interneurons generally. The withdrawal of this tonic facilitation would appear to modify both excitatory and inhibitory processes, and it is possible that the neuronal control of the plastic processes spoken of by Prof. Moruzzi may depend on these neurons. PLETSCHER:Dr. Evarts showed that some neurons are more active during sleep than during waking and others behave in just the opposite way. Is anything known as to whether these neurons react differentially on neurohumoral agents such as norepinephrine and acetylcholine? EVARTS: I regret that I have no direct information on possible chemical differences between large as compared to small pyramidal tract neurons, nor have I tested the excitability of pyramidal tract neurons to applied acetylcholine or norepinephrine during sleep and waking. JUNG : The interesting differences between neurons with small and thick axons during

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sleep now offer hope of a functional differentiation between different neuronal populations in the cortex. May I ask Dr. Evarts whether he has also found differences of activity in neurons of the motor and visual cortex during sleep in unrestrained cats similar to those which Lehmann et al.* have described in drowsy ‘enckphale-isolk-cats’. A periodicity of discharge rate occurred at similar intervals in these two cortical fields. However, the pattern of discharge was different: when longer pauses appeared in the motor cortex the visual cortex neurons often discharged high-frequency bursts with spike intervals below 5 msec. These bursts often gave way to random single spike discharges, when EEG spindles appeared. The motor cortex neurons showed grouped activity during these spindles as described earlier**. But these motor-cortex-grouped discharges did not show the bursts of very short spike intervals that appeared in visual cortex neurons before the spindles and when motor cortex neurons often showed no activity.

EVARTS:I agree with Prof. Jung that the effects of sleep are quite different in different n e a s of the brain. Unfortunately, I have not done any simultaneous recording in visual and motor areas. I do agree that discharge frequencies reach very high values during bursts of visual cortex units even during waking, whereas such high frequency bursts are uncommon during waking for pyramidal tract neurons.

* LEHMANN, D., MURATA,K., KOUKKOU, M., (1962); Simultane Periodik der Neuronaktivitat in verschiedenen Cortexfeldern der Katze. Naturwissenschaften, 49, 61 1-612. ** CREUTZFELDT, O., and JUNG, R., (1961); Ciba-Foundation Symposium. The Nature of Sleep. G . E. W. Wolstenholme and M. O’Connor, Editors. London, Churchill (p. 131-170).

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Rhythmic Enzyme Changes in Neurons and Glia during Sleep and Wakefulness H. HYDGN A N D P. W. LANGE Institute of Neurobiology, Medical Faculty, University of Goteborg, Goteborg (Sweden)

Physiological sleep belongs to the rhythmic phenomena. Diurnal oscillations of various types have been correlated with sleep and wakefulness but, from a biochemical point of view, few significant observations have been made on the central nervous system. No change in the oxygen consumption of the brain in young men was found during sleep (Mangold et al., 1955). Diurnal fluctuations have been observed in man, such as increased pituitary activity during the night and increased adrenal activity during the day (Von Euler and Holmquist, 1934). Halberg (1960) found indications for a 24-h rhythm in hormone secretion, e.g. that the ketosteroid excretion was controlled by the endogenous diurnal rhythm. The central nervous system seems not to be required for the adrenal cycle, however. Reversal of sleeping and excretion rhythm (water, K+, Na+) was found to take 2-9 days in man. In animals, few biochemical observations have been reported. A rise in acetylcholine content and a fall in the brain lactate were found during sleep in comparison with normal control animals (Richter and Dawson, 1948). Electrophysiologically, much more is known although the phenomenon of sleep is as obscure as before the last advances in electrophysiological research. (See review by Moruzzi, 1963.) It seems that there is an area within the lower reticular formation of the brain stem which has a damping influence on the upper part of the reticular formation and produces the characteristic EEG pattern of sleep ipsilaterally. It may also be an area in the rostra1 pons which maintains wakefulness by its activity. The present study is a first investigation of enzyme activities in nerve cells and in their surrounding glia of the lower part of the reticular formation of rabbits during physiological sleep and wakefulness. We chose the big nerve cells belonging to the nucleus reticularis giganto-cellularis and studied the succinate oxidizing enzyme system (Table I). This enzyme was chosen because of the unique position of succinate in the Krebs cycle with direct transfer of electrons to the cytochrome system of the respiratory chain. EXPERIMENTAL SET-UP : MATERIAL A N D METHODS

White rabbits weighing 1.5 to 1.7 kg were used. The.rabbits were trained to sleep in individual wooden boxes provided with a hole fitting around the neck. For each day

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TABLE I SUCCINOXIDASE ACTIVITY AND STANDARD ERROR OF M E A N @l.10-4 O*/CELLAND HOUR) OF SINGLE NERVE CELLS A N D GLIA OF THE NUCLEUS RETICULARIS GIGANTO-CELLULARIS OF THE RABBIT

Nerve cells

n Glia samples n

In cages

Wakefuhess

Sleep

2.74 f 0.21 39 1.74 f 0.17 37

1.30 f 0.25 24 3.06 f 0.24 28

3.41 f 0.51 29 2.34 f 0.18 25

a training period of 5 h was established between 10 a.m. to 3 p.m. in a quiet room with subdued light and observation glass in the door. The rabbits were trained for 12 days before they were killed during sleep 1.5 h after being placed in the boxes. Using this type of arrangement, Sterner (1963) studied the EEG of rabbits. He found that only 4-5 training periods were necessary for adapting the animals to the boxes in which they soon showed the synchronous EEG of sleep. Sterner used rabbits with implanted electrodes and studied the changes of the sleep rhythm during different conditions. Rabbits placed in their individual living cages were found readily to fall asleep between periods of feeding. For this reason, ‘active’ control animals were used in the present experiments. These rabbits were kept active and awake by gentle handling for at least 1 h, and are denoted as wakefulness. In all, 30 sleeping animals were used, 30 of the wakefulness group and 29 cage animals. The control animals were killed by severing the carotides after air embolus as described earlier (HydCn, 1959), the sleeping rabbits by guillotine. This instrument has a blunt edge and is operated by remote control. At the killing, the spinal cord together with the vertebrate column were completely severed, but the skin was kept intact. The skull was rapidly opened and a section through the nucleus reticularis giganto-cellularis of the brain stem at the lower level of the acoustic tubercles was removed. The section was im ediately placed in a 0.25 M sucrose or in a Krebs-Ringer solution. The big nerv cells, and the equivalent volume and dry weight of the glia surrounding the nerve cell body, were isolated by free-hand dissection according to a previously described technique (HydCn, 1959). Each glia sample contained an average of 8 glial nuclei. Determinations of the activity of the succinate-oxidizing enzyme system were carried out using a modified micro-diver technique (HydCn and Pigon, 1960), according to the Zeuthen method. The weight of the divers was 0.2 to 0.3 mg, corresponding to a gas volume of 0.10 to 0.15~1.The results are expressed in ,ul Oz-10-4 per nerve cell or glia sample and hour. Only one cell sample was used in each diver.

3

RESULTS

The enzyme activity of the nerve cells is almost three times higher during sleep than during wakefulness. The nerve cells from rabbits living in their individual cages show an enzyme activity the values of which are between those of wakefulness and sleep and References p . 95

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significantly different from both. This is interesting to note since the EEG recordings of such rabbits showed both the synchronous rhythm of sleep and the arousal pattern (Sterner, 1963). The enzyme activity of the glia cells is significantly lower during sleep than during wakefulness, thus the inverse of the status of the nerve cells ( P < 0.02). For the glial cells, however, the values of the enzyme activity in the case of the cage rabbits, fall in between those of sleep and wakefulness. If the quotients of the enzyme activities of nerve cells and glia respectively, are compared in the three different cases, the following values for cage, wakefulness and sleep are obtained: 1.58; 0.42; 1.46. A diurnal rhythm is clearly reflected by the ratio nerve cell/glia enzyme activity of wakefulness and sleep. The status of the cage animals with periods of wakefulness alternating with periods of sleep must be subjected to further studies. DISCUSSION

The low succinoxidase activity of the neurons and high activity of the glia during wakefulness, and the inverse changes found in sleeping animals, is clear. It brings up the question whether these changes in the caudal part of the brain stem reticular formation reflect the biological clock which regulates the oscillatory circadian sleep rhythm. Studies now in progress at this laboratory are under way to determine whether nerve cells and glia outside of the reticular formation and in the rostra1 part of this formation behave in the same way. Our aim is to elucidate the working hypothesis that the energy metabolism oscillates with inverse changes between the neuron and its glia during sleep and wakefulness. SUMMARY

By the micro-diver technique, the succinoxidase activity was determined separately in single, fresh nerve cells and their surrounding glia, belonging to the nucleus reticularis giganto-cellularis of rabbits, during sleep and wakefulness. During sleep, a high enzyme activity was found in the neurons and a low activity in their glia. During wakefulness, these values were found to be inversed. The findings are interpreted to reflect a diurnal rhythm. ACKNOWLEDGEMENT

Our thanks are due to Mrs. Kerstin Szerszenski and Miss Lena BrodCii for excellent technical assistance. This work has been supported by Grants from Torsten and Ragnar Soderberg’s Foundation and by the United States Air Force under Grant NO. EOAR 62-29 through the European Office, Office of Aerospace Research.

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REFERENCES HALBERG, F., (1960); Temporal coordination of physiologic function. Cold Spr. Harb. Symp. quant. Biol.,25, 289-308. HYDBN,H., (1959); Quantitative assay of compounds in isolated fresh nerve cells and glial cells from control and stimulated animals. Nature, 184, 433435. HYDBN,H., and PIGON,A., (1960); A cytophysiological study of the functional relationship between oligodendroglial cells and nerve cells of Deiters’ nucleus. J. Neurochem., 6, 57-72. MANGOLD, R., SOKOLOFF,L., CONNER, E., KLEINERMAN, J., THERMAN, P. O., and KETY,S.S., (1955); The effects of sleep and lack of sleep on the cerebral circulation and metabolism of normal young men. J. Clin. Invest., 34, 1092-1 100. MORIJZZI,G., (1963);Active processes in the brain stem during sleep. Harvey Lect. Ser. 58. New York, Academic Press @. 233-297). RICHTER,D., and DAWSON, R. M. C., (1948); Ammonia and glutamine content of brain. J. bid. Chem., 176, 1199-1210. STERNER, N., (1963); Provning av psykofarmaka med elektroencefalografi: 1. Studier av normala variationer i h j b b ar k en s elektriska aktivitet hos vaken kanin. Farm. Revy, 62, 121-132. VONEULER,U. S., and HOLMQUIST, A. G., (1934); Tagesrhythmik der Adrenalinsekretion und des Kohlehydratstoffwechsels b e i i Kaninchen und Igel. Pflugers Arch. ges. Physiol., 234, 210-224.

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Central Neuro-Humoral,Transmission in Sleep and Wakefulness* RACJL HERNANDEZ PEON Instituto de Investigaciones Cerebrales, A.C., Moras 445, Mexico 12, D.F. (Mexico)

Several attempts have been made in the past to relate the onset of sleep to humoral factors associated with general metabolic functions. The basic assumption in all of these hypotheses was that certain depressor substances accumulate in the bIood to a level in which their depressant action upon the brain becomes manifest as a state of sleep. However, none of the proposed substances (e.g. lactic acid, cholesterol, CO,, ‘hypnotoxin’, ‘leucomaines’, ‘urotoxins’, etc.) has been conclusively demonstrated to be responsible for physiological sleep. Furthermore, the theories postulating that sleep results from hypnogenic substances released from the body into the general circulation are disproved by experiments made by nature in parabiotic bicephalic monsters, and by Demikhov (1962) who grafted the head of a puppy onto the neck of an adult dog. In both cases, it was observed that one head may present all the behavioral manifestations of sleep while the other shows the typical behavior of wakefulness and alertness. Even assuming that in these cases the action of hypnogenic circulating substances depends on different degrees of resistance of each nervous system to the same chemical agent, the conclusion is inescapable that the main factor determining the onset of sleep depends on particular states of excitability in the brain. Although most humoral theories of sleep belong to the group of ‘passive theories’ which have considered sleep as a simple absence of wakefulness, a few authors such as Dubois (1901) postulated more complex hypotheses assuming a humoral action on a then hypothetical ‘sleep center’. At the present time all the available experimental evidence strongly supports the view that sleep is not the result of a passive deactivation of the neural structures responsible for wakefulness, but that sleep is induced by an active inhibitory process which requires the activity of specific hypnogenic brain structures. However, the question remains as to the humoral mechanisms involved in central synaptic transmission along the hypnogenic and arousing structures. Accepting current ideas about specific chemical transmission at central synapses in the mammalian nervous system, it is of crucial importance to determine which is the excitatory transmitter substance setting the hypnogenic neurons in action as well as the inhibitory substance released at the final link which reduces the excitability ofthe vigilance neurons by the well known process of membrane hyperpolarization. By the same token, it is of great interest to * This work was supported by the National Institute of Mental Health under Grant No. MH-10003-01 and by the Foundation’s Fund for Research in Psychiatry under Grant No. 64300.

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know the nature of the chemical excitatory transmitter needed for depolarizing and maintaining the activity of the vigilance neurons, as well as the chemical mediators released at the endings of reticulofugal fibers exerting important inhibitory and facilitatory functions upon motor, sensory and integrating elements. As a first experimental approach to this problem I decided to use the method of localized chemical manipulation of the brain with naturally occurring substances normally synthetized in the nervous system as possible synaptic transmitters as well as with pharmacological agents which are known to interfere with the synthesis, membrane action or destruction of those substances. Furthermore, because of the extensive overlapping of arousing and hypnogenic neurons within the brain it seemed likely that chemical intracerebral stimulation would yield more rewarding results in the mapping of each functional system than the method of massive electrical stimulation. With these ideas in mind, during the last three years in collaborative studies an extensive exploration of the centralnervoussystem has been performedinmy laboratories, introducing microcrystals of various chemical substances into the brain of unrestrained cats by a method to be described below. As will be shown in the section ‘Results’, a new concept of the neural organization of the hypnogenic structures is emerging, which fits well with all the apparently unrelated experimental evidence on sleep inducing mechanisms. In the final Discussion of this paper, I shall offer my unitary view of sleep based on the experimental results to be reported as well as some working hypotheses which may help to foster research into the pharmacological and pathological aspects of sleep. MATERIAL A N D METHODS

Cats of both sexes have been used in the present study. Under aseptic precautions and pentobarbital anesthesia, cannulae and electrodes were introduced into the brain with the aid of the stereotaxic instrument and fixed to the skull with dental acrylic. The

Fig. 1. Cannula in which the stainless-steel concentric needles can move through a lucite cylinder. References p . 1151116

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cannulae used in the first 139 cats have been described elsewhere (Hernhdez Peon et al., 1963). They consisted of a double stainless-steel needle which by a special brass device could be pushed down by 1 mm steps into the brain of the implanted awake animal. Modified cannulae have been used in the last 45 cats. In this new model, a lucite cylinder replaced the outer brass piece of the former model (Fig. I). In addition, the cannulae were able to descend at 1 mm steps for the exploration of a region 7 mm high. In a group of 7 cats in which cannulae were implanted into the spinal cord, an additional stainless-steel plate soldered to the cannula permitted the fixation of the cannula and the immobilization of 3 consecutive vertebrae. The metallic plates were fixed to the spinal processes by screws (Fig. 2), and dental acrylic contributed to

Fig. 2. Model of spinal cannula attached to the spinal processes of two vertebrae by screws passing through a metallic plate.

further fixation of the cannula to the vertebral column. The regions so far explored included : cortical and subcortical structures in the temporal lobe, basal and dorsal cortical regions of the frontal lobe, the cingulate gyrus, the thalamus, the septa1 and preoptic regions, the hypothalamus, the mesencephalic and pontine tegmentum, the cerebellum, and the lower cervical segment of the spinal cord. Bipolar or multipolar stainless-steel electrodes insulated except for 1 mm at their tips were implanted in the olfactory bulb, in the mesencephalic reticular formation, in the hippocampus, and in the entorhinal cortex. Screw electrodes were implanted in the frontal part of the skull and around the orbit for recording the cortical electrical activity from the convexity and the eye movements, respectiveIy. Intramuscular electrodes in the dorsum of the neck were used for recording the EMG of the neck muscles. In addition, in some animals lesioning electrodes were implanted either in the preoptic

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region or in the medial forebrain bundle. In some cats with spinal cannulae for chemical stimulation, an additional cannula was implanted above the former for localized injections of procaine. The effects produced by the electrolytic lesion made with d.c. current, and those produced by local anesthetic blocking of the spinal cord were tested by comparing the effects of chemical stimulation in experiments performed before and after the interrupting procedure. All the experimental observations were made in the freely moving animal placed in a shielded cage where it could be easily observed through a glass window. In the last group of experiments, a sound-proof cage with a one-way glass window was used. The behavior of the animal was continuously monitored by the experimenters and photographed at various intervals. The recordings were made with a Kaiser electroencephalograph. After a stable period of control, minute crystals of the following substances were introduced into the cannulae in different experiments throughout the various animals of the whole experimental series: acetylcholine alone or plus eserine, eserine alone, carbamylcholine, atropine sulphate, noradrenaline bitartrate, adrenaline hydrochloride, nialamide, strychnine sulphate, and y-amino butyric acid. Subsequent observation of the cat’s behavior and electrical recordings were made during 1-5 h following chemical stimulation. After completing the exploration of several points in each cat throughout several experimental sessions, the brain was perfused in situ with 10% formalin under pentobarbital anesthesia. Frozen or paraffin sections 30-5Op thick were stained by the Kluver-Barrera, or the Nissl or Weil methods for histological verification of placement of the cannulae and electrodes. RESULTS

( a ) Experimental sleep

The hypnogenic effects produced by cholinergic stimulation of Nauta’s limbic midbrain circuit have been reported elsewhere (Hernandez Pe6n et al., 1963; Hernandez P e h , 1964) and will be only briefly summarized in order to describe in more detail recent unpublished experiments carried out in collaboration with Dr. J. J. O’Flaherty, Dr. A. Mazzuchelli-O’Flaherty and Dr. J. Rojas-Ramirez. Limbic midbrain cholinergic sleep The typical behavioral and electrographic manifestations of both the synchronized and the desynchronized stages of sleep were produced shortly after local application of acetylcholine alone, acetylcholine plus eserine, or carbamylcholine in a highly circumscribed pathway extending from the preoptic region to the medial pontomesencephalic tegmentum. Eserine alone induced only the synchronized phase of sleep. The hypnogenic structures thus disclosed included : the medial forebrain bundle passing from the upper medial preoptic region to the lateral and postero-medial hypothalamus, the ventromedial part of the midbrain tegmentum through the interpeduncular nucleus, and the adjacent medial tegmental region involving Bechterew’s References p. 115/116

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and Gudden’s nuclei. The latency of the cholinergically induced sleep along the limbic midbrain circuit was shorter for the most caudal part of this circuit than for the rostra1 segments. In some experiments the cat fell asleep as soon as 20 sec after application of the cholinergic substance into the medial ponto-mesencephalic tegmentum, whereas very often 2 4 min elapsed before the onset of sleep when the forebrain areas were stimulated. The onset of sleep was determined not only by the typical behavior of sleep in the cat preceded by a stereotyped preparatory attitude, but also by the appearance of spindles and high voltage slow waves in the EEG, and a significant diminution of the EMG activity of the neck muscles. The appearance of the deep stage of sleep was clearly associated with a desynchronized EEG flattening of the neck EMG, and bursts of rapid eye movements as described by other authors (Hubel, 1960; Jouvet, 1961). This chemically induced sleep lasted for 1-3 h. It was longer when induced by carbamylcholine or acetylcholine plus eserine, and shortest when eserine alone was applied. A similar difference was observed in the depth of sleep produced by the various cholinergic substances. In some instances, the cat could not be aroused by nociceptive stimuli but only by electrical stimulation of the mesencephalic reticular formation with high intensities. Atropine blockade of the hypnogenic pathway Although acetylcholine applied locally along the hypnogenic pathway mimics the effects produced by electrical stimulation of those regions, this by no means represents sufficient evidence for postulating cholinergic synaptic transmission in that pathway. Other criteria must be fulfilled before the above-mentioned idea becomes highly probable. One criterion is that anticholinesterases, preventing the enzymatic destruction of naturally occurring acetylcholine, must mimic the effects produced by electrical or acetylcholine stimulation of the corresponding neurons. In fact, early experimental results demonstrated that eserine alone applied to the hypnogenic preoptic region induced sleep. Another criterion is that pharmacological agents which prevent the action of the chemical transmitter upon the subsynaptic membrane should produce-a synaptic blocking of the corresponding neural pathway. With this aim, minute crystals of atropine sulfate were introduced at various points of the limbic midbrain hypnogenic pathway. It was found that shortly after the local application of atropine either in the preoptic region, or in the interpeduncular nucleus, or in Bechterew’s or Gudden’s nuclei, a state of alertness ensued accompanied by the typical persistent EEG desynchronization and high voltage ‘arousal discharges’ in the olfactory bulb as described by Hernandez Pe6n (1 960). Moreover, when atropine was applied locally to caudal segments of the limbic midbrain hypnogenic circuit such as the interpeduncular nucleus, or Bechterew’s nucleus, cholinergic stimulation of a previously assessed hypnogenic point in the preoptic region became ineffective in inducing sleep. This finding strongly suggeststhat atropine blocked the action of acetylcholine normally released at presynaptic terminals of hypnogenic neurons along the above-mentioned pathway. Another conclusion to be drawn from these experiments is that the activity along that neuronal system is transmitted from the forebrain down to the midbrain.

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Electrolytic interruption of the limbic midbrain hypnogenic pathway The conclusion just mentioned was further supported by experiments in which electrolytic lesions were made bilaterally in caudal segments of the medial forebrain bundle (MFB). These lesions prevented sleep otherwise produced by cholinergic stimulation of the rostra1 portion of the MFB in the preoptic region. Another experiment which eliminated the possibility of an ascending direction of hypnogenic impulses within the limbic midbrain circuit consisted in testing the effect produced by cholinergic stimulation in caudal parts of the medial forebrain bundle after lesions had been made

Fig. 3. Sleep produced by application of a minute crystal of acetylcholine in the pyriform cortex at the point marked by the arrow. EM = eye movements; SSaC = supra-Sylvian anterior cortex; Hipp = hippocampus; EMG = electromyogram of the neck muscles. References p. I l S i l l d

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in its rostra1 segments. Indeed, sleep was induced from those caudal points just as well as before the rostral lesion was made. Fronto-temporalcholinergic sleep Since the preoptic region represents an anatomical site of convergence for fibers coming from the frontal and temporal lobes, and since in previous experitnental studies (Russek and Hernandez P e h , 1961) sleep had been observed as a result of electrical stimulation of basal regions in the temporal lobe, it was decided to explore with localized cholinergic stimulation the possible existence of frontal and temporal projections to the limbic midbrain hypnogenic pathway. In collaboration with Dr. J. J. OFlaherty and Dr. A. Mazzuchelli-O'Flaherty, 270 points in the temporal lobe and 42 p i n t s in the frontal lobe have been explored in 30 cats. The regions where sleep or somnolence have been induced by cholinergic stimulation are the following : all the pyriform and prepyriform cortex, the basolateral part of the forebrain, the diagonal band of Broca and the nucleus entopeduncularis. A typical experiment is illustrated in Fig. 3. The highly discrete anatomical localization of the hypnogenic temporal and frontal regions is shown by the finding that very often acetylcholine applied in the amygdaloid complex induced seizures and strong autonomic effkts, but when

I

0 SLEEP

SOMNOLENCE

o NO S L E E P

Fig. 4. This figure illustrates some anatomical areas in the pyriform cortex where sleep or somnolence was produced by local application of acetylcholine.

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cholinergic stimulation was applied in the same animal the next day 1 mm below in the region of the pyriform cortex the typical manifestations of sleep were observed. Fig. 4 illustrates the precise localization mentioned above. In order to determine whether the temporal hypnogenic projections from the pyriform cortex establish connections in the preoptic region with the limbic midbrain hypnogenic pathway, lesioning electrodes were implanted in 5 cats in the preoptic region simultaneously with a cannula in the pyriform cortex. After finding a hypnogenic point, an electrolytic lesion was made in the preoptic region under barbiturate anesthesia. When the animal had recovered, cholinergic stimulation applied to the same point of the pyriform cortex became ineffective. Therefore, the conclusion is warranted that the hypnogenic projections from the pyriform cortex descend through the preoptic region in order to join in all probability the limbic midbrain hypnogenic pathway. Future experiments designed to test the effects of interruption of the hypnogenic pathway further down at hypothalamic or mesencephalic levels will be needed to establish definite connections o f the hypnogenic pyriform cortex with the limbic midbrain circuit. When studying the distribution of hypnogenic points in deep structures adjacent to the temporal lobe, one is struck by the presence of hypnogenic areas in the globus pallidus. It is possible that some pyriform corticofugal hypnogenic projections pass at this level. Cingulate cholinergic sleep Since the cingulate gyrus represents part of the limbic cortex surrounding the hilus of the hemisphere, and since its anterior part sends connections to the septa1 and preoptic regions, it was decided to explore this cortical region with cholinergic stimulation. The exploration of 28 points performed in 6 cats has revealed a hypnogenic area in the anterior part of the cingulate gyrus. The rostra1 localization of this area is in sharp contrast with the absence of sleep when the posterior part of the cingulate gyrus was stimulated. Although cingulate cholinergic sleep was clearly and consistently obtained, the hypnogenic effect produced by cholinergic stimulation in this area seems to be less intense than that elicited from subcortical structures. Thalamic cholinergic sleep The pioneer work of Prof. Hess showing that electrical stimulation of a medial thalamic region in the vicinity of the massa intermedia induced sleep has been confirmed in recent years by a number of investigators (Monnier, 1950; Monnier et al., 1963; Tissot and Monnier, 1959; Russek and HernLndez Pe6n, 1961). Also it has become well established that the thalamic pool of hypnogenic neurons oxrerlaps anatomically with elements which can excite the mesencephalic arousing neurons through the region of the posterior commissure (Schlag et al., 1961). It therefore seemed reasonable that the method of localized chemical stimulation might permit a functional dissection of the hypnogenic and arousing elements at this level. With this aim, cannulae were implanted in the medial thalamic nuclei of 5 cats. The exploration of 35 points in that zone has revealed a definite hypnogenic area, which so far includes the following thalamic nuolei : nucleus rhomboidalis, nucleus centralis medialis, the References p . I I51I16

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limit of the nucleus centralis medialis and nucleus reuniens, nucleus centralis lateralis, and nucleus reticularis (Fig. 5). The sleep produced by cholinergic stimulation of the medial thalamus is striking in its short latency and long duration. We do not know yet the anatomical pathway utilized by the thalamic hypnogenic zone in order to inhibit the mesodiencephalic vigilance system. Experiments in progress in which lesions will be made along the limbic midbrain hypnogenic circuit will provide an answer as to possible connections between these two hypnogenic structures.

Fig. 5. Thalamic cholinergic sleep: Localization of effective areas of chemical stimulation. Midline and intralaminar nuclei are involved.

Striate cholinergic sleep In the course of mapping out temporal and forebrain regions, hypnogenic points have been found in the head and tail of the caudate nucleus, in the globus pallidus, in the limit of the putamen and globus pallidus, in the limit of the claustrum superior and pyriform cortex, in the limit of the pallidum and entopeduncular nucleus, and in the limit between the pallidum and amygdala. All these regions may represent parts of descending corticofugal hypnogenic pathways. Pontine cholinergic sleep In an initial systematic exploration of the caudal brain stem in order to map out the hypnogenic cholinergic structures at this level sleep has been elicited from a midline pontine region where the nucleus reticularis pontis caudalis is located. Again, sharp Iocalization is being provided by the method used in this study. Indeed, cholinergic

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stimulation of the upper part of the nucleus reticularis pontis caudalis elicited a generalized and marked hypotonia of the whole musculature while the cat remained behaviorally and electrographically awake with dilated pupils, and a desynchronized EEG without rapid eye movements. However, acetylcholine applied 1 mm below

Fig. 6. Sleep induced by local application of acetylcholinein the spinal gray substance at the level of C8. EM = eye movements. FC = frontal cortex. EC = entorhinal cortex. EMG = electromyogram of the neck muscles.

induced a typical state of sleep. Therefore, although undoubtedly this pontine region contains potent inhibitory neurons upon the motor outflow, a dissociation can be expected between those neurons belonging to inhibitory motor systems and those having more specific hypnogenic properties. Spinal cholinergic sleep From phylogenic considerations the hypothesis has been advanced (Hernhdez Pebn,

SLEEP

0

N O SLEEP

Fig. 7. Diagram of a transverse section of the cat’s spinal cord showing some areas where acetylcholine locally applied evoked sleep. References p. 115/116

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1964) that the vigilance and the sleep systems were early represented in the primitive neural tube, developing later in parallel with the CNS. According to this evolutionary hypothesis, through encephalization the essential part of each system became located in the brain stem, receiving descending corticofugal projections when the cortical mantle emerged. In order to test the possible existence of vestigial el ements of the sleep system in the spinal cord, in collaboration with J. Rojas-Ramirez, the specially devised cannulae previously described were implanted in 7 cats in the low est cervical segments. The experimental results confirmed our expectations in that cholin ergic stimulation of the spinal gray substance induced both stages of sleep (Fig. 6). Although the size of the cannulae employed only permits at the present moment a rough localization of the spinal hypnogenic pathway, this area seems to involve the commissural gray substance as well as the base of the posterior horns, and the spinal reticular formation located between the anterior and posterior horns (Fig. 7). As in any other part of the central nervous system so far tested, the method used has shown a discrete anatomical localization of the hypnogenic area, because very often cegative points were found in the same animal 1 mm away from hypnogenic points. The existence of spinal hypnogenic neurons logically presumes that their inhibitory action upon the vigilance system located in the rostra1 brain stem must be exerted by ascending connections. In order to test this obvious c3 nclusion, two cannulae were

Fig. 9. Inhibition of the tonic activity of the neck and anterior limb extensor muscles of a decerebrate preparation immediately after local application of acetylcholine in the spinal gray substanc- at C8.

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implanted in the adjacent regions of the spinal cord. A hypnogenic spinal point was located through the lower cannula and the following day a spinal blockade was achieved by intraspinal injection of procaine solution through the upper cannula. Acetylcholine applied into the lower cannula was ineffective in producing sleep 20 min later (Fig. 8). Therefore, it is clear that there are ascending hypnogenic influences originating in the spinal cord. This ascending inhibitory influence may well account for the Schiff-Sherrington phenomenon. If there are ascending spinofugal influences inhibiting the mesencephalic facilitatory reticular neurons responsible for decerebrate rigidity, it should be possible to produce inhibition of the muscular tone in a decerebrate preparation by localized spinal cholinergic stimulation. Indeed, this has been shown in one experiment in which decerebration was done by an extensive midbrain electrolytic lesion. The background tonic activity of the extensor muscles in the neck and anterior limbs was significantly reduced after local application of acetylcholine into the gray substance of the spinal cord (Fig. 9), whereas no effect was obtained 1 mm away in a more superficial spinal region.

(b) Experimental arousal and alertness Cholinergic arousal Throughout systematic exploration of the brain with cholinergic stimulation it was found that alertness is induced from telencephalic, diencephalic and mesencephalic levels. The arousal structures may be listed as follows : the gyrus parasplenialis‘, posterior part of the gyrus cinguli and its limits with area 32, the induseum griseum, Ammon’s horn, the claustrum, part of the amygdaloid complex (anterior amygdaloid area, nucleus amygdaloideus basalis and lateralis), origin of stria terminalis, the dorsal anterior commissure, the dorsal perifornical area, the dorsolateral hypothalamus above the medial forebrain bundle, the lateral habenular nucleus, the habenulointerpenduncular tract, the stria medullaris, the red nucleus, the medial and lateral mesencephalic reticular formation and the ventral central gray substance. As can .be seen, from the septum to the midbrain the cholinergic arousal pathway lies dorsal to the hypnogenic pathway. Usually the alertness produced by cholinergic stimulation of the above-mentioned regions was unspecific and sometimes associated with motor hyperactivity and sometimes not. Simultaneously with the behavioral state of alertness, the cortex presented a low voltage fast activity pattern, and ‘arousal discharges’ (Russek and Hernhndez P e h , 1961) were recorded in the olfactory bulb. A particular state of specific alertness which we have described as ‘magnetic attention’ was elicited by carbamylcholine when applied to the dorsal anterior commissure or to the ventrolateral part of the septum. During this state, the cat was capable of following for many seconds any indifferent object moving within its visual field. Adrenergic arousal In contrast with the extensive brain mapping carried out with cholinergic stimulation, few central regions have been explored with localized adrenergic stimulation.

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The application of microcrystals of noradrenaline in sleeping or drowsy cats produced the behavioral and electroencephalographic manifestations of arousal from the upper medial preoptic region, from the ventromedial hypothalamus and from the mesencephalic reticular formation. Although the number of experiments so far performed do not allow us to state definite conclusions, it seems that adrenergic stimulation of the mesencephalic reticular formation produces a state of alertness which resembles that observed in the cat when any mild novel stimulus evokes an orienting reaction. In contrast with this alerting state, in which detection of external environmental stimuli seems to be facilitated, the behavioral alertness elicited by adrenergic stimulation of the upper medial preoptic and ventromedial regions was usually associated with restlessness and motor hyperactivity which on some occasions was identifiable with an integrated ‘escape response’ (HernBndez Pebn et al., 1963). DISCUSSION

The problem of the chemical nature of central synaptic transmission is a difficult one to approach experimentally, because a congruent group of experimental data must be gathered before establishing that a given chemical agent is a central synaptic transmitter. The strongest evidence for the transmitter function of a compound is that the substance should be detectable in the extracellular fluid surrounding the activated synaptic region. In the central nervous system, this task involves technical difficulties inherent in the complex neuronal organization. Therefore, for the time being indirect evidence must be sought. Cholinergic excitatory synaptic action along the sleep system There are indications in the literature that acetylcholine may be closely related t o the induction of sleep. Working in human subjects, Hoffer (1954) found that injected acetylcholine produced sleepiness which resulted in an earlier onset of the usual night sleep. Dikshit (1934, 1935) seems to have been the first to produce sleep in cats by intraventricular and intrahypothalamic injection of acetylcholine. However, he described a long latency effect (10-30 min) as a ‘condition closely resembling sleep’. This state differs from the short latency effect obtained in our experi ents which is indistinguishable behaviorally and electrophysiologically from physiol gical sleep. The effects produced by pharmacological agents which interfere with the enzymatic destruction of acetylcholine and with the reaction of this substance with the postsynaptic membrane substantiate the view of excitatory synaptic transmission accomplished by acetylcholine released at presynaptic terminals along the hypnogenic pathway. In 1950 on the basis of the literature available at that time, Feldberg proposed an alternation of cholinergic and non-cholinergic synapses along central pathways. However, this postulate has not been conclusively demonstrated to have general application throughout the central nervous system. Even assuming that cholinergic synapses alternate with synapses utilizing other chemical mediators, the possibility remains that both kinds of synapses might be intermingled along a multisynaptic chain of neurons. Either type of synaptic organization can account for the finding that

3

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acetylcholine provokes sleep wherever it is applied within the hypnogenic path. Although all the accumulated evidence previously described strongly suggests that the excitatory synaptic transmitter along the sleep system is acetylcholine, the inhibitory transmitter acting upon the subsynaptic membranes of the arousing neurons remains to be identified. Certain features of physiological sleep as well as some experimental observations suggest that the initiation of sleep is associated with a cumulative phenomenon, and that termination of sleep is also progressive in nature. These observations would be accounted for by assuming that the activation of the sleep system releases a hypnogenic substance which accumulates because of a slow process of enzymatic destruction. This substance might well be the unknown inhibitory hypnogenic transmitter, which might pass in small amounts into the general circulation. The recent cross-circulation experiments carried out by Prof. Monnier and his associates (1963) fall in line with this view. Indeed, they have found that electrical stimulation of the thalamic hypnogenic area releases a substance into the general circulation of the donor animal which in turn can produce EEG synchronization in the recipient. This finding indicates that the hypnogenic substance is not rapidly n3r easily destroyed by the brain and blood enzymes, and that therefore, it must be something other than acetylcholine. A unitary view of the sleep inducing mechanisms Many reports in the literature have indicated that sleep can be induced by electrical stimulation of a number of central regions located in both the forebrain and the hindbrain. By the same token, lesioning experiments have demonstrated that the amount of sleep normally occurring in experimental animals can be significantly reduced by interrupting either forebrain or hindbrain structures. Our results reconcile many apparently unrelated findings and they have led us to conceive a single sleep system extending throughout the entire neuroaxis as depicted in Fig. 10. Such a neuronal sleep system appears to be made up of a multisynaptic pathway with two main components : (1) an ascending component originating in the spinal cord and extending into the medulla oblongata and the pons, which inhibits the mesencephalic vigilance system ; and (2) a descending component originating in the cortex and possibly the thalamus. Our results showing the existence of a hypnogenic cholinergic pathway within the gray substance of the spinal cord support the conclusion recently reached by Hodes (1964) that there is a flow of tonic ascending EEG synchronizing impulses from the spinal cord, based on the finding that procaine intraspinal block produced EEG desynchronization. It seems likely that the bulbar synchronizing area located in the region of the fasciculus solitarius, or some other more medially located hypnogenic neurons in the medulla oblongata (Cordeau et al., 1963) might represent an anatomical continuation of the spinal hypnogenic neurons. This anatomical continuity is by no means incompatible with the presence of tonic activity at each level. The descending component of the sleep system consists of pathways coming from the pyriform cortex in the temporal lobe, from the orbital and lateral cortex of the frontal lobe, from the anterior part of the gyrus cinguli and possibly from some other

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yet unidentified cortical regions. All these pathways seem to converge in the preoptic region at the level of the medial forebrain bundle, following then a circumscribed trajectory within the limbic midbrain circuit to join possibly the ascending component of the sleep system in the pons. Our more recent results of neurochemical stimulation strongly confirm the existence in the medial thalamus of a potent hypnogenic region demonstrated by the pioneer work of Prof. Hess (1933). The question to be answered by future experiments is whether the activity of the thalamic hypnogenic region is maintained by corticofugal impulses, or whether it persists in the absence of the neo- and paleocortex.

Fig. 10. Diagram illustrating the anatomical substrate of the sleep system disclosed by localized cholinergic stimulation. The system is composed of 2 components: a descending component with corticofugal projections from the pyriform cortex, the orbital surface of the frontal lobe and the anterior part of the gyrus cinguli which converge upon the limbic midbrain circuit extending down to the ponto-mesencephalic tegmentum. A midline thalamic area is shown. The descending component joins at the pontine level with an ascending component originating in the spinal cord.

