Principles of Autonomic-Somatic Integrations: Physiological Basis and Psychological and Clinical Implications [1 ed.] 9780816662562, 9780816604142

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To be fond of learning is near to wisdom.

CONFUCIUS

. . . like all great ends, singleness of mind is not an end but a beginning. . . . A countryman has it who, being himself very old and without hope of the event, goes upon his knees to plant an acorn in the ground. CHARLES MORGAN

OTHER BOOKS BY ERNST GELLHORN

Autonomic Regulations, New York, 1943 Physiological Foundations of Neurology and Psychiatry, Minneapolis, 1953 Autonomic Imbalance and the Hypothalamus, Minneapolis, 1957 Emotions and Emotional Disorders (with G. N. Loofbourrow), New York, 1963

P R I N C I P L E S OF

Autonomic-Somatic Integrations

Physiological Basis and Psychological and Clinical Implications

BY

Ernst Gellhorn, M.D., Ph.D. Professor Emeritus of Neurophysiology University of Minnesota

UNIVERSITY OF MINNESOTA PRESS Minneapolis

© Copyright 1967 by the University of Minnesota. All rights reserved PRINTED IN THE UNITED STATES OF AMERICA AT THE NORTH CENTRAL PUBLISHING CO., ST. PAUL 3

Library of Congress Catalog Card Number: 66-24533

PUBLISHED IN GREAT BRITAIN, INDIA, AND PAKISTAN BY THE OXFORD UNIVERSITY PRESS, LONDON, BOMBAY, AND KARACHI, AND IN CANADA BY THE COPP CLARK PUBLISHING CO. LIMITED, TORONTO

ANATOMICAL RELATIONS BETWEEN VARIOUS PARTS OF THE BRAIN DEALT WITH IN THIS BOOK

Frontispiece A. Extreme schematization of neural mechanisms related to the hypothalamus. HL: lateral preoptico-hypothalamic region; HM: medial and periventricular zones of the hypothalamus; LFS: limbic forebrain structures, hippocampus and amygdaloid complex; LMA: "limbic midbrain area," composed of the ventral tegmental area, interpeduncular nucleus, nuclei tegmenti of Gudden, nucleus centralis tegmenti superior of Bechterew, and central grey substance; GFC: frontal cortex. The shaded area represents the brain-stem reticular formation (actually, LMA forms a paramedian subdivision of the midbrain reticular formation). The heavy arrows outline the limbic system — midbrain circuit in which the lateral preoptico-hypothalamic region appears as a nodal way station. Arrow labeled 1 indicates the afferent connections of the circuit with the primordial spinobulbar lemnisci (e.g., spinothalamic tract); arrow 2, further ascending afferents of the circuit, relayed through the bulbar reticular formation. Probable additional transreticular afferents, in part directly to the hypothalamus, have not been indicated. Arrows 3, 4, and 5 represent afferents of the circuit from the frontal cortex to, respectively, each pole of the circuit and the hypothalamus. The diagram does not indicate the probable afferent connection from the olfactory cortex via the medial forebrain bundle. Arrows 6 and 7 represent pathways connecting both the lateral hypothalamus and the limbic midbrain area with largely multisynaptic fiber systems descending through the reticular formation. (From Nauta. Personal communication. ) Frontispiece B. General diagram of relations between the three major analyzer-integrator mechanisms. A: secondary sensory nucleus of "ancient" phylogenetic status (e.g., nucleus proprius of the spinal cord dorsal horn); B: brain-stem reticular formation; C: limbic and striatal forebrain structures; D: interneuronal (i.e., premotoneuronal) pool; E: secondary sensory nucleus of more recent phylogenetic development (e.g., nuclei gracilis and cuneatus of the spinal dorsal funiculus); F and G: thalamo-neocortical apparatus. Heavy arrows indicate neocortical connections bypassing the older analyzer-integrator mechanisms. Direct cortical projections to motor neurons (heavy arrow on right side of drawing) appear to exist virtually only in primates and involve exclusively somatic motor neurons. Note that the thalamo-neocortical apparatus receives, beside its extrareticular neolemniscal afferents, connections from both the reticular formation and limbic and striatal forebrain structures. (From Nauta. Central nervous organization and the endocrine motor system. In: Advances in Neuroendocrinology, Urbana, U. of Illinois Press, 1963, p. 16.)

