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.

I

EOG-q+ j &.-

I

1 sec

I

Vis. c x .

I

Lot. gen

I

I-

Nuchol EMC A

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

-.

I -

.-

a~

+.

2

...

1111

I N

~

3

.

m .

I

4

. * I.

5

.

.

II L 1

,

. *

' *

7

1

II

J I 6

111 a

I

8

*O0-y

ECG

150-

100-

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.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

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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

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8p.m.

9'p.m.

1dp.m.

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rnidnight

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2a.m.

30.m.

4a.m.

5a.m.

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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

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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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