The ultimate anatomical link between the hypnogenic pathway and the mesodiencephalic arousing neurons remains to be shown. In a previous paper (Hernhndez Pe6n et al., 1963)we suggested that radiatio grisea tegmenti fibers of Weisschedel, massively spreading from the region of Gudden’s nuclei in the periaqueductal gray substance into the midbrain tegmentum, might represent the final inhibitory link. However, it is passible that similar inhibitory connections might be established at the diencephalic level between other parts of the sleep system and the vigilance system. If this is the case, a brain stem transection eliminating the ascending hypnogenic influences and the distal end of the descending limbic-midbrain hypnogenic pathway would produce a dominance of the vigilance system. This has been shown to be the case in the midpontine preparation so well studied by Moruzzi and his group (Moruzzi, 1960, 1963). References p. 1151116

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But even in this case, the remaining inhibitory connections between the hypnogenic descending pathway and the mesodiencephalic vigilance neurons would take over in time by a process of neural equivalence, possibly through sensitization of the denervated arousing neurons which would become hyper-responsive to the action of the inhibitory hypnogenic transmitter. The existence of the above-mentioned two components of the sleep system can also account for the absence of a permanent insomnia following forebrain lesions at the preoptic level. It is understandable that interruption of the descending component of the forebrain does not prevent the inhibitory hypnogenic action of the ascending component. Thus, we may conceive sleep as a unitary phenomenon resulting from different degrees of activity along a well defined and anatomically circumscribed hypnogenic pathway. The two phases of sleep Our results are incompatible with the view proposed by Jouvet (1963) who believes that the two stages of sleep arise from anatomically different structures, ascribing the synchronized stage to the neocortex and the desynchronized stage to the pontine region involving the nucleus reticularis pontis caudalis. If this were the case, the desynchronized stage of sleep should not be initiated nor altered by stimulation or destruction of forebrain hypnogenic regions. However, in our experiments the desynchronized stage of sleep has been provoked by cholinergic stimulation of frontal and pyriform cortical areas much earlier than it usually appears during spontaneous sleep in the same experimental environment. On the other hand, CIemente and Sterman (1964) have found that forebrain lesions in the preoptic region result in a significant reduction of the duration of the two stages of sleep. It is more reasonable to admit that these two phases of sleep with different arousal thresholds result from different degrees of inhibition produced by the same functional hypnogenic neuronal system upon the vigilance neurons. As to the electrophysiological manifestations of sleep characterizing each phase, they may only represent effects produced by the changes in the pattern of activity occurring in these stages. For instance, the spindle bursts recorded from the cortex during the first stage of sleep can be accounted for by a release of thalamo-cortical recruiting circuits normally inhibited during wakefulness. The generalized muscular hypotonia occurring during the desynchronized stage of sleep may result from activity initiated in the inhibitory neurons in the upper part of the nucleus reticularis pontis caudalis which act upon the motor outflow. It would be wise to distinguish between genuine intrinsic neuronal activation and an increase of neurona1 discharges consecutive to disinhibition.

Reciprocal organization of the vigilance and sleep systems Concerning the neural organization between the vigilance and the sleep systems we have earlier proposed (HernBndez Pe6n et al., 1963) that they are probably reciprocally connected through important inhibitory tonic influences. The finding that interruption of neural transmission along the hypnogenic pathway, whether by lesions or by chemical procedures, yields a state of alertness or a prolonged state of wakefulness strongly suggests that the sleep system exerts a tonic inhibitory influence upon the

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vigilance system. It is not unreasonable to conceive that the comatose state produced by incomplete destruction of the vigilance system is further deepened by the inhibitory action of an intact hypnogenic system upon the remaining vigilance neurons. This may well be the explanation for the accelerated recovery observed in some comatose patients following parenteral administration of atropine. The intrinsic automatic activity of the main subcortical parts of the vigilance and of the sleep systems can be increased by excitatory impulses coming either from the sensory receptors or from higher levels of the CNS such as the neocortex or the limbic cortex. This view is illustrated in Fig. 11. While the vigilance system is predominantly

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activated by novel or significant stimuli, the sleep system would be preferentially activated by non-significant stimuli such as those producing habituation by monotonous repetition. In turn, the subcortical vigilance and sleep systems can be activated by cortical discharges related to more elaborate learning processes or to volition. It is reasonable to assume that sensory activation of the sleep system involves mainly the ascending component of the system including the bulbo-pontine synchronizing structures as Moruzzi (1960) has brilliantly suggested. On the other hand, sleep associated with habits or volition or psychogenic conflicts would utilize the corticofugal descending limb of the hypnogenic system. Recent experiments by Clemente et al. (1963) showing that the synchronizing cortical activity elicited by electrical stimulation of the forebrain can be conditioned to a tone, supports this hypothesis. Using Kleitman's initial terminology (1939), sensory activation of the subcortical vigilmce and sleep systems would be responsible for wakefulness of necessity and References p . 1151116

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sleep of necessity, whereas their corticofugal activation underlies wakefulness of choice and sleep of choice. SUMMARY A N D CONCLUSION

This paper surveys the results obtained during the last three years with the method of localized chemical stimulation of the brain concerning the experimental induction of sleep and wakefulness. Cannulae were stereotaxically implanted in cats at all levels of the central nervous system. In the unrestrained freely moving animal the behavioral and electrographic effects induced by intracerebral application of minute crystals of various chemical substances were studied. These effects may be summarized as follows : (1) Acetylcholine sleep. Local application of acetylcholine alone, eserine alone, acetylcholine plus eserine or carbamylcholine elicited sleep from the following structures : the orbital and lateral surface of the frontal lobe, the pyriform cortex, the anterior part of the gyrus cinguli, the medial thalamic nuclei, the head and tail of the caudate nucleus, the globus pallidus, the diagonal band of Broca, the nucleus entopeduncularis, the olfactory tubercle, the upper medial preoptic region, the medial forebrain bundle along the lateral and posteromedial hypothalamus, the ventromedial part of the midbrain through the inteqeduncular nucleus, Bechterew’s and Gudden’s nuclei, the lower part of the nucleus reticularis pontis caudalis, the anterior lingula of the cerebellum and the gray substance of the spinal cord at the lowest cervical level. (2) Atropine blockade of the limbic midbrain hypnogenic pathway. When atropine was locally applied in the interpeduncular nucleus or in Bechterew’s or Gudden’s nuclei, acetylcholine applied in the hypnogenic preoptic region became ineffective in inducing sleep. Other experiments with bilateral electrolytic lesions in the posterior part of the medial forebrain bundle confirmed the rostrocaudal direction of the excitatory process produced by acetylcholine stimulation in the rostra1 part of the hypnogenic limbic midbrain pathway. (3) Procaine blockade of the spinal hypnogenic pathway. Local intraspinal injection of procaine prevented sleep otherwise produced by acetylcholine stimulation of a slightly caudal hypnogenic point in the spinal cord. (4) Acetylcholine alerting. Arousal or alertness was produced by acetylcholine from the posterior part of the gyrus cinguli, Ammon’s horn, the septum, the mesencephalic reticular formation, the ventral tegmental area of Tsai, the habenular nucleus, the habenulo-interpeduncular tract and the ventral periaqueductal gray substance. ( 5 ) Noradrenaline alerting. Alertness was elicited by noradrenaline from the mesencephalic reticular formation, the ventromedial hypothalamus and the upper medial preoptic region. It is concluded that there is in the brain an anatomically circumscribed sleep system, the activation of which produces sleep through direct inhibition of the mesodiencephalic vigilance system. The sleep system consists of two components: a descending component located within the limbic midbrain circuit receiving corticofugal and possibly thalamic projections, and an ascending component originating in the spinal

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cord and traversing the medulla and pons to the midbrain. The results presented strongly suggest that acetylcholine is an excitatory synaptic transmitter released all along the multisynaptic sleep system. An evolutionary theory was proposed according to which the vigilance and the sleep systems must be two phylogenically old neural systems. Early represented in the primitive neural tube, through encephalization their essential part became localized in the brain stem, receiving corticofugal projections only later when the cortical mantle emerged. REFERENCES

CLEMENTE, C. D., and STERMAN,M. B., (1964); Personal communication. CLEMENTE, C. D., STERMAN, M. B., and WYRWICKA, W., (1963); Forebrain inhibitory mechanisms: conditioning of basal forebrain induced EEG synchronization and sleep. Exp. Neurol., 7 , 401417. CORDEAU, J. P., MOREAU,A., BEAULNFS,A., and LAURIN,O., (1963); EEG and behavioral changes following micro-injections of acetylcholineand adrenaline in the brain stem of cats. Arch. ital. Biol., 101, 3 M 7 .

DEMIKHOV, A.. (1962); Experimental Transplantation of vital Organs. New York, Consultants Bureau,. (p. 385).

DIKSI-IIT, B. B., (1934); Action of acetylcholine on the “sleep centre”. J. Physiol., 83, 42. DIKSHIT, B. B., (1935); The physiology of sleep. Lancet, i, 570. DUBOIS R., (1901); Le centre du sommeil. C.R. SOC.biot., 53, 229-230. FELDBERG, W., (1950); The role of acetylcholine in the central nervous system. Brit. med. Bull., 6, 3 12-321.

HERNANDEZ PEON,R., (1960); Neurophysiological correlates of habituation and other manifestations of plastic inhibition (internal inhibition). The Moscow Colloquium on Electroencephalography of Higher Nervous Activity. Electroenceph. elin. Neurophysiol., Suppl. 13,101-1 19. HERNANDEZ PEON, R., (1964); A cholinergic limbic forebrain-hindbrain hypnogenic circuit. Etectroenceph. clin. Neurophysiol., 17, 444-445. HERNANDEZ PEON,R., CHAVEZ IBARRA, G., MORGANE, J. P., and TIMOIAR~A, C., (1962); Cholinergic pathways for sleep, alertness and rage in the limbic midbrain circuit. Acru neurol. 1af.-amer., 8, 93-96.

HERNANDEZ PEON,R., CHAVEZIBARRA, G., MORGANE, J. P., and TIMOIARLA,C., (1963); Limbic cholinergic pathways involved in sleep and emotional behavior. Exp. Neurol., 8,93-111. HESS,W. R.,(1933); Der Schlaf. Klin. Wschr., 12, 129-134. HODFS, R., (1964) ; Electrocortical desynchronization resulting from spinal block : evidence for synchronizing influences in the cervical cord. Arch. ital. Biol., 102, 183-196. HOFFER, A., (1954); Induction of sleep by autonomic drugs. J. nerv. ment. Dis.,119,421477. HUBEL,D. M., (1960); Electrocorticogram in cats during natural sleep. Arch. ital. Biol., 98, 171-181. JOUVET, M., (1961); Telencephalic and rhombencephalic sleep in the cat. The Nature of Sleep. G. E. W. Wolstenholme, and C. M. OConnor, Editors. London, Churchill. JOUVET,M., (1963); A study of the neurophysiological mechanisms of dreaming. The physiologicak basis of mental activity. Electroenceph. clin. Neurophysiol., Suppl. 24, 133-1 56. KLEITMAN, N., (1939); Sleep and Wnkefuhess. Chicago, Univ. Chic. Press. MONNIER, M., (1950); Action de la stimulation electrique du centre somnegene sur l’electrocorticogramme chez le chat. (Reactions hypniques et reactions d’eveil.) Rev. neurol., 83,561-563. MONNIER, M . , and KOLLER, T., (1963); La transmission humorale du sommeil experimental. Rev. neurol., 108.5 1 9-5 3 1. MONNIER, M., KOLLER, T., and GRABER, S.,(1963); Hurnoral influences of induced sleep and arousah upon electrical sleep and arousal upon electrical brain activity of animals with crossed circulation. Exp. Neurol., 8, 264-277. MORUZZI,G., (1960); Synchronizing influences of the brain stem and the inhibitory mechanisms underlying the production of sleep by sensory stimulation. Electroenceph. din. Neurophysiol., Supp. 13,231-253. MORUZZI,G., (1963); Active processes in the brain stem during sleeping. Harvey Lect. Ser. 58, New York,London, Academic Press (p. 233-297).

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RUSSEK,M., and HERN~NDEZ PEON, R., (1961); Olfactory bulb activity during sleep induced by stimulation of the limbic structures. Acfa neurol. 1at.-amer., 7 , 299-302. SCHLAG, J. A,, CHAILLET, F., and HERZET, J. P., (1961); Thalamic reticular system and cortical arousal. Science, 134, 1691-1692. TISSOT, R.,and MONNIER, M. (1959); Dualitt du systkme thalamique de projection diffuse. Electroenceph. din. Neurophysiol., 11,75-86. DISCUSSION

EVARTS:I wonder if Dr. Hernandez Pe6n might elaborate on the question of whether or not the condition produced by the acetylcholine crystals should be called sleep. Certainly, the behavior of the animal that fell into its food dish is in no way similar t o that of an animal going to sleep. HERNANDEZ PEON : The state produced by local application of acetylcholine or eserine along the hypnogenic pathway is undistinguishable from ‘spontaneous’ sleep in the cat. This criterion is based on behavioral observation and electrophysiological recordings. Actually, the experiment that I reported on the hungry cat which fell asleep dropping its head inside the meat bowl illustrates the most dramatic case comparable to a narcoleptic attack. This effect is obtained when carbamylcholine or acetylcholine plus eserine is applied in the region of Bechterew’s and Gudden’s nuclei. But acetylcholine alone applied in any point of the hypnogenic system elicits a state of sleep from which the cat can be aroused.

PLETSCHER : Is the antagonistic effect of acetylcholine (sleep) and of noradrenaline {arousal) seen in all the hypnogenic zones you mentioned, or is this ‘antagonism’ localized to certain, definite brain areas? HERNANDEZ P E ~:N Although we have not yet made an extensive exploration of the brain with noradrenaline I can say that the arousing areas activated by noradrenaline and the hypnogenic areas activated by acetylcholine are not always overlapping. Therefore, I expect that with noradrenaline stimulation the vigilance system will be found to have an anatomical substrate different of that of the hypnogenic system ,disclosed by acetylcholine stimulation. HOSLI: Are the behavioral and electrographic sleep effects which you get in the preoptic region after application of acetylcholine the same as after electrical stimulation of this region?

HERNANDEZ P E ~ N :Yes. They are the same. KONZETT:Can you give some figures of the absolute amount of acetylcholine and atropine in the crystals you inject? This question arises from pharmacological observations that a certain relationship exists between a dose of acetylcholine and the antagonizing dose of atropine to block the muscarin-like and the nicotine-like action of acetylcholine.

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HERNANDEZ P E ~:N We have not made quantitative measurements of the amount of acetylcholine introduced through our cannulae, but it is certainly in the order of micrograms. WASER:What is the concentration of acetylcholine in the tissue surrounding the crystal? Ths information should be more important than the actual dose. How can hypertonic effects be ruled out? HERNANDEZ PEON: We have control experiments in which a variety of different chemical agents have been also locally applied. None of the substances tested (nialamide, y-amino butyric acid, strychnine, etc.) has ever produced sleep. These experiments rule out osmotic or mechanical changes as responsible factors for the specific hypnogenic effects obtained in our experiments. HEPPNER: From the studies of Bornstein* (1946) and Ward** (1950) we know that a state similar to sleep can be produced in experimental animals by injecting acetylcholine into the CSF. At the same time the EEG and tracings from the formatio reticularis of the brain stem show patterns similar to those in concussion. On the other hand it is a well-known fact, which I confirmed myself in 1951, that after brain trauma acetylcholine is found in the CSF in a quantity proportionate to the severity of the trauma. (This fact is the basis of our anticholinergic treatment of brain injury, Heppner and Diemath,*** 1958.) Hence I should have thought that to produce sleep it would be unnecessary to inject acetylcholine into the spinal cord and that injection of acetylcholine into the spinal fluid cavities would have sufficed. PEON: I was glad to hear Prof. Heppners observations which support HERNANDEZ our experimental findings regarding the hypnogenic effects of acetylcholine. In the cats with intraspinal implanted cannulae, sleep was only obtained when acetylcholine was applied in the gray substance whereas no effect was obtained from other intraspinal points in the dorsal columns or anterior horns located 1 mm away from hypnogenic points.

* BORNSTEIN, M. B., (1946); Presence and action of acetylcholine in experimental brain trauma. J. Neurophysiol., 9, 349-366. ** WARD,A., Jr.,(1950); Atropine in the treatment of closed head injury. J. Neurosurg., 7 , 398-402. *** HEPPNER, F., and DIEMATH, H. E., (1958); Klinische Erfahrung mit der anticholinergischen Behandlung des gedeckten Schadelhimtraumas. Mschr. Unfallheilk., 61, 257-265.

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Humoral Regulation of Sleep and Wakefulness by Hypnogenic and Activating Dialysable Factors MARCEL MONNIER

AND

L. HOSLI

Physiological Institute, University of Bade, Bade (Switzerland)

During our investigations on experimental sleep in the rabbit we observed that electrical stimulation of the hypnogenic thalamic area induces sleep which often persists beyond the stimulation (Hosli and Monnier, 1962). Similarly, electrical stimulation of the midbrain reticular formation induces a sustained tonic arousal, suggesting that a humoral factor may prolong the neural action.

‘EEG recording Fig. 1. Cross circulation in rabbits. The proximal end of the carotid artery in the upper animal is connected with the distal end of the carotid in the lower animal, and vice versa for the jugular veins. The stereotaxic implants allow electrical stimulation and EEG recording in both animals. (Monnier et al., 1963.)

Re/erences p .

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These considerations led us in 1962 to investigate the humoral transmission of sleep and wakefulness. In a first series of experiments we investigated on rabbits with crossed circulations whether stimulation of the donor’s hypnogenic thalamus moderates the electrical brain activity both in the donor and in the recipient (Monnier et al., 1963) (Fig. 1). The simultaneous recording of the electrical brain activity in donor and recipient shows a significant increase of slow d-activity symptomatic of sleep, both in donor and recipient (Fig. 2). This &increase, objectively measured with an automatic frequency analyser, suggested that a moderating factor is transmitted from the donor to the recipient. The statistical analysis confirmed that a slow d-activity, significant of sleep, increases not only in the donors, but also in the recipients during electrical stimulation of the hypnogenic thalamus in the donor. This does not occur in control animals during sham-stimulation of the thalamus : their 8-activity on the contrary decreases. These results confirm that the blood of the sleeping donor contains a substance capable of moderating the brain activity in the recipient. Furthermore they confirm statistically previous qualitative results of Kornmiiller el al. (1961) in the cat. On the other hand, rabbits with crossed circulations show, during electrical stimulation of the midbrain reticular system in the donor, an arousal reaction with desynchronization in the motor cortex, not only in the stimulated donor, but also in the recipient. Automatic frequency analysis confirms the decrease in d-activity characteristic of arousal. Here again, the waking effect is transmitted from the donor to the recipient. These results agree with those of Purpura (1956) who observed in cats with enckphale is016 and crossed circulations that stimulation of the donor’s reticular system activates the recipient’s brain within 30-80 sec. In a recent series of experiments, we examined whether the hypnogenic factor of a sleeping donor is dialysable and whether this factor does or does not depend on unspecific metabolic conditions. For this purpose, we developed a method allowing cerebral venous blood from a cranial sinus to flow extracorporeally into a dialysing system (Koller et al., 1964) and back to the femoral vein. The cerebral venous blood is drained by a small metal canula, introduced into the sinus (confluens sinuum). The blood is then propelled by means of a roller pump through the dialysing system. As dialyser we used the artificial kidney of Kuhn et al. (1957). The small capacity of this dialyser (5 ml blood and 30 ml dialysing fluid) secures a relatively high concentration of the moderating factor in the 30 ml dialysing fluid. The blood is dialysed during 80 min in the rabbit kept asleep by electrical stimulation of the thalamus. The experiment ends with the injection of 20 ml dialysate into the ear vein of a normal rabbit, in order to test the action on behaviour and EEG. After intravenous injection of 20 ml dialysate, the following alterations occurred in the recipient (Fig. 3) : ( I ) Dialysate from a sleeping donor induces in the recipient a sleep of moderate intensity which does not differ in behaviour and EEG from physiological sleep. This sleep is reversible at once by tactile or acoustic stimulation, like normal sleep. The

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quantitative analysis confirms the increase of &activities starting 10 min after the injection, reaching a maximum after 25 min and lasting 40 min or more. This 6-increase is significant, compared with the values before the injection. On the contrary, dialysate from control donors (after sham-stimulation of the thalamus) slightly activates the behaviour and EEG. Therefore, if we compare the &activities of recipients after injection of sleeping donor's dialysate with those after injection of control donor's dialysate, we find a significant increase in the former. Our experiments support the concept that sleep can be transmitted humorally, since dialysate from sleeping donors induces corresponding alterations in the recipients. This dialysate seems to contain a hypnogenic substance. References p. I23

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MARCEL MONNIEK A N D L. HOSLI

Control experiments already allow us to state that the sleep effects observed are not due to unspecific factors, such as circulation, respiration, pH and electrolytes (Naf, K+, Ca‘f, inorganic phosphate). The fact that sleep may be transmitted humorally is in agreement with previous observations of PiCron (1912), confirmed by Schnedorf and Ivy (1939). However, the sleep mediated by our hypnogenic factor differs in its physiological character from the toxic sleep-like state induced by PiCron’s hypnotoxins. (2) Dialysate f r o m an alert donor, activated by stimulation of the midbrain reticular formation, induces in the recipient an alert behaviour, with numerous rhinodiencephalic symptoms such as restlessness, tendency to escape, licking of genital organs and coprophagy. These symptoms are similar to those elicited by electrical stimulation of the hippocampus and related hypothalamus (Monnier and Tissot, 1962). Electrographically, the &activity decreases in the cortex, indicating arousal and alertness. Statistically this activation of the recipient is significant in comparison with the values before the injection. The rhino-diencephalic activation is definitely greater than in control animals. These results agree with those of numerous investigators, who found that stimulation of the reticular system elicits activation effects which must be attributed to a humoral transmission. They entitle us to hope that it will be possible one day to replace the present psychotropic drugs by specific psychotropic substances similar to the substances produced by the body itself. SUMMARY

Dialysis of cerebral venous blood was performed on rabbits during sleep induced by electrical stimulation of the medio-central intralaminary thalamus, or during sustained wakefulness elicited by stimulation of the activating reticular system in the midbrain. From the whole dialysate (30 ml) obtained during 80 min from the stimulated donor animal, 20 ml were injected intravenously to normal free-moving animals (recipient). The latters’ behaviour was filmed and analyzed with a kinesimeter, and the electrical brain activity was continuously recorded. The results showed that injection of dialysate from a sleeping donor elicits in the recipient a moderate sleep, which does not differ in behaviour and EEG from normal sleep. The action of dialysate from sleeping donors is significantly different from that of control donors after sham-stimulation of the thalamus. Injection of dialysate from alert donors elicits a behavioural and electrographic arousal with numerous symptoms of rhinodiencephalic type (exploring, sniffing, licking, grooming). These sleep and arousal effects induced in the recipients by injection of dialysate from sleeping or alert donors suggest that dialysable humoral factors play a role i n the mediation of sleep and wakefulness.

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REFERENCES

HOSLI,L., and MONNIER, M., (1962); Schlaf- und Weckwirkungen des intralaminaren Thalamus. Pfriigers Arch. Res. Physiol., 275, 439-451. KOLLER, TH., MONNIER, M., and GAMP,R., (1964); Technik der Kaniilierung des Confluens sinuum beim Kaninchen fur Versuche mit partiellem extrakorporellem Kreislauf. Experientia, 20, 108-1 10. KORNMULLER, A. E., LUX,H. B., WINKEL,K., and KLEE,M., (1961); Neurohumoral ausgeloste Schlafzustande an Tieren mit gekreuztem Kreislauf unter der Kontrolle von EEG-Ableitungen. Naturwissenschaften, 48, 503-505. KUHN,W. L:, MAJER,H., HEUSSER, H., and ZENRUFFINEN, B., (1957); KiinstlicheNieremit KapilIarsystem fur den Stoffaustausch. Expeuientia, 13, 469471. MONNIER, M., KOLLER, TH.,and GRABER, S., (1963); Humoral influences of induced sleep and arousal upon electrical brain activity of animals with crossed circulation. Exp. Neurol., 8, 264-277. MONNIER, M., and TISSOT,R., (1962); Action de la stimulation systematique de l’hippocampe sur le comportement et sur l’activite Clectrique cerebrale du lapin. Physiologie de I’Hippocumpe. No. 107, Paris CNRS, 373490. PIBRON, H., (1912); Le P r o b l h e physiologique du Sommeil. Thesis. Paris, Masson. PURPURA, D. P., (1956); A neurohumoral mechanism of reticulo-cortical activation. Amer. J . Physiol., 186, 250-254. SCHNEDORF, J. G., and IVY, A. C., (1939); An examination of the hypnotoxin theory of sleep. Amer. J. Physiol., 125, 491-505.

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Sleep and Sleep Disturbances in the Electroencephalogram R. HESS, JR. EEG-Department, University Hospital, Zurich (Switzerland)

The insight into brain function afforded us by the conventional EEG is very limited. Qualitatively, because we are observing only electrical concomitants, and only those produced synchronously by larger groups of cells ; and quantitatively, since the activity tapped by scalp leads comes exclusively from the cerebral hemispheres. Nevertheless the EEG is important particularly for the understanding of sleep, since the electrical activity of the brain undergoes a series of quite characteristic changes in this state of physiologically reduced consciousness which can be recorded continuously, for hours if necessary, to produce a longitudinal tracing of the whole cycle, which is unequalled by any other method. What little is known so far of the bioelectrical activity of subcortical structures during sleep in man refers naturally not to the normal subject but only to certain pathological states. Somewhat more is known about the cat in particular. In this favourite experimental animal, cortical and subcortical tracings seem largely to resemble each other, apart from certain specific structures such as the reticular formation in the brain stem and the hippocampus. The semi-interdependence first noted by Spiegel (1936) is often observed, i.e. individual wave-forms and patterns occurring synchronously and almost identically in the subcortex and in certain cortical areas; yet the correlations are not necessarily always the same. The sleep patterns were assumed by many workers to arise first in the thalamus, and conclusions were drawn from this to the initiation of sleep. I doubt this as far as macropotentials are concerned. We should know more about many other subcortical areas before we can say ‘sleep waves’ really begin in a specific place. This would however not preclude primary sleep inducing impulses emanating from quite different structures, possibly in a form we cannot record. Single cell studies have shown that here the thalamus may have a special part to play. For macropotentials, at least the usual distinction between animal and human must be borne in mind. Even the difference in brain size must exert an influence for purely physical reasons as to which form of brain activity is best picked up. I believe that wave forms looking similar in different species do not necessarily have the same biological significance. This can be seen by comparing basic frequencies. Caveness’ (1962) Atlas of the EEG in the Macaca mulutta confirms that the waking EEG in this monkey at all stages of development can best be compared with that in a much younger human child. For the cat such similarities are still less obvious. The forms References p . 1381139

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looked upon as sleep spindles in man, for instance, are not always associated with sleep behaviour in the cat. Experience gained from animals will, however, continue to be decisive for understanding the sleep EEG in man. The basic mechanisms are certainly the same. This applies especially to the capital question of the relationship between macropotentials of the conventional EEG and the potential changes produced by single cells. I shall confine myself to the purely phenomenological description of the EEG in human sleep. The names of the investigators who discovered the principal features of the sleep EEG and later extended this knowledge are well known : Davis et al. (1938, 1939), Loomis et al. (1935, 1938), Blake and Gerard (1937), Liberson (1945), Brazier (1949), Kleitman (1961), Aserinsky and Kleitman (1955), Dement and Kleitman (1957) and others. The original division of sleep activity into stages A to E has survived through the years, and it is possible in most sleep tracings to distinguish them. This nomenclature is entirely suitable for rough orientation. Undoubtedly there are individual stages which cannot be fitted into any of these classical categories. Nor can the different stages be clearly distinguished from one another, because of the smooth transitions and the rapid changes between the different forms of sleep activity; one would have to agree on a minimal time a pattern has to be present before it can be called a sleep stage of its own. It is therefore quite possible and for many purposes useful to merge these stages and sometimes to further differentiate and supplement them. I consider, however, that official revision of these categories can safely be left until we know more of their correlation with the underlying biological processes. The individual graphic components can more easily be defined than the stages which they make up; it must be assumed that each of these elements is produced by a particular form of activity of a definite cell population and that this is in connection with functions characteristic of sleep. I regard my task here as the description of these patterns and the consideration of what is known or can be assumed regarding their significance. I shall do this more or less in the order in which the phenomena occur with the onset of sleep, not without emphasizing the many variations which may occur under physiological and pathological conditions and of which I can only refer to a few. This is true of the normal waking EEG, our starting point: there is as a main characteristic the well-developed a-rhythm in the postcentral and posterior temporal regions, the disappearance of which announces readiness for sleep. The correlations between consciousness and the presence of the a-rhythm has been beautifully demonstrated by Simon and Emmons (1956). There are people, however, whose waking EEG has little or no a-activity (though this is rarely the case in the relaxed state before sleep). It can be very difficult in these subjects to discern the precise moment of falling asleep from the EEG. This applies also to patients with a pathological EEG, in which the a-rhythm is replaced even in the waking state by slow waves. On the other hand it also happens in normal subjects that, before the basal rhythm disappears, groups of &waves appear, mostly in frontal but also in temporal or occipital leads, and generally speaking the younger the patient, the more frequent and extensive is this phenomenon.

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In young children, high-amplitude paroxysmal discharges are even recorded and, before Gibbs and Gibbs (1950) drew attention to this fact, were often misinterpreted as epileptic manifestations. Nevertheless, in the young adult falling asleep, the most common EEG changes are as follows: the a-rhythm ceases first for a few seconds, then for a little longer, the tracing at first being flat, but with more and more slow waves, mainly in the &range, in each succeeding episode. Often at the same time there is an increase of /3-activity, especially in bursts at the beginning of each of the ever shorter a-periods. This stage, corresponding to B,, is unstable and may at any time return to the waking pattern. When a-free periods have occurred repeatedly, lasting up to 10-20 sec, a new element appears in young subjects: paroxysmal high 0-waves, usually single at first or in pairs. They are symmetrical and show a marked voltage maximum in the vertex regions. This marks the beginning of the B2 stage. The individual transients often take the shape of blunt spikes, becoming sharper as the amplitude increases ; sometimes they can hardly be distinguished from epileptic ‘sharp waves’, especially in chldren. These transients often appear as the first sign of the B, stage and if they do so at times they are unilateral. As the other 0-paroxysms, they occur either pre- or postcentrally, showing steep gradients, mainly in the lateral direction, so they hardly show up in the temporal regions. These spectacular single waves may present themselves as response t o external stimuli (best known for acoustic ones). It has been shown by various

Fig. 1 . Paroxysmal vertex transients, first singly, then clustering together along with spindles, &waves and an increasing amount of slower components. All this activity shows much less in the temporal leads, in particular the sharp transients. References p . 1381139

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authors (Gastaut, 1953; Bancaud et al., 1953) that these waves, although with lower voltage, may in many subjects also appear in the waking state after sudden noises. It is difficult to interpret them as signs of an arousal reaction, however, when one sees how they often occur without external stimuli, form clusters and, together with other &bursts, apparently accompany transition to deeper sleep (Fig. 1). We shall return to this point later on. In the same B, stage, another wave pattern begins to appear, or to develop from the ordinary &rhythm, though in only a certain proportion of sleepers in distinct form. These are the positive spike-like waves described by Gibbs and Gibbs (1950) (Fig. 2). They have received little attention and because ofthe unfortunate name

Fig. 2. ‘Positive spike-like waves’ (Gibbs, 1950) in stage C of sleep. They show monophasic asymmetrical shape, main deflection positive, voltage maximum near the occipital poles. These patterns closely resemble 1.-waves which occur during pattern vision, and also single responses t o flashes. They are often seen in the light and medium sleep but rarely as high as shown here. ZK = time constant. F 70 = 70 cjs reduced to 70% of amplitude at the input.

were sometimes confused with the 6 and 14 CISpositive spikes, with which they have nothing in common. Their individual characteristic is quite distinct: origin near the occipital poles, saw-toothed form, main phase positive, usually bilateral but often with asymmetrical amplitude. Roth et al. (1956) have regarded these too as a response to external stimuli and attributed them to a particular light stage of sleep; both suggestions seem doubtful.

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Normally the next phenomenon is the appearance of the well-known spindles. They are often introduced by groups of low, irregular j3-waves and it has therefore been assumed that spindles are slowed j3-rhythms (yet common j3-waves still appear alongside the spindles). They are probably the most characteristic individual sleep pattern, although similar rhythms may, rarely, be found in young people when awake. Spindleshaped envelopes are infrequent; regular bursts of 0.5-1 sec duration, 13-15 CIS frequency, usually low voltage, arise at first in the vertex region, then in the frontal and postcentral areas, with marked medial predominance. This spatial distribution suggested a possible analogy with the waxing and waning potentials of the recruiting effects. The spindles sometimes associate with groups of paroxysmal 0-waves or 'vertex spikes', sometimes they appear in isolation. In the intervals the tracing is flat for a few seconds, so that intermittent activity results which corresponds to stage C, i.e. light sleep. This is when accompanying muscle potentials often disappear and the sleeper is less likely to return from this stage to the waking state. It sometimes happens that spindles occur at the same time as the paroxysmal 8waves or instead of them, since the latter are less evident in older subjects or even completely lacking. Here stage C develops almost imperceptibly from the flat tracing of stage B1. If sleep is not interfered with, another change takes place simultaneously: an in-

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N Fig. 3. Two K-complexes induced by a sudden noise (N).They consist of 3 slow waves each with but few superimposed faster components. No arousal ensues. References p . 1381139

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creasing amount of slower waves mix with the 8-bursts. These single waves finally form transients which differ markedly from the 8-paroxysms in localization and spread. Their maximum amplitude tends to be frontal, but less clearly defined, their gradient is less steep. There is close resemblance to the K complex which can be elicited by acoustic and other external stimuli and which may be followed by a lighter stage of sleep or by wakefulness (described by Davis et al. as early as 1938) (Fig. 3). They often stand out as particularly high negative potential changes and can sometimes be recorded simultaneously in the temporal regions with positive polarity, thus implying their origin deep in the mesial structures of the brain. A regular component, accordiig t o the literature, but not always spectacular in my own view, are runs of fast waves, of spindle or a-frequency, superimposed on the slow waves. The same complexes can also appear spontaneously. When induced they do not follow indiscriminately any stimulus, but only those which may be of significance; they can be conditioned, subject to habituation, and may be followed by a refractory phase (Schwab et al., 1954; Sharpless and Jasper, 1956; Roth et al., 1956; Pampiglione and Ackner, 1958; Oswald et al., 1960). Important findings have just been reported by Vetter and Boker (1962) : they obtained a significantly higher number of responses to a standard sound when given during a spontaneous or induced K complex than during the interval. They also observed that responsiveness was higher during the superimposed fast activity than during the usually preceding slow components. We have already mentioned that the sharp vertex waves of stage B, as well as the K complex can be induced by external stimuli. Many authors do not distinguish' between the two types of transients, although in their typical forms they are quite different in shape, localization and spread. Gastaut (1953) holds that they are basically the same phenomenon which varies according to depth of sleep, i.e. in light sleep appearing as single vertex spikes and in later stages combined with slower components of the K complex, finally merging into the latter. This may well be true, with the qualification that both forms of response may be seen alternately (Fig. 4). A further resemblance appears with increasing depth of sleep : single &complexes become increasingly frequent, form into groups and trains which get gradually longer until they fuse to continuous &activity. The question arises why wave forms which may accompany an arousal reaction on the other hand become more prominent as depth of sleep increases. Walter (1953) has suggested a tentative answer: the K complex has the function of screening the brain from external stimuli. From all we know today, the explanation should be qualified : the K complex accompanies a process which protects the brain from an unnecessary arousal reaction when the stimulus has been recognized to be without significance. The vertex spike might have the function of an initiator. But how is the higher responsiveness during this inhibitory process to be explained? In so far as this mainly holds for the phase of superimposed fast activity, it seems reasonable to suppose that the latter stands for the opposite, i.e. the arousal tendency, and that the depth of the subsequent sleep stage depends on which of the components prevails : occasionally it may be deeper. We do in fact find that a K complex may be followed by diffuse activity mainly of the a-frequency band, often combined with slower and faster

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Fig. 4. Comparison of ‘vertex spikes’ (left) with K complex (right) to demonstrate more rostra1 voltage maximum and wider spread of the latter. Both do not show up essentially in temporal leads. A small ‘vertex spike’ seems to precede immediately the first slow wave of the K complex. Referential electrode on the nose.

rhythms. I am not sure whether this corresponds to the ‘diffuse a-phase’ of Fischgold et al. (1959); it is certainly a quite specific pattern. Whenever this activity persists for several seconds, it generally gives way to a waking EEG which may be of short duration only (Fig. 5). These arousal reactions are usually accompanied by muscle potentials. In children we find a particularly dramatic response to arousal stimuli : prolonged trains of high, rhythmical S-waves may last for up to 30 sec, after which the waking pattern finally appears (especially when there were some superimposed faster rhythms, according to Kellaway and Fox (1952). Such interruptions may be frequent in a sleep tracing, usually followed by return of sleep, more quickly and with less fluctuation than when it first set in, and typical vertex spikes are sparse. Typically the a-rhythm is soon interspersed with &waves and apparent K complexes occur first singly then in groups and lead over to more or less continuous &activity. This, together with spindles, the incidence of which varies considerably from one individual to another, characterizes what is known as stage D. When this has been reached, sleep usually lasts longer and any arousal phase tends to be incomplete and transitory. In this moderate depth of sleep, the 8-waves at first are predominantly median in localization, with maxima between frontal and central areas and little spread to the temporal leads. Numerous 0-waves are superimposed everyReferences p. 1381139

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Fig. 5. K complex arising in stage D of sleep without any known exterior stimulus. The slow component comprises two negative deviations with maximum amplitude in parasagittal frontal areas. Immediately prior to the higher first wave a small sharp transient occurs which might be interpreted as vertex spike merging into the complex. On the second half of the slow components, activity out of the higher a-band is superimposed and goes on together with slower and faster rhythms for several seconds, until muscle potentials indicate partial arousal.

where and in the occipital regions monophasic Mike potentials are frequent. The spindles spread over most of the convexity and in the frontal regions they slow towards 12 c/s. A frequent and sometimes persistent sleep phase cannot be fitted easily into the

Fig. 6. Alternating stage D of sleep, characterized by waxing and waning of slow waves, some of which could be interpreted as spontaneous K complexes: steep rise of amplitude, parasagittal frontal maximum, superimposed faster activity. Increased slow waves may coincide with behavioural signs of decreased depth of sleep.