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Preface

WORK during the past two decades has made it abundantly clear that somatic sensory and motor functions, as well as visceral, are subject to fundamental regulation by hypothalamic and reticular mechanisms. Their roles in functions representing various fragments of behavior have been assiduously investigated and reported in great detail. The importance of their central position, anatomically and functionally, for the integration of diverse systems and functions has been emphasized. It is believed, however, that a few basic principles of operation play a primary role in the integration of a complex maze of organs and processes into coherent patterns of total behavior. It is the purpose of this book to attempt a broad physiological interpretation of behavior in the light of these principles and to examine some clinical problems in the same light. No gland, center, or single organ — even the brain — bears full responsibility for organismic behavior. But undeniably the endocrine and central nervous systems are essential to the integrative action required. Nor can it be doubted that a hierarchy exists within them with respect to responsibility and authority. Near the apex stand the hypothalamus and the limbic and reticular systems. The neocortex, with its detectors, analyzers, computers, and dispatchers is a sine qua non for their effective operation and their lines of communication with it are abundant. Physiological work discussed in this book, as well as Nauta's anatomical studies (see pp. vi-vii), stress the importance of the hypothalamic-limbic-reticular "hub" of the integrative machinery. Two fundamental and pervasive features of the influence radiating from this integrative "hub" are the ergotropic (arousal) and the trophotropic (lethargy and sleep) effects which may be selectively induced by appropriate stimulation. But such terms as arousal and sleep are not adequate to characterize the widespread and varied modulating effects of the ergotropic and trophotropic systems. Within the framework of total integration individual organs show alterations differing in degree and kind. Despite the obvious fact that total behavior is the resultant of interaction of all the IX

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parts, one cannot assume that when the organism sleeps all activities are depressed or that when it is aroused all are augmented. The problem is to determine which of them contribute more significantly to the total behavioral picture and how they do so. If the principles governing their operation in the integrated whole can be determined, they should provide important keys to the analysis of disordered behavior and its rational treatment. Relationships will be shown to exist between the states of autonomic balance in numerous normal and abnormal behaviors. Altered balance will be shown to be related to alterations in behavior including anxiety, neuroses, and conditioning in a systematic and predictable fashion. It will be emphasized that the alterations in autonomic balance are not merely reflections of changes in over-all behavior but are causally related to them. Our journals and books provide evidence that a major part of present neurophysiological work attempts to elucidate the function of smaller and smaller units (single neurons and their constituent parts). These important studies need to be supplemented by the analysis of organismic functions which was inaugurated by the fundamental experiments of Claude Bernard, Pavlov, J. Barcroft, and Walter B. Cannon. It is the aim of this book to contribute to this area of research: to determine some of the "system-laws of the organism" (von Bertalanffy) and to show their significance for neurophysiology, the physiology of behavior, and selected problems of medicine and neuropsychiatry. To bring the book up to date I have listed and briefly commented upon in a bibliographical appendix relevant publications which came to my attention during the production of the book. I acknowledge gratefully my indebtedness to Dr. K. H. Pribram for reading several chapters, to my friend and former associate Dr. G. N. Loofbourrow for reading the whole manuscript and giving me the benefit of his keen criticism, to Mrs. R. J. Fingal for secretarial services, and to Mrs. J. F. Case for stylistic advice. This work was aided by grants NH 06552-03-05 from the National Institutes of Health. ERNST GELLHORN 2 Fellowship Circle Santa Barbara, California September 5, 1966