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present categories : sequences of comparatively low-voltage 0- and &waves alternate every few seconds with trains of high 8-waves and superimposed spindles (Fig. 6). Under the circumstances required for EEG recording, most subjects do not progress beyond the middle stages of sleep; children in particular may reach deeper levels. This is manifested by a receding of &activity, further slowing of frontal spindles to 10-12 c/s and generalization of 8-waves, gaining high amplitude also in the temporal areas, independent on the two sides. In the parasagittal regions on the other hand, with maximum frontal to central, groups of bilateral synchronous 1 c/s rhythms predominate. The spindles become lower and sparse which marks deep sleep, stage E. The paradoxical phase of sleep discovered by Kleitman (1961) and collaborators (Aserinsky and Kleitman, 1955; Dement and Kleitman, 1957) can always be observed when recording is carried on long enough. It seems obvious that this is what was reported by Blake and Gerard (1937), called by them 'null stage' and interpreted as deep sleep. The latter point is controversial. Jung (1963) assumes that, while bodily

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sleep is particularly deep in this stage, consciousness is little diminished despite the high arousal threshold. In keeping with this view is the EEG since it does not correspond to a really vigilant state but rather to a sort of half-sleep in which discontinuous a-activity is mixed with low-voltage slow waves, as often seen in the short intermediary stages following brief arousal (Fig. 7). I also believe that what Gibbs (1950) describes as ‘early morning sleep’ is the same pattern. We have already mentioned that some of the most striking sleep patterns are most conspicuous in young subjects and become less distinct with advancing age. In old women Vetter and Boker (1964) found rather undifferentiated sleep tracings. On the other hand, sleeping and waking states can scarcely be distinguished in early infancy, as slow waves are dominant in both, the patterns typical for sleep developing only in the course of the first few months. So much for the EEG in normal sleep. We now turn to the disturbances of sleep. As for the insomnia so frequent in neurotic patients, we confine ourselves to pointing out that in people who claim not to have slept all night, typical sleep patterns are regularly observed. Neurotics also readily present signs of light sleep in the EEG when behaviourally awake. But this is not abnormal in itself as most of our younger subjects reach stage B at least during EEG examination if left undisturbed for a while. The same is much more pronounced in states of excessive fatigue. It is well known that soldiers after prolonged sleep deprivation can sleep on the march. This is a partial sleep, affecting only the higher cerebral functions, as must be assumed also for true somnambulism, which of course has nothing to do with epilepsy. It is, however, related to narcolepsy, a dysregulation of the sleepwaking mechanism in which trophotropic tendencies predominate and the normally coordinated functions of sleep fall apart. Thus the narcoleptic’s brain may be asleep while he is walking, working, etc. Such patients in the usual resting state will show a normal waking pattern which is frequently interrupted by sleep activity. The latter is indistinguishable from normal sleep, except that it comes on with excessive readiness, reaches deep levels faster than usual, often immediately after the subject has been awakened and even occurs during activationprocedures, such as hyperventilation or photic stimulation. But exactly the same can be observed in healthy persons in states of overfatigue. In the cataplectic attack the EEG is equally normal, as has been found repeatedly by other workers and ourselves. Generally a waking rhythm is seen with greatly reduced aactivity, simultaneous muscle potentials and movement artefacts betraying the effort to overcome the condition. Some observers have reported sleep potentials in the atonic state. In our own view they probably represent secondary sleep similar to that under curarization. During sleep paralysis EEG recording is seldom possible. Daly and Yoss (1957) obtained a normal waking record in such a case, interspersed with some sleep activity. The plausible suggestion put forward by Jung (1963) is that the condition corresponds to a form of paradoxical sleep in which bodily and cerebral sleep dissociate, in the opposite way from somnambulism. In symptomatic narcolepsy, pathological EEG signs do exist, but they reflect the abnormalities associated with the underlying disease. Another less clearly understood disturbance of the sleepwaking rhythm is found

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in the Kleine-Levin syndrome. During the hypersomnia which persists for days at a time only normal sleep tracings are seen. Nothing further is known about this strange condition. Cases of Von Economo’s encephalitis, in which sleep regulation is massively disrupted, have not to my knowledge been investigated with the EEG as scarcely any have been seen since the introduction of the method. It may be presumed that the findings would vary according to the extent of the process, as is the case with other cerebral lesions. Disturbances of consciousness of organic origin give rise to a variety of EEG findings. In rare cases, the tracing is normal even in profound coma, probably when the lesion is in the caudal part of the waking centre (Loeb et al., 1959) and the cerebrum itself is intact. More frequently a rather normal sleep tracing is obtained, again with circumscribed lesions, presumably situated in more rostra1 parts of the brain stem. The greater the involvement of the cerebral hemispheres in the pathological process, the more the sleep potentials are superseded by undifferentiated slow waves. In most severe conditions slow activity is continuous and cannot be interrupted by any stimuli. If such interruption is possible, therefore, this is a favourable sign. Often an alternation between high &waves and flatter periods can be seen, the latter corresponding to deeper unconsciousness, since the high amplitudes reappear on stimulation. Similar alternation is found in the Cheyne-Stokes type of respiration, when flattening is seen during respiratory arrest, high amplitudes during breathing. When the cortex is completely incapable of functioning, e.g. after CO poisoning or cardiac arrest, the EEG is silent. The last disturbance of consciousness to be mentioned is general anesthesia. Depending on the agent and especially the stage of anesthesia, the EEG is dominated first by fast activity, later by slow waves and presents at most a superficial resemblance to the sleep tracing. The fast rhythms proxinent in barbiturate anesthesia or intoxication are not exclusive to this group of drugs. The barbiturate spindles well known particularly to the neurophysiologist should not be confused with the spindles of normal sleep. It is clear that all such drugs affect not only the subcortical centres regulating the sleep-waking cycle, but also have direct influence on the neurons of the cerebral cortex, and it is the activity of these which is mainly recorded. In this respect, the information supplied by the EEG in conditions involving the whole of the brain is more than limited. Yet it affords clear indications of the basic differences between such unnatural modifications of the conscious state and physiological sleep. In experimental research above all we cannot pay too much attention to this distinction. SUMMARY

The EEG offers a limited but continuous insight into one aspect of brain function and during sleep it shows characteristic changes. The classical stages are mentioned, the most important sleep patterns described. The vertex spike and the slow component of the K complex are supposed to accompany a process inhibiting arousal, while the latter tendency itself may be represented by the superimposed faster activity. After References p. 1381139

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interruption of sleep it usually returns faster and more directly to deeper stages than at the beginning. In the youngest and oldest age group there are important deviations from the usual sleep patterns. Apart from insomnia which in a strict sense does not exist, sleep disturbances are mainly found in narcolepsy, where the EEG shows normal waking and sleep records. Organic brain disease with loss of consciousness is compatible with a normal EEG and also with sleep patterns, but they are distorted by abnormal slow waves in proportion to the involvement of the hemispheres by the pathological process. General anesthesia is at the most a sleeplike condition but the very EEG record demonstrates the fundamental difference compared with physiological sleep. REFERENCES N., (1955); Two types of ocular motility occurring in sleep. J. appl. ASERINSKY, E., and KLEITMAN, Physiol., 8, 1-10. BANCAUD, J., BLOCH,V., and PAILLARD, J., (1953); Contribution EEG I l'etude des potentiels kvoques chez l'homme au niveau du vertex. Rev. neurol., 89, 399418. H., and GERARD, R. W., (1937); Brain potentials during sleep. Amer. J . Physiol., 119,632-703. BLAKE, BLAKE,H., GERARD, R. W., and KLEITMAN, N., (1939); Factors influencing brain potentials during sleep. J . Neurophysiol., 2, 48-60. BRAZIER, M. A. B., (1949); The electrical fields at the surface of the head during sleep. Electroenceph. clin. Neurophysiol., 1, 195-204. CAVENESS, W. F., (1962); Atlas of Electroencephalography in the developing Monkey, Macaca mulatta. Addison-Wesley, Reading, Mass. ; Palo Alto; London. DALY,D. D., and Yoss, R. E., (1957); Electroencephalography in Narcolepsy. Electroenceph. clin.. Neurophysiol., 9, 109-120. DAVIS,H.,D~vrs,P. A.,LooMIs,A. L., HARVEY, E. N.,and HOBART, G. A., (1938); Changes in human brain potentials during the onset of sleep. J. Neurophysiol., 1, 24-38. DAVIS,H., DAVIS, P. A., LOOMIS, A. L., HARVEY, E. N., and HOBART, G. A., (1939); Analysis of the electrical response of the human brain to auditory stimulation during sleep. Amer. J. Physiol., 126, 474475. DEMENT, W. C., and KLEITMAN, N., (1957); Cyclic variations in EEG during sleep and their relation to eye movements, body motility and dreaming. Electroenceph. elin. Neurophysiol., 9, 673-690. FISCHGOLD, B. A.. and DREYFUS-BRISAC. Indicateur de l'etat de presence et . H.,. SCHWARTZ, . C.,. (1959): . tracks Blectroencephalographiquesdans le sommeil nembutalique. Electroenceph. clin. Neurophysid., 11,23-33. GASTAUT, Y., (1953) ;Les pointes negatives CvoquCes sur le vertex. Leur signification psychophysiologique et pathologique. Rev. neurol., 89, 382-399. GIBBS,F. A., and GIBBS,E. L., (1950); Atlas of Electroencephalography. 2nd Ed. Addison-Wesley Press, Cambridge, (Mass.). JUNG,R., (1963) ; Der Schlaf. PhysioIogie und Physiopathologie des vegetativen Nervensystems. Band 11. Stuttgart, Hippokrates Verlag (p. 650-684). KELLAWAY, P., and Fox, B. J., (1952); Electroencephalographic diagnosis of cerebral pathology in infants during sleep. I. Rationale, technique, and the characteristics of normal sleep in infants. J . Pediat., 41, 262-287. KLEITMAN, N., (1961); The nature of dreaming. The Nature of Sleep. G. E. W. Wolstenholme and M. O'Connor, Editors. Churchill, London (p. 349-364). LIBERSON, W. T., (1945); Functional electroencephalography in mental disorders. Dis.nerv. Syst., 5, 1-8. LOEB,C., ROSADINI, G., and POGGIO,G. F., (1959); Electroencephalograms during Coma. Neurology, 9, 610-618. LOOMIS,A. L., HARVEY, E. N., and HOBART, G. A., (1935); Potential rhythms of the cerebral cortex during sleep. Science, 81, 597-598. LOOMIS, A. L., HARVEY, E. N., and HOBART, G. A., (1938); Distribution of disturbance-patterns in the human EEG with special reference to sleep. J. Neurophysiol., 1, 413430.

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OSWALD, I., TAYLOR, A. M., and TREISMAN, M., (1960); Discriminative responses to stimulation during human sleep. Brain, 83, 440-453. PAMPIGLIONE, G., and ACKNER, B., (1958); The effects of repeated stimuli upon EEG and vasomotor activity during sleep in man. Brain, 81, 64-74. ROTH,M., SHAW,J., and GREEN,J., (1956); The form, voltage distribution and physiological significance of the K complex. Electroenceph. clin. Neurophysiol., 8, 385402. SCHWAB, R.S., PASSOUANT, P., and CADILHAC, J., (1954); Action des stimulations auditives rhythmkes sur le sommeil humain. Montpellier me& 44, 501-514. SHARPLESS, S., and JASPER, H. H., (1956); Habituation of the arousal reaction. Bruin, 79, 655-689. SIMON,C. W., and EMMONS, W. H., (1956); EEG, consciousness and sleep. Science, 124, 1066-1069. SPIEGEL, E. A., (1936); The electrothalamogram. Proc. Soc. exp. Biol. ( N . Y . ) , 33, 574-576. VETTER,K., and BOKER,W., (1962); Zur Funktion des K-Kornplexes im Schlaf-Elektroencephalogramm. Nervenarzt, 9, 390-394. VETTER, K., and BOKER,W., (1964); Die Analyse von Einschlaf- und Schlaf-Elektrencephalograrnmen. Psychiat. et Neurol., 147, 3 0 4 3 . WALTER, W. G., (1953); The living Brain. G . Duckworth, London.

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Neuropliysiological Studies of Abnormal Night Sleep and the Pickwickian Syndrome RICHARD JUNG

AND

WOLFGANG K U H L O

Department of Clinical Neurophysioiogy, University of Freiburg, Freiburg (Germany)

Studies of nocturnal sleep by continuous recording methods have yielded valuable information regarding the physiology and the pathology of sleep. Night sleep recordings were made in normal persons by Fischgold and Schwartz (1961) and in abnormal sleep syndromes by Schwartz et al. (1963), Oswald et al. (1963) and Rechtschaffen et al. (1963). The purpose of this report is to review these investigations and to present the findings in a syndrome of periodic somnolence which is of special interest for both physiologists and clinicians. The Pickwickian syndrome has been mentioned only recently in medical literature (Auchincloss et al., 1955; Burwell et al., 1956; Doll and Steim, 1963; Drachman and Gumnit, 1962; Gerardy et a/., 1960; Gotzsche and Petersen, 1958; Hackney et al., 1959; Kretschy and Muhar, 1964; Meyer et al., 1961; Sanen, 1958) although long known to the novelist: more than 100 years ago Charles Dickens gave a lively description of a ‘fat boy’ and his frequent naps in the Pickwick Papers (1836). Most studies of this syndrome have been made by internists who concentrated their investigations on cardiovascular findings and on changes in CO, and 0, during hypoventilation. Simultaneous changes of EEG and respiration were noted in passing (Drachman and Gumnit, 1962; Gerardy et al., 1960). This syndrome, as other abnormal phenomena, may be regarded as a caricature of normal neuronal coordination. Thus it may give us some hints for the investigation of mechanisms of sleep and respiration in the brain stem of man. Until now no continuous recordings of night sleep were reported in Pickwickian patients. This we have done now in three typical cases and the results will be described in context of a review of nocturnal sleep investigations in other sleep disturbances.

INVESTIGATlON OF NOCTURNAL SLEEP IN CLINICAL SLEEP DISTURBANCES

I . Insomnia Among the various clinical syndromes of sleep disturbances the following two have been investigated thoroughly by others with recordings of nocturnal sleep : (1) neurasthenic sleep disorder (Schwartz et al., 1963), (2) depressive sleep disturbance in melancholia (Oswald er al., 1963). An essential difference has been found between these two kinds of insomnia employing EEG recordings although it may be difficult t o

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distinguish them by the subjective complaints of the patients alone. Both groups tell the doctor that they are ‘sleepless’.

( 1 ) Neurasthenic insomnia The most common sleep disturbance found in medical practice is the emotionally charged neurasthenic insomnia. The patients usually describe their complaints with some exaggeration: they were ‘completely sleepless’ or ‘did not sleep a wink‘, ‘could not close their eyes the whole night’, ‘heard every stroke of the clock’, and ‘slept only a few minutes in the morning if at all’. EEG records of night sleep in these ‘sleepless’ patients by Schwartz et al. (1963) have shown that the objective nature of this sleep disturbance is remarkably different from the subjective complaints of sleeplessness: these patients had very similar EEG patterns of sleep to normal subjects of the same age group. The short periods of waking EEG records which all normal persons show at night without recollection are somewhat longer and more frequent in the neurasthenics. But in between these waking periods the patients reach the same deep sleep stages D and E as normal persons. It seems likely that the somewhat prolonged periods of waking are exaggerated by two factors : relatively low arousal threshold, and emotional charge. The same mechanisms are probably operathe in normal people with cccasional sleep disturbance during emctional stress. The thresholds for waking stimuli may be somewhat lower in the neurasthenic group although this has not yet been studied specifically.One may only assume lower thresholds from such reports as that of ‘hearing the clock at intervals’. Probably the patients actually wake up briefly on the occurrence of these stimuli to perceive them. They differ from normal people who do not pay attention to the striking of a clock whereas the neurasthenic counts the strokes and worries over his failure to sleep. Thus the waking periods are perceived and the sleep periods remain unnoticed. Similar observations have been made after sleep deprivation and fatigue. If we consider that night recordings from sleepless people were done in the rather unusual milieu of the laboratory and yet the patients reached the D and E stages, and slept in total nearly as long as normals, one may be certain that their sleep deficit cannot be so marked as the patients report. One may conclude that neurasthenic sleep disturbances are mainly due to overemphasis of short periods of wakefulness which normal people overlook. This has some practical importance for therapy: it seems unnecessary to prescribe sleeping drugs to these patients as they get a sufficient amount of sleep during the night, although they do not know it. I t may be better to assure them that no serious sleep deficit exists, and that the normal periodic interruptions of night sleep are only more marked and overevaluated by their anxiety. Psychotherapy with reduction of their anxiety may be more effective in these patients than pharmacotherapy by hypnotic drugs. (2) Depressive insomniu

Disturbance of sleep is the most common and constant complaint in endogenous References p. 1581159

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depression. Other somatic symptoms such as constipation and loss of appetite, or the various psychic disturbances such as depressed mood, anxiety, lack of drive, ideas of self-reproach or hypochondria are more variable. Therefore insomnia may be regarded as the main symptom (Achsensymptom) of depressive psychosis or melancholia. This has been well known to clinicians for more than hundred years, but an objective recording of nocturnal sleep in depressives was lacking until recently. Oswald et al. (1963) published the first study of continuous nocturnal recording of EEG, eye movements and body movements in depressives. These were compared with normal controls. Brief reports of similar investigations have also been given by Van Rey and Wissfeld (1964). Nocturnal sleep recordings in depressives showed significantly longer waking periods during the night. These periods of wakefulness with a-rhythm in the EEG occurred at irregular intervals and had no relation to the dream periods of paradoxical sleep with rapid eye movements. The duration of the waking periods was very prolonged, up to 43 h, whereas in normals continuous periods of wakefulness were not observed for longer than 3 h. The percentage time of paradoxical sleep in patients with depression did not differ significantly from the controls. But Oswald et al. (1963) found a decrease of stage C and an increase of stage B sleep in depressive patients. The percentage time spent in stage E sleep also was significantly greater in depressive patients. This was explained by sleep deprivation during the long periods of wakefulness, similar to the larger percentage of stage E sleep following sleep deprivation in normals. Van Rey and Wissfeld (1964) used Tonnies’ EEG Intervalanalyser for sleep EEG investigations in depressives. They also found longer periods of wakefulness, up to 3 11, alternating with normal deep sleep in some depressives. More often they found another type with alternation of brief periods of wakelfulness with lighter sleep stages. Barbiturates have been reported by Oswald et al. (1963) to decrease the duration of paradoxical sleep and the frequency of eye movements within these periods, and to shorten the time awake especially in the early morning.

II. Hypersomnia ( I ) Narcolepsy The EEGin narcolepsy was already mentioned by Hess (p. 136) and clinical features have been discussed by Heyck and Hess (1954), Roth (1962) and Jung (1963). Diurnal recording with closed eyes in many cases of narcolepsy shows abortive sleep phases with flattening but usually no a-slowing. This abortive sleep scarcely differs in the EEG from the transitory dozing of a fatigued normal subject, though the brief B stages are often prolonged in narcolepsy. Unlike the Pickwickian syndrome, there are no prolonged apneic phases in the abortive sleep of the narcoleptic. According to Roth (1962), patients in this prolonged B stage sometimes appear to be still awake; sometimes the episode is a brief dreaming phase, sometimes a short spell of narcolepsy. If the EEG is recorded with the patient lying down, it is impossible to distinguish between a waking cataplectic attack and a brief sleep attack in the EEG. In the seated

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patient, cataplexy may leave the EEG unchanged (Hess, 1949). In narcoleptic episodes, stage E of deep sleep is seldom attained. Night sleep of the narcoleptic differs from normal night sleep. Recent studies by Rechtschaffen et al. (1963) using continuous recording of night sleep EEG and eye movements in narcolepsy revealed early dream stages with rapid eye movements in place of the normal stage B sleep, fewer slow &waves and more frequent a-waves over the frontal half of the cranium and greater motor restlessness. These authors found all criteria of paradoxical sleep (REM phase) in 7 out of 9 narcoleptics immediately after they went to sleep, while in normal subjects and other patients they only occurred after 1-3 h. This early dream phase agrees with the clinical experience that narcoleptics often complain of sleep disturbances in the first part of the night, with visual hallucinations and dream-like states. In narcolepsy, there is thus a typical disturbance of sleep periodicity. Such a disordered periodicity of the night sleep in narcolepsy can also be assumed on the basis of clinical experience. Subjective and clinical observations reveal a wide range of dissociation in the different functions of sleep. This has been discussed by Roth (1962) but has not previously been sufficiently investigated by means of the EEG and recording of respiration. Respiratory studies during sleep by Biilop, and Ingvar (1961, 1963) in both normal and narcoleptics show that similar apneic intervals occur. The neurophysiological equivalent of the cataplectic ‘waking spells’ (Wachanfalle), also called ‘sleep paralysis with hallucinations’ (Schlaflahmung), has been insufficientlystudied. It is not yet certain whether it occurs in early or subsequent dream phases or in other stages of sleep. Cataplectic episodes occurring during the day (affektiver Tonusverlust) have also rarely been investigated by means of the EEG (Hess, 1949; Roth, 1962). They have been regarded as disinhibition of the lower reticular system. Since the bulbopontine reticular formation also controls eye movements and muscle tonus, both cataplexy and the dream stage of sleep seem to be caused principally by deeper brain-stem mechanisms, which may function independently of higher diencephalic sleep regulation. In narcolepsy with cataplexy the dissociation between lower and higher reticular centres appears to be more marked. The relative predominance of one or the other system may determine the symptoms : when the diencephalic sleep mechanisms predominate, narcoleptic attacks are the most frequent and important symptom, and where the pontine reticular formation is disinhibited, the less common cataplectic states arise. This dissociation of sleep mechanisms and the rarity and short duration of apneic intervals distinguish true narcolepsy from the Pickwickian syndrome.

( 2 ) The Pickwickian syridrome This syndrome consists of frequent short episodes of spontaneocs sleep with apnea, alveolar hypoventilation with hypercapnia, and obesity. Our recordings of nocturnal sleep show that apneic pauses lasting up to 40 sec and followed by periodic deep snoring respirations also occur during the night, related to certain stages (B, C) of sleep. These patients with their severe respiratory disturbances consisting of apneic References p . 158/159

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pauses and severe cyanosis are clearly differentiated from narcoleptics. Also in contradistinction to narcoleptics these patients do not report hypnagogic hallucinations and have no cataplexy. METHODS

The EEG was recorded continuously on eight channels using a Schwarzer machine, or an Elema ink-writing recorder. Respiration was studied by (a) recording of chest movements by means of an inflatable belt, the pressure changes being transferred photoelectrically to the polygraphic tracer; (b) continuous determination and recording of the CO, content of expired air by infrared absorption (see Fig. 5a). The CO, tracing obtained from continuous breathing does not correspond exactly to alveolar CO,, but it is subject to the same changes, and this gives sufficient indication of increases or decreases in the alveolar CO, concentration. Parallels between continuous recording of CO, in expired air and alveolar and arterial pC0, have been studied and established by Biilow (1963). We shall refer therefore simply to ‘alveolar pC0; although only ordinary expired air was measured. RESULTS

Case reports: Case 1 (M. Oe.) 46 years, 110 kg, 1.82 m. The patient had been obese since adolescence. There was a n increase in weight and spontaneous sleep during the day since 1961. Neurological findings and skull X-rays were negative. Diurnal EEG: early onset of slowing and flattening of the a-rhythm and occurrence of sleep spindles concomitant with sleep episodes which lasted up t o 20 sec (Fig. 1). During this time apnea, cyanosis and myoclonic jerks occurred. No focal finding. X-ray showed moderate elevation of diaphragm. Blood gases were normal. No polycythemia. Follow-up study after half a year: weight loss of 10 kg. Clear subjective improvement. Diurnal EEG: repeated sleep episodes with apnea. During stage B nocturnal sleep, shallow respiration and short apneic pauses (Fig. 2a). With slow waves and spindles, apneic episodes lasted longer with an average of 28 sec (Fig. 2b). Case 2 (Kl. BI.) 26 years, 88 kg, 1.67 m. Since the age of 20, episodes of sleep which also occurred while standing and walking during the day, and at night work. He fell against bystanders in these episodes. No cataplectic attacks. Since this time progressive dyspnea. Clinical findings: R.B.C. 6 500 000; Hb. 130%. Pneumoencephalography: dilatation of the left lateral ventricle and temporal horn. EEG: focal dysrhythmia in the left temporal region. The diurnal EEG shows flattening and spindles concomitant with apnea, which occurs periodically. During the sleep periods lasting 9-1 5 sec there is either complete apnea or small frequent ineffective respiratory movements, with cyanosis and myoclonic jerks. Follow-up study two years later: weight loss of 10 kg. Clear subjective improvement. In diurnal EEG repeated sleep episodes with apnea (Figs. 3 and 5), voluntary apnea without sleep is shown in Fig. 4. There were also apneic pauses with abortive respiratory movements during the night similar to those illustrated in Figs. 5 and 6. Case 3 (A. Gr.) 45 years, 101 kg. Until 1952 the patient was quite thin. In 1947 already, according to his wife, he had periodic snoring with apnea in sleep. Since 1958 marked increase in weight; since 1961 sleep episodes during the day. Clinical findings: K.B.C. 5 800 000; Hb. 118%. Neurological findings and pneumoencephalography were normal. EEG of a-type. Diurnal EEG’s showed periodic sleep phenomena including the appearance of spindles, associated with apnea and cyanosis. No focal findings. Follow-up study after 34 years: weight 83 kg. Clear subjective improvement. No further spontaneous sleep during the day. Diurnal EEG was normal, without sleep phenomena. Nocturnal recording showed a less periodic respiration with rare short apnea.

References P. 1581159

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In the superficial stages of sleep (B) at the beginning of the night, apneic intervals of 5-15 sec appear. They are usually preceded by 1-3 shallow, slow respirations. aRhythm becomes 1-3 c/s slower, synchronously with the shallow breathing, the waves become smaller and the tracing flatter. These apneic phases in stage B resemble falling asleep in the daytime. These patients normally reach stage C within a few minutes and remain there most of the night. Respiration in stage C is always periodic, with apneic intervals much longer than in stage B or during the daytime (20-40 sec, average 28 sec). During these pauses, there is increasing cyanosis, due to insufficient CO, elimination, and bradycardia (45-55/min). In addition, some myoclonic jerks appear in the limbs. During the apneic intervals, very frequent abortive inspirations (about 5&60/min) occur (Figs. 5 and 6), tongue and pharynx remaining completely atonic and blocking the airway. Even when the jaw and base of the tongue are raised manually (this can be done without waking the Pickwickian), breathing remains periodic. This apnea or abortive breathing is interrupted at intervals of about 2 W O sec by 1-3 deep, usually snoring, irregular respirations. These may be accompanied by pronounced motor restlessness, the patient may wake up and free the pharyngeal block. There is no further snoring then, but breathing rapidly becomes shallower and apnea returns. Before and during active respiration with EEG arousal, the heart rate increases to up to 100/min (Fig. 2b). The EEG in nocturnal sleep also shows periodic changes in the pattern, synchronous with the periodicity of respiration. During apnea and abortive breathing, sleep spinand &waves predominate. Finally higher &waves and sharp waves appear. dles, €'With the first deep inspiration, there is an arousal reaction with desynchronization and a return of a-waves, mostly somewhat slower than the basal waking arhythm; occasionally, however, there may be a-activity of a normal frequency. The sharp waves and the subsequent arousal are evidently the manifestations of an emergency reaction to the increasing hypoxia (Fig. 2b). Stage D sleep of any appreciable duration was observed only once in a single patient who had lost 15 kg. He still snored slightly, and his respiration was shallow but regular (about 18/min). No stage E sleep was recorded, not even transitorily. In two patients who lost weight, prolonged 'paradoxical' dream phases, with rapid eye movements, appeared. Weight loss of 10-20 kg in all three cases led t o a marked subjective improvement. The tendency to fall asleep during the day was much less, but the nocturnal respiration remained periodic and apneic pauses occurred. In only one case the completely apneic phases were replaced by shallow, slow breathing alternating with deep, snoring inspirations. Lobeline and micoren activated respiration for 2-3 min. Simultaneous recording of CO, in the expired air, the EEG and the mechanical respiratory movements reveal a markedly increased CO, level also before the apneic intervals (Fig. 5). The further rise in CO, during the apnea is not evident from the graph, since in the absence of expired air the CO, cannot be measured. It only becomes visible with the first deep respiration afterwards.

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Fig. 5. Apneic periods and sleep phases with CO, recording and EEG (case 2). (a) Continuous recording of C 0 8 of the expired nasal air. Multiple apneic episodes with rapid shallow abortive respiratory movements (6Ojmin). (b) EEG and mechanical trace of respiration simultaneous with recording of CO, content in the expired nasal air in the second row of (a). This relationship clearly shows the influence of the depth of respiratory excursions on the COBcontent. For example the first 3 deep respirations in the lower record of (b) are associated with the reduction of the CO, to normal values. The succeeding shallow respirations with flattening of the EEG (light sleep) are followed by an increase in the level of CO, content. This cycle is repeated in the next period of the recording. In (a), row 6, high CO, values occur after voluntary apnea but without sleep.

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Fig. 6. Schematic representation of EEG, respiratory activity and heart rate during a typical apneic episode in nocturnal sleep of Pickwickian patients. The apnea occurs during the C-phase of sleep with the following sequence: A brief awakening pattern with a-rhythms and snoring is followed by a respiratorypause, bradycardiaand slower EEG with spindles. The average duration of apnea is 28 sec. It is terminated by an increase in heart rate, a deep breath with a snore and a-activation. DISCUSSION

The various forms of insomnia and narcolepsy have been discussed in detail by Schwartz et al. (1963), Oswald el a/. (I963), and Rechtschaffen et al. (1963) in connection with their investigations of nocturnal sleep. We shall therefore restrict our discussion t o the Pickwickian syndrome. In early reviews of narcolepsy, it was noticed that some patients were remarkably obese and cyanotic. Wilder (1935) in his handbook article had already pointed out the resemblance of this type to the fat boy, Joe, in Dickens' 'Pickwick Papers'. Detailed' studies were lacking, however, until Auchincloss et al. (1955) and Burwell et al. (1956) described the syndrome more fully from the point of view of the internist. In recent years, numerous papers have appeared, concerning chiefly circulatory studies and with measurements of pC0, and pOz in this condition (Doll and Steim, 1963; Gotzsche and Petersen, 1958; Hackney et a/., 1959; Sanen, 1958; Scherrer, 1961). Correlation of the EEG with circulatory function was investigated especially by Gerardy et al. (1960) and by Drachman and Gumnit (1962). There were no prolonged recordings of nocturnal sleep in Pickwickian subjects, however, until we obtained the present series. The following points appear to deserve closer consideration : the relationship to physiological coordination of sleep and respiration in the waking and sleeping states ; the significance of this for the development of the Pickwickian syndrome; and certain correlations between the EEG and autonomic functions. Before the Pickwickian syndrome was recognized, descriptions of these patients in the earlier literature and in our own material did not distinguish them sufficiently clearly from narcoleptics. Indeed, the boundaries are not clear-cut. Birchfield et al. (1958) found increased $0, values in definite cases of narcolepsy and Bulow and Ingvar (1963) report variable, rapidly fluctuating C 0 2 sensitivity in narcoleptics. One of Birchfield's two narcoleptics, however, presented marked obesity and impaired pulmonary function, and was therefore probably a case of Pickwickian syndrome. The studies of Biilow and Ingvar (1963) with spirography and alveolar pC0, recording in narcoleptic attacks gave results similar to the onset of sleep in healthy subjects. Ventilation and alveolar pC0, in the waking state, unlike those of Pickwickians,

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were normal. CO, changes during sleep attacks occurred more rapidly than during normal sleep in healthy individuals. A similar correlation between the EEG and respiration was observed in these cases. In one case of narcolepsy, shown in Fig. 1 of the paper by Biilow and Ingvar (1963), the recording ofthe initial stage of sleep contains prolonged apneic intervals of 8-30 sec, with a corresponding rise in pC0,. EEG changes in the Pickwickian syndrome

Apart from the sleep attacks with apnea, the EEG of Pickwickian patients is usually normal. Our second case, however, had a definite abnormality, with paroxysmal sharp waves in the left temporal lead (Figs. 3 and 4). This is probably unrelated to the illness, although it may occur in narcolepsy (Oepen, 1960). The simultaneous occurrence of apnea and flattening of the EEG has been described in Pickwickian patients, and is interpreted by Gerardy et ul. (1960) as a neurogenic effect. The flattening of the EEG corresponds to the onset of normal sleep, associated with a slowing of the a-activity (Fig. 1) as described by Kuhlo and Lehmann (1964). The flat EEG is a stage B sleep tracing, and not desynchronization with arousal, as has been erroneously assumed. Such activation occurs only during sleep as a periodic alarm or emergency reaction to prolonged apnea. Gerardy et ul. (1960) rightly concluded that this arousal is produced by the increased pC0,. Because there was a time lag between the rise in pCOz and the fall in pOz,these authors also discuss the possibility of control by the O,chemoreceptors, as shown experimentally by Hugelin et ul. (1959). During the apneic intervals, a transitory fall into deeper sleep, with episodes of stages C and D and high-voltage &waves, is frequent (Fig. 2b). When the EEG reverts t o the waking state at the end of the apnea, a-activity appears but flattening is inconstant. A short period of flattening may follow the &waves which may be similar to K complexes. The tachycardia usually precedes the EEG changes, which suggests that the autonomic system is in an ergotropic state. The a-period is not experienced subjectively as wakening. Fig. 6 shows a synopsis of our findings. The involuntary myoclonic jerks so often described in Pickwickians were seen chiefly in the apneic intervals in our patients, and not in the paradoxical sleep phases (REM stages). Gerardy et ul. (1960) observed these jerks only when the EEG was desynchronized and concluded that they were due to ascending reticular activation. As they were recorded only in the waking state or during short daytime sleep phases, this flattening of the EEG can certainly not be compared with paradoxical sleep.The jerks rather correspond to those seen in stage B in healthy subjects falling asleep. The discharges of the left temporal convulsive focus observed in our first case were not clearly correlated with the muscle jerks. It is noteworthy that in the paradoxical phases, in so far as any were recorded (cases 2 and 3), respiration became regular and there were no apneic intervals. Whether this is related to the cortical activation of the REM stage or to the increased rhombencephalic activity postulated by Jouvet (1962) remains open. It agrees with Biilow’s observation (1963) of reduced hypoventilation in healthy dreamers. We avoided arousal stimuli as far as possible in order not to disturb nocturnal sleep. References p . 158/159

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However, unintentional disturbances occasionally led to activation of breathing, confirming the coordination of ventilation with waking and sleeping states as described by Biilow and Ingvar (1961). In pathological disturbances of consciousness and in petit ma1 there is a similar coordination of breathing and EEG. When a petit ma1 attack is interrupted by an arousal stimulus, respiration is usually activated before the EEG becomes flattened (Jung, 1939). This may indicate an involvement of the bulbar reticular system in arousal reactions (Jung, 1954).

Sleep and respiration Ventilation has Iong been known to be reduced and the blood pC0, increased in the healthy person during sleep. Corresponding investigations and the earlier literature were surveyed by Magnussen in 1944. Bulow and Ingvar (1961, 1963) studied minute volume a n d ’ C 0 , concentration in healthy sleepers in detail. They used a similar method of continuously recording C 0 2in expired air by means of infrared absorption. They found a reduction of 3-4 l/min in the minute volume compared with the waking state and medium sleep. Even with the slight reduction of wakefulness (‘floating’) in the initial stage, with flattening of the EEG, respiration becomes shallower in the normal person. On stimulation, with the return of a-activity the respiration increases and the slight hypercapnia diminishes. From this, Bulow and Ingvar (1961, 1963) conclude that the respiratory centres are less sensitive to CO, during sleep. This reduced sensitivity is located in the reticular system. The involvement of the chemo-‘ receptors is not discussed, since in their investigation the 0, level of inspired air was kept constant. To judge from these findings in healthy subjects, the Pickwickian syndrome seems to be the result of an exaggerated interaction between sleep and respiration. It is to some extent a caricature of the normal hypopnea in sleep and fatigue. In the Pickwickian syndrome apnea occurs principally when the patient is inactive, especially sitting or lying, and rarely when he is standing. The sudden falling asleep with the interruption of breathing is certainly abnormal, but it resembles the sudden transition from waking to sleep in normal persons. More recent studies by Biilow (1963) on respiration and wakefulness in man reveal some parallels between healthy adults and the apneic intervals in the Pickwickian syndrome. Although in most healthy subjects, falling asleep is accompanied by hypopnea without interruptions in breathing, there are individuals who present total apnea for 10-20 sec. Bulow’s EEG tracings show that these apneic intervals occur mainly in stage B simultaneously with the flattening of EEG. Since Bulow found occasional instances of prolonged apnea (once as long as 1 min), we may conclude that these persons were ‘abortive Pickwickians’, who, given more pronounced obesity and hypoventilation, might present the full syndrome. Bulow’s investigations further revealed a clear relationship between the diminished sensitivity to CO, and the depth of sleep. In stages D and E, the ratio of minute volume to pC0, was considerably lower, and the shape and position of the curve of sensitivity to CO, were altered. This was confirmed not only for the different CO,

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concentration, but also for different 0, concentrations of inspired air. A further interesting parallel to the findings in Pickwickians was presented by paradoxica! sleep in healthy subjects :in the dream stage with rapid eye movements, threshold values for COz sensitivity were nearer those of drowsiness than those of classical sleep (stages B-E). In the Pickwickian syndrome, too, respiration was more regular and apneic intervals were absent during paradoxical sleep. Wide variations in periodic breathing between individuals and limited variation in the single individual also agree with our findings in the Pickwickian syndrome. Periodic breathing in nocturnal sleep is a highly constant individual feature in the Pickwickian syndrome, remaining unmodified for years regardless of the obesity. Further studies on a larger normal population are needed to determine whether mild, abortive forms of the Pickwickian syndrome with apneic intervals during nocturnal sleep are more frequent than has been believed so far. The role of the chemoreceptors is still not clear. In the healthy sleeper it is probably simply a matter of a shift in the CO, regulation in the respiratory centre. It is unlikely that the carotid glomus receptors and other chemoreceptors sensitive to 0, and CO, change their threshold within a second during the rapid passage of the organism from the waking to the sleeping state. In the Pickwickian, however, the CO, chemoreceptors might generally have a lowered threshold which would favour the more rapid onset of total apnea through reduced afferent stimulation. No exact measurements of glomus sensitivity to serotonine and other substances have been made so far, but we plan to test glomus function in this respect in the Pickwickian syndrome, narcolepsy and the normal state, using the method of Skinner and Whelan (1962). Since physiologists specially interested in respiratory function have not yet reached a generally accepted theory on the role of peripheral and central factors of CO, sensitivity in respiratory control, we may abstain from a further discussion ofthis question in the Pickwickian syndrome. Termination of apnea as emergency reaction and arousal The deep breath following each period of apnea during sleep may also be regarded as a caricature of normal respiratory regulation : i.e. an increased pC0, and decreased PO, is known to cause arousal. It is likely to represent an emergency reaction to extreme hypercapnia and severe anoxia leading to arousal (Fig. 2b). This arousal shows the autonomic accompaniments of an ergotropic reaction in the sense of Hess (1933): the heart rate increases, probably by an early sympathetic discharge, in association with the change of EEG patterns from sleep to wakefulness. The first deep inspiration always causes a snore but the following inspirations mostly occur without snoring, apparently through return of muscular tone to the palate with arousal. It seems that in spite of diminished CO, sensitivity in these patients their threshold of CO, arousal is overcome by the severe hypercapnia during the apneic periods. After several deep breaths which may restore normal CO, and 0, levels the respiration again becomes shallower and a new cycle of hypoventilation and eventual apnea begins. Rrlcrrnres p . 1581159

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RICHARD J U N G A N D W O L F G A N G K U H L O

Interpretation of the Pickwickian syndrome

Most of the papers on the Pickwickian syndrome were written from the standpoint of the internist. They emphasize the part played by obesity with elevation of the diaphragm and limitation of respiratory excursion as the cause of hypercapnia and the sleep phenomena. Most obese people; however, present no diurnal sleeping syndrome, and so far as is known no nocturnal apnea, so that the Pickwickian should have ssme central disturbance of respiration and arousal. Further evidence for such a disorder, independent of obesity, is seen in the fact that our third patient presented apneic intervals in his sleep 10 years before the typical Pickwickian syndrome with obesity appeared, at a time when he was severely emaciated. What do our observations contribute to the understanding of the Pickwickian syndrome? Both neurophysiological and clinical findings suggest a coordinated disturbance of respiratory rhythm and sleep-waking regulation in the brain stem. This is already suggested by observation of normal persons. The explanation offered by the specialist in internal medicine, that hypoventilation causes sleep attacks, cannot be substantiated from either our findings or general observations on pC0, and EEG. An increased CO, level in the blood has rather the opposite effect, viz. arousal. Conversely, with hypocapnia and hyperventilation, the EEG is slowed and sleep may eventually occur. While hypercapnia produces arousal in the waking subject, nevertheless in the pre-sleep stage of fatigue and in normal sleep itself, there is marked hypercapnia. This ‘sleep hypercapnia’, however, is due to altered regulation, affecting both respiration and wakefulness at the same time; it is also seen in normal individuals, and is referred to by Biilow (1963) as ‘shift of CO, sensitivity’. This diminished CO, sensitivity occurring transitorily in normal sleep, apparently persists in the Pickwickian for long periods even during the waking day, thus permitting hypoventilation and hypercapnia, without provoking the counter-regulatory arousal. CO, hyposensitivity in the Pickwickian, as in the healthy individual is related to the process of falling asleep, and therefore disposes him to frequent naps in the absence of strong arousal stimuli. The neurophysiological actions of peripheral and central CO, receptors and their coordination with 0, receptors have not yet been investigated in detail. The following six features in the Pickwickian syndrome are in favour of its being due to an interrelated disturbance of respiratory regulation and sleep, with a primary tendency to apneic intervals, and speak against the sleep attacks being caused only by hypoventilation. In the diurnal waking state: (1) The apnea occurs simultaneously with the onset of sleep and the flattening of the EEG; in some cases, the latter may even slightly precede the respiratory arrest. (2) Voluntary apnea does not lead to sleep. In nocturnal sleep: (3) The occurrence of apneic intervals is also a prominent feature during nocturnal sleep. During sleep the apnea lasts longer than in the waking state.

ABNORMAL SLEEP A N D PICKWICKIAN SYNDROME

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(4)Apneic intervals occur in nocturnal sleep before obesity and hypoventilation have developed. (5) Nocturnal apnea persists after weight reduction and improvement in ventilation. (6) Similar apneic intervals occur in healthy young people and adults during nocturnal sleep without signs of respiratory insufficiency (Biilow, 1963). There is, however, a relationship between hypoventilation and sleep attacks which has not yet been explained neurophysiologically. The favourable effect of slimming and the resulting improvement in pulmonary ventilation and reduced incidence of daytime sleep have been confirmed repeatedly. Follow-up examination has shown that these patients, after weight reduction, return to almost normal pC0, and p 0 2 levels. This may be explained by the improved pulmonary ventilation resulting from mechanical factors such as the lower position of the diaphragm and greater excursion of the lungs, favouring normal CO, sensitivity. On the other hand, the apneic intervals during nocturnal sleep persist after slimming. In the Pickwickian syndrome, therefore, there must exist a primary and persisting tendency to CO, hyposensitivity, which causes respiratory depression whereas in the healthy individual this occurs only transitorily and in coordination with the sleep mechanism. SUMMARY

Abnormal sleep syndromes which were investigated with continuous recordings during nocturnal sleep are reviewed. Special reference is made to the Pickwickian syndrome. Among the forms of insomnia, depressive sleep disturbances represent a rea1 diminution of night sleep, which is interrupted by prolonged periods of wakefulness. In contrast, the sleep disturbance of neurasthenics is mainly an overemphasis of short waking periods during the night with sufficient total amounts of sleep. The Pickwickian syndrome of periodic somnolence with obesity and hypoventilation is reported in detail with studies of respiration and EEG during nocturnal sleep. The short diurnal periods of light sleep (10-12 sec duration) in Pickwickian patients are characterized by apnea, increased cyanosis and muscular relaxation, simultaneous with sudden flattening of the EEG and slowing of the a-rhythm. The night sleep of Pickwickian patients is interrupted by long apneic periods up to 20-40 sec duration, terminated by 1-3 deep irregular snoring breaths. During the apnea, EEG rhythms are usually slowed and the amplitude increased. &Waves and sharp waves appear associated with spindles. At this time there is bradycardia and deep cyanosis. With the return of respiration a-waves appear and the heart rate increases. Pickwickian patients rarely attain the deep sleep stages D and E and long periods of rapid eye movements are lacking. When such paradoxical REM stages occurred in 2 patients, the respiration became more shallow and regular. In stage C sleep, which is the predominant sleep stage in these patients, the apneic periods were most pronounced. The termination of the apneic period with a deep breath and increase of heart rate References p. l S 8 l I S 9

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is interpreted as an emergency reaction to severe hypercapnia and hypoxia. The higher threshold of CO, sensitivity in Pickwickian patients requires a longer period of apnea to achieve CO, arousal. The physiological coordination of sleep and respiration is discussed in relation to the Pickwickian syndrome. Nocturnal sleep in Pickwickian patients with apneic pauses may be regarded as a caricature of normal hypoventilation during sleep. It is postulated that the diminution of CO, sensitivity present in normal subjects only during sleep may occur as a permanent disturbance in the Pickwickian patients. This lowered CO, sensitivity results in chronic hypoventilation in the waking state with phasic spontaneous diurnal sleep. The role of chemoreceptors is still unknown. REFERENCES AUCHINCLOSS, J. H., JR., COOK,E., and RENZETTI, A. D., (1955); Polycythemia of unknown cause with alveolar hypoventilation. J . elin. Invest., 34, 1537-1545. A.,(1 958); Alteration in blood gases during natural BIRCHFIELD, R. J., SIEKER,H. O., and HEYMAN, sleep and narcolepsy. A correlation with the electroencephalographic stages of sleep. Neurology, 8, 107-1 12. BULOW,K., (1963); Respiration and wakefulness in man. Actaphysiol. scand., 59,Suppl. 209. BULOW,K., and INGVAR, D. H., (1961); Respiration and state of wakefulness in normals, studied by spirography, capiiography and EEG. Acta physiol. scand., 51, 230-238. BULOW, K.,and INGVAR,D. H., (1963); Respiration and electroencephalography in narcolepsy. Neurology, 13. 321--326. R. D., and BICMELMANN, A. G., (1956); Extreme obesity BURWELL, C. S., ROBIN,E. D., WHALEY, associated with alveolar hypoventilation. A Pickwickian Syndrome. Amer. J . Med., 21, 81 1-81 8. DOLL,E.,and STEIM, H., (1963); Uber die Ursachen der arteriellen 0,-Untersattigung beim PickwickSyndrom. K h i . Wsclzr., 41, 423-427. D.B.,and GUMNIT, R. J.,(1962); Periodicalteration ofconsciousness in the “Pickwickian”DRACHMAN, Syndrome. Arch. Neurof., 6, 471477. H., and SCHWARTZ, B. A., (1961); A clinical, electroencephalographic and polygraphic FISCHGOLD, study of sleep in the human adult. CIBA Foundation Symposium on the Nature of Sleep, G . E. W. Wolstenholme and M. O’Connor, Editors. London, Churchill (p. 209-231). GERARDY, W.,HERBERG, D., and KUHN,H. M.,(1960); Vergleichende Untersuchungen der Lungenfunktion und des Elektroencephalogramms bei zwei Patienten mit Pickwickian-Syndrom. Z. klin. )Wed., 156, 362-380. GOTZSCHE, H., and PETERSEN, V. P., (1958); Obesity associated with cardiopulmonary failure - the Pickwickian-Syndrome. Acta med. scand,, 161, 383-390. CRANE, M. G., COLLIER, C. C., ROKAW,S., and GRIGGS,D. E., (1959); Syndrome of HACKNEY, J. D., extreme obesity and hypoventilation. Studies of etiology. Ann. intern. Med., 511541-552. HESS,R.,(1 949); Electrencephalographische Beobachtungen beim kataplektischen Anfall. Arch. Psychiat. Nervenkr., 183, 132-141. HESS,W. R., (1933); Der Schlaf. Klin. Wschr., 12, 129-134. HEYCK,H., and HESS, R., (1954); Zur Narkolepsiefrage, Klinik und Elektroenzephalogramm. Forrsclzr. Neurol. Psychiat., 22, 53 1-579. HUGELIN,A., BONVALLET, M., and DELL, P., (1959); Activation rkticulaire et corticale d’origine chkmoreceptive a u cours de I’liypoxie. Elecrroenceph. Neurophysiol., 11, 325340. JOUVET,M., (1962); Recherches sur les structures nerveuses et les mecanismes responsahles des differentes phases du sommeil physiologique. Arch. ital. Biol., 100, 125-206. JUNG, R.,(1939): Uber vegetative Reaktionen und Hemmungswirkung von Sinnesreizen im kleinen epileptischen Anfall. Nervcnarzt, 12,169-1 85. JUNG,R.,(1954);Correlation of bioelectrical and autonoxic phenomenawith alterations ofconsciousness and arousal in man. Brain Mechanisms and Consciousness, Symposium. E. D. Adrian, F. Bremer, H. H. Jasper, J. F. Delafresnaye, Oxford, Blackwell Scientific Publ. (p. 310-344.). JUNG,R., (1 963); Der Schlaf. Physiofogie und Pathophysiologie des vegetativeti Nervensystems, Vol. 2 M. Monnier, Editor. Stuttgart, Hippokrates (p. 650-684).

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KRETSCHY, A., and MUHAR,F., (I 964); Formes frustes bzw. Friihfalle vom Pickwick-Syndrom. Wien. klin. Wschr., 76, 389-393. KUHLO,W., and LEHMANN, D., (1964); Das Einschlaferleben und seine neurophysiologischen Korrelate. Arch. Psychiat. Nervenkr., 205, 687-716. MAGNUSSEN, G., (1944); Studies on the Respiration during Sleep. A Contribution of the Physiology of the Sleep Function. London, Lewis (p. 276). MEYER, J. S., GOTHAM, J., T4ZAK1, Y., and GOTOH,F., (1961); Cardiorespiratory syndrome of extreme obesity with papilledema. Neurology, 11, 950-958. OEPEN,H., (1960); Schlafanfalle und Dammerattacken. Beitrag zur Differentialdiagnose der Narkolepsie und temporalen Epilepsie. Arch. Psychiat. Nervenkr., 200, 567-584. OSWALD, I . , BERGER, R. J., JARAMILLO,R. A., KEDDIE, R. M., OLLEY, P. C., and PLUNKETT, G. B., (1963); Melancholia and barbiturates: a controlled EEG, body and eye movement study of sleep. Brit. J . psychiat. soc. Work, 109, 66-78. RECHTSCHAFFEN, A., WOLPERT, E. A., DEMENT, W. C., MITCHELL, S. A., and FISHER, C., (1963); Nocturnal sleep of narcoleptics. Electroenceph. din. Neurophysiol., 15, 599-609. ROTH,B., (1962); Die Narkolepsie und die Hypersomnie vom Standpunkt der Physiologie des Schlafes. Berlin, VEB-Verlag, Volk und Gesundheit. SANEN,F. J., (1958); Das Pickwicksche Syndrom: Fettsucht, Hypoventilation, Rechtsinsuffizienz des Herzens, Sornnolenz, Hyperkapnie. Med. Klin., 53, 1360. SCHERRER, M., (1961); Stiirungen des Gasaustacisches in der Lunge. Bern, Huber. SCHWARTZ, B. A., GUILBAUD,G., and FISCHGOLD, H., (1963); Etudes electroenckphalographiques sur le sommeil de nuit. 1. L’insomnie chronique. Presse Medicale, 71, 1474-1476. SKINNER, S. L., and WHELAN, R. F., (1962); Carotid body stimulation by 5-hydroxytryptaminein man. J . Physiol., 162, 3 5 4 3 . VANREY,W., and WISSFELD, E., (1964); Registrierung von Schlaftiefe und Schlafrhythmus mit einem EEG-Intervallanalysator bei Gesunden und schlafgestorten Depressiven. Zbl. ges. Neurol. Psychiat., 176, 205. WILDER,J., (1935); Narkolepsie: Handbuch der Neurologie, Vol. 17. 0. Bumke, and 0. Foerster, Editors. Berlin, Springer (p. 87-141).

160

Some Psychophysiological Features of Human Sleep IAN OSWALD Department of Psychological Medicine, University of Edinburgh, Edinburgh (Great Britain)

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What is sleep? It is a state of inertia and unresponsiveness. Responses, as they can be seen by the ordinary observer, are diminished. So too are our inner, private responses that we call perceptions. Fig. 1 shows a recording made from a young man who is RESPIRATION

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drowsy. He has been pressing a switch whenever he heard a fairly loud tone which recurred every 10 sec. He is very bored. In the upper excerpt his a-rhythm is present. He hears the stimulus and he responds. In the lower excerpt, a-rhythm of low voltage can be seen briefly on the left, then it is replaced by low voltage slow waves. He is

SOME PSYCHOPHYSIOLOGICAL FEATURES OF HUMAN SLEEP

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lightly asleep. Now he does not hear the tone. Because it is familiar he is not awakened by it. He does not respond. After lying down in bed, as we become more sleepy, the control of our thoughts escapes us. Our ability to discriminate between fantasy and reality become lost. Our thoughts lack precision. If we are suddenly roused at this time we may describe hypnagogic hallucinations. Visions, sudden voices, absurd or bizarre sentences or words passing through our minds; often new words or neologisms (Oswald, 1962). One cannot objectively demoiistrate these inner manifestations of lowered cerebral vigilance but the impairment in our powers of organisation can be shown if, when sleepy, we are also engaged upon a simple motor task. Only when the EEG shows signs of wakefulness is accurate performance possible. Fig. 2 illustrates this. The subject is moving his legs and pressing a hand switch in time with the rhythm of music. LFP RFP LPO RPO

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To the left of the excerpt his a-rhythm is largely absent and movement is poorly executed. At one point hand movement ceases, leg movement is reduced and the heart slows. On the right, where a-rhythm has returned, precisely executed rhythmic movements are to be seen. I said that if suddenly roused we may describe hypnagogic hallucinations and other experiences. Many people deny them, just as other people deny dreaming. But the denials are based on memories that remain the next morning. The events of light sleep, and the memories of our dreams, are lost unless almost immediately recalled. We cannot learn while asleep. Emmons and Simon (1956) made a tape recorder play a list of ten words throughout the night. Provided the EEG was monitored all night and the words switched off whenever a-rhythms appeared, no memory of those ten words could be detected the next day. The unresponsiveness of sleep extends to those inner responses which underly the storage of information. One of the most important lessons that we have learned from simultaneous studies of both the EEG and of bodily activity is that light sleep can come and go very rapidly, that it can be present for only a few seconds at a time, with concurrent impairment of thinking and activity (Oswald, 1962). Brief periods of lowered cerebral vigilance reveal themselves in persons who have been deprived of sleep, especially if deprivation has lasted 60 h or more. The brief ‘microsleeps’, as they have been called, can be most easily displayed by requiring sustained, continuous attention. Given a group of sums to do, the sleep-deprived person may perform perfectly accurately. He determines his own speed of working and can take little rests between each sum, If, however, he is required to work at a speed determined by someone else, or if he has to work at some References p. I68

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IAN OSWALD

task in which he is required to respond at once to each of a continually varying but endless sequence of signals, he soon makes failures. The longer he goes on, the worse he performs. Again and again his responses are delayed, or fail completely to appear because he is in one of his recurrent little microsleeps (Williams et al., 1959). Like the drowsy person in bed, the sleep-deprived man may have hallucinations. A volunteer medical student at Edinburgh, after 60 h without sleep, kept seeing unpleasant old women peering at him (Berger and Oswald, 1962a). As he walked along the road he would see them vanish as he drew near, sometimes the body disappearing before the head. Then, when he turned round again, there they were once more! A second volunteer showed another of the common features of sleep-deprivation, a paranoid psychosis. The delusion grew that a drug had secretly been put into his coffee so that he saw handwriting on his companion’s coat. He made the latter take off his coat for closer examination while walking along the street. He thought he heard people speak of him, he thought that the water at the dinner table tasted bitter (a sign of further drugs). He made repeated obscure remarks and hints to show that he had discovered the drugging. When being driven in a car he believed he was being taken away to be locked up, that his companion was hypnotised, and that he must have been responsible for some recent mysterious fires. And so on. After a good night’s sleep his psychotic features disappeared.

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It is as if such men were living in an unpleasant dream, a nightmare dream while walking about with open eyes. Following the pioneer work in Chicago by Dement and Kleitman (1957a,b) and others we now know that nocturnal dreaming is universal, that it recurs for some 20 min at a time, some 4,5 or 6 times a night and that unless the dreamer is awakened at the time, he will have forgotten all of it by the morning. The dream periods are accompanied by jerky rapid eye movements, and, we now realise, occur during a physiologically distinct phase of sleep (Oswald, 1964a). The rapid eye movements appear to be related to the visual content of the dream (Roffwarg et af.,1962). They are absent in men blind from birth whose dreams lack visual imagery (Berger and Oswald, 1962a). The more active the adventures dreamed about, the more profuse the rapid eye movements (Berger and Oswald, 1962b). At the present time there is insufficient information concerning the relation between these dream periods and enuresis in small children. In young adults enuresis occurs not during the dreaming or paradoxical phase of sleep, but during orthodox sleep with large slow EEG waves and sleep spindles. During his studies Gf enuresis my colleague, Dr. J. I. Evans, did meet an occasion where the wet-bed signal appeared during a dream. This was a sexual dream, a so-called ‘wet-dream’ shown in Fig. 3. The study of paradoxical sleep with its rapid eye movements is revealing many facts about idiopathic narcolepsy. These patients show a characteristic abnormality. On first falling asleep they do not pass into orfiodox sleep (Rechtschaffen et al., 1963) but into paradoxical sleep (Fig. 4). They pass therefore into a state of widespread muscle paralysis. They are prone to pass into this state when, by day, they sit in a chair. During it they dream, but, having been awake only just before, retain some orientation. They will say, for example, that they somehow knew they were in their own room at home, but that various bizarre events, often frightening, were going on there. They tried to move and found themselves paralysed. This is often called sleep paralysis. Dr. Evans and I have lately been studying these patients. Following a previous observation that the essential amino-acid, laevo-tryptophan, eaten at bedtime can make a rapid eye movement period start early in normal people (Oswald, 1963),we gave 5 g of laevotryptophan to our narcoleptics 15 min before we let them go to bed. This caused their sleep-onset rapid eye movement period to continue, not for the usual quarter of an hour, but for half an hour. The duration was doubled. Of special interest was one man who had a peaceful dream on the eight occasions when he had not received tryptophan, but an unpleasant dream or nightmare on each of the four times he had received laevotryptophan. Muscle twitches and strangled cries interrupted his dream, with periods of rapid eye movements for 10-20 sec between his cries, a dream from which he struggled to escape, but which, in a state of paralysis, he had to endure. In these dreams there is, therefore, some intertwining with the current situation, a n intertwining of fantasy with present reality. Such a process is not wholly absent in dreams which occur after some hours of sleep. Although the cat in paradoxical sleep appears highly unresponsive to meaningless electrical stimulation of the reticular formation, the human is not unresponsive to meaningful stimulation given through his sense organs. He may not awaken, but may nevertheless respond by weaving the References p . 168

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stimulus into his dream. We had already shown that, in orthodox sleep arousal signs in the EEG and galvanic skin responses would, for example, follow significantly more often after meaningful stimuli, such as words, than after physically identical but meaningless stimuli, such as words played backwards by a tape-recorder (Oswald et ul., 1960). My colleague, Berger (1963) found that, by playing a word over and over again during a rapid eye movement period, the sound of the word influenced the content of the dream. It did so in a manner which enabled the word later to be identified by an independent judge significantly more often than chance alone could explain. As an example, when the English girl's name, 'Sheila', was played repeatedly during a rapid eye movement period, the man described how he had dreamed he had ieft behind his book at the University, his copy of Schiller. Sheila, a girl's name-Schiller,

165

SOME PSYCHOPHYSIOLOGICAL FEATURES OF H U M A N SLEEP

the German poet. When the girl's name, 'Jenny', had been played, a dream was described of opening a safe with a jemmy (a tool used by British thieves). When the boy's name, 'Robert', had been played, a girl, after awakening, described a dream of seeing a rabbit, a rabbit which, she said, 'looked distorted'. 'Robert', a distorted rabbit. Is dreaming confined to rapid eye movement periods? There is a growing body of evidence that mental life may continue during all stages of sleep (Foulkes, 1962). I have been able to study some patients with jactatio capitis nocturna-violent rhythmic head and body rocking during the night. This abnormality always starts in childhood. Rhythmic rocking is a comfort habit (just as is thumb-sucking) which occurs in infant humans, infant chimpanzees and infant monkeys when they are lonely or unhappy. The rhythmic rocking movements occur when the infant is put to bed. In rare persons they persist into adult life when they occur actually during sleep. Most often, in my experience, they occur during a rapid eye movement period, perhaps as a response to an unhappy dream. But they also sometimes occur abruptly during orthodox sleep (Fig. 5).

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I regard this rocking as a form of sleep behaviour which is motivated in nature and suspect that it is occurring in sleep because of some concurrent unhappy thoughts of a References p. I68

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kind from which the individual long ago learned to seek relief in rhythmic activity. Patients who suffer from depression will often say they have unpleasant dreams and seem to get no peace of mind during sleep. At Edinburgh we compared their sleep with that of controls of the same age and sex and confirmed one of their other complaints- of insomnia. They woke spontaneously and repeatedly at any time of the night. Heptobarbitone significantly increased their duration of sleep. It decreased the duration of their rapid eye movement periods and decreased the number of eye movements per minute during those periods. If eye movements relate to the dream content, perhaps their dreams were more placid in content after the barbiturate! A huge quantity of barbiturates and other sleeping pills is prescribed throughout the world. They represent 10% of all British National Health Service general practitioner prescriptions. Enormous amounts of pills of the anphetamine type are consumed by day, often with barbiturates, or to waken up by day those who had barbiturates at night. It often goes on year after year. Once a patient is started on these pills it is very difficult to stop. If one doctor tries to persuade the patient to give them up he meets all kinds of trickery. The patient goes to another doctor. She feels a craving for the pills. This is a psychological experience. Can we detect some physiological correlate of this craving? No, not a direct one, but an associated one. When we give a patient barbiturates, or amphetamines, or both, over a long period, his nervous system seems to grow so accustomed to the presence of the drug that the early abnormalities in sleep pattern caused by the drug become lost. If, however, we now suddenly withdraw that drug, sleep is made abnormal and it is possible to find a a l o80 l0

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abnormalities persisting for as long as two months after stopping the drug which is, of course, long after the drug has been eliminated from the body. Fig. 6 illustrates one feature of human sleep that we happen to be able very conveniently to measure. It shows that after withdrawing drugs (amphetamine/barbiturate mixture) which have been taken regularly over a long period, the delay in minutes between first falling asleep at night and the onset of the first rapid eye movement is made abnormally short and several weeks are needed for return to normal function. 35-

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RECOVERY NIGHTS

Fig. 7. Effect of Mogadon, 15 mg. Ordinate: nightly on % of night spent in REM (paradoxical) sleep. Habituation and rebound. An example of a measurable characteristic of sleep which shows gradual adaptation or habituation to the effects of a drug, followed by a rebound. The values each night are means for the two volunteers. On the first drug night the proportion of the night spent in paradoxical (REM) sleep is grossly reduced. On the second, third and fourth night after withdrawal, the values are again outside the normal range.

Recently Dr. R. Priest and I have been making similar observations where a hypnotic drug alone has been regularly in use. Again sleep is made abnormal upon drug withdrawal and only after a delay does it return to normal (Fig. 7, experiment with Dr. R. Priest). Apart from hypnotic drugs for relief of insomnia, there are also available machines for inducing sleep by, for example, rhythmic electric shocks to the head. Apart from the skin sensations, these would be expected to produce rhythmic visual phosphenes. ‘Electro-sleep’ machines, I believe they are called. The psychologist must remain sceptical of a direct sleep-promoting effect on the brain. Any form of rhythmic stimulation, especially if it is impressive (as are electric shocks to the head) will induce sleep. I have, in the past, carried out experiments in which sleep was very easily induced by electric shocks to the legs (Oswald, 1959). Most potent in my experience was a combination of brilliant flashing lights, synchronised with electric shocks to the legs, all synchronised with the rhythm of very loud jazz music, where the volunteer’s eyes were stuck open with glue and adhesive tape. It was an impressive, all-embracing form of rhythmic stimulation. What I should be interested to learn is whether, following frequent repetition of the ‘electro-sleep’technique there comes a night when the effect, having declined on previous nights, is altogether lost. My guess is that this would not happen for a very long time. Rrfcrences p. I68

168

IAN OSWALD

The study of sleep offers much of interest to the psychologist, but today he must walk hand in hand with the physiologist and the pharmacologist. SUMMARY

The passage from wakefulness to sleep is accompanied by increasing disorganisation of human overt activity and thmking, and by failure of memory storage. These phenomena are seen, often with hallucinations, or even delusions, in sleep-deprived people. Periods of paradoxical sleep with rapid eye movements are accompanied by dreaming and paralysis of much of the body. It is into this kind of sleep that the narcoleptic patient quickly passes on falling asleep by day. His dream may be unpleasant and he may become aware of his paralysis. Outside noises may not awaken the sleeper but can recognizably alter the dream content. Mental life may also be present during the orthodox phase of sleep, during which both jactatio capitis nocturna and enuresis can occur. The regular intake of some hypnotic drugs is accompanied by a degree of dependence, with a craving for them and disturbance of sleep if they are suddenly withdrawn. ‘Electro-sleep’ is probably only one example of the sleep-promoting effects of rhythm. REFERENCES

R. J., (1963); Experimental modifcation of dream content by meaningful verbal stimuli. BERGER, Brit. J. Psychiat., 109, 722-740. BERGER, R. J., and OSWALD, I., (1962a); Effects of sleep deprivation on behavior, subsequent sleep, and dreaming. J. ment. Sci., 108,457-465. BERGER, R. J., and OSWALD, I., (1962b); Eye movements during active and passive dreams. Science, 137,601. DEMENT, W.C., and K L E ~ M AN., N , (1957a); The relation of eye movements during sleep to dream activity: An objective method for the study of dreaming. J. exp. Psychol., 53, 339-346. DEMENT, W. C., and KLEITMAN, N., (1957b); Cyclic variations in EEG during sleep and their relation to eye movements, body motility and dreaming. Electroenceph. elin. Neurophysiol., 9, 673-690. EMMONS, W. H., and SIMON,C. W., (1956); The non-recall of material presented during sleep. Amer. J . Psychol., 69, 76-81. FOULKES, W. D., (1962); Dream reports from different stages of sleep. J. abnorm. soc. Psycho/., 65, 14-25. OSWALD, I., (1959); Experimental studies of rhythm, anxiety and cerebral vigilance. J. ment. Sci., 105, 269-294. OSWALD, I., (1962); Sleeping and Waking: Physiology and Psychology. Elsevier, Amsterdam. OSWALD, I., (1963); Two kinds of sleep. Discovery, 24, No. 1 1 , 36-39. OSWALD, I., (1964a); Physiology of sleep accompanying dreaming. The Scientific Basis of Medicine Annual Reviews. Sir James Paterson Ross, Editor. University of London, the Athlone Press (p. 103124). OSWALD, I., (1964b); The mechanism of sleep disorders. Znt. J. Neurol., in the press. OSWALD,I., TAYLOR,A. M., and TREISMAN, M., (1960); Discriminative responses to stimulation during human sleep. Brain, 83,440-453. I., and THACORE, V. R., (1963); Amphetamine and phenmetrazine addiction : physiological OSWALD, abnormalities in the abstinence syndrome. Brit. med. J., 2, 427431. RECHTSCHAFFEN, A., WOLPERT,E. A., DEMENT, W. C., M ~ C H E L S. L , A., and FISHER, C., (1963); Nocturnal sleep of narcoleptics. Electroenceph. clin. Neurophysiol., 15, 599-609. ROFFWARG, H. P., DEMENT,W. C., MUZIO,J. N., and FISHER, C., (1962); Dream imagery: relationship to rapid eye movements. Arch. gen. Psychiat., 7,235-258. WILLIAMS, H. L., L n m , A., and GOODNOW, J. J., (1959); Impaired performance with acute sleep loss. Psychol. Monogr., 73,No. 14.

SOME PSYCHOPHYSIOLOGICAL FEATURES OF H U M A N SLEEP

169

DISCUSSION

KUHLO:EEG investigations with D. Lehmann on the psychology of falling asleep demonstrated that even slight retardation of the a-rhythm, which may be the first EEG change before the actual onset of sleep, is associated with subjective variations of consciousness. Practised subjects correctly indicated a-retardation of 10-1 5% and 1-2 sec duration in about SO% of cases. The illustration shows a continuous tracing of the regular 11.5-12 c/s a-rhythm in the waking state with several phases of retardation of 1-2 sec to 9-10 c/s which were experienced and indicated by the subject as a short ‘floating away’.

MORUZZI: I should like to call attention to the agonizing experience of being paralysed which is characteristic for nightmares. Marchiafava, and Pompeiano* have shown that pyramidal movements are blocked in the cat during desynchronized sleep and I understand that the same observation has been made independently by Evarts on monkeys. Several lines of evidence suggest an inhibition at spinal levels. CAHN : The muscular hypotonia of dreaming, which is most probably mediated through the inhibitory reticular formation, is triggered by the same mechanism which induces all the cerebral events of paradoxical sleep : rapid eye movements, fast EEG, etc. Both ascending and descending phenomena are triggered from the same region ofthe pons, but the neuronal organisation of this pontine region is still unknown. But there is no evidence that muscular hypotonia per se may induce dreaming.

OSWALD : Certainly relaxation and immobility promote sleep. A major relaxation occurs as orthodox sleep begins, but a more profound one with paradoxical sleep.

PLETSCHER : Do you agree that your ‘rebound phenomenon’, as observed with hypnotics, is not specific for this class of drugs? This is a rather general principle which can be seen with any drug and which the pharmacologists call counterregulation (Gegenregulat i o11).

OSWALD : I agree, this is an example of a general principle. But the rebound helps US to realize the disturbance of metabolism that may lie behind the patient’s demand for renewal of her sleeping pills.

_-__ * MARCHLAFAVA, P. L., and POMPEIANO, O., (1964); Pyramidal influences on spinal cord desynchronized sleep. Arch. itnl. Biol., 102, 500-529.

during

170

Objective Correlates of the Refreshing Effects of Sleep G. A. LIENERT

AND

E. OTHMER

Psychological Institute, University of Hamburg, Hamburg (Germany)

The purpose of the investigation reported here was to ascertain some objective criteria correlated with the subjectively reported experience of refreshing sleep. It was hypothesized that reports of such experience are related (1) to greater depth of sleep as defined through EEG patterns (Loomis et al., 1937); (2) to minimal movements of facial muscles as determined by EMG criteria; and (3) to minimal body movements as evinced by actographic recordings. From a total sample of 127 unselected male students 11 emotionally labile subjects and 11 emotionally stable subjects were differentiated according to a factor of emotional stability-lability which was derived from factorial analyses of questionnaire performances, autonomic functioning, and body measurements. A combined scale of three questions, each with six degrees of freedom, furnished an index of the degree of 9

a 7 6 5 4

3

2 1

1 2 3 4 5 6 h Fig. 1. Depth of sleep (EEG criteria in Stanine units) in emotionally stable and labile subjects. TABLE I DEPTH OF SLEEP (T VALUES BASED ON EEG CRITERIA) AND AVERAGE DURATION OF EACH STAGE OF SLEEP (NUMBER OF EEG SAMPLES INDICATING EACH STAGE) IN EMOTIONALLY STABLE A N D LABILE SUBJECTS

Duration of stage C

Emotionally stable Emotionally labile

262++(+) 216

Duration Of sfage D

Duration of medium depth of sleep

77 90

51 49 ~

++(+)

= significant at 0.25% level (N = 8).

171

REFRESHING EFFECTS OF SLEEP

reported freshness following sleep. Inasmuch as an earlier investigation (Othiner, 1965) disclosed that emotionally labile subjects feel less refreshed following sleep than emotionally stable subjects, it is also possible, for convenience of the present study, to designate the above two groups of subjects as subjectively ‘good’ (emotionally stable) and subjectively ‘bad’ (emotionally labile) sleepers. Statistical comparisons of these two groups of subjects revealed the following characteristics with respect to depth of sleep, movements of facial muscles, body movements, and the relationship between objective criteria of sleep and reported feelings of freshness on waking. ( I ) Depth of sleep. Fig. 1 shows the average pattern of sleep for stable and labile subjects, while Table I records statistical differences between these values (Lienert, 1962). On the basis of the data provided, the following interpretations may be made : (a) The average depth of sleep does not differ between the two groups. (b) The duration of sleep (stage D) does not differentiate stabile and labile subjects. (c) Stable subjects remain significantly longer in a medium depth of sleep (stage C ) than do labile subjects. In the light of these findings, the first hypothesis must be rejected since average depth of sleep fails to differentiate subjects enjoying refreshing sleep from subjects reporting less-refreshing sleep. (2) Movements of facial muscles. Fig. 2 records facial movements in emotionally stable and emotionally labile groups. As summarized in Table 11, statistical compari9 0

7 6 5 4 3 2 1

1

2

3

4

5

6

h

Fig. 2. Movements of facial muscles (number of EMG pulses per hour in Stanine units) in emotionally stable and labile subjects.

TABLE I1

SHALLOW SLEEP

NUMBER OF FACIAL MUSCLE MOVEMENTS (EMG) AND DURATION OF STAGE B OF (NUMBER OF B SAMPLES) I N EMOTIONALLY STABLE A N D LABILE SUBJECTS

Emotionally stable Emotionally labile +

=

significant at 5% level (N

References p . 174

=

Number of facial muscle movemenls (whole night)

Number of facial muscle movements (first half of night)

301 314

101

6 and N

164+ =

8).

Duration of stage B 88 118+

172

G. A. LIENERT A N D E. OTHMER

sons between the two study groups indicate that (a) labile subjects display significantly more frequent innervations of facial muscles during the first half of the night and that (b) they remain longer in stage B of sleep. If stage B of sleep and movements of facial muscles, particularly rapid eye movements, can be taken as rough indicator of dreaming (Kleitman, 1963), then labile subjects would appear to dream more frequently than emotionally stable subjects. The second hypothesis may be accepted since results of the present investigation indicate that movements of facial muscles occur more frequently in conjunction with reports of unrefreshing sleep. ( 3 ) Body movements. The frequency and differential amplitude of the two groups with respect to body movements are shown in Fig. 3a and b, respectively with statistical

+-

0---

1

2

3

4

5

6

h

1

2

3

4

+ = Loblle 5

6

4 ~

-

-

h

Fig. 3. (a): Body movements (number of movements per hour in Stanine units) in emotionally stable and labile subjects. (b): Body movements (intensity of movements per hour = mean amplitude in * Stanine units) in emotionally stable and labile subjects. TABLE 111 NUMBER OF BODY MOVEMENTS (MECHANOGRAPHIC) A N D AMPLITUDES I N EMOTIONALLY STABLE A N D LABILE SUBJECTS

Emotionally stabile Emotionally labile +

= significant at

Number of body movements

Intensity of body movements

62'

7.53' 4.55

35

5% (N = 6).

differences recorded in Table 111. From these data it may be concluded that : (a) labile subjects display, particularly during the second half of the night, significantly fewer body movements as well as (b) much feebler body movements for the same corresponding period than do emotionally stable subjects. On the basis of these findings, the third hypothesis must be rejected since the group which enjoys less refreshing sleep manifests statistically fewer and weaker body movements. ( 4 ) The relationship between objective sleep criteria and subjectivefeelings of freshness on waking. Rank and multiple correlations between objective criteria and the degree of reported freshness on waking are shown in Table IV. Analyses of these data permit the following conclusions to be drawn : (a) there is no significant relationship between degree of reported freshness on waking and depth of sleep; (b) a negative

173

REFRESHING EFFECTS OF SLEEP

TABLE IV R A N K CORRELATIONS (cs) A N D MULTIPLE R A N K CORRELATIONS (RS ACCORDING T O MORAN) BETWEEN OBJECTIVE CRITERIA O F SLEEP A N D SUBJECTIVE FEELING OF FRESHNESS AFTER SLEEP

(COMBINED QUESTIONNAIRE RESULTS)

Number Duration Duration Duration of stage of stage of ofsleep D ofsleep sleep

c

Amplitude of EEG during mediumdeep sleep

of

facial muscle

(EMG)

-

Number of facial muscle mOvemet,tS

(EMG)

during the night

during first half of night

0.19

0.52f

of Intensity body ofbody movements movements (mechano-) (mechano-) graphic) graphic)

Cs = RS = +

0.39

= significant at

0.20

0.12

0.28

0.64f 0.52+ 0.80++

0.80++ 5% level (N = 12);

++

= significant at

1% level (N = 12).

relationship exists between the degree of reported freshness on waking and the number of movements of facial muscles during the first half of the night, i.e. the fewer the facial movements during the first half of sleep, the greater the degree of reported freshness following sleep; (c) a positive relationship exists, contrary to expectations, between both the number and the amplitude of body movements on the one hand and the degree of reported freshness on the other, i.e. the more frequent and the more pronounced body movements are during sleep, the greater is the feeling of freshness reported in waking. SUMMARY

The present investigation sought to establish certain objective correlates of refreshing and unrefreshing sleep. Two groups consisting of 11 emotionally stable and 11 emotionally labile subjects were selected from a larger sample of 127 randomly selected male students. Differentiation of these two study groups was made by a measure of emotional stability-lability established through factorial analyses of questionnaire data, body measurements, and measures of autonomic functions. In the present investigation, average depth of sleep as evidenced by EEG criteria failed to differentiate the two study groups. Findings of the present study, however, indicate that emotionally labile subjects (1) manifest more movements of facial muscles during sleep and, as shown by actographic recordings, (2) they display less body movements as well as (3) less pronounced body movements during sleep than emotionally stable subjects. Multiple correlation of these indices with the questionnaire-scale utilized to assess subjective feelings of freshness following sleep yielded a highly significant coefficient of 0.80. On the basis of the above results, objective correlates of sleep subjectively reported to be refreshing consist of: (1) minimal movements in facial muscles and (2) a maximum of pronounced body movements during sleep. As measured by EEG potentials, depth of sleep appears to be unrelated to the degree of freshness on waking. References p . I74

174

G. A. L I E N E R T A N D E. OTHMER

ACKNOWLEDGEMENT

This work was supported by a grant from the Deutsche Forschungsgemeinschaft which is gratefully acknowledged. REFERENCES KLEITMAN, N., (1963); Sleep and Wakefulness. Chicago, University of Chicago Press (p. 552). LIENERT, G. A., (1962); Verteilungsfreie Methoden in der Biostatistik. Meisenheim am Glan, A. Hain Verlag (p. 361). LOOMIS, A. L., HARVEY,E. N., and HOBART, G. A., (1937); Cerebral states during sleep as studied by human brain potentials. J . exp. Psycho/., 21, 127-144. QTHMER, E., (1965); Das Schlafverhalten als Funktion von Personlichkeitsmerkmalen, pharmakologischen und sozialpsychologischen Faktoren (in preparation).