Table of Contents

INTRODUCTION

3

CHAPTER I. THE PHYSIOLOGY OF THE BASIC PATTERNS OF ERGOTROPIC AND TROPHOTROPIC REACTIONS 5 I. The activation of the Ergotropic and Trophotropic Systems through Spinal Reflexes, 5; II. The Trophotropic and Ergotropic Systems at Supraspinal Levels, 8; 1. Some Basic Observations on Hypothalamic Functions, 9; 2. Arousal from Reticular Formation and Related Structures, 11; 3. On the Psychophysiology of Arousal, 13; 4. The Trophotropic Supraspinal System, 14; 5. On the Separability of Trophotropic and Ergotropic Effects, 17; 6. The Behavior of Single Neurons in Evoked States of Synchronization and Desynchronization of the Cerebral Cortex, 20; 7. Brain Stem and Ergotropic and Trophotropic Balance, 22; III. Reciprocal Relations and Related Problems, 24; 1. Reciprocal Ergotropic-Trophotropic Relations at the Spinal and Medullary Levels, 24; 2. Reciprocity at the Hypothalamic Level, 24; 3. Reciprocal Relations between Extrahypothalamic Ergotropic and Trophotropic Systems, 27; 4. Medullary Lesions and Hypothalamic Ergotropic and Trophotropic Effects, 33; IV. Concluding Remarks, 33; V. Summary, 37 CHAPTER II. PHYSIOLOGICAL ANALYSIS OF ERGOTROPIC AND TROPHOTROPIC IMBALANCES; APPLICATION TO VARIOUS STATES OF CONSCIOUSNESS 40 I. Deviations in Autonomic Nervous Functions from the Principle of Reciprocity, 40; 1. Observations on Reflexes and Hypothalamic Stimulation, 40; 2. Changes in Internal Environment, 41; 3. Further Examples, 43; 4. The Ergotropic and Trophotropic Systems and Deprivation of Sleep, 45; II. Dominance of the Trophotropic System, 47; 1. The "Tuning" of the Hypothalamus, 47; 2. Autonomic Balance in Sensory Deprivation, 49; 3. Narcolepsy, 49; III. Interpretation, 52; IV. Dissociations between the Upward and Downward Discharges of the Ergotropic System, 53; 1. Mental Activity and the Striated Muscles, 53; 2. The Yoga Trance and the Significance of Muscular Relaxation, 54; 3. Paradoxical Sleep, 55; 4. Depression of Cortical and Release of Ergotropic Functions, 59; V. Dissociation between Reticular and Hypothalamic Upward Discharges, 61; 1. Hypnosis, 61; VI. Discussion and Conclusions, 65; VII. Appendix. Problems of Homeostasis, 68

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CHAPTER III. THE ROLE OF THE ERGOTROPIC AND TROPHOTROPIC SYS TEMS IN CONDITIONING 71 I. Some Characteristics of the Conditional Response, 71; II. Electroencephalographic Changes during Conditioning, 72; III. Cortico-Cortical Conditioning, 76; IV. The Role of Subcortical Structures, 78; V. Influence of Hypothalamic and Reticular Lesions on Conditioning, 79; VI. Convulsions and Conditioned Reflexes, 82; VII. Hypothalamic Stimulation and Conditional Reflexes, 83; VIII. Conditioning, Self-Stimulation, and Spreading Depression, 84; IX. Hypothalamic-Cortical and Thalamo-Cortical Discharges in Conditioning, 87; X. Limbic Brain and Conditioning, 89; XL Observations on Hormonal Secretion and Conditioning, 91; 1. The Adrenal Cortex, 93; 2. The Adrenal Medulla, 97; XII. Some Observations on Drugs, Neurohumors, and Conditioning, 98; XIII. Reinforced Conditional Stimuli and the Ergotropic System, 101; XIV. Internal Inhibition and the Trophotropic System, 104; XV. Ergotropic-Trophotropic Balance and Conditioning, 110; XVI. Concluding Remarks and Summary, 111 CHAPTER IV. THE PHYSIOLOGY OF EXPERIMENTAL NEUROSIS AND OF STATES OF ANXIETY 116 I. Physiology of Experimental Neurosis, 117; 1. The Production of Experimental Neurosis, 117; 2. Conditioned Responses during Experimental Neurosis and Related States, 119; 3. General Symptomatology of the Experimental Neurosis, 121; 4. The Hypothalamic System in Experimental Neurosis and Related Conditions, 122; 5. Physiological Mechanism Underlying Neurosis-Producing Procedures, 124; 6. Pavlov's Phasic (Hypnotic) Phenomena, 129; 7. The Physiological Basis of the Excitatory and the Inhibitory Form of Experimental Neurosis, 131; II. Physiological Differentiation between Acute Fear, Subacute Fear, and Chronic Anxiety, 133; 1. Physiological Basis of Acute Fear, 133; 2. Subacute States of Fear, 133; 3. Anxiety, 138; III. Physiological Considerations Concerning the Therapy of Neuroses, 139; 1. Experimental Neurosis, 139; 2. Clinical Neurosis, 140; IV. Conditioning Processes in Abnormal Mental States, 143; V. Summary, 148 CHAPTER V. ASPECTS OF RETICULO-SOMATIC INTERACTIONS

150

I. Effect of Reticular Formation on the Motor System, 150; 1. Facilitation of Movements through the Reticulo-Hypothalamic System, 150; 2. Pain and Movements, 152; 3. Facilitation of Convulsive Discharges, 155; II. Interrelations between the Sensory and the Reticular Systems, 156; III. The Contribution of Afferent Impulses to the Emotions, 160; 1. Posture and Mood, 160; 2. Facial Movements and Emotions, 162; 3. The Significance of Loss of Facial Expression, 165; 4. On Empathy, 167; IV. Emotion and Perception, 168; V. Summary, 170 CHAPTER VI. PHYSIOLOGICAL COLLISIONS AND PSYCHOLOGICAL CONFLICTS 173 I. Physiological Collisions Involving the Nutritive Reflex, 173; II. Further Examples of Physiological Collisions, 176; III. Collision of Physiological Processes Underlying Instincts, 178; IV. Substitutive Behavior, 180; V. Psychological Conflicts, 181; VI. Summary, 182

Table of Contents CHAPTER VII. PATTERNS OF ERGOTROPIC DISCHARGES

xiii 183

I. Sympathetico-Adrenal Discharge, 184; II. The Physiological Significance of Adrenomedullary Secretion, 185; III. Sympathetic Vasodilatation as Part of the Sympathetico-Adrenal Discharge, 188; IV. The Transition of Sympathetic to Sympathetico-Adrenal Activity, 191; V. Partial Ergotropic Discharges in Man and Animals, 194; VI. Insulin Hypoglycemia and Related Conditions, 197; VII. The Ergotropic Discharge in the Paradoxical Phase of Sleep, 198; VIII. Intermediate Summary and Interpretation, 199; IX. Intraergotropic Adjustment Reactions, 206; X. Variations in the Cortical Activation Pattern Originating in Hypothalamus and Reticular Formation, 209; XL Concluding Remarks, 212 CHAPTER VIII. INTERNAL SECRETIONS AND THE ERGOTROPIC AND TROPHOTROPIC SYSTEMS .215 I. The Thyroid Gland, 215; II. Hypothalamic Balance and ACTH, 220; III. Hypothalamus and Sexual Functions, 222; IV. Interpretation and Summary, 224 CHAPTER IX. THE ROLE OF THE NEUROHUMORS IN SLEEP AND AROUSAL