175

The Effects of Certain Drugs on the Sleep Cycle in Man R. TISSOT Department of Psychiatry, University Hospital, Geneva (Switzerland)

Recent interest in paradoxical sleep in man directed our attention to the action of certain drugs upon the various phases of the sleep cycle in man. Since other investigators had observed that slightly higher than average dosages of benzodiazepine derivatives enhanced the patient’s recollection of dreams, we administered diazepam (Valium), another benzodiazepine derivative (Mogadon), and phenprobamate (Ganiaquil), to our patients. In view of the similarity between the EEG tracing of paradoxical sleep and that obtained in the animal under reserpine (Monnier and Gangloff, 1956), we also used the alkaloid of Rauwolfia serpentina. In contrast to the barbiturates, known to reduce the duration of paradoxical sleep (Oswald et al., 1963) all these drugs caused a significant increase of this phase as shown in Table I. TABLE I DRUGS INCREASING THE DURATION OF PARADOXICAL SLEEP

Number of nights

Control nights

20

Diazepam

Duration of paradoxical sleep in % of total

Number of paradoxical phases

22

3.0

10-30 mg Phenprobamate

9

39 (P < 0.01)

3.9 (P < 0.02)

800 mg Mogadon 30-40 mg

7

33 (P < 0.01)

3.2

3

30

4.3

5

41 (P < 0.01)

4.6 (P< 0.02)

3

17

3.0

Reserpine 3 4 mg

Barbiturate 25&500 mg

More interesting still than the slight but significant increase in the duration of paradoxical sleep would appear to be the observation that this inciease occurs at the expense of stages 111-IV of classic sleep and not of stage 11. Furthermore, in the recordings of control nights we were struck, as had been others (Delange et al., 1961), by the fact that the paradoxical phases regularly occurred between those of type 11. Even in the early stages of the night, when the paradoxical phase usually follows a deep sleep of type 111-IV, a transitory phase of type I1 was References p. 177

176

K. TISSOT

regularly observed. What is more, it is by no mean6 rare, even without drugs, to observe elements of type 11, especially spindles characterizing the onset of sleep, during the paradoxical phase. After administration of the tranquilizers this tendcncy is markedly greater. These two observations-that the duration of pnradoxical sleep is increased by tranquilizers and reserpine at the expense of slow sleep 111-IV and not of stage 11, and that the appearance of stage I1 elements between characteristic paradoxical phases is increased by tranquilizers-led us to wonder whether the dualistic concept of the nature of classic, slow sleep and paradoxical sleep would not have to be mcdified somewhat (Jouvet, 1962). Whereas the contrast between paradoxical sleep and sleep of type 111-IV appears certain, the linkage between the paradoxical phase and stage I1 of classical sleep seems an indication of synergistic background mechanisms. The following brief account indicates how we have attempted to resolve the problem. By systematically computing from our tracings the times of the beginning and end of each of the classic stages 11, 111-IV and paradoxical sleep (P) we f0ur.d that a correlation exists between the duration of one such stage and the time that elapses before its recurrence. In general the longer a stage lasts, the longer is the interval before the next of the same type. This correlation can be expressed by a regression line of which the slope provides the most probable relationship between the two periods. But like all cyclic activity, a correlation between the consummatory activity and the period of rest that follows is the expression of a need. Thus-and this recalls the intuitive genius of Claparbde-we feel that the slope of our regression line expresses the quantitative need of each stage of sleep. It will be found that the greater the slope, the smaller the requirement. On this basis it is possible to approach the study of the sleep cycle from the point of view of the relationship between the slopes, i.e. between the need for each successive stage of sleep. Our results appear to show that the slopes of stages 111-IV and P, i.e. their reciprocal requirement, have a hyperbolic relationship. That is to say, that as the need for stage 111-IV increases, the need for stage P decreases along a hyperbola. The same relationship exists between stages 11 and 111-IV. If, now, two variables are each hyperbolic functions of a third, they will vary synergistically and according to a parabolic function. If our demonstration corresponds to the facts, the concept of a general opposition between classical and paradoxical sleep requires a certain modification. There is a competitive relationship between slow, deep sleep, stage 111-IV,on the one hand, and paradoxical sleep and stage 11 on the other, whilst between these two last mentioned a synergism exists. Medication affects the relationships between the different stages of sleep. Whereas in control nights the synergism between stages P and I1 is expressed by a very narrow, vertical parabola, it is represented by a flat parabola in the case of tranquilizers and an intermediary position in the case of reserpine. The hypothesis is put forward that the increase in the paradoxical phase due to the tranquilizers and reserpine occurs by very different mechanisms. It is likely that these tranquilizers, which the clinician often terms sleep-inducers, act by increasing the need for phase I1 of the onset of sleep, with the indirect result that the duration of Dara-

EFFECTS OF CERTAIN D R U G S ON THE SLEEP CYCLE

177

doxical sleep is increased. On the other hand, reserpine probably acts by directly increasing the need for paradoxical sleep, which in turn produces a relative increase in stage 11. Encouraged by the support of Monnier and Gangloff (1956), and Monnier and Tissot (1958), we have resumed our study of the action of reserpine in animals in an attempt to confirm or disprove this hypothesis. These studies are well under way. SUMMARY

In conclusion, our study of sleep-inducing tranquilizers and of reserpine led us via a quantitative evaluation of the human sleep cycle to cast doubt on the overall opposition of slow, classic sleep and paradoxical sleep. We believe that, while there does in fact exist an opposition between the respective needs of stage 111-IV on the one hand and of stage TI and paradoxical sleep on the other, paradoxical sleep and stage I1 are synergistic. This concept illustrates well the continual interdependence of the various stages of sleep on the basis of their reciprocal requirements. It implies that the appearance of a given stage does not depend on its .own regulatory mechanism alone, but also on the interrelations between this mechanism and those of other stages. This would tend to confirm the subjective view of the unity of a normal night’s sleep in the adult. Far from lessening the sense and significance of the differences and oppositions between both the nervous structures and the mechanisms regulating the different phases of sleep, it shows that as a higher function of the CNS, sleep reestablishes a unity by integrating them, in the real sense of the word, into a single process of interactions of closely related elements. REFERENCES J., and PASSOUANT, P., (1961); Etude EEG des divers stades du DELANGE, M., CASTAN, P., CADILHAC, sommeil de nuit chez I’enfant. Considerations sur le stade IV ou d‘activite onirique. Rev. Neurol., 105, 176-181. JOUVET,M., (1962); Recherches sur les structures nerveuses et les mkanismes responsables des diffkrentes phases du sommeil physiologique. Arch. itul. Biol.,100, 125-206. H., (1956); Action of chlorpromazine, reserpine and serotonin on the MONNIER, M., and GANGLOFF, unanesthetized rabbit’s brain. Electroenceph. elin. Neurophysiol., 8, 700-701. M., and TISSOT, R., (1958); Action de la reserpine et de ses mediateurs (5-hydroxytryptoMONNIER, phane-serotonineet DOPA-noradrenalin e) surle comportement et le cerveau du lapin. Helv. physiol. pharmacol. Acta, 16,255-267. OSWALD, I., BERGER, R. J., JARAMILLO,R. A., KEDDIE, R. M., OLLEY,P. C., and PLUNKETT, G. B., (1 963); Melancholia and barbiturates: A controlled EEG, body and eye movement study of sleep. Brit. J . Psychiut., 109, 66-78.

178

Amplitudes and Evoked Responses in the EEG in Humans during Sleep and Anesthesia J. KUGLER

AND

A. DOENICKE

Department of Neurology and Department of Anesthesiology, Surgical University Policlinic, University of Munich, Munich (Germany)

For the purpose of assessing the periodic transitory trophotropic-ergotropic fluctuations in clinical electroencephalographic and psychometric tests during sleep and anesthesia the EEG has been found superior to other methods. It produces no psychosensory stimuli that interrupt sleep, recording can be continuous, and quantitative analysis is possible by simple means.

( 1 ) Integration of amplitudes during sleep EEG tracings were made in 10 healthy volunteers under standard conditions from the 50th t o the 90th min after oral administration of 100 mg phenobarbital, 5 mg of a benzodiazepine and 700 mg of a urea derivative. A minimum of 1 week was left between tests on the same individual. The variations in potential from the right parietooccipital pair of electrodes were recorded through a second EEG apparatus with a recording speed of 0.2 mm per sec, and transmitted to an electronic integrator which registered values proportional to the amplitude integral o f the curve every 10 sec. A curve of the depth of sleep was also made, showing the time in minutes of the classic stages of sleep as observed visually. The amplitude integral drops below the initial level in stages B 0 and B 1, and increases in stages C and D. It expresses the fluctuating synchronization processes which in sleep cause the appearance of waves of high amplitude. The increase in values during sleep are interpreted as trophotropic and their transitory drop as ergotropic regulation. The balance between these two influences varies at all levels of consciousness. The depth of sleep fluctuates at every stage. The periods of paradoxical sleep with low, fast activity have various surface integrals. Paradoxical sleep with its dissociation of activating and inhibiting systems is encompassed in the periodicity of trophotropic-ergotropic regulation. The absolute and relative duration of sleep was measured in the EEG. It was shorter with phenobarbital (55% of the registered duration) than with the benzodiazepine (78%) and urea derivatives (69%). If the ordinates of the sleep depth curves are graduated, mean value curves can be made for each test series and basic values for the average depth o f sleep calculated. The depth of sleep is markedly less after phenobarbital (factor l .4) than the benzodiazepine (2.16) and urea derivatives (2.22).

AMPLITUDES AND EVOKED RESPONSES I N THE EEG

179

The sleep stage curves show no significant variations to occur in the distribution of light (around 2073, medium (around 60%), and paradoxical (around 20%) sleep between the three medications used. After phenobarbital the individual curves often show a slow onset of sleep with multiple initial light sleep stages. The benzodiazepine derivative induces sleep with relatively slight fluctuations. The subjects can be wakened at any time, and no clinical side effects are observed. Fluctuations in depth of sleep are more common and greater after the ureide. Increasing the dose of ureide causes dizziness and other side effects and a decrease in the average depth of sleep in 2 out of the 10 subjects. (2) Integration of amplitudes under anesthesia

EEG tracings, amplitude integrals and evoked responses were recorded following intravenous administration of various anesthetics. The so-called ultra-short anesthetics of the barbiturate series (methchexital 150 mg) produce an after-effect of drowsiness lasting for 12-24 h. This would make the subject unfit to drive a motor vehicle (Fig. 1, upper tracings).

Fig. 1. Top: right parieto-occipital EEG and amplitude integration following barbiturate anesthesla (inethohexital). Recording speed 0.2 mmjsec. Anesthesia and sleep depth curve with several stages o f sleep over 12 h. Below: EEG, amplitude integration, anesthesia and sleep depth curve following propanidide: short-lived anesthesia, n o post-anesthetic sleep over 12 h.

In contrast propanidide (Epontol@,Bayer), 500 mg i.v., produces shorter anesthesia and analgesia than barbiturate and no post-anesthetic sleepiness (Fig. 1, lower tracings). Propanidide produces more rapid activity in EEG than barbiturates. ReJerences p .

182

180

J . K U G L E R A N D A. DOENICKE

In the first few minutes after injection of Thalamonal@ (25 mg Droperidol and Q.5 mg Fentanyl) there is no high voltage slow activity in the EEG, and yet the analgetic effect is remarkable. The subjects often require artificial respiration. The dissociation between EEG and clinical signs of anesthesia are similar to that in paradoxical sleep (Fig. 2). Only 20 to 30 minutes after the analgesic effect has disappeared,

Fig. 2. Above: EEG in waking state and maximum depth of anesthesia. Depth of anesthesia and sleep over 12 h following [email protected]: EEG in waking state and maximum depth of anesthesia. Depth of anesthesia and sleep over 12 h following propanidide. At maximum depth of anesthesia following Thalamonalm n o high, slow activity as with propanidide. Abundant post-anesthetic sleep after Thalamonal@.

sleep patterns are recognizable in the EEG which last for several hours. The subjects may complain of dizziness, nausea and weakness in the legs and collapse when trying

References p . 182

AMPLITUDES AND EVOKED RESPONSES IN THE EEG

.. a $

% -

3$ a m

Y

181

182

J. KUGLER A N D A. DOENICKE

to stand. These side effects are relieved by 0.5 mg Akineton@(3-piperidino-I-phenyl1-bicycloheptenyl-propanol-1lactate).

(3) Evoked responses in anesthesia Evoked responses in the occipital region were produced by rhythmical light flashes in 9 healthy persons under anesthesia with propanidide and 4 under methohexital. The average value of every hundred such discharges was determined electronically with the algebraic averaging apparatus of Keidel.* The electrodes were placed in occipitoparietal, paramedian, and bipolar positions according to Brazier : the flashes were produced by means of an ordinary stroboscope at a frequency of 3.8 per sec held 5 cm before the closed eyes of the subject. Upon rapid absorption of propanidide (500 mg i.v.) the wave I (Cighnek) is not effaced in the early stages with high voltages, slow activity; waves I11 and V display changes in amplitudes and peak times (Fig. 3). An increase of evoked responses is noticeable with the advent of fast activity. Interestingly, propanidide produces a lot of fast cortical activity; yet, the amplitudes of waves I and I11 are often greater in this stage of anesthesia (shortly before awakening) than in the drug-free waking state. SUMMARY

Under standard conditions the EEG of normal subjects shows the average duration. and depth of sleep after 100 mg phenobarbital to be smaller than after 5 mg of a benzodiazepine and 700 mg of a urea derivative. No statistically significant differences in the distribution of light, medium and paradoxical sleep appeared. Tests in healthy subjects with various short acting barbiturate anesthetics showed a tendency to sleep lasting over 12 h ; this did not occur after propanidide. After Thalamonal@there was a dissociation between the degree of synchronization in the EEG and the clinical signs of anesthesia, comparable to that seen in paradoxical sleep. The algebraic means of evoked occipital responses after propanidide, which causes a lot of fast cortical activity, showed a dissociation between the degree of synchronization in the EEG and the synaptic transmission mechanisms in the systems of visual projection. ‘Paradoxical’ phases are phenomena that occur not only in sleep but also during the course of drug induced stages of anesthesia. REFERENCES

BRAZIER, M. A. B., (1962); The analysis of the brain waves. Scientific American, 206/6, 142-153. CIGANEK, L., (1961); The EEG response (evoked potential) to light stimulus in man. Electroenceph. clin. Neurophysiol., 13, 165-172. KEIDEL, W. D., (1 959); Elektronisches Rechenwerk zur Mittelwertsbildung statistisch streuender periodischer bioelektrischer Potentiale. Zschr. Biol., 111, 969-999.

__* This work was supported by ‘Deutsche Forschungsgemeinschaft’.

IV. THERAPEUTIC ASPECTS OF SLEEP

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Pharmacology of Hypnotic Agents H. KONZETT Pharmacological Institute, University of Innsbruck, Innsbruck (Austria)

Synthetic substances for inducing sleep have been in use for almost a century. The ball was opened by Liebreich with chloral hydrate in 1869. Only a few years later Cervello (1883) announced in connection with his investigation of the somnifacient action of paraldehyde that, in view of the toxicity of chloral hydrate ‘the discovery of a safe substitute... must undoubtedly be regarded as a welcome advance’. This same desire and hope of finding an ideal hypnotic without harmful side effects has stimulated chemists and pharmacologists for decades to go on synthesizing new substances and testing their hypnotic effect. Sedatives and hypnotics have played not a small part in the drug explosion (Modell, 1961) which is giving concern in so many circles today. Requirements of a good hypnotic are high. Given orally, it must produce a state as similar and equivalent to natural sleep as possible, the effect ceasing after an appropriate time without undesirable after-effects (e.g. hangover), allowing the sleeper to awaken fit and refreshed. Prolonged use should not lead to habituation nor physical dependence, nor cumulative effects on body functions. Overdosage should not entail a danger to life. When one considers that natural sleep is a highly complex process, of which neither the occurrence nor the neurophysiological and biochemical characteristics are fully understood (Eccles, 1961), one sees the difficulties of a systematic search for a superior hypnotic. While the ideal substance, which would leave nothing to be desired, has not yet been found, there are a number of drugs available with which the doctor can treat disturbances of sleep. A prerequisite for their correct use is a knowledge of their action. The following considerations are intended as a contribution to this knowledge : circumstances require that it be restricted principally to the important common properties of this class of substances and only briefly mention their individual characteristics. Methods of testing hypnotics For testing the hypnotic effect of a substance experimentally, abolition of the righting reflex is most often used. In small animals (mouse, rat) first of all the dose is determined which causes them to lie on their back or side and the time is measured to the point at which the righting reflex returns. This gives a rough indication of the strength and duration of action. With typical hypnotics the state of sleep which can be interrupted by external stimuli can easily be transformed into the stage of general anesthesia References p . 1921193

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by increasing the dose. In contrast, sedatives (tranquilizers)-even in high dosesare not general anesthetics. In large animals (e.g. rabbit, cat, dog, monkey) observation of the righting reflex is supplemented by electroencephalography, changes known to be associated with natural sleep being noted :the appearance of high-voltage, slow frequencies (synchronization) with brief bursts, or spindles of medium-voltage waves, raised threshold for response to sensory stimuli, etc. After administration of hypnotics and sedatives, the first sign in the EEG to appear may be an increase of fast rhythms with large /?-waves (Von Stockert, 1942; Cohn and Katsenelbogen, 1942); this initial temporary phase of excitation is regarded as corresponding to a release of the cortex from inhibition (Brazier, 1963). Appropriate electrophysiological techniques enable stimuli to be given and recordings- taken in deeper brain areas. By this means, the site of action of central depressant substances can be located. Barbiturates in hypnotic doses, for example, depress the activity of cortex, hypothalamus, limbic and reticular systems. Small doses of barbiturates can increase the excitability of the diffuse thalamic projection system which causes a recruiting response in the cortex (Domino, 1962). Recording of action potentials and tonus in striated muscle can also be instructive. When the hypnotic effect of a substance has been determined by observation of animal behaviour and by electroencephalographic, electrophysiological and myographic tracings, a general pharmacological analysis is still required to assess toxicity and side effects.

Methods of testing sedatives In addition to hypnotics, the specific effect of which is to cause sleep and general anesthesia in animal experiments, the sedatives or tranquilizers (Taeschler and Schlager, 1962) have attained considerable importance as sleep-facilitating or sleepinducing substances. Numerous experimental models have been used to test a sedative (tranquilizing) effect, without sleep or general anesthesia; these methods have reached a certain degree of perfection in the last few years (Parkes, 1961; Stille, 1962). For example, increased motor activity produced in small animals by change of environment or by stimulants, is inhibited by sedatives. The specific sedative effect can be particularly clearly characterized by a ratio, e.g., when the dose reducing stimulated motility is much smaller than that affecting the righting response. Intensification and prolongation of the effect of hypnotic and anesthetic agents (potentiated narcosis), anticonvulsive effects against strychnine and cardiazol shock and electroshock and inhibition of polysynaptic reflexes (muscle relaxation due to blocking of interneuronal transmission) are also typical properties of sedatives. Electrophysiological techniques have enabled a selective inhibitory effect of certain tranquilizers (e.g. chlordiazepoxide) on the limbic system to be demonstrated (Himwich et al., 1962). Other sedatives present rather unspecific central depressant effects similar in many ways to those produced by the hypnotics in low doses. It does not appear possible at present with electrophysiological methods alone to make a clear

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distinction between certain tranquilizers and low doses of barbiturates (Domino, 1962, 1963; Berger, 1963). Sedative effects, finally, can be recognized from the behaviour of animals in situations of coordinated aggression requiring considerable integrative ability (taming effect) and on the performance of trained animals in conditioning techniques. Critique of present methods

Thus hypnotic-anesthetic effects and sedative effects can be recognized and distinguished experimentally. A sharp discrimination, however, is difficult because hypnotics and sedatives have properties in common within broad limits of dosage. Pharmacological sleep (especially after high doses of hypnotics), however, is usually closer, as regards both the animal’s behaviour and electrophysiological criteria, to anesthesia than to natural sleep. In contrast to natural sleep, the whole reticular system and the recruiting intralaminary system of the thalamus are depressed by hypnotics in higher doses, and this is considered to be the cause of the difficulty of wakening from deep pharmacological sleep (Gangloff and Monnier, 1957). In finches, certain postural and righting reflexes have been shown to be conserved in natural but not in pharmacologicallyinduced sleep (Hondelink, 1932). Further, it is possible that hypnotics change the relationship between classical sleep (slow sleep) and the paradoxical phase of sleep (Jouvet, 1961 ; Gresham et al., 1963). We can thus say that pharmacological and natural sleep have features in common but also distinct differences, and this experimental finding is also valid for man (Jung, 1963). Natural sleep is distinguished from the waking state by alterations in cerebral activity, total neuronal activity being nearly undiminished (Kety, 1961) ;pharmacologically-induced deep sleep on the other hand is characterized by extensive inhibition of cerebral activity, manifested by the absence of neuronal discharge (Jung, 1963). Moreover, sleep in animals differs not inconsiderably from that in man, in regard to periodicity, duration etc. It is noteworthy for example that thalidomide induces sleep in man but no general anesthesia-even in high doses-in animals (Kuhn and Van Maanen, 1961). To explain the hypnotic effect of this substance by interference with a natural ‘hypnagogic’ agent is not justified. Human testing and application

In testing hypnotics in man, depth and duration of sleep may be measured actographically by means of sensorimotor reaction tests or by the EEG. The after-effects on awaking may be demonstrated in psychological tests (e.g. measurement of reaction time, concentration tests, psychomotor coordination etc.). The aim in administering a hypnotic to a human subject is to select a dose which will produce and maintain sleep for a certain length of time without a transition to anesthesia. In using sedatives (and tranquilizers) for the treatment of sleep disorders, the aim is to facilitate and induce sleep. References p. 1921193

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The mechanism and the indications for the use of hypnotics and sedatives are thus (cum grano sulis) different.

Classification of hypnotics and sedatives Hypnotics and sedatives may be classified according to various principles. For example, they can be divided up into different groups according to chemical structure. For practical therapeutic purposes, the differentiation of sleep-inducing agents (with rapid onset and short duration of action) and sleep-maintaining agents (with slow onset and prolonged action) may be useful, although recent studies in man have thrown doubt on the validity of this distinction (Lasagna, 1956 Hinton, 1961;). In normal doses the former should induce sleep within 15-30 min, lasting only 2-4 h, while the latter, acting 30-60 min after administration, should produce sleep with a duration of 4-8 h. Onset and duration of sleep depend on absorption, metabolic fate and elimination of the hypnotic. Corresponding studies have shown wide individual variations for the barbiturates (Lous, 1954). Where appropriate, for instance, in anxiety states, sedatives or tranquilizers may be given not only just before retiring but spread over the whole day in order to facilitate sleep at the appropriate time.

Chemistry Alcohols, aldehydes, carbamates, ureides, barbiturates, piperidine and quinazolone derivatives form the most important hypnotics in practical use. For the doctor not used to chemical nomenclature, it may often be difficult to obtain from the unfamiliar and complicated details given, a clear idea of the chemistry of a hypnotic. Phenobarbital (Luminal@),for instance, can be referred to as acidum phenylaethylbarbituricum, 5-phenyl-5-ethyl-barbituric acid, phenylethylmalonylurea, phenylethylmalonylureide, and also as 5-phenyl-5-ethyl-2,4,6-trioxohexahydropyrimidine or S-phenyl-5-ethyl-hexahydropyrimidine-2,4,6-trione. These acrobatics of nomenclature suggest that the confusion, especially in pharmaceutical pamphlets, is not entirely unintentional. Hypnotics of the alcohol series include tertiary amyl alcohol (amylenehydrate) and unsaturated non-nitrogen carbinols. The latter are given in capsule form on account of their unpleasant smell and taste. Ordinary ethyl alcohol is usually not classed as a hypnotic in view of its central stimulating action, though it is sometimes employed in isolated cases as a hypnotic. Diacetone alcohol has been established as an active constituent of ‘sleepy grass’ having central depressant properties (Epstein e l al., 1964). Unsubstituted barbituric acid has no hypnotic effect. Substitution of alkyl and aryl radicals in 5,5 position leads to useful compounds. N-Methylation and replacement of the oxygen on the carbon atom in position 2 by sulfur shortens the duration of action. The barbiturates used as short-acting anesthetics are not considered in the present connection. Non-barbiturate hypnotics were developed and recommended in the belief that

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they would avoid the undesirable effects of the barbiturates and that poisoning would be less common. Unfortunately this wishful thinking was not fulfilled. The case of thalidomide has more than proved that a non-barbiturate may also have dangerous effects. The acute toxicity of some non-barbiturate hypnotics in man may be somewhat less than that of certain barbiturates; but the difference is purely quantitative. The harmful effects of chronic use are the same in both cases. The label ‘non-barbiturate’ is thus no very special recommendation. While piperidine derivatives still show a fairly close structural relationship to the barbiturates this is lacking in the quinazolone derivatives. The sedatives (tranquilizers) are either hypnotics given in small doses or else derivatives of aliphatic alcohols and their carbamates or heterocyclic compounds of diverse structure. The neuroleptics, which also have sedative effects when given in low doses, are not included here as their main field of indications lies elsewhere. This survey already shows that neither hypnotic nor sedative effects are related to a particular chemical configuration, but that compounds of quite diverse chemical structure may produce sleep in the one case and sedation in the other. Knowledge of the chemical composition of these substances, however, helps one to find one’s way in this extensive field.

Fate in the body All the usual hypnotics are adequately absorbed from the gastrointestinal tract, though in varying degrees, so that rectal or parenteral administration is only exceptionally required. Physicochemical characteristics, such as lipid solubility, and in the case of the barbiturates ionization, which is dependent on pH, are of significance for absorption. In the blood, partial reversible binding of the barbiturates to proteins takes place. For penetration of the central nervous system, which is after all the most important aspect, lipid solubility is the decisive factor (Mayer et al., 1959). Distribution of the barbiturates and other hypnotics and sedatives in the brain, so far as has been determined, is fairly uniform, without any special concentration in particular areas (Domek et al., 1960; Emmerson et al., 1960). Elimination from the plasma varies widely from one barbiturate to another. The hourly fall-off in plasma concentration of barbital and phenobarbital is about O.S%, of pentobarbital and aprobarbital24X and of hexobarbital about 10% (Richards and Taylor, 1956). Chloral hydrate is metabolized to trichloroethanol and trichloroacetic acid. Paraldehyde and methylpentynol are completely broken down to carbon dioxide and water. Degradation of barbiturates takes place mainly by oxidation of the radicals in position 5, removal of those attached to the N atoms and hydrolysis of the barbiturate ring. The metabolites can be identified in the urine. Although the liver is vital for the degradation of many barbiturates and other hypnotics, it is only in the presence of major liver dysfunction that their action is prolonged. Barbiturates are eliminated via the kidneys : 90% of barbital, 30% of phenobarbital, References p , 1921193

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allobarbital and aprobarbital are excreted in this way, the other barbiturates only in very small residues. When kidney function is disturbed, barbiturates dependent on this mode of excretion should not be given. Elimination of barbiturates by the intestine and in the expired air is negligible. Paraldehyde is largely eliminated through the lungs, and only to a much smaller extent through the kidneys. Methylpentynol is found in the urine only after high doses. Renal excretion of glutethimide takes place very slowly. Toxicity

Experimentally, all hypnotics in high doses depress respiratory and circulatory functions. Administration of average hypnotic doses to subjects with a sound cardiovascular system, however, produces only insignificant respiratory, circulatory and cardiac changes such as are seen also in normal sleep. The peripheral ganglionblocking effect of these substances which can be demonstrated experimentally (Brucke et al., 1947; Kewitz and Reinert, 1952) can also be ignored in man at the usual doses. When respiratory function is impaired, however, e.g. in severe emphysema, any hypnotic in high doses may reduce the minute volume, the 0, saturation and the p H of the arterial blood and increase the CO, concentration. Paraldehyde appears to depress respiration slightly less than barbiturates in hypnotic doses. Respiratory paralysis is the main danger in acute intoxication with all hypnotics, including the non-barbiturates : deaths have also been reported from non-barbiturate hypnotics e.g. glutethimide (Ibe et al., 1961). In toxic but not in therapeutic dosage, barbiturates and other hypnotics (e.g. chloral hydrate, methyprylone and the ‘non-barbiturate’ glutethimide) produce marked hypotension. Cardiac arrhythmia with corresponding electrocardiographic changes has also only been repoi ted after toxic doses of barbiturates (Kirkegaard and Nerrregaard, 1950; Schaffer and Seegers, 1956). Isolated cases have been observed of reduced intestinal motility after high doses of hypnotics similar to the change occurring in natural sleep. A hepatotoxic effect after normal doses of hypnotics is extremely rare and can be interpreted as a hypersensitivity on an allergic basis (Shideman, 1961). Single intravenous doses of pentobarbital did not obviously affect hepatic function in patients with liver disease (Sessions et al., 1954). Basal metabolic rate and blood sugar showed no change following administration of various barbiturates in sedative-hypnotic dosage, but abnormal glucoset olerance curves were occasionally seen after higher doses (Merivale and Hunter, 1954). Megaloblastic anemia resulting from prolonged consumption of barbiturates has been recorded (Calvert et al., 1958; Chanarin et al., 1960). Direct manifestations of local intolerance in the mucosae may occur after administration of barbiturates and chloral hydrate, and also from the break-down of paraldehyde which contains acetic acid in considerable concentration. Allergic dermatitis of various degrees of severity has been reported after barbiturates and other hypnotics (Shideman, 1961).

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Acquired tolerance, habituation and addiction Acquired tolerance of hypnotics means the need to increase the dosage in order to maintain the hypnotic effect in chronic use. The development of such a tolerance towards various barbiturates, also cross-tolerance (Gruber and Keyser, 1946), chloral hydrate (Wallace, 1912) and paraldehyde (Carmichael et al., 1942), has been demonstrated in laboratory animals (rat, rabbit, dog). In man also experimental administration of high doses of pentobarbital and secobarbital(O.4 g) led to tolerance of these two barbiturates developing within two weeks (Belleville and Fraser, 1957). Uninterrupted consumption of barbiturates in high doses over long periods in the insurmountable desire for a sedating or on the other hand a stimulating, euphoriant effect-both are possible-may lead to physical dependence. Signs of intoxication following chronic misuse of barbiturates have been repeatedly described, especially in recent years (Bay, 1960; Scheid et al., 1961; Laubenthal, 1964). Speech disturbances, clouding of consciousness, dizziness, uncertainty, tremor, nystagmus, dysarthria and ataxia have been observed. If the drug is suddenly stopped, withdrawal symptoms such as anxiety states, muscle twitching, tremor, fatigue, weakness, visual disturbances, vomiting, insomnia, loss of weight, postural hypotension, and even convulsions and delirium occur. Sudden withdrawal may even be fatal, with violent convulsions, fall in blood pressure and hyperpyrexia (Fraser et al., 1953). Unlike the opiates, only extremely high doses of barbiturates lead to habituation and dependence, with withdrawal symptoms. Small doses can be taken for years without danger of addiction (Shideman, 1961). Not only the barbiturates are dangerous. Chloral hydrate and paraldehyde and also the newer non-barbiturate hypnotics can produce addiction (Creve and Schonberg, 1961;Laubenthal, 1964). Tranquilizers such as meprobamate are also potentially addicting (Shaw and Felts, 1959). Hollister et al. (1961) managed to produce a withdrawal reaction with chlordiazepoxide by giving enormous doses (8-20 times higher than usual) for 5-6 months and then abruptly discontinuing it. CONCLUSIONS AND SUMMARY

In attempting a synopsis of the field of sedatives and hypnotics, one comes to the conclusion that there are a whole series of effective products available, with which the doctor can fulfill most therapeutic requirements. Hypnotics and sedatives are largely innocuous for short-term use. In chronic use, which is mostly misuse, harmful effects are to be expected. Strict observation of the indication for treatment on the one hand and proper information of the patient on the other seem especially important for the prevention of injurious use in this particular field. It is probably preferable that the doctor select a few hypnotics and sedatives with distinct modes of action out of the large number available and only relinquish them in favour of new substances when experimental and clinical results have convincingly demonstrated a significant advance. A certain conservatism in this respect particularly is no doubt of advantage. Hypnotics and sedatives with completely new or different characteristics from those References p . 1921193

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known hitherto may be discovered by chance or as a result of more profound understanding of the nature of sleep afforded by continuing neurophysiological and biochemical investigations. REFERENCES BAY,E., (1960); Der Arzneimittelmissbrauch des “modernen Menschen”. Dtsch. med. Wschr., 85, 1676-1680. H. F., (1957); Tolerance to some effects of barbiturates. J. Pharmacol. BELLEVILLE, R. E., and FRASER, exp. Ther., 120, 469-474. BERGER, F. M., (1963); The similarities and differences between meprobamate and barbiturates. Clin. Pharmacol. Ther., 4, 209-231. BRAZIER, M. A. B., (1963); Effects upon physiological systems. Physiological Pharmacology, Vol. 1. W. S. Root and F. G. Hofman, Editors. New York and London, Academic Press (p. 219-238). BRUCKE, F., MACHO,W., and WERNER, G., (1947); Uber die lahmende Wirkung von Schlafmitteln auf vegetative Ganglienzellen. Wien. klin. Wschr., 59, 537-540. CALVERT, R. J., HURWORTH, E., and MACBEAN, A. L., (1958); Megaloblastic anemia from methophenobarbital. Blood, 13, 894-898. CARMICHAEL, E. B., KAY,F. A., and PHILLIPS,G. W., (1942); Development of tolerance in guinea pigs by repeated administration of large doses of paraldehyde. Fed. Proc., 1, 13-14. CERVELLO, V., (1883); Uber die physiologische Wirkung des Paraldehyds und Beitrage zu den Studien uber das Chloralhydrat. Naunyn-Schmiedeberg’s Arch. exp. Path. Pharmak., 16, 265-290. CHANARIN, I., LAIDLAW, J., LOUGHRIDGE, L. W., and MOLLIN,D. L., (1960); Megaloblastic anemia due to phenobarbitone. Brit. med. J., 1, 1099-1102. COHN,R., and KATSENELBOGEN, S., (1942); Electroencephalographic changes induced by intravenous sodium amytal. Proc. Soc. exp. Biol., 49, 560-563. CREVE,W., and SCH~NBERG, F., (1961); Sucht und Entziehungserscheinungen bei barbituratfreien Schlafmitteln. Dtsch. med. Wschr., 86, 106-1608. DOMEK, N. S., BARLOW, C. F., and ROW, L. J., (1960); An ontogenetic study of phenobarbital-CI4 in cat brain. J. Pharmacol. exp. Ther., 130, 285-293. DOMINO, E. F., (1962); Sites of action of some central nervous system depressants. Ann. Rev. Pharmacol., 2, 215-250. DOMINO, E. F., (1963); Commentary on ‘The similarities and differcnces between meprobamate and barbiturates’. Clin. Pharmacol. Ther., 4, 231-233. J. C., (1 961); Chairman’s Closing Remarks. Ciba Foundation Symposium on the Nature of Sleep. ECCLES, G. E. W. Wolstenholme and M. O’Connor, Editors. J. and A. Churchill, London (p. 397-400),. EMMERSON, J. L., MYA,T. S., and YIM, G. K. W., (1960); The distribution and metabolic state of Carbon-14 meprobamate in the rat brain. J. Pharmacol. exp. Ther., 129, 89-93. K., and KARLER, R., (1964); The hypnotic constituent of Stipa vasegi, sleepy EPSTEIN, W., GERBER, grass. Experientia, 20, 390. FRASER,H. F., SHAVER, M. R., MAXWELL, E. S., and ISBELL, H., (1953); Death due to withdrawal of barbiturates. Ann. Intern. Med., 38, 1319-1325. GANGLOFF, H., and MONNIER, M., (1957); Topische Wirkung des Phenobarbitals auf Cortex, Rhinencephalon, Nucleus caudatus, Thalamus und Substantia reticularis des Kaninchens. NuunynSchmiedeberg’s Arch. exp. Path. Pharmakol., 231, 211-218. GRESHAM, S. C., WEBB,W. B., and WILLIAMS, R. L., (1963); Alcohol and caffeine: Effect on inferred visual dreaming. Science, 140, 12261227. GRUBER, C. M., and KEYSER, G. F., (1946); A Study on the development of tolerance and cross tolerance to barbiturates in experimental animals. J. Pharmacol. exp. Ther., 86, 186-196. HIMWICH, H. E., MORILLO, A., and SEINER,W. G., (1962); Drugs affecting rhinencephalic structures. J. Neuropsychiat., 3, Suppl. 1, 15-26. HINTON,J. M., (1961); The actions of amylobarbitone sodium, butobarbitone and quinalbarbitone sodium upon insomnia and nocturnal restlessness compared in psychiatric patients. Brit. J. Pharmacol., 16, 82-89. HOLLISTER, L. E., MOTZENBECKER, F. P., and DEGAN,R. O., (1961); Withdrawal reactions from chlordiazepoxide (‘librium’). Psychopharmaco/ogia, 2, 63-68. HONDELINK, H., (1932); Schlafmittelversuche an Finken. Naunyn-Schmiedeberg’s Arch. exp. Path. Pharmakol., 163, 662-671.