227

I. Adrenaline and the Initiation of Arousal, 227; II. Some Pharmacological Observations, 228; III. Adrenaline, Acetylcholine, and the Brain Stem, 231; IV. On the Biochemical Basis of Sleep, 232; V. Further Studies on the Action of Acetylcholine on Sleep, 233; VI. Acetylcholine, Noradrenaline, and Arousal, 235; VII. Some Unresolved Problems, 235; VIII. The Neurohumoral Transfer of Sleep and Arousal, 238; IX. Concluding Remarks, 239; X. Summary, 242 CHAPTER X. BEHAVIORAL IMPLICATIONS

244

I. The Ergotropic and Trophotropic Systems and Behavior, 244; II. Self-Stimulation and the Trophotropic-Ergotropic Systems, 248 REFERENCES

253

BIBLIOGRAPHICAL APPENDIX

299

INDEX

311

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PRINCIPLES OF

AUTONOMIC-SOMATIC INTEGRATIONS

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Introduction

OUR concept of the autonomic nervous system, based on the classical work of Gaskell (323) and Langley (611), has undergone a fundamental change in the last decades. The work of these investigators established structural and functional differences in the organization of the peripheral autonomic and somatic systems. In contrast to somatic efferent nerves, autonomic nerves involve two synaptically linked neurons. Physiological and pharmacological tests disclosed that in most instances the viscera receive two types of autonomic nerves which exert antagonistic effects on the target organs. The antagonistic effects are mediated by the parasympathetic division originating in the tectal, bulbar, and sacral parts of the cerebrospinal axis and by the sympathetic outflow from the thoracolumbar section of the spinal cord. These two divisions comprise the autonomic system which, as Langley emphasized, is an efferent system. It innervates the viscera and is, with rare exceptions, not subject to voluntary control. It is autonomous inasmuch as structural integrity and function of autonomically innervated organs are preserved after the influence of the central nervous system on these structures has been eliminated by surgical procedures. Thus, extirpation of the sympathetic chains does not interfere with continued activity of the viscera, whereas sectioning of spinal nerves leads to paralysis and atrophy of striated muscles. Nevertheless, it must be stressed that autonomic functions are greatly curtailed by decentralization, since parasympathetic and sympathetic actions are also controlled by the somatic nervous system from the cerebral cortex to the spinal cord. The intimate interrelation existing between the somatic and autonomic nervous systems was clearly recognized by Hess (460) in 1925, long before these concepts were implemented by his own studies on the hypothalamus. Cannon (147) and Hess (462) agree, in spite of slight differences in their formulations, that the parasympathetic system tends to enhance the restitution of cellular functions through anabolic processes, reduction in activity, and increase in blood supply and gastrointestinal functions, 3

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combined with the excretion of waste products. By contrast the sympathetic division creates favorable conditions for the maximal performance of the somatic nervous system through cardiovascular adjustments, rise in blood sugar, delay in fatigue, etc., particularly under emergency conditions (147). The systematic exploration of the hypothalamus and adjacent parts of the diencephalon and the mesencephalon with electrical stimuli (Ranson and collaborators,* Hess, and many others) and the ablation studies of Cannon and Bard furnished further material .supporting the interrelatedness of autonomic and somatic functions. This work induced Hess (463) to coin the terms "ergotropic" symptoms and "trophotropic" symptoms, the former characterized by sympathetic discharges associated with increased activity of the motor apparatus (skeletal and respiratory muscles) and the latter consisting of parasympathetic effects associated with a lessened activity and responsiveness of the somatic nervous system. The syndromes thus range from maximal excitation in states of aggression to "adynamia" and sleep. Obviously, profound alterations in cortical and subcortical activity occur under these conditions which affect the somatic and the autonomic systems. The target of autonomic activity is not only the viscera under these circumstances but, as Hess pointed out, the somatic nervous system as well. His assumption that even the most complex functions of the brain which underlie the psychic processes are thus altered has been validated by the finding that hypothalamic excitation changes cortical potentials and psychic behavior. It is the aim of this book to investigate the normal reaction patterns of the ergotropic and trophotropic systems and to discuss the underlying physiological mechanisms; to investigate their mutual relations and to evaluate the significance of deviations from these patterns in special physiological and also in pathological conditions; and to show the importance of these systems for the study of behavior. "See The Hypothalamus, edited by Fulton (308).

I

The Physiology of the Basic Patterns Ergotropic and Trophotropic Reaction

I. THE ACTIVATION OF THE ERGOTROPIC AND TROPHOTROPIC SYSTEMS THROUGH SPINAL REFLEXES

NUMEROUS investigations since Sherrington's classic work (892) have shown that the stimulation of nociceptive nerves leads to sympathetic as well as somatic effects. The ergotropic syndrome appears as a rise in blood pressure and heart rate, dilatation of the pupil, retraction of the nictitating membranes, piloerection, and secretion of sweat. There is also an increase in the blood sugar level, provided that the adrenals are not denervated. This intense sympathetic (or sympathetico-adrenal) action is combined with withdrawal (flexor) reflexes. Similar effects are produced when the viscera are stimulated, particularly through a pull on the mesentery (709). The sympathetic effects are associated with flexor reflexes in the legs and contraction (rigidity) of the abdominal muscles (238, 698, 1015) in both man and animals. The difference between the somato-visceral and the viscero-somatic reflexes is only quantitative and seems to be accounted for by the lesser density of the nociceptive receptors in the viscera (261a). Studies using the pupil as an indicator have shown that the described effects result from stimulation of the C-fibers which conduct at a rate of 0.7 to 1.0 m/sec (270). In view of our subsequent comments on the role of the gamma fibers in the physiology of the ergotropic and trophotropic systems, it is of interest to mention that an increase in the pressure of the bladder which induces viscero-motor reflexes causes a parallel increase in the rate of discharge of the gamma fibers, indicating that the muscle spindles play a part in the activation of the accompanying flexor reflexes (1, 271). The reader is reminded that whereas the striated muscle fibers are innervated by large, fast-conducting nerves of the alpha neurons of the motor horn cells, the gamma fibers (axons of small diameter originating in the gamma motoneurons) end in the polar contractile regions of the intrafusal fibers. The nuclear bag which contains the endings of the mus-

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cle spindle is located in the central portion of the intrafusal fibers. The activity of the afferent nerves originating in the muscle spindles increases as the muscle is stretched and a similar effect is produced when the gamma fibers are stimulated. At a given stretch of the muscle the proprioceptive discharges increase with increasing rate of stimulation of the gamma system. This system contributes, therefore, to the reinforcement of voluntarily and reflexly induced movements although, in the mammalian organism, it is by itself unable to evoke a contraction of striated muscles.* Changes in the environmental temperature may serve as a further example of a reflexly induced activation of the autonomic and somatic systems. Since the role of the hypothalamus in the response to thermal stimuli will be discussed later, we confine our discussion at present to the effects of cold and heat on skin receptors. Common observation shows that exposure to cold leads to increased muscular activity and shivering, this activation of the somatic system again being associated with a generalized sympathetic and sympatheticoadrenal discharge (329, 432). Both components of the ergotropic system contribute to homeostasis: sympathetic vasoconstruction reduces the loss of heat whereas the secretion of adrenaline and the increased activity of the striated muscles raise the production of heat. Gopfert et al. (397) have demonstrated the parallelism on exposure to cold between basal metabolism and muscle activity (indicated by frequency and amplitude of the action potentials) and emphasize that the action potentials are increased even before shivering becomes visible. Conversely, spontaneous activity and muscle tone are lessened in a warm environment while the autonomic balance is shifted to the trophotropic side. This is due to a lessening of the sympathetic tone, indicated by cutaneous vasodilatation and relaxation of the nictitating membrane, and also to an increase of parasympathetic discharges leading to pupillary constriction and sleep. Complex reactions occur when nausea results from vestibular reflexes involving angular or linear acceleration or develops in various clinical conditions.! In general, parasympathetic symptoms (fall in blood pressure and heart rate, 725; and increased salivary secretion) predominate and are associated with a loss in muscle tone. The interpretation that this syndrome is chiefly due to a trophotropic discharge is supported by the observation that stimulation of the parasympathetic division of the hypothalamus produces licking movements and parasympathetic symptoms such as pupillary constriction, fall in blood pressure and heart rate, salivation, and retching. These phenomena are accompanied by signs of fatigue and loss in muscle tone (463). *For the literature see 398. fSee 370, Chapter 16, for further details.