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IBE,K., NEUHAUS, G., and REMMER, H., (1961); Die akute Doridenvergiftung. Internist, 2,247-260. JOUVET, M., (1961); Telencephalic and rhombencephalic sleep in the cat. Ciba Foundation Symposium on the Nature of Sleep. G. E. W. Wolstenholme and M. OConnor, Editors. London, J. and A. Churchill (p. 188-206). JUNG,R., (1963); Der Schlaf. Physiologie und Pathophysiologie des vegetativen Nervensystems, Vol. 2. M. Monnier, Editor. Stuttgart, Hippokrates-Verlag (p. 650-684). KETY,S. S., (1961); Sleep and the energy metabolism of the brain. Ciba Foundafion Symposium on the Nature of Sleep. G . E. W. Wolstenholme and M. O’Connor, Editors. London, J. and A. Churchill (p. 375-381). KEWITZ,H., and REINERT, H., (1952); Prufung pharmakologischer Wirkungen am oberen sympathischen Halsganglion bei verschiedenen Erregungszustanden. Naunyn-Schmiedeberg’s Arch. exp. Path. Pharmak., 215, 547-555. KIRKEGAARD, A., and N0RREGAARD, S., (1950); Elektrocardiogrammet ved svaer akut barbituratforgiftning. Nord. Med., 44, 1954-1959. KUHN,W. L., and VANMAANEN, E. F., (1961); Central nervous system effects of Thalidomide. J. Pharmacol. exp. Therap., 134, 60-68. LASAGNA, L., (1956); Study of hypnotic drugs in patients with chronic diseases; comparative efficacy of placebo; methyprylon (Noludar); meprobamate (Miltown, Equanil); pentobarbital; phenobarbital; secobarbital. J. chron. Dis., 3, 122-133. LAUBENTHAL, F., (1964); Sucht und Missbrauch. Stuttgart, Thieme-Verlag. LIEBREICH, O., (1869); Das Chloral, ein neues Hypnoticum und Anastheticum. Berliner Klin. Wschr., 6, 325-327. Lous, P., (1954); Plasma levels and urinary excretion of three barbituric acids after oral administration to man. Acta pharmacol., 10, 147-165. MAYER, S., MAICKEL, R. P., and BRODIE, B. B., (1959); Kinetics of penetration of drugs and other foreign compounds into cerebrospinal fluid and brain. J. Pharmacol. exp. Ther., 127, 205-211. MERIVALE, W. H. H., and HUNTER, R. A., (1954); Abnormal glucose-tolerance tests in patients treated with sedative drugs. Lancet, ii, 939-942. MODELL, W., (1961); The drug explosion. Clin. Pharmacol. Ther., 2, 1-7. PARKES, M. W., (1961); Tranquillizers. Progress in Medicinal Chemistry, Vol. 1 . G . P. Ellis and G. B. West, Editors. London, Butterworths (p. 72-131). RICHARDS, R. K., and TAYLOR, J. D., (1956); Some factors influencing distribution, metabolism and action of barbiturates. A review. Anesthesiology, 17,414458. A. I., and SEEGERS, W., (1956); Effects on methyprylon (Noludar) and phenobarbital on SCHAFFER, the electrocardiogram. J. Amer. Gcriat. SOC.,4, 1078-1079. SCHETD, W., BRESSER, P. H., and HUHN,A., (1961); Erhebungen zur Frage der Haufigkeit des Medikamentenmissbrauches. Dtsch. rned. Wschr., 86, 929-935. J. T., MINKEL, H. P., BULLARD, J. C., and INGELFINGER, F. J., (1954); The effect of barbituSESSIONS, rates in patients with liver disease. J. clin. Invest., 33, 11 16-1 127. SHAW,C. C., and FELTS,P. W., (1959); Treacherous tranquilizers. Amer. J. med. Sci., 237, 141-149. SHIDEMAN, F. E., (1961); Clinical pharmacology of hypnotics and sedatives. Clin. Pharmacol. Ther., 2, 31 3-344. STILLE,G., (1962); Zentrale Muskelrelaxantien. Arzneimiitel-Forsch., 12, 340-347. TAESCHLER, M., and SCHLAGER, E., (1 962); Psychopharmaka, 2. Mitteilung, “Tranquillizer”. Schweiz. Apoth. Ztg., 100, 61-86. VONSTOCKERT, F. G., (1942); Klinische und therapeutische Auswertung des Evipanversuches in der Psychiatrie. Nervenarzt, 15, 185-191. G. B., (1912); Chronic chloral poisoning. J . Pharmacol. exp. Ther., 3, 462463. WALLACE,

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Neuropharmacological Aspects of the Action of Hypnogenic Substances on the Central Nervous System A. SOULAIRAC, J. CAHN. C. GOTTESMANN

AND

J. A L A N 0

Psychophysiological Laboratory of the Faculty of Sciences and Centre for Experimental Therapeutics, Piti6 Hospital, Paris (France)

The problem of the action of hypnotic substances was for a long time closely bound up with that of the physiology of anesthetics. The discovery of chloral already raised the question of its action in terms of that of chloroform. In the nineteenth century, studies of the effects of alkaline bromides on the central nervous system were essentially directed towards their anti-epileptic action and merely secondarily towards the hypnotic effects, and it is only later that one begins to find research into their mode of action. Theories o f differential solubility in lipids and other body fluids gave rise to numerous investigations, some of which show a preoccupation with discovering the site of action of these substances. The history of the barbiturates is similar: first used essentially for their anti-epileptic effects, they were then found to possess a powerful hypnotic action, and, after more than thirty years of studies too numerous to detail here, showed more and more signs of an elective action upon diencephalic structures. Contemporary research into the properties of the reticular formation has reopened the question, the important influence of the barbiturate group on this system having been demonstrated with the help of recent electrophysiological techniques. Discovery of large numbers of new substances with hypnotic properties makes it imperative to know whether these effects are always produced by modification of the same nervous structures. It was in search of an answer to this question that we undertook the investigations the essential results of which form the subject of the present report. Cahn (1961,1964) reported for the first time experimental data showing that the modification of postural tonus and the muscular relaxation produced by Librium caused at the same time EEG patterns apparently specific for proprioceptive deafferentation. In the rabbit these patterns are characterized essentially by ‘spiking activity’ : the appearance of numerous bursts o f rapid sharp waves (14-16 c/s) of high amplitude (200-25 pV), persisting as long as there is a sufficient degree of muscle hypotonia, while the slow (2-3 cis) or very slow (0.5-1.5 c/s) high-amplitude waves generally decrease fairly rapidly. It may be asked whether the presence of such modifications in the electrocorticogram is not merely evidence of synchronization. Certain experimental findings tend to invalidate this explanation, however: ( I ) Drugs of the type of MR 710 (dicyclo-

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propylketoxine), practically without central depressant effects but with powerful muscle-relaxant properties, also produced these same rapid spiking discharges in the EEG; (2) While evident cortical synchronization is produced in the EEG in the rabbit by i.v. injection of Taractan (chlorprothixene) in a dosage not affecting muscle tone, i.v. injection of Librium releases these rapid spiking bursts which are quite unlike either the ‘spindle bursts’ of barbiturate sleep or the rapid bursts of physiological sleep. Finally a recent article by Hodes (1962) shows that, in the cat, i.v. administration of curere for several hours causes cortical synchronization and inhibition of the response to certain sensory stimuli. Domino (1955, 1956) reported inhibition of the activation response under mephenesine; the same author described a pattern of ‘deactivation’ (see above) which is also seen with meprobamate. It was in order to clarify certain physiological aspects of this problem that we studied the action of different hypnogenic substances in the rat and rabbit. INVESTIGATION IN THE RAT

Material and methods

All investigations were performed in the male rat using electrodes permanently implanted according to the stereotaxic atlas of De Groot (1959). All animals had electrodes implanted in both frontal and both parietal areas of the cortex, in the dorsal hippocampus, the olfactory bulb and the mesencephalic reticular formation. Other electrodes enabled the tonus o f the neck muscles and ocular movements to be recorded at the same time electromyographically. Respiration was also recorded simultaneously. The animals were unrestrained and in a sound-proof box. Studies were first made of the animals’ physiological sleep and especially of the rhombencephalic stage. The threshold for cortical and behavioural arousal on electrical stimulation of the midbrain reticular formation (300 c/s) and the electrophysiological responses to a moderate noise stimulus were also determined. Three substances were then investigated under the same conditions; all were administered by mouth : Nembutal (ethylmethylbutylbarbiturate sodium) in doses of 15 and 25 mg/kg; Mecloqualone (methyl 2(chloro-2 phenyl)3-quinazalone 4) in a dose of 50 mg/kg; Mogadon (7 nitro-5 phenyl-(3H)-1,4-benzodiazepin-(lH)-Zone) in a dose of 10 mg/kg. The following findings will be presented : (1) Modifications of electrical activity recorded in different structures. (2) Effects of electrical stimulation of reticular formation (including any changes in threshold) and of auditory stimulation. (3) Changes in rhombencephalic phase of sleep. Experimentalfindings

We shall not consider the characteristics of physiological sleep in the rat as there is nothing of special interest. Typical rhombencephalic phases are seen in this animal, References p. 219/220

196

A. SOULAIRAC

. . . . , . . . , , I

MR

et al.

-. . ,,

,

..,.

. . ..

'1

Fig. 1. Effects of Nembutal on different sleep stages. Top: normal animal. Centre and bottom: same animal after 25 mg/kg Nembutal. During slow sleep of classic form barbiturate-type waves appear in cortex, midbrain reticular formation is depressed and muscle activity is considerably reduced. During deep sleep phase, high-amplitude waves persist in cortex, numerous spindles in reticular formation. Scale: 1 sec, 5 0 p V . &br. used in figures: FL = bifrontal lead; PL = biparietal lead; FPr = frontoparietal, right; FPI = frontoparietal, left; HPC = hippocampus; OB = olfactory bulb; EM = eye movements; N = neck muscles; MR = midbrain reticular formation; Resp = respiration; Ret. St. = reticular stimulation (300 cis).

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with cortical, hippocampal and reticular activation patterns, complete relaxation of neck muscles, bursts of ocular movements and irregular respiratory rhythm (Soulairac et al., 1964). The threshold for cortical arousal on reticular stimulation is relatively constant for each animal, behavioural arousal usually occurring later and sometimes at a higher threshold. Auditory stimulation always produces an excellent cortical, hippocampal and reticular activation response. ( a ) Eflect of Nembutal This substance in the two doses used provokes the classic barbiturate changes. At the cortical level, highly characteristic spindles are seen, and sometimes rapid waves. Hippocampal activity is not fundamentally different from normal sleep. There is marked depression of the reticular formation. At the same time the electromyogram shows considerably less activity than normal. Reticular stimulation produces much less effect than during normal sleep and the threshold is considerably raised. Moderate auditory stimuli are mostly without any effect. Nembutal does not prevent the appearance of rhombencephalic phases, but there is a difference compared with the untreated animal :the characteristic barbiturate spindles persist and the higher amplitude waves are sometimes more distinct, as Jouvet et al. (1959) have already reported. From the reticular system also pronounced spindles are obtained. Figs. 1 and 2 illustrate these classic effects of Nembutal.

(6) Eflect of Mecloqualone Administration of this substance produces very rapid effects on the behaviour of the animal. Between 3 and 5 min later, the rat begins to stagger, but before sleep behaviour appears, there is a very transitory slight agitation with masticatory and grooming movements suggesting a short period of mild excitation. Electrophysiological changes are as follows. At the cortical level, a sleep pattern appears rapidly, characterized by high-amplitude waves of comparatively moderate frequency but more rapid than at the start of the experiment. This sleep recording is regular and rapid waves are rarely observed. When the animal moves, relatively rapid waves with a sustained high amplitude are occasionally seen. The arousal pattern is generally not atypical. Briefly, the sleep EEG is merely more 'sustained' than normal, the relatively minor modifications sometimes being more apparent in fronto-parietal leads. In the dorsal hippocampus, the record is basically little changed, remaining in the 4-8 CISrange. A few spikes may be observed, which give the appearance of hippocampal arousal. In the olfactory bulb, initial bursts disappear. More numerous spikes are seen on a rapid background. The reticular formation is markedly depressed and sometimes a tendency towards synchronization is observed in a regular recording. It may be mentioned that the respiratory depth is occasionally irregular, though there is no change in the heart rate. Electrical stimulation of the reticular formation gives results similar to those in References p . 2191220

198 A. S O U L A I R A C

et ul.

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normal sleep : EEG and behavioural arousal occur at thresholds identical with those in the untreated animal. Auditory stimuli, on the other hand, are clearly less effective, and never produce a startle reaction. About 1 h after administering Mecloqualone, we see rhombencephalic phases of

Fig. 3. Effects of mecloqualone on slow sleep. Above: normal recording. Below: recording of the same rat under Mecloqualone 50 mg/kg. Note: cortical recording regular but denser than usual, because more synchronized and slightly more rapid, under effect of substance; midbrain reticular formation somewhat more depressed; considerable reduction in muscle potentials of neck, in which heartbeat appears. (Calibration: 1 sec; 50 pV.) References p . 219/220

200

A. SOULAIRAC

et a].

sleep; a certain dissociation is apparent here, however, as in spite of complete hypotonia and eye movements a cortical sleep record is still often found. Figs. 3-5 show the essential electrophysiological effects of Mecloqualone.

PL

g

g

Fig. 4. Effects of stimulation of midbrain reticular formation under Medoqualone. Above: normal rat. Below: same rat under Mecloqualone. Slow sleep recordings differ. Under Mecloqualone, waking cortical record consists of very rapid waves, but amplitudes are not reduced as in normal animal. Dorsal hippocampus recording unchanged. (Calibration: 1 sec; 100 pV.)

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FL 0

HPC 08

MR

1 c,

Fig. 5. Action of Mecloqualone on deep sleep phase. Above: normal rat. Below: same rat under mecloqualone. Mecloqualonedoes not prevent appearance of deep sleep phases. Essential differences seen in depressed cortical and reticular recordings. (Calibration : 1 sec; 50 pV.)

(c)

Effect of Mogadon

Behavjourally, this substance possesses a definite effect on the musculature. Between 3 and 5 min after administration, the rat begins to stagger, although motor coordination does not appear particularly disturbed. Again there are quite frequent masticaReferences p. 219/.?20

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et al.

tory movements. The animal does not assume its usual sleeping position, but presents rather an attitude of general muscular relaxation. The following are the electrophysiological changes: A t the cortical level there is synchronization with waves of very uniform amplitude. These waves are so rapid that

1

Fig. 6 . Action of Mogadon on slow sleep. Above: normal record. Below: record of same animal under Mogadon, 10 mg/kg. This substance causes cortical dualism: recording of rather rapid spindles, compared with normal animal, followed by sequence of very rapid waves. Marked reduction in muscle potentials of neck, in which only heartbeat appears. (Calibration: 1 sec; 50pV.)

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Fig. 7. Effects of Mogadon on electrocorticogram during slow sleep. Above: normal animal. Below: same animal under Mogadon, 10 mg/kg. Demonstration of dualism in recording: high amplitude waves of fairly rapid frequency (15 c/s) followed by extremely rapid waves. Note weak echo of these two activities in dorsal hippocampus. (Calibration: 1 sec; 100 pV.)

even when the animal appears asleeF, the record is more dense than in the normal state. On arousal, and especially when the animal moves, the frequency increases without the usual accompanying reduction in amplitude, so that the density becomes even greater. All these changes are most clearly visible in multiple leads. The most characteristic sleep recording thus combines slow high-amplitude waves (7-10 c/s) with rapid activity (up to 40 c/s). I n the dorsal hippocampus rapid waves (up to 25 CIS) appear superimposed on the Rejerences p.

2I91.220

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et al.

normal record (4-8 c/s). While the basic pattern is not distorted, there is here too a certain duality in the electrophysiological response. The reticular formation is generally little affected; low-amplitude spindles may be seen. There is some slight depression here, however, and the spindles do not always m

I

08

N

-

Fig. 8. Effects of direct electrical stimulation of midbrain reticular formation in rat under Mogadon Above: normal recording. Below: recording of same rat under Mogadon, 10 mg/kg. Classic cortical records of arousal modified : frequency increased but with paradoxical increase in amplitude. Dorsal hippocampus shows same changes. (Calibration: 1 sec; 100 pV.1

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FL

-

Fig. 9. Effects of Mogadon on arousal by direct electrical stimulation. Above: normal rat. Below: rat under Mogadon. Arousal obtained under Mogadon is characterized by paradoxical increase in frequency and amplitude of cortical discharges. (Calibration: 1 sec; 100pV.)

coincide with those in the cortex. The olfactory bulb also seems slightly depressed, and spikes appear often more noticeable than in the untreated animal, Respiration and heart rate are generally slightly accelerated. Responses to electrical stimulation of the reticular formation seem to be unaffected References p.2191220

206 A. SOULAIRAC

et al.

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by Mogadon. The arousal threshold is practically unchanged. Behavioural arousal is distinctly more difficult to obtain, but it seems that this is essentially due to the motor inhibition which delays accomplishment of the behavioural intention. Moderate auditory stimuli lose much of their effectiveness, and the startle response is always suppressed. In none of the treated animals were rhombencephalic sleep phases observed during the action of Mogadon. It must be admitted, however, that detection of these phases becomes difficult in animals in which the reticular and cortical recordings may be of no use because of the experimental changes and in which muscular relaxation is maximal from the start. The only remaining criterion is then the appearance of eye movements, and these we have never seen. Yet it must be remembered that these external eye movements may also be strongly inhibited by the muscle-relaxing effect of the substance. Figs. 6-10 illustrate the principal phenomena reported.

INVESTIGATION I N THE RABBIT

Material and methods

All these investigations were carried out in male rabbits using cortical and subcortical electrodes implanted according to the stereotaxic method of Monnier and Gangloff (1961). Three hours before starting the experiment, electrodes were implanted in the following structures : motor cortex, anterior hypothalamus, caudate nucleus, dorsal hippocampus, median and ventrolateral thalamus, mesencephalic and hypothalamic reticular formation. Electrical activity of these structures was recorded for 4 h without interruption with the animal restrained in a strictly physiological position in a darkened sound-proof box. The effect on these structures of a constant noise stimulus was systematically studied before and 2 and 4 h after administration of each drug. The course of physiological sleep in control animals was compared with that of the following orally administered compounds: Secobarbital (allylmethylbutylbarbitone sodium) in a dose of 50 mg/kg; Doriden (glutethimide; 3-phenyl-3-ethyl-2,6-dioxopiperidine) in a dose of 300 mg/kg; Librium (7-chloro-2-methylaniino-5-phenyl(3H)-1,bbenzodiazepin 4-oxide) in a dose of 50 mg/kg; Mogadon (7-nitro-5-phenyl(3H)-l,Cbenzodiazepin-(lH)-2-one) in a dose of 20 mg/kg. The following findings will be presented : (1) Modifications of electrical activity recorded in the different structures under the influence of the various compounds studied in order to define if possible their mode of action. (2) Effects of treatment on the response to noise stimuli. (3) Results of sequential analysis, hour by hour, during the recording of 4 h in each area explored. This sequential analysis required the necessarily arbitrary calculation of the duration of the waking, somnolent and deep sleep stages. This method of analysis enabled the extent and duration of the effects of the different substances studied to be compared.

R&rcncrs

P. 2191220

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et al.

NeurophysioZogical aspects of sleep under the influence of hypnogenic substances ( a ) Physiological sleep in the mbbit This is characterized by an extreme variability in the level of sleep. In stage I or the sub-arousal stage, the cortex is unchanged, but synchronization of the suboortical structures becomes irregular and frequencies slightly slower (4 c/s) especially in the dorsal hippocampus. In stage 11, bursts of rapid high spikes (I 1-13 c/s) are seen in the motor cortex. This

Fig. 11. Physiological sleep in the rabbit.

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spiking activity is also found in the caudate nucleus and the median thalamus. Finally there is desynchronization in the dorsal hippocampus. In stage I11 the rapid cortical bursts (1 1-13 c/s, 150-200 pV) are closer together and show a certain periodicity. Activity of the subcortical structures remains identical with that in 11. Stage IV corresponds to the stage of deep sleep. In the cortex the rapid discharges are interspersed with slow waves, which extend to the caudate nucleus, the hypothalamus, thalamus and sometimes even the reticular formation. The basic synchronized type (3-5 c/s) is practically no longer visible in the hippocampus. The slightest sensory stimulation is liable to desynchronize the sensorimotor and motor cortex immediately and reintroduce a more rapid, regular, synchronized, basal rhythm (5-7 c/s) in the thalamus, rhinencephalon and mesencephalic reticular formation (Fig. 11).

( b ) Secobarbital sleep Secobarbital produces uniform high-amplitude, slow waves (1-2 c/s) especially in the motor cortex. The same high-amplitude slow activity is found in the caudate nucleus and the ventrolateral thalamus. In the cortex and caudate nucleus particularly it is interspersed with irregular bursts of spiking activity (12-14 c/s), sometimes periodic and generally of moderate amplitude. The two forms persist together throughout the 4 h. Several arousal stages occur, however, suppressing the disorganized slow activity interspersed with rapid frequencies in the dorsal hippocampus, and substituting a basal 3.5-5 c/s rhythm, which does not, however, attain the synchronization of arousal provoked by a sensory stimulus during physiological sleep (5-7 c/s). The same pattern is seen in the midbrain reticular formation. During the 1st h, the action of secobarbital appears to affect all subcortical structures uniformly. By the 4th h, however, when the effect is beginning to wear off, slow activity persists in the caudate nucleus and the mesencephalic reticular formation, whereas the dorsal hippocampus has already more or less recovered its initial synchronization (Fig. 12). ( c ) Doriden sleep The slow activity produced by Doriden is less pronounced than that produced by secobarbital. It seems to be limited, moreover, especially in the 1st h, to the motor cortex, the anterior hypothalamus and, to a lesser extent, the caudate nucleus, the ventrolateral thalamus and the midbrain reticular formation. Synchronization of the hippocampus is not disturbed but the permanent high degree of synchronization characterizing paradoxical sleep is never seen. This slow activity is interspersed with rapid bursts of 12-14 c/s, especially in the motor cortex, often periodic and more numerous than with secobarbital. These rapid discharges are also seen in the caudate nucleus. The slow activity becomes less marked between the 2nd and 4th h in the motor cortex but persists in the anterior hypothalamus and to a lesser extent in the midbrain reticular formation. Rapid, high amplitude spikes then become more numerous in the caudate nucleus and the motor cortex. References p. 2191220

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Before treatment M o t o r Cortex

- 4 w - w

Ant. Hypothal.

-fiw.v-w

Caud. Nucl.

-

N

v

f

L

,

v

W

Midbrain Ret. '

Fig. 12. Secobarbital sleep (50 mg/kg).

Arousal periods are also more rapid than with secobarbital(4.5-6 c/s). After the 2nd h, the hippocampus has recovered its synchronized basal activity. The action of Doriden thus mainly affects the motor cortex, anterior hypothalamus, mesencephalic reticular formation and, to a lesser degree, the caudate nucleus. The anterior hypothalamus appears subject to its action the longest (Fig. 13). ( d ) Sleep under Librium The effect of Librium is characterized by three features: the slow rhythms seen especially in the motor cortex and caudate nucleus are very labile and disappear completely after the 2nd h. The spikes superimposed on this slow activity are more

ACTION OF HYPNOGENIC SUBSTANCES ON THE

Motor

Caud

CNS

21 I

Cortex

Nucl

Hippocampus

Midbrain Ret.

Fig. 13. Doriden sleep (300 mg/kg).

rapid than with Doriden or secobarbital (15-16 c/s). They are regular, often periodic and sometimes more distinct in the caudate nucleus than in the motor cortex. These same discharges continue to characterize the action of Librium throughout the following 3 h. During the 4 h observation, synchronization of the dorsal hippocampus is slightly delayed, especially during the 1st h, and rapid frequencies are superimposed on the basal rhythm. Arousal periods are shown by 5-6 CISactivity, clearly visible in rhinencephalic structures and the thalamic nuclei. The action of Librium thus appears to be mainly limited to the motor cortex and References p . 2191220

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-A. SOULAIRAC

Jotor

Cortex

A n t Hypothal

et al.

Midbrain Ret.

tlh

1rnPVL. $ sec

Fig. 14. Sleep under Librium (50 mg/kg).

the caudate nucleus. The midbrain reticular system and the ventrolateral thalamus are only very transitorily affected (Fig. 14).

( e ) Sleep under Mogadon The effect of this substance resembles that of Librium, but the high-amplitude slow waves (1.5-3 c/s) which are seen exclusively in the motor cortex and caudate nucleus and are seldom uniform, persist until the 2nd h, particularly in cortical leads. Typical of the action of Mogadon are regular, periodic bursts of rapid activity (14-15 c/s) persisting practically throughout the 4 h observation; from the 3rd hour, however, they are less distinctly individualized. These rapid frequencies are seen in the motor

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cortex, caudate nucleus, dorsal hippocampus and ventrolateral thalamus. Arousal phases are very rare and the corresponding basal rhythm in the dorsal hippocampus never exceeds 4 c/s. The action of Mogadon is thus characterized by a somnolent phase following a period of deeper sleep (Fig. 15).

Fig. 15. Sleep under Mogadon (20 mg/kg).

Modijications of the response to sensory stimulation

We studied the response of the various subcortical structures to a noise stimulus of constant duration in the 2nd and 4th h after administration of each substance. Duringphysiologicalsleep, an acoustic stimulus always produces cortical desynchroReferences p . 219/220

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et al.

nization and subcortical synchroniz&ion, especially in the dorsal hippocampus (7-8 c/s). In general, the response outlasts the duration of the stimulus. In the presence of secobarbital, cortical desynchronization is minimal and subcortical Controls Motor Corter Hippocampus V.L. Thal.

Midbrain Ret

Secobarbital

Doriden

Librium

Mogadon

400pv~ isec

Fig. 16. Modifications of the response to sensory stimulation (2nd h).

synchronization slow and irregular and does not persist after stimulation. This is true both 2 h and 4 h after administration; the frequencies merely become slightly greater (4.5 c/s). Under Doriden, acoustic stimulation gives rise to normal cortical desynchronization, the subcortical synchronization (dorsal hippocampus) is slightly more rapid (5 cis)

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and lasts slightly longer than the stimulus. Responses during the 2nd and 4th h are identical. After Librium, a noise stimulus always gives rise to cortical desynchronization, and subcortical synchronization is a little more rapid still (6 c/s). It is irregular and sometimes persists beyond the stimulus in both the 2nd and 4th h. The effect of Mogadon is somewhat unusual compared with the changes in brain potentials previously noted. While an auditory stimulus does cause cortical desynchronization, the subcortical synchronization in the dorsal hippocampus is often irregular and slower than with Librium at both the 2nd (4.5-5.5 c/s) and the 4th h (5-5.5 c/s); above all, it rarely outlasts the stimulus (Fig. 16). Sequential analysis of sleep tracings under the influence of hypnogenic substances

This sequential analysis, based on the duration during each hour of waking, somnolent and sleep phases, raised no particular difficulty in the case of the cortex. For the subcortical structures, on the other hand, it was not so easy; we assumed that the arousal corresponded to periods of regular synchronized rhythm of 4-7 c/s, somnolence to the disappearance of this synchronization and the presence of high-amplitude, slow waves, usually with a tendency to uniformity. Recordings on all animals during the lst, 2nd and 4th h after administration of the substances, and on control animals during comparable periods,were analysed in this way. Tables I and I1 present the overall results of this analysis, each figure representing the average of all animals in the particular series. TABLE I SEQUENTIAL ANALYSIS OF SLEEP I N THE RABBIT

(first hour) -~______

Control W

Motor cortex

S

S W Caudate nucleus

S

S

W Hippocampus

S

S W

Midbrain ret.

S

S W

Ventrolateral thalamus Anterior hypothalamus

S

S W S

S

20 34 6.14 14 41.30 4.30 15 42 2.54 11 46 2.41 15 41.30 3.27 12 44 5.03

W = duration of waking phases; s All values in minutes and seconds. References p . 2191220

Secobarbital

3

44 14.09 1.46 37 21 1.51 52 6 1.10 48 10.47 2 40 17.28 2.38 52 4.46 = duration

Doriden

Librium

Mogadon

12.30 34 13.13 8.57 40 10.48 7.47 51 1.08 5.32 41 13.19 8.30 45 6.36 6.30 31 16.03

6.30 46 8.19 6 46 7.51 7 50 3.14 14 41 4.43 8 47 4.45 7 46 6.36

0.04 45 13.58 0.42 53 6.09 1.37 59 0.30 1.14 56 2.37 1.09 55 3.47

of somnolent phases; S

= duration

of sleep phases.

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TABLE I1 SEQUENTIAL ANALYSIS OF SLEEP IN THE RABBIT

(fourth hour) ~

Control

Secobarbital

Doriden

Librium

Mogadon

20 34 5.30 14 40 5.12 12 45 2.45 11 46 2.49 13 44 3.21 13 42 5.18

10 46 4.32 8 39 12.35 5.21 50 3.56 2.24 48 9.18 10 44 5.29 9 49 1.23

16 37 6.21 10 44 5.92 11 51 0.10 13 42 5.25 13 45 2.20 7.12 41 12

18 42 0.28 13 46 1.11 10 49 0.13 13 43 3.39 9 49 I .43 9 51 0.12

10 41 3.21 6 51 2.23 5 55 0.01 12 48 0.43 4 53 1.49

~

W Motor cortex

S

S W

Caudate nucleus

S

S

W Hippocampus

S

Midbrain ret.

S W s S

W

Ventrolateral thalamus

S

Anterior hypothalamus

S

S W S

W = duration of waking phases; s = duration of somnolent phases; S All values in minutes and seconds.

=

duration of sleep phases.

( a ) Physiological sleep During the 3 h selected for sequential analysis, there is a remarkable stability in the duration of the sleeping, somnolent and waking phases, in both cortical and subcortical recordings. The rabbit appears to doze rather than sleep profoundly, as shown by the extreme brevity of the deep sleep phases in the dorsal hippocampus, midbrain reticular formation and thalamus. ( b ) Secobarbital sleep Secobarbital banishes waking phases in the motor cortex almost entirely during the 1st h and reduces them by about half in the 2nd and 4th h (compared with controls). Somnolent phases are correspondingly prolonged throughout the 4 h, but the duration of deep sleep is increased only in the 1st h. In subcortical structures, waking phases are uniformly reduced, but only during the 1st h ; after the 2nd h, regional differences occur, showing that the effect wears off especially in the ventrolateral thalamus and the anterior hypothalamus. This reduction in the waking phase is accompanied by a considerable increase in the deep sleep phase, particularly in the caudate nucleus, motor cortex, ventrolateral thalamus and midbrain reticular formation during the first 2 h. In the 4th h, there is a discrepancy between duration of deep sleep shown by the motor cortex and that shown by the caudate nucleus, where there is still much slow activity. In general, the caudate nucleus and the ventrolateral thalamus seem to be the structures most sensitive to the effects of secobarbital.

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( c ) Doriden sleep Doriden reduces the waking periods more noticeably in the motor cortex and the hypothalamus than in other subcortical structures. After the 2nd h, however, the waking periods become longer until they are almost identical with those in physiological sleep. Deep sleep is seen, apart from the cortex, mainly in the hypothalamus and to a lesser extent in the midbrain reticular formation. In the hippocampus, on the other hand, there is an overall indication of somnolence. In all areas, the duration of somnolence is identical with that in controls, from the 1st to the 4th h. In the hippocampus, it appears somewhat longer. The phase of deep sleep is prolonged only in the 1st h, duration of this phase decreasing progressively between the 3rd and 4th h, except in the hypothalamus and the midbrain reticular area. At its point of maximum effect, Doriden thus appears to influence chiefly the motor cortex, the caudate nucleus, the midbrain reticular formation and the anterior hypothalamus.

( e ) Sleep under Mogadon The action of Mogadon is quite different from that of Librium and also of Doriden out the 4 h' observation. This is associated with a reduction in the waking periods, at least up to the 3rd h. The duration of sleep phases is slightly increased only during the 1st h. These effects are most noticeable in the cortex and hippocampus as far as waking and somnolent phases are concerned, and in the caudate nucleus during deep sleep. The effect of Librium appears to be limited to the 1st h after administration. During the remaining hours, sleep is practically identical with that in untreated controls. ( e ) Sleep under Mogadon The action of Mogadon is quite different from that of Librium and also of Doriden and secobarbital. There is a marked reduction in the duration of waking periods, in all areas throughout the 4 h after treatment. Equally noticeable is the stability of the somnolent phases, which are especially marked in the dorsal hippocampus, ventrolateral thalamus and mesencephalic reticular formation. Deep sleep is prolonged only in the 1st h and in the motor cortex. DISCUSSION A N D GENERAL CONCLUSIONS

This electrophysiological study of the nervous structures influenced by various hypnogenic substances has shown that there are considerable differences in their action, although the final result is always sleep behaviour associated with more or less the same neuromotor phenomena. Analysis of the functions of the various nervous substrates seems to indicate quite distinct modes of action. In the rat, there are significant differences between the action of a barbiturate like Nembutal and that of mecloqualone or Mogadon. With the two latter, there is not the characteristic effect on cortical electrogenesis, and sometimes there appears to be a dissociation between the action on the cortex and that on subcortical areas. Thus in the Retrrcncrs p. 219/220

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A. SOULAIRAC

et al.

case of Mogadon we have reported the unusual response in the cortex, where activity relatively close to that of arousal seems to persist. Results obtained from study of reticular thresholds are even more convincing. While with Nembutal reticular depression is shown by a considerable rise in the threshold to electrical stimulation, sleep produced by mecloqualone and Mogadon does not modify this threshold. Electrophysiological depression of the reticular formation caused by this type of sleep must therefore be of quite different physiological significance from that produced by the barbiturates. Furthermore, it should be observed that there are differences of degree between these substances too, as Mogadon appears to produce the greater dissociation between cortical and reticular responses. Cortical records during sleep elicited by Mogadon differs from the recordings of both physiological and barbiturate sleep. The effects of acoustic stimuli in these different forms of sleep appear difficult to interpret at present. In the rabbit, the substances studied can again be divided into two broad groups: the first including secobarbital and Doriden which produce deep sleep accompanied by impairment of the cortical and subcortical responses to sensory stimuli; the second comprising the benzodiazepines which only briefly induce deep sleep. This is followed by an almost permanent state of somnolence, practically identical with natural sleep. The action of these substances is characterized by limited (Librium) or diminished (Mogadon) cortical and subcortical responses to acoustic stimuli, whatever the depth of sleep. This is the major difference between the sleep induced by benzodiazepines (particularly Mogadon) and physiological somnolence in which the slightest sensory stimulus causes cortical desynchronization and subcortical synchronization persisting beyond the duration of the stimulus. These factors enable us to make a clear distinction between secobarbital and Mogadon. The first is hypnogenic because it produces deep sleep and limits the response to stimulation. The second is sleep-inducing because its effect on the response to sensory stimuli is not linked with depression of cortical and subcortical structures. One of the important features which is constant with hypnogenic substances is the marked inhibition of muscle tone, and it is tempting to relate this phenomenon to the sleep itself. Yet the difference in cortical reactions to the sleep produced by these substances suggests that the muscular inhibition may not have the same significance in all cases. Our findings lead us to submit that this proprioceptive inhibition is secondary to the central effect in the case of the barbiturates but may precede the central action in the case of a substance like Mogadon. Among the phenomena of sleep, it would be most interesting to study in detail the timing of this proprioceptive inhibition. The changes observed in the caudate nucleus of the rabbit undoubtedly throw a new light on the participation of central motor structures in the induction of sleep. While it is perhaps difficult to reach exact conclusions regarding the mechariism of action of the substances studied, the work we have reported leads us to submit that hypnogenic substances may now be divided into two major groups :the true hypnotics, the classic examples of which are the barbiturates, acting indiscriminately on all the

ACTION OF HYPNOGENIC SUBSTANCES O N THE

CNS

219

nervous structures concerned with maintaining vigilance; and the sleep-inducing substances, represented here by mecloqualone and Mogadon, which affect sleep only to the extent that they suppress one of the usual mechanisms for maintaining vigilance, in particular by inhibiting proprioceptive function. SUMMARY

The comparative study of various hypnotics differing entirely one from the other in their chemical composition demonstrates that the production of the single behavioural state of sleep can implicate various cerebral centres. By the technique of implanting electrodes in various cerebral centres of the rat and rabbit it can be established that substances such as mecloqualone and benzodiazepine derivatives (Librium or Mogadon) produce electrophysiological changes very different to those characteristic of the action of the barbiturates. The most salient fact appears to be that the barbiturates markedly depress the mesencephalic reticular structures and to a lesser extent the cortex, whilst with the other type of substances the neocortical and hippocampal effects outweigh the reticular effects. It was thus observed that the threshold for arousal on reticular stimulation was very much increased by barbiturates and hardly affected by mecloqualone or Mogadon. Furthermore, it was often noted that with Mogadon the neocortical reactions were not synchronized with the reticular reactions. Study of the paradoxical phase of sleep (rhombencephalic sleep) also yields interesting facts; thus, Mogadon, whilst producing a profound state of hypotonia, did not provide experimental evidence of this paradoxical phase. Sequential analysis of sleep in the rabbit, 1 and 4 h after administration of the various trial substances, confirms the absence of a mesencephalic reticular and hippocampal effect and the clear predominance of the action at the level of the motor cortex and caudate nucleus. All the results taken together permit the conclusion that the hypnogenic action of the barbiturates occurs by way of inducing profound sleep and limiting the response to sensory stimulation, whilst Mogadon is sleep-inducing, not through a depressant action on the reticular structures but by its profound action on muscular tonus and sensory stimulation. REFERENCES CAHN, J., (1961); Panel on human electroencephalography and psychopharmacology. 3rd World Congress Psychiatry. Montreal, in Electroenceph. clin. Neurophysiol., 15, 134. F., and HEROLD, M., (1964); Relation entre les modifications du tonus CAHN,J., ALANO,J., HAUSER, postural et de l'tlectrocorticogramme chez le lapin. NeuropsychophartnacoIogy,Vol. 3. P. B. Bradley, F. Fliigel and P. Hoch, Editors. Amsterdam, Elsevier (p. 490-493). DE GROOT,J., (1959); The rat forebrain in stereotaxic coordinates. Proc. kon. ned. Akad. Wet., Second Series. Amsterdam, North-Holland Publ. Co., 52, No. 4. DOMINO, E. F., (1955); Pharmacological analysis of the functional relationships between the brain stem arousal and diffuse thalamic projections systems. J. Pharmacol., 115, 449463. DOMINO,E. F., (1956); The correlation between animal testing procedures and clinical effectiveness of centrally acting muscle relaxants of the mephenesin type. Ann. N.Y. Acud. Sci., 64,705-729.

220

A. SOULAIRAC e t

al.

HODES,R., (1962); Electrocortical synchronization resulting from reduced proprioceptive drive caused by neuromuscular blocking agents. Electroenceph. din. Neurophysiol., 14, 220-232. JOUVET, M., MICHEL,F., and CounJoN, J., (1959); L’activite electrique du rhinenckphale au cours du sommeil chez le chat. C.R. SOC.Biol., 153, 103-105. MONNIER, M., and GANGLOFF, H., (1961); Rabbit Brain Research, Vol. 1 . Atlas et technique stereotaxique pour le cerveau du lapin eveille. Amsterdam, Elsevier. SouLAInAc, A., GOTTESMANN, C . , and THANGAPREGASSAM, M. J., (1964); Nouvelles donnks sur les variations de I’electrogen~secorticale du rat par la stimulation de la formation reticulaire mksencephalique. C.R. SOC.Biol.,258, 1080-1082.

All-night EEG recording of normal and drug-induced sleep in human

I should like to present all-night EEG and polygraphic recordings of sleep induced by a new hypnotic drug (10 mg Mogadon orally) as compared with placebo effects in two subjects suffering from sleep disorders. For this purpose we considered it preferable to compare the detailed course of sleep during the whole night in a few individuals rather than to evaluate average overall length of individual sleep stages in a large number of subjects. Depth of sleep was evaluated on the basis of continuous polygraphic recordings of EEG, ECG, respiration rate and motor activity (using a ‘jiggle’bed). The data were summated in periods of 10 min and graphically represented.

Hours1

1

I

2

3

4

5

6

7

8

1

0

1

10

b

Fig. 1. All-night sleep record in a subject without medication (a) and under 10 mg Mogadon (b). Upper and lower blocks represent polygraphic data summated over 10 min periods. The EEG criteria were classified according to three degrees of intensity and recorded as blocks of varying thickness. ECG frequency (P) and respiration (A) are recorded by a continuous horizontal line (mean frequency); increased frequency is represented by an up-stroke and reduced frequency by a down-stroke. Motor activity is recorded according to three degrees of intensity, corresponding to the number of movements in the 10 min period, and represented by a single stroke, double stroke or block (maximum) under B. a = Increased amplitude and spread of a-activity; a = Decreased a-activity; V. Sp. = Vertex spikes; Sp. = Spindles; 0 = lsolated 8-waves; 80 = @-Activity; 6 = Isolated 6-waves; 66 = &Activity; K = K complex; F1 Flattening of curve. The middle block represents the evaluation of depth of sleep. Continuous line = without medication. Broken line = with medication.

222

K. PATEISKY

The first subject (Fig. 1) was a 41-year-old patient with a history of chronic abuse of sleeping tablets. The first all-night record was taken after hypnotics had been withdrawn for 10 days. Without a hypnotic the subject woke up regularly at 3 0-clock in the morning. One week later another record was msde under the influence of 10 mg Mogadon. As a consequence the tracings indicated a more rapid onset of sleep and a bridging of the early morning sleep disruption. The patient felt refreshed after sleep. The second subject (Fig. 2) was a sensitive 57-year-old music teacher suffering from M.W 57a lHoursl

-7-

A

1

2

3

1

4

j

5

r

6

1

7

1

8

1

~j

10

a

Fig. 2. All-night sleep record in a patient receiving (a) placebo (continuous line in the centre diagram) and (b) 10 mg Mogadon orally (broken line). For explanation see Fig. 1.

endogenous depression after attempted suicide. Ten days after withdrawal of a11 drugs the patient slept well under placebo and experienced a true-to-life dream of a musical performance. After normal onset of sleep the curve representing sleep-depth showed marked changes with a-periods (paradoxical sleep periods). It must be borne in mind that the patient was an active musician and able to experience his dream as if it were real. One week later, the first oral dose of 10 mg Mogadon was given and the curve showed a somewhat slower onset of sleep. However, depth of sleep presented a more regular pattern and sleep was longer than under placebo. Subjectively, the patient experienced this sleep less pleasant and complained of tiredness during the following day. Since the patient later reported pleasant and refreshing sleep under 5 mg Mogadon it may be assumed that the first dose of 10 mg was too high.