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7

That stimulation of the abdominal organs may lead to a vagal slowing of the heart and to circulatory collapse was first demonstrated in 1863 by Goltz (392). This reflex accounts for the loss of consciousness of boxers hit below the belt. The quickness and intensity of this reaction suggest that not only parasympathetic effects on heart and circulation (with reciprocal decline in sympathetic tone) but also a loss in muscle tone are involved. Distention of abdominal organs (295) and stimulation of afferent muscle nerves of the C-group (528), which probably mediate pain sensations, lead likewise to vasodilatation and a fall in heart rate and blood pressure. In view of the fact that pain originating in the skin elicits ergotropic effects but that arising from muscle and viscera causes trophotropic effects, it is appropriate to call attention to psychological and biological differences between the two types of pain. Wolff & Wolf (999a) state that "cutaneous pain differs from visceral pain in possessing a bright quality which seems to exert an exhilarating action and commonly incites the individual affected to fight or flight. This pattern has biologic usefulness since assaults from a hostile environment are likely first to strike the skin. Visceral pain, on the other hand, is characterized by a deeper, aching quality which seems to exert a depressing effect, is commonly associated with nausea and followed by inactivity. This pattern, too, appears to have biological significance since fight or flight would be fruitless against assaults from within." It is suggested that the different psychic and behavioral responses are due to the fundamentally different cortical and subcortical excitation patterns of the ergotropic and trophotropic systems respectively. In addition to the receptors for pressure and warmth in the skin and those of the vestibular apparatus, the baroreceptors of the sino-aortic area are important regulators of trophotropic functions. Increased pressure in the sino-aortic area or stimulation of the sinus nerve leads to a fall in blood pressure and heart rate and to increased tone and activity of the gastrointestinal tract. At the same time there is a loss in tone of the striated muscle and a tendency to sleep (586, 881). Similar effects produced by the injection of adrenaline (363) likewise depend on the rise of the blood pressure and its action on the carotid sinus (980). In a convulsive animal the convulsions are reduced when through drugs or appropriate postures the pressure in the sino-aortic area rises (379). In the "head-down" position blood pressure, heart rate, and pupillary diameter decline while the tone of the abdominal muscles decreases (1015). Since these effects are absent after denervation of the sino-aortic area, it may be said that the stimulation of the baroreceptors induces increasing degrees of activity in the trophotropic system. Conversely, a fall in pressure in the isolated carotid sinus or a change in this pressure resulting from hemorrhage (350) or from tilting into the "head-up" posi-