BIOELECTRICAL CHANGES DURING ADMINISTRATION OF HYPNOGENIC DRUGS

223

The evaluation of all-night sleep recordings of EEG, respiration, ECG and motor activity demonstrate that depth of sleep is more regular under Mogadon and that the paradoxical sleep phases are reduced. Psychiatric-Neurological Clinic of the University of Vienna, Vienna (Austria)

K. PATEISKY

Bioelectrical changes in subcortical areas of the brain during the administration of bypnogenic substances (preliminary report)* During stereotaxic brain operations electroencephalographic recordings can be made in precisely defined subcortical areas. Not only spontaneous activity but also the effects of various drugs can be shown. Since the results of electrophysiological examinations made during sleep are often very variable and difficult to assess, we were interested in investigating the electrobiological changes in areas of the human brain stem (ventral thalamus and amygdala) during the administration of hypnogenic substances. On account of its great accuracy we used the well-known method of RiechertMundinger. The depth recordings were made on a bipolar basis (3 or 7 mm between the electrodes). In order to exclude undue interference of factors other than drug effects the stereotaxic operation and recordings were carried out 2 weeks after air studies and 1 week after drilling of the burr holes. In collaboration with Dr. H. Lechner and Dr. S . Enge we have so far made depth recordings in 79 patients, 17 of whom had been given a hypnogenic drug (diazepam, chlordiazepoxide, Mogadon). The control group comprised 26 patients (Table I). TABLE I DEPTH RECORDINGS DURI NG ADMINISTRATION OF A HYPNOGENIC DRUG

Substance

Dose i.v.

Chlordiazepoxide Diazepam Mogadon Total Controls

25-100 mg 5-20 mg 5 mg

Number of patients 6 7 4

11 26

-

Lead NV ND NA H 3 7 1 11 26

3 3

3 3

1 1

NV = Nucleus ventralis oraiis thalami; ND = Nucleus dorsomedialis thalami; NA = Nucleus amygdalae; H = Hippocampus.

The effect of diazepam was studied in 7 patients. A pronounced increase of high frequency activity at the thalamic and subsequently at the cortical level was noted in all cases 3-6 min after the beginning of the infusion with diazepam (Fig. 1, top). Some patients became drowsy and tired, but there was no marked correlation between this

* This investigation was supported by US Public Health Service Research Grant RF 28 from National Institutes of Health, Bethesda, Md. (U.S.A.).

224

H. E. DIEMATH

Fig. 1. Above: K. K., male, 67 years, bilateral postencephalitic parkinsonism. Lead from nucleus ventralis oralis posterior thalami sin. Left: before; right:during i.v. administration of 8 mg diazepam. Marked increase in fast frequencies in depth lead and cortex. Below: F. A., female, 43 years, torticollis spastica of uncertain etiology. Lead from nucleus ventralis oralis posterior thalami dext. Left: before; right: during i.v. administration of 5 mg Mogadon. No change.

clinical effect and EEG changes. Naturally, the patients received no additional medication, anesthesia not excepted. Only when the target ring was placed in position small amounts of local anesthetic were employed.

Fig. 2. M. H., male, 15 years, erethism of uncertain etiology. Lead from nucleus arnygdalae dext. Left: before; right: during administration of 5 rng Mogadon. Disappearance of typical high amygdala potentials, reduction of slow waves, slight increase in frequency.

EFFECT OF MOGADON O N NIGHT-TIME SLEEP

225

Depth recordings were taken after administration of chlordiazepoxide in 6 patients (Table I). Here too, there was an increase in high frequencies in the depth leads and at the cortex. We were above all interested to know whether Mogadon would cause the same bioelectric effects as diazepam and chlordiazepoxide. In 3 patients records were taken from the amygdala. During the administration of 5 mg Mogadon a marked diminution or disappearance of the typical high amplitude amygdala activity was noted and in one case a slight increase in frequency occurred in the amygdaloid nucleus and in the cortex (Fig. 2). In one patient hippocampal activity was recorded and no changes of activity were seen. All 4 patients required general anesthesia, but the depth of anesthesia was maintained at a constant level during and after drug administration. It is therefore unlikely that the observed EEG changes were caused by the anesthetic. It must be especially emphasized that the reported changes consistently followed the administration of hypnogenic substances and usually disappeared within 8-10 min of its withdrawal. In one patient, records were taken from the nucleus ventralis oralis posterior (Fig. 1, below); no changes in the depth lead or the cortical lead were found. According to these findings there is a difference between diazepam and chlordiazepoxide on the one hand and Mogadon on the other, since Mogadon showed no change in the thalamic lead nor in the cortex. Neurosurgical Section and Department of Surgery, University Hospital, Graz (Austria)

H. E. DIEMATH

Effect of Mogadon on night-time sleep For our investigation we had 9 volunteers, medical students aged between 19 and 23 years. During the study, all went to bed at the usual time. For each subject EEG recordings of sleep throughout the night were made on 2 successive nights. In the 1st night normal sleep was recorded; in the 2nd, sleep after taking 10 mg Mogadon. All subjects were asked each morning how they had slept, and the answers were charted. EEG tracings were made with bipolar temporal high central leads. In order to reduce inconvenience to the subject to a minimum, we used collodion electrodes. Recording continued uninterrupted throughout the night until normal waking. The stages of sleep were determined at 20 sec intervals. The EEG changes were classified according to Loomis et al. (1938).* In order to study the reaction to Mogadon, the incidence of the stages of sleep was compared with normal sleep in each individual, and the increase or decrease per hour calculated. After individual responses had been determined, the results were expressed numerically for the whole group of subjects. This showed that the number of waking _

_

~

~

~

* LOOMIS,A. L., HARVEY, E. N., and HOBART, G. A.,

(1938); Distribution of disturbance patterns in the human EEG with special reference to sleep. J . Neurophysiol., 1, 413-430.

226

H. LECHNER

TABLE I EFFECT OF TWO TABLETS MOGADON (+)ON COURSE OF SLEEP COMPARED WITH NO MEDICATION (-) .~

.____

Stages

____

W A B C D E

1”

2”

3”

4”

Duration of sleep 5h 6h

7”

+__ - -~ + - + - + - + - + - + - + - 105 - 40 - 13 47 89 - 71 - 46 1 - - 1 8

8 - 213 - 43 71 - 82 6 - 115

- 95 - - 13 38 300 - - 57 - - 23 92 - 3 2 - 2 9 - 4 4 1

188 68 - 3

8 23 - 215 - 186 9 -

8h

10 - 40 - 14 - - 73 45 - 298 - 149 84 - 70 76 82 - 127 - 38 3 - -

1 Oh

9“

+ - + - 27 3 3 9 - - - 16 87 - 28 17 7 - - - 1 - I -

stages in the 1st h declined, while stages A and B underwent a marked increase. There was also an increase in EEG changes referrable to stages C and D during the 1st h. A single E stage observed at this point may be discounted. During the remainder of the night, stages D and E were notably reduced, whereas stage B was increased from the 2nd h on, reaching a maximum in the 7th h. It was particularly striking that under the medication the EEG changes identical with those of waking were greatly reduced during the night as a whole compared with normal sleep. In terms of the EEG, one gets the impression on studying the tracings that the whole sleep process has shifted in favour of stages B and C ; moreover, sleep was usually prolonged. If the effect of Mogadon on sleep is compared with the normal standard, we find a shortening of the initial phase, prolonged duration of sleep with simultaneous reduction in depth. Correlating this with the subjective statements of the individuals concerned, 5 of the 9 subjects reported that they had slept better under the drug while 4 could distinguish no difference. Disregarding the effect of suggestion these results raise the question as to whether deep sleep is more restful than prolonged sleep for man. This question cannot yet be answered, but it would be interesting to discover whether hypnotics are at all capable of increasing the depth of sleep, or if their effect consists wholly and exclusively in a decrease in the waking phases, leading to a reduction in the unconscious experience of these phases. These are all speculations, however, which have value only as a basis for working hypotheses to encourage further investigations. If we consider in the light of what we have said the effect of Mogadon on the course of sleep compared with normal sleep, we must conclude that the difference is due to the medicament. A further argument in favour of this is that there was a reduction in the wide individual variations. While many questions are still open-e.g. how wide are the variations in normal sleep, to name just one-it may be concluded that with this method of investigation evidence of the pharmacodynamics of hypnotics can be obtained. This possibility is of great importance since our knowledge of the pathophysiology of sleep disorders must be regarded 8s small. Psychiatric-Neurological Clinic, University of Graz, Graz (Austria)

H. LECHNER

HYPNOTICS A N D EUHYPNICS

227

Hypnotics and euhypnics Trials were carried out in 2250 patients to determine the varying clinical effects of barbiturates on the one hand and the benzodiazepine derivatives Librium, Valium Roche and Mogadon on the other. The latter were grouped together under the name euhypnics since - with Mogadon as the best example - they have a regulatory effect on the physiological sleep rhythm. Unlike hypnotics, the euhypnics induce sleep that is felt to be natural, accompanied neither by hang-over nor drowsiness. They cause no change in autonomic functioning, as is characteristic of hypnotics; addiction and withdrawal symptoms were not observed. The intensity of action depends not on dosage and mode of application but principally on the sensitivity of the patient. Particular modifications in the EEG, produced during deep sleep by high doses of euhypnics, are interesting and still unexplained.

Diferences between hypnotics and euhypnics in respect of clinical action Hypnotics

(1) Consistent action progressively affecting the various layers of consciousness in the following order: reduced mental activity, sedation, drowsiness, confusion, sleep, coma, death. In non-intoxication symptoms regress in reverse order. (2) Constant side effects, the intensity depending on degree of intoxication and dosage. (3) Intensity of action directly dependent on :preparation, mode of administration, dosage. (4) Marked influence on autonomic functions :pulse, temperature, blood pressure, respiration. ( 5 ) Acquired tolerance fairly frequent (also cross-tolerance). (6) Addiction and withdrawal symptoms. (7) Action on sleep: (a) Onset of sleep accompanied by drowsiness. (b) Sleep is forced and subjectivelyfelt to be abnormal.

Euhypnics (1) Variable effect depending rather on the condition of the patient. No narcotic action, but facilitate induction of anesthesia.

(2) Generally without after-effects even in high doses. Any after-effects due to the patient’s hypersensitivity rather than the preparation. (3) Intensity of action dependent chiefly on patient’s reactions. (4) Virtually no modification of autonomic functions even in high doses. (5) Acquired tolerance rare.

(6) No addiction or withdrawal symptoms (7) Action on sleep: (a) Onset of sleep rarely accompanied by drowsiness. (b) Sleep is felt to be induced and hence natural.

228

G . HARRER

(c) Patients can only be wakened with difficulty. (d) Immediate onset of sleep.

(e) Hypnotic action immediate in all subjects whether suffering from insomnia or not. (f) Frequent excitation and slight efficacy in pain-produced insomnia.

(c) Patients can be wakened at any time. (d) Sleep induced at the normal times regardless of the time of day the drug is administered. (e) Effect more marked in subjects suffering from insomnia. (f) No excitation and good efficacy in pain-produced insomnia. J. GALEANO MuGoz

Clinic of Psychiatry, Medical Faculty, Montevideo (Uruguay)

Experience with Mogadon Mogadon was tested clinically with regard to its hypnotic properties. Over 500 patients received oral doses varying from 5 mg to a maximum of 20 mg Mogadon and were observed for periods of up to 6 months. Gastrointestinal tolerance was good, and no allergic symptoms occurred. No signs of habituation were observed. Clinical observations suggest that Mogadon creates the conditions, i.e. ‘paves the way’, for physiological sleep, but that it also exerts a hypnotic effect. After an oral dose of 5 mg in the evening, patients were consistently free of side effects (hangover, etc.) the following morning. Doses of 10 mg and more sometimes caused a mild dazed feeling, dizziness, or similar effects. Clinical observations made in outpatients, and inpatients of a neurological ward, a psychiatric care unit, and a neurogeriatric ward for men and women were consistent in the details described above. Only in a women’s psychotic ward were results less favourable. Prolonged jiggle-bed tests showed Mogadon to be more effective than (in descending order of efficacy) Valium 5-10 mg, LuminalO.1-0.2 g and placebo. No disturbance of equilibrium (Romberg’s test with reduced standing surface) was demonstrable by a quantitative method. Near-point measurements revealed no accommodation changes due to Mogadon. The acoustic pain threshold, measured at a frequency of 100 c/s, was not affected by Mogadon. Measurement of tremor and fine motor function by a quantitative method showed changes only after doses of 10 mg and more. All the above tests were made in the early morning, 12 h after the oral administration of Mogadon. Tests of reaction times by means of the Beck apparatus showed even better results with Mogadon as a sedative when the initial state had been one of nervousness. No

229

EFFECT OF MOGADON ON AROUSAL REACTION IN RABBITS

deterioration was observed in the morning 12 h after administration of doses up to 10 mg. EEG recordings made before, during and after intravenous injection of 7.5-10 mg Mogadon gave the following results : (a) Clinically, onset of deep sleep without corresponding EEG sleep pattern; (b) Good correlation between clinical sleep and EEG; (c) No clinical sleep in spite of 7.5-10 mg Mogadon i.v., frontal @-activityin EEG. In all these cases where Mogadon was administered i.v. there occurred nystagmus, ataxic disturbances and slurred speech. G. HARRER

State Neurological Clinic, Salzburg (Austria)

Effect of Mogadon on the arousal reaction in rabbits A new derivative from the group of the benzodiazepines-Mogadon (1,3-dihydro7-nitro-5-phenyl-(2H)- 1,4-benzodiazepin-2-0ne)-was recently developed by Roche and has been shown clinically to be of value as a hypnotic. The effect of this substance on the arousal reaction of non-curarized rabbits when awake was compared with that of Valium (diazepam) and Nembutal. The arousal reaction was produced by high-frequency electrical stimulation (250 c/s, pulse duration 0.5 msec) of the TABLE I EFFECT OF

MOGADON, VALIUMAND NEMBUTAL ON THE AROUSAL REACTION OF NON-CURARIZED RABBITS

Substance

Dose mglk

Ro 4-5360 Mogadon

Mean increase in threshold for production of arousal reaction (control=100%; number of tests in brackets) neocortex hippocampus

0.625 0.81 1.25

131 (3) 155 (3) 171 (5)

2.5

229 (5)

RO 5-2807 Valium

1.25 2.5 5.0

163 (3)

Nembutal

5.0

6.5 10.0 ____

184 (3) 210 (3)

165 (3) 224 (3) 636 (3) ~

Duration Of efect minutes

155 (3) 197 (3)

40 (3)

{;’” ; {?,:;

50 ( 3 ) 67 (5) 99 ( 5 )

199 (3) 232 (3) 1299 (2)

I*

42 (3) 75 (3) 125 (3)

(1)

139 (3) 178 (3) {:90

43 (3) 67 (3) 100 (3)

;;

~

~~

* Typical hippocampal arousal reaction (i.e. &rhythm) no longer occurred even with the strongest stimuli.

230

G. GOGOLAK A N D B. PILLAT

mesencephalic reticular formation and proprioceptive stimulation. The resulting EEG changes were recorded in the neocortex and dorsal hippocampus. Table I summarizes the results. As will be seen, Mogadon produces a considerably greater rise in the threshold than Valium or Nembutal. No precise information on the relative activities is possible, as the dose-effect curves apparently do not run parallel. It is nevertheless conspicuous that the two benzodiazepine derivatives increase the threshold of a &rhythm in the hippocampus to a greater extent than that of an arousal reaction in the neocortex, whereas the barbiturate acts in a contrary manner in this respect. Whilst at the present time it does not always seem justified to differentiate between tranquilizers and barbiturates on the basis of electrophysiological criteria alone, the potent action of Mogadon on the arousal reaction is nevertheleqs noteworthy. There are very few substances which produce a definite increase in the threshold in rabbits on a dose of 1 mg/kg i.v. Clinically, the hypnotic effect of Mogadon was found to be some 10-20 times more potent than that of phenobarbital. Pharmacological Institute of the University of Vienna, Vienna (Austria)

G . GOGOLAK B. PILLAT

23 1

Effects of Benzodiazepines on Spontaneous EEG and Arousal Responses of Cats WILLIAM SCHALLEK

AND

ALFRED KUEHN

Department of Pharmacology, Research Division, Hoffmann-La Roche Inc., Nutley 10, N.J. (U.S.A.)

INTRODUCTION

We previously observed distinct differences between the actions of certain benzodiazepines and those of other psychodepressant drugs on the limbic system of the cat (Schallek et al., 1964). The present report extends these observations to the spontaneous EEG and to the arousal response induced by electrical stimulation of the reticular formation. All experiments were conducted on unanesthetised cats with chronically implanted electrodes. The benzodiazepines studied were chlordiazepoxide (Librium@) and diazepam (Valium@).Their effects were compared with those of chlorpromazine, meprobamate and phenobarbital. METHODS

The procedure was slightly modified from that described by Schallek et al. (1964). That paper may be consulted for additional details. Preparntion of animals. Cats were anesthetised with pentobarbital, 35 mg/kg i.p. The cranium was exposed and holes drilled in the skull with a dental burr at sites determined by a stereotaxic instrument. Electrodes consisted of two stainless steel wires, insulated except at the tips, twisted together so that the tip of one wire was 1.5 mm below the other. (The anesthetic needle and hook-shaped electrodes used previously were found to damage the brain on withdrawal.) Two pairs of stimulating electrodes were set in the mesencephalic reticular formation at the following locations : frontal plane : lateral plane : horizontal plane:

anterior 2 mm right 3 mm minus 1 mm

anterior 4 mm left 2 mm minus 2 mm

Recording electrodes were inserted on the surface of right and left frontal and parietal cortex. Our record, strictly speaking, was an electrocorticogram ; for brevity we will call it EEG. The upper parts of the electrode wires were fastened to the skull with acrylic plastic, and their ends soldered to Amphenol connectors. A mold of plastic sheeting References p.

2371238

232

WILLIAM SCHALLEK A N D ALFRED KUEHN

was now set on the skull; the connectors were placed in the mold, which was then filled with acrylic plastic. The skin was sutured tightly around the base of the mold. The cat was injected intramuscularly with penicillin, 600 000 units. Experiments began 1 month after this preparation. Experimentalprocedure. Cats were fed lightly and allowed to play on the laboratory floor for half an hour. They were then placed in the observation box; stimulating and recording leads were connected. The inside of the box was illuminated with a small bulb, while the laboratory was darkened. This arrangement permitted the observer to watch the cat, while the cat did not seem to notice the observer. After exploring the box or grooming for several minutes, the cat would curl up on a pillow and apparently fall asleep. The spontaneous EEG was recorded at this time. The reticular formation was now stimulated with increasing voltages until behaviora! arousal was observed. The most dependable endpoint was opening of the eyes; slightly higher voltages caused lifting of the head. Stimulation parameters were as follows : frequency : 200 CIS pulse duration : 2 msec duration of stimulation : 10 sec interval between stimulations : 5 min Intensity of stimulation was increased by steps of 0.2 V in successive stimulations until the threshold for arousal was reached. The cat was now taken out of the box. The drug being tested was given orally in a’ gelatin capsule. One hour later the cat was again observed for behavior on the laboratory floor, and then replaced in the box for EEG recording and determination of arousal threshold. These observations were repeated 2 h after drug administration. The minimum dose of each drug causing distinct changes in gross behavior was determined in preliminary experiments ; all experiments described in this report were performed at this dose level. Four cats were used in these observations; each cat was tested twice with each drug, as well as four times with dextrose controls. Treatments were given in random sequence. EEG records were measured by hand. Statistical analysis was made with two-way analysis of variance (Dixon and Massey, 1957) and multiple comparison ‘t’ tests (Dunnett, 1955). Change in response for each drug (difference between pre-drug and post-drug values) was compared with change in response for dextrose controls. Electrode locations were verified by the Kliiver-Barrera technique. RESULTS

Behavioral effects. Doses causing distinct behavioral changes in at least 3 out of 4 cats are listed in Table I, together with changes observed on the laboratory floor and in the observation box. Diazepam was the most potent compound in these experiments, followed by chlordiazepoxide and chlorpromazine. All drugs caused ataxia (locomotor incoordination) when the cats were placed on the laboratory floor; the

EFFECTS OF BENZODIAZEPINES ON SPONTANEOUS

EEG

233

TABLE I OBSERVATIONS OF BEHAVIOR*

Drug

Dose, mg/kg P.O.

On floor

Behavioral changes In box

5

No change Ataxic (7/8)

~~

Dextrose Diazepam Chlordiazepoxide Chlorpromazine Phenobarbital Meprobamate

10 10 40 160

Ataxic Ataxic Ataxic Ataxic

(5/8)

(7/8) (7/8) (6/8)

Less playful (2/16) Restless (4/8) Less playful (3/8) Restless (5/8)** Less playful (7/8) Less playful (6/8) Less playful (7/8) Restless (1/8)

* Figures in parentheses show number of tests in which behavior was observed, and total number of tests. ** In three of these tests, grooming behavior was evident. benzodiazepines differed from the other drugs in producing a greater degree of restlessness in cats placed in the observation box. Spontaneous EEG. Drug-induced changes in the spontaneous EEG are shown in Table 11, while statistical analysis of the data appears in Table IV. Diazepam caused TABLE I1 FREQUENCY PER SEC OF SPONTANEOUS

Number of

Drug

experiments

15 8

8

8 8 8

Dextrose Diazepam 5 mg/kgp.o. Chlordiazepoxide 10 mg/kg p.0. Chlorpromazine 10 mg/kg p.0. Phenobarbital 40 mg/kgp.o. Meprobamate 160 mg/kgp.o.

Before drug (BD)

9.125 f- 1.454 8.715 f 0.759 8.500 0.534 8.555 f 1.669 9.000 f 1.851 8.750 It 1.164

EEG*

Mean f standard deviation of sample ~. Ih 2h I h-BD after drug after drug

9.312 & 1.451 1O.OOO & 1.290 9.875 & 1.457 8.222 f 1.717 9.375 5 2.326 9.250 f 1.388

f 0.187 f 1.833 1.285 & 1.496 1.375 f 1.407 - 0.333 & 1.936 f 0.375 & 2.559 0.500 f 1.772

+ +

+

8.812 & 1.603 12.142 1.958 10.250 1.581

8.000 2~ 1.224 9.625 41 1.060 9.250 f 2.052

- .

~~

-~

h-BD

- 0.312 & 2.151 3.428 f.1.813 1.750 f 1.581 - 0.555 & 2.185 0.625 & 1.922 0.500 & 1.603

+ +

+ +

____.

_-

* In the original data, frequency was measured to the nearest second (e.g., 9 per sec). an increase in frequency which was significant in ‘t’ tests at the 0.01% level, while chlordiazepoxide caused an increase significant at the 0.05% level. The other compounds produced no significant changes. The effects of diazepam and phenobarbital are compared in Figs. 1 and 2. Arousal threshold. Changes in the threshold for behavioral arousal are shown in Table 111, with statistical analysis in Table IV. Phenobarbital caused an increase in threshold which was significant in ‘t’ tests at the 0.01% level, while diazepam and chlorpromazine produced increases significant at the 0.05% level. There was no significant References p . 237/238

234

WILLIAM SCHALLEK A N D ALFRED KUEHN

- v - -

1

10.30 A.M.

-

L

4 I?OO/lV

12v 11: 15 A.M.

DIAZEPAM

t

5 mg/kg

2.0 sec

I

RO. RPC

--

t

Q . . p

I -

1:45 PM.

Lpc

LFC

1.6 V

Fig. 1. Effects of diazepam, 5 mg/kg p.0. Arousal threshold before drug 1.2 V, after drug 1.6 V. Frequency of spontaneous EEG before drug 9 per sec, after drug 11 per sec. (Recording on Sept. 25, 1963). In each figure the upper row is before, the lower row after, oral administration of drug. In each row, the left panel is before, the right panel after, stimulation of reticular formation at threshold voltage for behavioral arousal (opening of eyes). Both figures are on cat 34. Stimulation was in left reticular formation. EEG measurements were made on right parietal cortex. EEG leads are right parietal cortex, left parietal cortex, right frontal cortex. Paper speed 30 mm per sec.

change with chlordiazepoxide ;effects of meprobamate were significant on analysis of variance but not o n ‘t’ tests. Other changes. No significant changes were observed in the amplitude of the spontaneous EEG, or in either frequency or amplitude of the activated EEG.

/

~1~ €3:

55 A M.

1OV

2 0 sec

11 :15 A.M. P H E N O B A R B I T A L 40rng/kg P.O.

w-

-._L

1:55RM.

- - ,

LPC

>LFC 1.6 V

Fig. 2. Effects of phenobarbital, 40 mg/kg p.0. Arousal threshold before drug 1 .O V, after drug 1.6 V. Frequency of spontaneous EEG before and after drug is 9 per sec. (Recording on Oct. 2, 1963.)

EFFECTS OF BENZODIAZEPINES ON SPONTANEOUS

EEG

235

TABLE I11 THRESHOLD VOLTAGE FOR B E HAVIOR AL AROUSAL*

Mean f standard deviation of sample

Number of experiments

15

Drug

Dextrose

Before drug ( B D )

1.737

f 0.681 8 8 8

8

8

Diazepam 5 rng/kg p.0. Chlordiazepoxide 10 mg/kg P.O. Chlorpromazine 10 mg/kg p.0. Phenobarbital 40mg/kgp.o. Meprobamate 160 mg/kg p.0.

1.942 & 0.952 1.771 & 0.726 1.955 5 0.974 1.825 i 0.774 1.825 i 0.781

I h after drug

I h-BD

1.750 f 0.667 2.228 0.845 1.857 f 0.660 2.111 0.782 2.075 f 0.747 1.975 0.671

0.012 f 0.185 0.285 f 0.227 0.085 i 0.157 0.155 & 0.343 0.250 i 0.297 0.150 i 0.256

*

*

.

+ + + + + +

2h afrer drug

1.725

i 0.619 2.228 & 0.970 1.942 0.621 2.466 f 0.680 2.300 f 0.667 2.200 f 0.848

__

2 h-BD

- 0.012 f 0.185 0.285 0.227 0.171 f 0.293 0.511 0.480 0.475 & 0.260 0.375 f 0.406

+ + + *+ +

* In the original data, threshold was measured to the nearest 0.2 V. TABLE IV STATISTICAL ANALYSIS VALUES O F ‘P’, D R U G VE R SUS DEXTROSE

Drug

Frequency per sec of spontaneous EEG 2-way analysis Mult. comp. ‘t’ test 1 h-BD 2 h-BD of variance

Diazepam Chlordiazepoxide Chlorpromazine Phenobarbital Meprobamate

0.005 0.025 N.S. N.S. N.S.

N.S. N.S. N.S. N.S. N.S.

0.01 0.05 N.S. N.S. N.S.

Threshold voltage for behavioral arousal 2-way analysis Mult. comp. ‘t’ test I h-BD 2 h-BD of variance

0.025 N.S. 0.005 0.01 0.025

0.05 N.S. N.S. N.S. N.S.

0.05 N.S. 0.05 0.01 N.S.

N.S.= Not significant (P > 0.05). DISCUSSION

When the present results are compared with those obtained previously, it is evident that each drug showed a distinct pattern of activity on the central nervous system of the cat (Table V). This suggests that there are differences in the sites of action of these compounds. Evidence for this suggestion is reviewed in the following paragraphs. Magoun (i950) described two functions of the brain stem reticular formation : (1) a caudal influence on spinal centers, regulating motor performance; (2) a cephalic influence on the cerebral cortex, controlling the state of wakefulness. Drug effects on both these influences were observed in the present experiments. The ataxia produced by each compound in our cats indicates that all these drugs have depressant effects on locomotor systems. The action of chlorpromazine on motor reflexes was analysed by Hudson and Domino (1963). They concluded that the principal site of chlorpromazine depression of these reflexes is probably the bulbar facilitaReferences p. 2371238

236

WILLIAM SCHALLEK A N D ALFRED KUEHN

TABLE V SUMMARY OF DRUG EFFECTS ON UNANESTHETISED CATS

________---

Drug

Diazepam Chlordiazepoxide Chlorpromazine Phenobarbital Meprobamate

Threshold of after-discharge* amygdala hippocampus

N.S.E.

N.S.E.

Significant increase Significant decrease Significant increase -

N.S.E.

EEG Arousal frequency _______Significant increase Significant increase N.S.E.

N .S.E. Significant increase

N.S.E.

-

N.S.E.

Significant increase N.S.E. Significant increase Significant increase N.S.E.

-.

* Data from SCHALLEK et al., 1961. N.S.E. = No Significant Effect.

tory area of the reticular formation. Activation of spinal reflexes induced by stimulation of this area was abolished by meprobamate (Del Castillo and Nelson, 1960). We have found no reference to comparable experiments with phenobarbital. However, Preston (1956) observed that pentobarbital depressed reflexes in the spinal cat at doses which in other experiments depressed reticular activation of the cortex. This suggests that barbiturates may act at spinal as well as at higher levels. Experiments on the sites of action of the motor depressant effects of benzodiazepines are now under way. Effects of drugs on the cephalic influences of the reticular formation were reviewed by Killam (1962). There is abundant evidence that the sedative action of the barbiturates is exerted through selective depression of the reticular formation; such evidence is largely lacking for chlorpromazine or meprobamate. The observations of Kid0 and Yamamoto (1962) lend some support to these conclusions. They found that the threshold for behavioral arousal induced by reticular stimulation in the cat was markedly increased by phenobarbital, while only moderate increases were obtained with chlorpromazine and meprobamate. In our experiments only phenobarbital produced increases in arousal threshold which were highly significant (P = 0.01) by both analysis of variance and ‘t’ test. We have found no report on the effects of benzodiazepines on behavioral arousal to reticular stimulation in the cat. Chlordiazepoxide caused a slight rise in the threshold for this response in the rabbit (Monnier and Graber, 1962). In cats immobilized with Flaxedil, chiordiazepoxide elevated the threshold for EEG activation induced by stimulation of the reticular formation; diazepam had the same effect but at lower doses (Requin el al., 1963). Diazepam had no effect on reticular activation of the cortex in enckphale isole cats (Morillo, 1962). In our experiments neither chlordiazepoxide nor diazepam produced a highly significant increase in the threshold for behavioral arousal. This suggests that depression of the cephalic outflow of the reticular formation plays only a minor role in the action of these drugs. Chlordiazepoxide and diazepam differed from the other drugs in two ways: they produced greater restlessness when our cats were in the observation box, and they increased the frequency of the spontaneous EEG. Increased EEG frequencies have been

EFFECTS OF BENZODIAZEPINES ON SPONTANEOUS

EEG

237

observed in cats with chlordiazepoxide (Roldan and Escobar, 1961), while rapid rhythms were seen with both chlordiazepoxide and diazepam (Requin et al., 1963). Fast activity has been noted in the EEG’s of patients on chronic medication with meprobamate (Henry and Obrist, 1958), chlordiazepoxide (Winfield and Aivazian, 1961) or diazepam (Gibbs and Gibbs, 1962). In other studies we observed that chlordiazepoxide had a depressant effect on the septa1area of the brain (Schallek and Kuehn, 1960; Schallek et al., 1962). Perhaps both the restlessness and the increased EEG frequencies just described are associated with depression of the septum or other forebrain inhibitory areas. Further experiments are needed to verify this hypothesis. ACKNOWLEDGEMENTS

We wish to thank Dr. Jacob B. Chassan for the statistical analysis, and Miss Norma Pietrusiak for the histology. SUMMARY

Five psychodepressant agents were tested in unanesthetised cats with chronically implanted electrodes. Each drug was tested at the minimum dose causing distinct changes in gross behavior. All drugs produced ataxia when the cats were placed on the laboratory floor. Diazepam was the most potent agent, followed in turn by chlordiazepoxide, chlorpromazine, phenobarbital and meprobamate. The frequency of the spontaneous EEG was increased at the 0.01% level of significance by diazepam, and at the 0.05% level by chlordiazepoxide. The threshold for behavioral arousal induced by electrical stimulation of the reticular formation was increased at the 0.01% level by phenobarbital and at the 0.05% level by chlorpromazine and diazepam. Comparison of the present results with those obtained previously indicates that each of these drugs has a distinct pattern of activity on the central nervous system of the cat. REFERENCES DELCASTILLO, J., and NELSON, T. E., Jr., (1960); The mode of action of Carisoprodol. Ann. N.Y. Acad. Sci., 86, 108-142. DIXON, W. J., and MASSEY, F. J., (1957); Introduction to Statistical Analysis. 2nd Ed. New York, McGraw-Hill (p. 140-141). DUNNETT,C. W., (1955); A multiple comparison procedure for comparing several treatments with a control. J . Am. Statist. Assoc., 50, 1096-1121. GIBBS,F. A., and GIBBS,E. L., (1962); Clinical and pharmacological correlates of fast activity in electroencephalography. J , Neuropsychiat., 3, suppl. I , S73-S78. HENRY,C. E., and OBRIST, W. D., (1958); The effect of meprobamate on the electroencephalogram. J. new. ment. Dis., 126, 268-271. HUDSON,R. D., and DOMINO, E. F., (1963); Effects of chlorpromazine on some motor reflexes. Znt. J. Neuropharmacol., 2, 143-162. KIDO,R., and YAMAMOTO, K., (1962); Analysis of tranquilizersin chronically electrode implanted cat. Int. J. Neuropharmacol., 1,49-53.

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KILLAM,E. K., (1962); Drug action on the brain-stem reticular formation. Pharmacol. Rev., 14, 175-223. MAGOUN,H. W., (1950); Caudal and cephalic influences of the brain stem reticular formation. Physiol. Rev., 30, 459-414. MONNIER, M., and GRABER,S., (1962); Classification Clectrophysiologique des substances psycholeptiques. Arch. int. pharmacodyn., 140, 206-216. MORILLO, A., (1962); Effects of benzodiazepines upon amygdala and hippocampus of the cat. Znt. J . Neuropharmacol., 1, 353-359. PRESTON, J. B., (1956); Effects of chlorpromazine on the central nervous system of the cat: A possible neural basis for action. J. Pharmacol. exp. Ther., 118, 100-115. REQUIN,S., LANOIR,J., PLAS,R., and NAQUET, R., (1963); Etude comparative des effets neurophysiologiques du ‘Librium’ et du ‘Valium’. Compt. rend. SOC. b i d , 157,2015-2019. ROLDAN, E., and ESCOBAR, A,, (1961); Control de la actividad convulsivay efecto sobre la transmision aferente producidos por el metaminodiazepoxido. Estudio experimental en el gato. Bol. Znst. Estud. Med. Biol. Mex., 19, 125-153. SCHALLEK, W., and KUEHN,A., (1960); Effects of psychotropic drugs on limbic system of cat. Proc. Soc. exp. Biol., 105, 115-1 17. SCHALLEK, W., KUEHN,A., and JEW, N., (1962); Effects of chlordiazepoxide (Librium) and other psychotropic agents on the limbic system of the brain. Ann. N.Y. Acad. Sci.,96, 303-312. SCHALLEK, W., ZABRANSKY, F., and KUEHN,A., (1964); Effects of benzodiazepines on central nervous system of cat. Arch. int. Pharmacodyn., 149, 461483. WINFIELD, D. L. and AIVAZIAN, G. H., (1961); Librium therapy and electroencephalographic correlates. J . nerv. ment. Dis.,133, 240-246.

V. SUMMARY STATEMENTS

This Page Intentionally Left Blank

24 1

Summary Statement G . MORUZZI Physiological Insiituie of the Universiiy of Pisa, Pisa (Italy)

I would like to make some remarks regarding the analysis of the functional significance of sleep as a recovery process. We are now rather well informed on the neural mechanisms which lead to sleep or to arousal, but we know surprisingly little about the fundamental problem which was raised by Professor Hess. It can be stated very simply and with only one sentence : why do we sleep? I am afraid, however, that several years ofjoint effort by neurophysiologists, neurochemists and neuropharmacologists will be needed before we can give an answer to this question. Neurophysiology may at least help to concentrate our attention on the hard core of the problem. It is not very difficult, even now, to draw a distinction between the main problems of sleep physiology and those which are related with what one might call the epiphenomena of sleep. Let us start with Von Economo’s old distinction between sleep of the body and sleep of the brain. All the manifestations of sleep of the body, interesting as they undoubtedly are, seem to be rather peripheral with respect to the main problem. Muscular relaxation? It is absent in the forelimb and in the neck ofoxen. Eye closure? It is extremely rare in oxen, and short-lasting manifestations of lagophthalmos have been described even in man. Abolition of the righting reflexes? They are present in birds, which can sleep while perching. We may end with a very simple consideration. When we lie sleepless in bed, we are fully aware that the main aim of sleep is not to give a period of rest to our body. Hence, sleep of the brain should receive all of our attention. But for several centers of the encephalon there is no need of sleep, at least if we define sleep as a long period of inactivity, or of decreased activity. The validity of this definition can be undoubtedly accepted for the neural structures underlying the processes of consciousness. However, the vasomotor center, the vagal cardioinhibitory center, the respiratory center do not sleep, although their activity may be modified by sleep or arousal. It has been tacitly accepted that these were really not exceptions to the rule, since sleep would concern only the brain. Obviously all the structures which are essential for life should not be expected to interrupt their activity during sleep. But the experiments of Evarts (1962, 1964, 1965) have made untenable such an explanation. He has clearly shown that neocortical neurons may be as active, indeed occasionally even more active, during synchronized sleep as during relaxed wakefulness. It is true that the discharge of these neocortical neurons may be deeply modified by the different stages Rrfrrences p . 243

242

G . MORUZZI

of sleep, as shown by the beautiful microelectrode investigations of Evarts (1962, 1964, 1965), and by the work of Arduini et al. (1963) and of Marchiafava and Pompeiano (1964) on the pyramidal discharges during sleep. These observations are of great interest, but again one is left with the impression that these changes are the consequences, not the very reason, of the state of sleep. Evarts (1965) has reported that the firing rate of the small neurons of the monkey’s motor cortex clearly decreases during synchronized sleep. These neurons are tonically active in the absence of movements and their continuous discharge is simply decreased during desynchronized sleep. We have no data yet on the GoIgi I1 neurons nor on the nerve cells of the motor cortex which do not give rise to pyramidal axons. Let us suppose that future investigation will show that to decrease or stop firing during synchronized sleep is the rule for the small neurons of the cerebral cortex. Should we conclude that we are unconscious one third of our life in order to give a period of rest to the cortical interneurons? It is rather unlikely that all the recovery processes which are connected with all-ornone impulses or with usual synaptic transmission should be regarded as basically different in the large and in the small cortical neurons. The time required for the fast processes of recovery is of the order of the millisecond, while sleep lasts hours! Let us assume that sleep is concerned with a slow process of recovery from an entirely different type of activity. Memory, conditioning and generally all the so-called higher nervous activities are associated with plastic processes which go on exclusively or almost exclusively during wakefulness. Sleep may be concerned with recovery from plastic activities, which could be simply more intense in the small association neurons of the cerebral cortex. Were these neurons to fall into a period of inactivity whenever they need some hours of rest, we should never be completely asleep nor fully awake. We should spend our life in a state of ‘dormiveglia’, to use an Italian word that cannot be easily translated into English. Recovery from plastic activities must therefore be concentrated into given periods of time, otherwise a given species would hardly be expected to survive. We lose one third of our life in an ‘abject mental annihilation’, to adopt the definition of sleep which Professor Eccles gave at the Ciba Symposium (1961), in order to be really awake during the other two-thirds. To achieve this concentration of all slow recovery processes in a well defined period of time is the aim of the subcortical structures which are concerned with sleep and wakefuhess. An attempt is made by me to visualize the function of these subcortical structures at the Symposium on Brain and Consciousness organized by the Pontifical Academy. The work on these structures has been rather intense during the last few years, but we should never forget that the first experiment which provided a really convincing evidence of the subcortical regulation of sleep was made here in Zurich almost 40 years ago. I am sure I interpret the feelings of all of us when I express to Professor Hess our sentiments of admiration and gratitude.

SUMMARY STATEMENT

243

REFERENCES ARDUINI,A., BERLUCCHI, G., and STRATA, P., (1963); Pyramidal activity during sleep and wakefulness. Arch. ital. Biol., 101, 530-544. EVARTS, E. V., (1962); Activity of neurons in visual cortex of cat during sleep with low voltage fast EEG activity. J. Neurophysiol., 25, 812-816. EVARTS, E. V., (1964); Temporal patterns of discharge of pyramidal tract neurons during sleep and waking in the monkey. J. Neurophysiol., 27, 152-171. EVARTS, E. V., (1965); Relation of cell size to effects of sleep in pyramidal tract neurons. Progress in Brain Research, Vol. 18: Sleep Mechanisms. K. Akert, Ch. Bally and J. P. Schade, Editors. Amsterdam, Elsevier (p. 81). MARCHIAFAVA, P. L., and POMPEIANO, O., (1964); Pyramidal influences on spinal cord during desynchronized sleep. Arch. ital. Biol., 102, 500-529. WOLSTENHOLME, G . F. W., and OICONNOR, M., (Editors) (1961); A CZBA Foundation Symposium on the Nature of Sleep. Boston, Little, Brown.

244

Summary and Conclusion from the Internal Medical Aspect F. HOFF I . Medical Clinic of the University of Frankfort-on-Main, Frankfort-on-Main (Germany)

Our president, Prof. Akert, has asked for a few closing remarks from a clinician. I shall therefore attempt to point out certain connections from the aspect of clinical research, selecting, as I proceed, some of the points made during the papers we have listened to. Perhaps I shall succeed in establishing some correlations which seem to me vital for the interpretation of the sleep phenomenon but which have not emerged sufficiently during the symposium.

Rhythm and polarity of sleep

I shall begin with the subject of our distinguished colleague and doyen Hess : ‘Sleep as a phenomenon of the integral organism’. Without doubt sleep is a basic function, which, as everything else in life, is characterized by rhythm and polarity. It is just as much the basis of life as systole and diastole or inspiration and expiration. We know from our own experience that sleep is a process of recovery; but we are unable to explain how the process functions. So far all attempts and methods have proved inadequate. I think that Hyden’s paper has contained some of the most important results presented a t this symposium. It has at least made us aware of enzyme changes in the neuron and glia related to sleep and wakefulness. We can perhaps hope to understand in the future how this recovery process comes about through sleep. Another aspect that was repeatedly mentioned was the phenomenon of polarity to which I have already alluded. The daytime with its associated activity is characterized by ergotropic function and the night with its sleep by trophotropic function. We have had an idea of ergotropic function for some time. A fundamental contribution in this field was made by Cannon (1915, 1928), who called attention to ‘the emergency reaction’ and the r6le of adrenalin. Both Langley (1922) and my own teacher Miiller (1931) demonstrated the polarity of the vagal and sympathetic systems. Both of these terms are considered inadequate today and Hess described the two systems in the terms ergotropic and trophotropic. When Akert spoke of a dichotomy of the sleeping and waking systems and Hernandez Pe6n compared the association acetylcholine and sleep with that of noradrenalin and arousal, polarity was again the phenomenon being discussed. The fact that noradrenalin and adrenalin as wel? as ACTH and corticoids are secreted in higher quantities during the day than the night, points i n the same direction. Monnier cast a new light on the problem when he maintained that we must

CONCLUSION FROM THE INTERNAL MEDICAL ASPECT

245

assume the presence of a humoral factor during sleep which is absent during the waking state. Not only sleep but many other autonomic functions-Aschd€ (1955a, b) has enumerated forty-are also subject to a simultaneous regulation. The clinician is familiar with polarity not only from the diurnal rhythm but also from situations in which a sudden and powerful increase in performance is required of the organism such as during physical exertion, excitement, fever, bacterial infection and central nervous stimuli. As in the polarity between waking and sleeping the concept of a ‘total autonomic switch-over’, which comprises first an ergotropic then a trophotropic phase, is the decisive element. The effect of light

Although this total switch-over is a spontaneous central act of the organism, external influences and especially light play an important role. According to Hollwich (1955) an energetic component of the optic pathways is involved here. Light produces increased secretion of noradrenalin and adrenalin, as was demonstrated many years ago by Lehmann in Dortmund and again recently by Von Euler (1956). The fact that we work in light and sleep in darkness prompts us to inquire into the significance of this afferent light stimulation. Winterstein (1 953) thought that sleep was the normal state of the brain, only interrupted by stimuli through the senses. Monnier has demonstrated, however, that interruption of all the afferent pathways does not necessarily produce sleep and that sleep is possible even in the presence of intact pathways. Nevertheless light and other afferent stimuli are decisive influences on sleeping and waking. My physiology teacher Hober used to tell the story-it originated from Striimpell(1878)-of the cobbler’s apprentice who, probably as a result of encephalitis, was deprived of his sensitivity and had only one intact eye and ear. As soon as his one eye was covered and the ear blocked he would fall into a deep sleep. When his ear and eye were uncovered he rapidly ‘came to’ and maintained that he had been fast asleep. I myself have observed how the unilateral hemiballism, accompanied by athetosis in an encephalitic patient, disappeared when the patient’s eyes were covered or even when the curtains were drawn. Evidently motor restlessness was in this case produced by the presence of light. Such afferent stimuli cannot, however, be measured purely quantitatively; they are controlled by our senses and interpreted according to their significance. The soldier is able to sleep during gunfire and will wake up when silence suddenly occurs. Partial switch-over and its consequences

The switch-over is completely synchronized only in ideal circumstances ; in modern man it is often dissociated by disturbance of the phases. On a voyage around the world the inner clock may adjust itself gradually to the cosmic clock. But on a jetflight round the world the inner clock will be put out of order and disturbances of synchronization will arise. Such irregularity on the day-night rhythm is doubtless conducive to disease, while normal rhythm, especially regular sleep, promotes health. We are all acquainted with the studies of Kleitman (1939) and the experiments in Spitsbergen and in caves when daytime has been artificially determined. The results shed light on the conditions Rrferonrrr n.

2 4

246

F. HOFF

to which nightworkers are subjected: an adaptation takes place but it is only partial and concerns more readily the so-called voluntary action systems. Other components of the organism maintain the cosmic rhythm for months or even years, as Menzel (1956) has shown. Nightworkers often complain of tiredness and insomnia; the incidence of gastric ulcer is eight times (Duesberg and Weiss, 1939) and that of cardiac infarct twice as great as in control groups. There is also increased incidence of pulmonary edema, angina pectoris and apoplexy at night. The fact that the various autonomic functions are controlled by widely differing regulatory systems gives rise to disturbances of synchronization. The speed of adaptation depends on the nature of each factor. Functions controlled by noradrenalin or a d r e n d n , such as heart and circulation, adapt themselves immediately, whereas water, electmlytes, temperature, hepatic glycogen, hematopoiesis etc. change gradually. Hematopoietic shifts require 3-6 days, and water and electrolytes even longer. This is h w dissociations arise within the integral function of the autonomic system, which in their turn may cause disease and insomnia.

Cause of sleep disturbances Besides these factors there are a number of conditions that lead to sleep disturbances. Insomnia is often encountered in neurasthenic and depressive patients. Jung has pointed out that there are marked differences between these two. The depressive patient presents not only insomnia but also deep-seated disorders of other autonomic functions. Healthy sleep is represented on the EEG by high amplitudes resembling veritable mountain peaks. The depressive patient shows much flatter tracings-a sign that periods of deeper sleep are absent (Figs. I and 2). Neither is the sleep disturbance Depressive p a t i e n t s Years

029

059

? . .. ..... .. .. ... -. .. . . _ _ ...... . ~~~

8p.m.

9'p.m.

1dp.m.

I1b.m.

rnidnight

lam.

Fig. 1.

2a.m.

30.m.

4a.m.

5a.m.

6o.m.

CONCLUSION FROM THE INTERNAL MEDICAL ASPECT

247

Normal cases

Fig. 2.

an isolated phenomenon of narcolepsy nor of the Pickwickian syndrome. Both the obesity and the polycythemia, if present, are certainly of central nervous origin. Jung contends that faulty central regulation cannot be corrected by specific therapy, but that rigorous slimming produces good results. We have found that venesection also helps. Cardiac insufficiency is a further cause of insomnia. As a result of his difficult breathing the patient mobilizes the ergotropic function, which prevents him from getting to sleep. In this case strophanthine is the best treatment for insomnia. We physicians are not completely blameless in the matter of sleep disturbances when we give our patients stimulants during the day. The extensive use of pills and tablets is in itself also an important factor. Analgesics, theophylline, cardiazole and preparations containing caffeine and strychnine, nicotine, tea and coffee are often to blame. Sleep pills ruin the capacity for spontaneous sleep. Oswald has shown that it takes two months for a patient to recover from sleep disturbance after a regular course of sleeping pills. The doctor should bear in mind that patients who ask him for sleeping pills take them regularly and not by -way of exception.

248

F. HOFF

The value of healthy sleep Some sound advice on the value of healthy sleep would be helpful to the patient. Sleep is not only a sign of good health but also an important factor in convalescence. When I was ill as a child my mother used to say ‘sleep until you’re better!’ This notion contains a good deal of truth. How often do we break the rules of sleep in our modern way of life. The sick patient in particular requires sleep but will hardly find it in an over-lit hospital ward or when the nurse wakes him in the middle of the night for an injection. In many ways we murder sleep, like Macbeth, and this is the worst of crimes. It is our task as doctors to preserve and protect natural sleep. REFERENCES

J., (1955a); Exogene und endogene Komponente der 2CStunden-Periodik bei Tier und ASCHOFF, Mensch. Naturwissenschaften, 42, 569-575. ASCHOFF,J., (1955b); Der Tagesgang der Korpertemperatur beim Menschen. Klin. Wschr., 131, 545-551. CANNON, W. B., (1915); Bodily Changes in Hunger, Fear, Pain and Exercise. New Haven (Conn.), Yale Univ. Press. W. B., (1928); Die Notfallsfunktionen des sympathico-adrenalen Systems. Ergebn. Physiol., CANNON, 27, 380406. DUESBERG, R., and WEBS,W., (1939); Reichs-Ges. BI. 3, Arbeitsschr. 8, (Abstract). HOFF,F., (1962); Klinische Physiologie und Pathologie. 6. Aufl. Stuttgart, Thieme Verlag. HOLLWICH,F., (1955); Auge und Zwischenhirn, Bucherei des Augenarztes, Beiheft der klin. Monatsbl. f. Augenheilkd., 23, 95-136. KLEITMAN, N. (1939); Sleep and Wakefulness as Alrerning Phases in the Cycle of Existence. Chicago, Univ. of Chicago Press. LANGLEY, J. N., (1922) ;Das autonome Nervemystem. Berlin, Springer-Verlag. LEHMANN, G., (1950); Srrahlentherapie, 83, 109, (Abstract). G., (1954) ; Srrahlentherapie, 95, 447, (Abstract). LEHMANN, G., and KINZIWS, H., (1951); Adrenalinogen, Adrenalin und Sympathicusreiz. Pflugers LEHMANN, Arch. ges. Physiol., 253, 132-151. LEHMANN, G., and KINZIWS, H., (1951) ;Adrenalinogenspiegelund Rmdenhormon. Pfliigers Arch. ges. Physiol., 253, 257-261. MENZEL, W., (1956); Menschliche Tag-Nacht-Rhythmik und Schichtarbeit. Basel, Schwabe. MONNIER,M., (1963); Physiologie und Pathophysiologie des vegetativen Nervemystem. Stuttgart, Hippokr ates-Verlag MULLER,L. R., (1931); Die Lebensnerven. 3. Aufl. Berlin, Springer-Verlag. STRUMPELL, A., (1878); Beobachtungen uber ausgebreitete Anaesthesien und deren Folgen fur die willkiirliche Bewegung und das Bewusstsein. Dtsch. Arch. klin. Med., 22, 321-361. VONEULER,U. S., (1956); Noradrenuline. Springfield (Ill.), Charles C. Thomas. WINTERSTEIN, H., (1953); Schlaf und Traum. Berlin, Springer-Verlag.

.

249

Author Index* Abe, K., 14 Abrahamian, H. A., 68 Ackner, B., 132 Adey, W. R., 53 Aivazian, G. H., 237 Akert, K., 9-19 Akirnoto, H., 14 Alano, J., 194-230 Albe-Fessard, D., 21 Allen, M. B., Jr., 15 Allison, T., 68 Anderson, B., 14 Arduini, A., 68,242 Aschoff, J., 245 Aserinsky, E., 128, 135 Auchincloss, J. H. Jr., 140, 152 Bailey, P., 10 Bancaud, J., 129 Bard, P., 32, 34,49 Barlow, C. F., 189 Batini, C., 12 Baxter, C. F., 76 Bay, E., 191 BeauInes, A., 15, 110 Belleville, R. E., 191 Bental, E., 81, 84 Berger, F. M., 187 Berger, R.J., 141,142,152,162,163,164,175 Berlucchi, G., 24,242 Bessrnan, S. P., 50 Bickelrnann, A. G., 140,152 Biggart, J. H., 11 Bihari, B., 81, 84 Birchfield, R. J., 152 Birzis, L., 47 Bizzi. E., 24. 35 Blake, H., 128, 135 Bloch, V.,129 Baker, W., 136 Bonvallet, M., 13, 15, 153 Borenstein, P., 63 Bornstein, M. B., 117 Boyd, I. A., 87 Brazier, M. A. B., 128, 182, 186 Bremer, F., 12 Bresser, P. H., 191 Brodal, A., 49, 52 Brodie, B. B., 189 Brookhardt, J. M., 66

Brooks, D. C., 24,35 Briicke, F., 190 Buchwald, N. A., 14 Bullard, J. C., 190 Biilow, K., 143,144,152, 153,154, 156 Burwell, C. S., 140,152 Buser, P., 63 Cadilhac, J., 28, 37,46,48, 132, 175 Cahn, J., 194-230 Calvert, R. J., 190 Campbell, A. C. P., 10,11 Candia, O., 12, 13, 39,46,47, 51 Cannon, W. B., 244 Carmichael, E. B., 191 Caspers, H., 14,73 Castan, P., 48, 175 Caveness, W. F., 127 Cervello, V., 185 Chaillet, F., 103 Chanarin, I., 190 Chambers, W. W., 12 ChhvezIbana, G., 14, 15, 98, 99, 109, 111, 112 Churchill, J. A., 14 Cier, A., 44 Ciganek, L., 182 Clemente, C. D., 14, 112, 113 Cohn, R., 186 Collier, C. C., 140, 152 Colon, E., 76 Cook, E., 140,152 Cordeau, J. P., 12, 15, 110 Corner, E., 92 Corner, M. A., 70-78 Courjon, J., 20, 22, 24, 25, 197 Cowan, W. M., 14 Coxon, R. V., 52 Crane, M. G., 140,152 Creutzfeldt, O., 91 Creve, W., 191 Daly, D. D., 136 Davis, H., 128, 132 Davis, P. A., 128, 132 Davison, C., 10 Dawson, R. M. C., 92 Degan, R. O., 191 De Groot, J., 195 Delange, M., 48, 175

* Italics indicate the pages on which the paper of the author is printed.

250

AUTHOR INDEX

Del Castillo, J., 236 Dell, P., 13, 153 Delorme, J. F., 20, 26,28 Dement, W. C., 20,47,48, 53,63,128, 135, 140, 143,152,163 Demikhov, A., 96 Dempsey, E. W., 14 Demuth, E. L., 10 Denavit, M., 21 De Robertis, E., 52 Desmedt, J. E., 15 Diemath, H. F., 117 Dikshit, B. B., 109 Dixon, W. J., 232 Doenicke, A., 178-182 Doll, EJW, 152 Domek,,TU. S., 189 DDmiirO, E. F., 186,187,195,236 Drachman, D. B., 140,152 Draganesco, S., 10 Dreyfus-Brisac, C., 132 Dubois, R., 96 Duesberg, R., 246 Dunnett, C. W., 232

Eccles, J. C., 86, 185 Eccles, R. M., 86 Edstrom, R., 52 Emmerson, J. L., 189 Emmons, W. H., 128,161 Epstein, W., 188 Escobar, A., 237 Evarts, E. V., 47, 68,81-91, 241, 242

Faure, J., 40 Favale, E., 20, 37, 39, 47, 51 Feldberg, W., 109 Felts, P. W., 191 Fischgold, H., 132, 140, 141, 152 Fisher, C., 48, 140, 143, 152, 163 Foulkes, W. D., 165 Fox, B. J., 133 Fraser, H. F., 191 Fulton, J. F., 10

Camp, R., 120 Gamper, E., 17 Gangloff, H., 71, 175, 177, 187,207 Gastaut, Y., 129, 132 Gayet, M., 10 Gerard, R. W., 128, 135 Gerardy, W., 140, 152, 153 Gerber, K., 188 Gerschenfeld, H. M., 52 Giaquinto, S., 47

Giarman, N. J., 50,51 Gibbs, E. L., 129, 130, 135,237 Gibbs, F. A., 129,130,135,237 Giussani, A., 20, 37,39,47, 51 Goff, W. R., 68 Goodnow, J. J., 161 Gotham, J., 140 Gotoh, F., 140 Gottesmann, C., 194-230 Gotzsche, H., 140, 152 Graber, S., 103,118, 119, 120, 236 Granit, R., 13, 15, 86 Grastyan, E., 50 Green, J., 130,132 Gresham, S.C., 187 Griggs, D. E., 140, 152 Gruber, C. M., 191 Guilbaud, G., 140,141,152 Gumnit, R. J., 140,152 Hackney, J. D., 140,152 Haggqvist, G., 87 Halberg, F., 92 Hara, T., 20, 37 Hartmann, K., 1 0 , l l Harvey, E. N., 128,132, 170 Hassler, R., 6, 14 Hauser, F., 194 Hendley, C., 24 Henry, C. E., 237 Heppner, F., 117 Herberg, D., 140, 152, 153 Hermann, H., 26 Hernandez Peon, R., 14,16,46,96-117 Herold, M., 194 Herz, A., 63-69 Herzet, J. P., 103 Hess, R., Jr., 14, 127-139, 142, 143 Hess, W. R.,3-8, 11, 13, 14, 15,111, 149, 155 Heuser, G., 14 Heusser, FI., 120 Heyck, H., 142 Heyman, A., 152 Himwich, H. E., 70, 186 Hirnwich, W. A., 70 Hinton, J. M., 188 Hobart, G. A., 128, 132, 170 Hobson, J. A., 24 Hodes, R., 110, 195 Hodgkin, A. L., 86 Hoff, F., 244-248 Hoffer, A., 109 Hollister, L. E., 191 Hollwich, F., 245 Holmquist, A. G., 92 Hondelink, H., 187 Hosli, L., 118-123 Hubel, D. H., 20,81,100

AUTHOR INDEX

Hudson, R. D., 236 Hugelin, A., 13,153 Huhn, A., 191 Hunter, R. A., 190 Hurworth, E., 190 Huttenlocher, P. R., 47, 81,84 Hydkn, H., 53,92-95

Ibe, K., 1 9 0 Ingelfinger, F. J., 1 9 0 Ingvar,D. H., 143,152, 153,154 Isbell, H., 191 Ivy, A. C., 122

Jansen, J. K. S., 81,87 Jarmillo, R. A., 141, 142, 152, 175 Jasper, H. H., 14,132 Jeannerod, M., 20,23,24,25 Jew, N., 238 Jouvet, D., 20,24,26,28,29,32,33,39,53,71 Jouvet, M., 15, 2042, 63, 65, 68, 71, 100, 111, 153,154,175,187,197 Jung, R., 3,91, 136,140-159, 187

Kaada, B. R., 13, 15 Kanzow, E., 47 Karler, R., 188 Karmos, G., 50 Katsenelbogen, S., 186 Kawakami, M., 40,65 Kay, F. A., 191 Keddie, R. M., 141,142,152, 175 Keidel, W. D., 182 Kellaway, P.. 133 Kety. S. S., 92, 187 Kewitz, H., 190 Keyser, G. F., 191 Kido, R., 236 Killam, E. K., 236 Kinzius, H., 248 Kirkegaard, A., 190 Klee, M., 120 Klein, M., 20,26, 27,47 Kleinerman, J., 92 Kleitman, N., 3, 53, 113, 128, 135, 163, 172, 245 Knighton, R. S., 14 Knowles, W. B., 12 Koch, E., 39 Koella, W.-P., 14 Koller, Th., 103, 118, 119, 120 Konzett, H., 183-193 Kornmiiller, A. E., 120 Koukkou, M., 91 Krause, D., 47 Krayenbiihl, H., 10, 11

Kreindler, A., 10 Kretschy, A., 140 Kuehn, A., 231-238 Kuehnel, H., 47 Kugler, J., 178-i82 Kuhlo, W., 140-159 Kuhn, H. M., 140, 152,153 Kuhn, W. L., 120,187

LaGrutta, V., 15 Laidlaw, J., 190 Lange, P. W., 92-95 Langley, J. N., 244 Lanoir, J., 21, 236 Lasagna, L., 188 Laubenthal, F., 191 Laurin, O., 15. 110 Lehmann, D., 91, 153,245 Levitt, M., 12 Liberson, W. T., 128 Liebreich, O., 193 Lienert, G. A., 170-174 Lin, C. N., 12 Lindsley, D. B., 12 Lissak, K., 50 Livingston, R. B., 13 Loeb, C., 137 Loomis, A. L., 128, 132, 170 Loughridge, L. W., 190 Lous, P., 188 Lubin, A,, 161 Lundberg, A., 86 Lux, H. B., 120

MacBean, A. L., 190 Macho, W., 190 Macht, M. B., 32,34,49 Magnes, J., 15, 46 Magnussen, G., 140 Magoun, H. W., 12, 13, 15,49,66,235 Maickel, R. P., 189 Majer, H., 120 Mancia, M., 12 Mangold, R., 92 Marchiafava, P. L., 169, 242 Marinesco, G., 10 Martin, J. P., 10 Masahashi, K., 14 Massey, F. J., 232 Matthews, P. B. C., 81, 86, 87 Mauthner, L., 1 1 Maxwell, E. S., 191 Mayer, S., 189 Menzel, W., 246 Merivale, W. H. H., 190 Meyer, J. S., 140

25 1

252

AUTHOR INDEX

Michel, F., 20,22, 24, 25, 26, 197 Mikiten, T., 24 Minkel, H. P., 190 Minobe, K., 12, 13,46 Mitchell, S. A., 48, 140, 143, 152, 163 Modell, W., 185 Mollin, D. L., 190 Monnier, M., 71, 103, 110, 118-123, 175, 177, 187,207,236.244 Moreau, A., 15; 110 Morgane, J. P., 98, 99, 109, 111, 112 Morillo, A., 186, 236 Morison, R. S.. 14 Moruvi; G., 6; 12, 15,21, 24, 32,46, 66, 68, 92, 111,112 Motzenbecker, F. P., 191 Mounier, D., 44 Mouret, J., 20, 23, 24, 25 Muhar, F., 140 Miiller, L. R., 244 Murata, K., 91 Muzio, J. N., 163 Mya, T. S., 189

Nakagawa, T., 14 Nakamura, I., 14 Naquet, R., 21,236 Nauta, W. J. H., 14,40 Nelson, T. E., Jr., 236 Neuhaus, G., 190 Niebyl, P., 24 Niemer, W. T., 38,66 Nsrregaard, S., 190

Obrist, W. D., 237 Ochs, S., 76 O’Connor, M., 243 Oepen, H., 140, 153 Okabe, K., 14 Okuma, T., 14 Olley, P. C., 141, 142, 152, 175 Orthner, H., 10 Oswald, I., 132, 141, 142, 152, 160-169, 175 Othmer, E., 170-174

Paillard, J., 129 Palestini, M., 12, 68 Pampiglione, G., 132 Parkes, M. W., 186 Parmeggiani, P. L., 6, 15 Pascoe, E. G., 74, 76, 77 Passouant, P., 28, 37, 48, 132, 175 Passouant-Fontaine, T., 28, 37, 46 Pavlov, I. P., 14, 15 Peters, J. J., 70-78

Petersen, V. P., 140, 152 Phillips, C. G., 86 Phillips, G. W., 191 Pieron, H., 122 Pigon, A., 53, 93 Pisano, M., 68 Pfas, R., 236 Plunkett, G. B., 141, 142, 152, 175 Poggio, G. F., 137 Pompeiano, O., 15, 37, 46, 47, 49, 169, 242 Powell, T. P. S., 14 Preston, I. B., 236 Proctor, L. D., 14 Purpura, D. P., 70, 120 Rechtschaffen, A., 24, 25, 48, 140, 143, 152, 163 Reinert, H., 190 Reinoso-Suarez, F., 38 Remmer, H., 190 Renzetti, A. D., 140, 152 Requin, S., 236 Rhines, R., 13, 15, 49 Richards, R. K., 189 Richter, D., 92 Ritchie, J. M., 86 Roberts, E., 77 Robin, E. D., 140, 152 Robson, K., 12 Roffwarg, H. P., 48, 163 Rokaw, S., 140,152 Roldan, E., 237 Rosadini, G., 68, 137 Rosner, B., 68 Rossi, G. F., 12,13,20,37,39,46,47, 51,68 Roth, B., 140, 142, 143 Roth, L. J., 189 Roth, M., 130, 132 Roth, R. H., 50 Rothballer, A. B., 13 Rowe, S. N., 10 Russek, M., 102, 103, 108 Sacco, G., 20, 37 Sager, O., 10 Salvi, G., 24 Sanen, F. J., 140, 152 Sawyer, C. H., 40,65 Schadt, J. P., 70-78 Schaffer, A. I., 190 Schallek, W., 231-238 Schaltenbrand, G., 10 Scheibel, A. B., 52 Scheibel, M. E., 52 Scheid, W., 191 Scherrer, M., 152 Schlag, J. A., 103 Schlager, E., I86

AUTHOR INDEX Schmidt, K. F., 51 Schnedorf, J. G., 122 Schonberg, F., 191 Schreiner, L. H., 12 Schwab, R. S., 132 Schwartz, B. A., 132, 140, 141, 152 Seegers, W., 190 Sessions, J. T., 190 Sharpless, S., 132 Shaver, M. R., 191 Shaw, C. C., 191 Shaw, J., 130, 132 Sherrington, C. S., 86 Shideman, F. E., 190, 191 Sieker, H. O., 152 Simon, C. W., 128,161 Skinner, S. L., 155 Skoglund, S., 86 Skolnik, S. J., 50 Snyder, R. S., 38 Sokoloff, L., 92 Somogyi, I., 47 Soulairac, A., 194-230 Spiegel, E. A., 127 Sprague, J. M., 12 Stamm, J. S., 75 Steg, G., 86 Steim, H., 140, 152 Steiner, W. G., 186 Stellar, E., 12 Sterman, M. B., 14,112,113 Stern, E. W., 52 Sterner, N., 93 Stille, G., 186 Strata, P., 24,242 Straub, R. W., 86 Strumpell, A., 245 Swett, J. E., 15, 37,49 Tachibana, S., 47 Taeschler, M., 186 Taylor, A. M., 132,164 Taylor, J. D., 189 Tazaki, Y., 140 Thacore, V. R., 167 Thangapregassam, M. J., 197 Therman, P. O., 92 Timo Iaria, C., 96, 99, 109, 111, 112 Tissot, R., 103, 122,175-177 Torri, H., 14

Treisman, M., 132, 164 Tschirgi, R. D., 52 Valatx, J. L., 20,24,28,29,33,44,47,71 Van Backer, H., 76 Van Harreveld, A., 74, 76 Van Maanen, E. F., 187 Van Rey, W., 142 Vetter, K., 136 Vimont, P., 20,25, 26,28 Von Economo, C., 9,10,11,37,40,68 Von Euler, U. S., 92,245 Von Stockert, F. G., 186 Wald, F., 52 Waldvogel, W., 15 Wallace, G. B., 191 Walter, W. G., 132 Ward, A., Jr., 117 Webb, W. B., 187 Weiss, W., 246 Werner, G., 190 WhaIey, R. D., 140, 152 Whelan, R. F., 155 Wilder, J., 152 Williams, H. L., 161 Williams, R. L., 187 Winfield, D. L., 237 Winkel, K., 14, 120 Winterstein, H., 245 Wissfeld, E., 142 Wolpert, E. A., 48; 140,143,152, 163 Wolstenholme, G. F. W., 243 Wurtz, R. H., 47 Wyers, E. J., 14 Wynvicka, W., 113 Yamaguchi, N., 14 Yamamoto, K., 236 Yasargil, M. G., 10, 11 Yim, G. K. W., 189 Yoss, R. E., 136 Zabransky, F., 231 Zadunaisky, J. A., 52 Zanchetti, A., 12 Zen Ruffinen, 120

253

254

Subject Index Brain stem, arousal system, 15, 16 grey matter, 15 sectioning, paradoxical sleep, 41 y-Butyrolactone (G.B.L.), induction of paradoxical sleep, 44, 50, 54

Acetylcholine, relation to sleep, 109 Acoustic stimuli, effect in awake state, 7 waking K complex, 132 Alertness, hippocampal function, 22 Amphetamine, sleep pattern, 165-167 Anesthetics, evoked response, 178-1 82 relation to hypnotics, 194 Apnea, during sleep, 149, 155, 156 Arousal reaction, muscle potential, 133 Ataxia, response to benzodiazepines, 236 Atropine, blockage of hypnogenic pathway, 100 Autonomic system, arousal system, 13 cholinergic transmitters, 15 ergotamine, sleep inducer, 15 Awakeness, characterization of sleep, 3 EEG, 82 environmental circumstances, 3 evoked potentials, 63-68 humoral regulation, 118-123 hypnagogic hallucination, 161 maturation, chick, 70, 71 muscular hypertonia, 33 neuro-humoral transmission, 96-1 17 paradoxical sleep, 34 reticular formation, lesion, 31 rhythm pattern, 133 rhythmic enzyme change, 92-95 vigilance as sleep systems, 112

Dendrites, maturation of synapses, 75, 76 Desynchronization, maturation, brain waves, 74 sleep characteristics, 46, 112 spreading depression, 76 Dreaming, influence from depression, 166 occurrence in sleep, 161 tryptophan administration, 163 word sound, I 6 4

Barbiturates, depressive activity, 186 effect on reticular formation, 236 function, 194, 218, 219 Behavior, brain waves, maturation, 72, 73 effect of chemical stimulation, 99 Behavioral sleep, synchronizing influences, 46 Benzodiazepine, arousal response, 231 effect on EEG, 231, 238

EEG, anesthesia, 137 behavioral aspects, 71 Cheyne-Stokes respiration, 137 coma, 137 effect of atropine, 100 benzodiazepines, 23 1-238 Doriden, 209,210 hypnotic agents, 186, 187 Librium, 194, 195, 210-212 Mecloqualone, 197 Nembutal, 197 encephalitis, 136, 137

Cataplexy, mechanisms, 49, 50 Caudate nucleus, influence of Librium, 212 sleep system, 14 Cerebral cortex, activation paradoxical sleep, 50 arousal discharge, 108 auditory evoked potential, 63-68 behavioral sleep, 20 influence of curare, 195 Librium, motor cortex, 211, 212 maturation, sleep, 69 neuronal activity, sleep, 12 spreading depression, 72-15 thalamo-cortical system, 15 Consciousness, disturbances, EEG, 137 Curare, cortical effect, 195

SUBJECT INDEX

evoked response, sleep, 178-182 hypnogenic pathway, 110 insomnia, 136 Kleine-Levin syndrome, 136 limbic midbrain cholinergic sleep, 99, 100 maturation, chick, '71-74 narcolepsy, 136, 143 neurasthenic insomnia, 141 related to enzyme activity, 93 sleep, hypnotic substances, 215-219 sleep disturbances, 127-139 sleep induced by acetylcholine, 105 Slow sleep rhythms, 70 slow waves, behavioral sleep, 72 spinal cholinergic sleep, 106 Pickwickian syndrome, 144-1 52 vertex spikes, 131, 133, 137 'Electro-sleep' machine, induction of sleep, 167 Enuresis, occurrence in children, 163 Environment, awareness in awake stage, 4, 5 Enzymes, neuronal changes, sleep, 92-95 Evoked potential, arousal reaction, I33 cortical, sleep, 63-68 subcortical auditory, 63 Eye movement, characterization in sleep, 3 narcolepsy, 143 neurasthenic insomnia, 141 phasic aspects, 23 Pickwickian syndrome, 152 relation to dreaming, 163-165 reticular formation, pontine, 143 Facial muscles, relation to refreshing sleep, 171, 172 Feedback, inhibitory cortico-reticular system, 77 Gyrus, precentral, EEG recording, 83 Hallucinations, sleep-deprived subject, 162 Hippocampus, &activity, 21, 22 dorsal, influence of drugs, 203, 204, 211, 213 dorsal, influence of Librium, 21 1 evoked potentials, 64,65, 66 Hormone, arousal system, 13 Hypercapnia, related to sleep, 149-151, 152, 153, 154-157 Hypersomnia, sleep disturbances, 9, 142-144

Hyperthermia, effect on paradoxical sleep, 44, 50 Hypnotics, breakdown, 189, 190 classification, 188, 189 effect on sleep pattern, 165-167 pharmacological properties, 194-220 physiological aspects, 208-21 3 tolerance habituation, 191 Hypophysis, hormonal regulation, sleep, 6 paradoxical sleep, 40, 50, 54 Hypothalamus, arousal activation, 13, 16 hyperkinesia, 11 paradoxical sleep, 40,41, 50, 54 Hypothermia, effect on paradoxical sleep, 43,44, 50 Inhibition, factor in sleep, 14, 46 inhibitor transmitter, 110 maturating dendrites, 75 muscular tone, 22 sleep, active inhibitory process, 96 vigilance and sleep system, 112 Insomnia, depressive insomnia, 142 neurasthenic insomnia, 141, 142 sleep disturbances, 9 sleep patterns, 136, 140-142 Learning process, capacity in sleep,"161 Libriurn, function, 194, 195, 210-212 Maturation, cerebral cortex, related to sleep, 69 Mecloqualone, effect on sleep, 197, 218 Medulla oblongata, activating arousal system, 12 somnolence center, 11 Memory process, paradoxical sleep, 53 sleep, 161 Mesencephalon, &activity, 20 somnolence center, 11 Wernicke's polioencephalitis, 11 Mogadon, effect of, 201, 207, 210, 212, 213, 217 Narcolepsy, EEG pattern, 136, 142, 143 Nerve, deafferentiation, 39, 50

255

256

SUBJECT INDEX

Nerve fibers, deafferentiation, 39,40, 50 intrafusal fibers, 87 a-motor neurons, 86 size, related to activity, 86 Neuroglia, enzyme changes, 92-95 periodic mechanisms, 52 related to paradoxical sleep, 36, 52 Ontogeny, maturation of sleep, 28 Osmolarity, effect on paradoxical sleep, 44-46, 51 Paradoxical sleep, cholinergic association, 51 cyclic metabolic process, 51 deprivation, 51 drug adaptation, 166 EEG pattern, 136 effect of tranquilizers, 176 idiopathic narcolepsy, 163 innate mechanism, 48,49-53 nature, 52, 53 periodical glial mechanism, 52 Pathway, adrenergic arousal pathway, 109 cholinergic arousal pathway, 108 hypnogenic cholinergic pathway, 110, 112 hypnotic, 100-102 sleep system, multisynaptic, 110 Pickwickian syndrome, EEG, 144-152, 153, 154 physiological activity, 140-159 Pons, 0-activity, 20 lesions, effect on paradoxical sleep, 24, 31-36 phasic aspect, 24-26 pontile animal, 37, 42, 43, 52 sleep in chronic pontile cat, 32, 33 sleep mechanism, 49 somnolence center, 11 Psychosis, paranoid, induced by sleepdeprivation, 162 Pyramidal tract, activity during sleep, 85 antidromic response, 84, 87 relation of cell size, 81-91 Reflex, monosynaptic, spinal, 47 process, paradoxical sleep, 37-39 production, 49-53 Regulatory mechanism, nervous and hormonal, 5 Reserpine, effect on paradoxical sleep, 176 Respiration,

relation to Pickwickian syndrome, 151 relation to sleep, 152, 154156 Response, adrenergic arousal, 108, 109 cholinergic arousal, 108 effect of benzodiazepines, 231-238 evoked response, sleep and anesthesia, 178-1 82 hypnagogic hallucinations, 161, 162 paranoid psychosis, 162 sleep, 160 Reticular formation, activity, effect of drugs, 197, 198-201 changing blood osmolarity, 45 control, eye movement, 143 influence of barbiturates, 236 inhibitory process, 46, 49, 52 lesions in pontine part, 31 localization of arousal system, 12 rhythmic enzyme change, 92 Sedatives, breakdown, 189, 190 classification, 188, 189 effect on sleep pattern, 166 Sl,=P, acoustic stimulus, 213, 215 active inhibitory process, 96 anatomical substrate, 9-19 behavioral sleep, 20, 27 body movements, 172 center, 6 central neuro-humoral transmission, 96-1 17 cholinergic excitatory synaptic action, 109 chronic pontile cat, 32, 33 cingulate cholinergic sleep, 103 cortical-subcortical relation, 15 deprivation, 162 depth, relation to refreshing sleep, 171 desynchronized-synchronized pattern, 74 differentiation between brain and body sleep, 67 disturbances, 136, 246, 247 duality of states of sleep, 20-36, 4 6 4 9 EEG, 82, 127-1 39 effect of certain drugs, 175-177, 209-210, 214, 215, 217 effect of lesions, 31-36 effect of reticular coagulation, 46 electro-sleep, 167, 168 enzyme changes, 92-95 facial muscles, 172 fronto-temporal cholinergic sleep, 102, 103 humoral factor, 96 hypnogenic factor, 118-123 inhibitory transmitter, 110 integrated functional process, 7 K complex, 132, 137 limbic midbrain cholinergic sleep, 99, 100

SUBJECT INDEX

maturation, chick, 70 microsleep, 161 natural sleep, 81 ontogenic aspects, 27, 28 paradoxical sleep, 20-62 paranoid psychosis, 162 peripheral afferents, 15 persistent sleep phase, 133 pharmacological sleep, 187 phylogenetic aspects, 26, 27 pontine cholinergic sleep, 104 positive DC displacement, 72-75 psychophysiological features, I6C169 refreshing effects, 170-174 rhythm and polarity, 244, 245 spinal cholinergic sleep, 105 spinal hypnogenic neuron, 107 striate cholinergic sleep, 104 Spinal cord, vestigial elements of the sleep system, 107 Stimulation, awake response, 160 deprivation, 30 effect of light on sleep, 245 electrical, diencephalon, 4 evoked K complex, 132 proprioceptive, sleep reflex, 39 word sound, influence on dreaming, 165

Subcortical, auditory evoked potentials, 63-68 electrical activity, 127-1 39 Succinic oxidase, neuronal activity, sleep, 94 Synapse, central transmission, 109 cholinergic excitatory, 96 transmitter in sleep, 96, 97 Synchronization, maturation, brain waves, 74 sleep aspects, 46, 112 spreading depression, 75 Telencephalon, origin of slow sleep, 46 Thalamus, evoked potential, sleep, 64, 65 hypnogenic factor, 120 sleep system, 14, 21 thalamo-cortical system, 15 Thalidomide, effect on sleep, 187 Tractus solitarius, cortical activity, sleep, IS Tryptophan, eye-movement, 163

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