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tion leads to increasing sympathetic and somatic discharges (and even to convulsions): the ergotropic system is released. Since the chief difference between ergotropic and trophotropic action as far as the somatic system is concerned lies in the degree of muscle tone, it is of importance to mention that the gamma system plays a decisive although not an exclusive role in the regulation of muscle tone.* This is evident from the study of tonic reflexes in decerebrate rigidity. Deafferentation abolishes these reflexes although the muscle spindles continue to show increased discharges on turning of the head. Apparently the extrafusal fibers need the "ignition by the spindle loop" for their activation (248, 400). If during and following a rise in the pressure of the isolated carotid sinuses the activity of a single gamma fiber is recorded in the anterior root of the lumbar cord, it is found that a brief increase in gamma activity is followed by a complete inhibition which outlasts the period of stimulation by several minutes. A similar effect is seen when the afferent muscle spindle discharges are recorded. This inhibitory action (but not the temporary phase of excitation) is absent after denervation of the carotid sinus, indicating that the diminution in muscle tone associated with increased pressure in the carotid sinus is due to a lessened activity of the gamma system. The alpha fibers are not significantly involved (878). Hypercapnia (induced by inhalation of gas mixtures rich in CO2) and asphyxia produce generalized sympathetic discharges and also an increased tone of skeletal and abdominal muscles (179, 329, 1015). The chemoreceptors of the sino-aortic area contribute to the activation of the ergotropic system under these conditions, in part through their effect on the gamma motoneurons (877). Of the reflexes discussed thus far the viscero-somatic and somatovisceral reflexes are demonstrable in the spinal animal, whereas the sinoaortic reflexes originating in baroreceptors and chemoreceptors require the integrity of the medulla oblongata. II. THE TROPHOTROPIC AND ERGOTROPIC SYSTEMS AT SUPRASPINAL LEVELS!

The purpose of this section is twofold: to present examples of the activation of these systems from brain stem and cortex and also to show that the trophotropic and ergotropic syndromes are more complex in the intact organism than in the spinal or in the deeply anesthetized animal .in which cortex and brain stem are functionally eliminated. As Hess (463) already pointed out, the activation of the trophotropic or ergo* Recent work has shown that small alpha neurons likewise contribute to the regulation of the tonus of striated muscles (401). fSee Fig. 1-1 and also the frontispieces.

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9

tropic system evokes behavioral changes which find characteristic expression in effects on the electroencephalogram (EEG). 1. Some Basic Observations on Hypothalamic Functions Starting with the classical work of Hess (463) on the hypothalamus we see that stimulation of its posterior part leads to a syndrome of ag-

Ftg. 1-1. Diagram showing the relative positions in a sagittal plane of the hypothalamic nuclei in a typical mammalian brain, and their relation to the fornix, stria habenularis, and fasciculus retroflexus. A: anterior commissure; Ch.: optic chiasma; Hyp.: hypophysis; 1: lateral preoptic nucleus (permeated by the medial forebrain bundle); 2: medial preoptic nucleus; 3: para ventricular nucleus; 4: anterior hypothalamic area; 5: suprachiasmatic nucleus; 6: supraoptic nucleus; 7: dorsomedial hypothalamic nucleus; 8: ventromedial hypothalamic nucleus; 9: posterior hypothalamic nucleus; 10: medial mammillary nucleus; 11: lateral mammillary nucleus; 12: premammillary nucleus; 13: supramammillary nucleus; 14: interpeduncular nucleus (a mesencephalic element in which the fasciculus retroflexus terminates); 15: lateral hypothalamic nucleus (permeated by the medial forebrain bundle); 16: stria habenularis; 17: fornix; 18: fasciculus retroflexus of Meynert (habenulo-peduncular tract). (From LeGros Clark. Morphological aspects of the hypothalamus. In: The Hypothalamus, Edinburgh, Oliver & Boyd, 1938, p. 7.)

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gression consisting of strong somatic discharges (apparent from the curvature of the back, the unsheathing of the claws, hissing, etc.) and of a generalized sympathetic discharge including adrenomedullary secretion.* The sympathetic cardiovascular and somatic discharges seen in exercise, anticipated exercise (trained dogs!), and on posterior hypothalamic stimulation are similar (841, 994). In contradistinction to this, ergotropic syndrome stimulation of the anterior hypothalamus (including preoptical and supraoptical areas and septum) produces mainly parasympathetic effects, such as fall in blood pressure, pupillary constriction, salivary secretion, and urination and defecation. Cortically induced movements and respiration are reduced at the same time (405). The parasympathetic symptoms frequently appear in association with a hypodynamia or adynamia of the skeletal muscles (trophotropic syndrome). The functional difference between anterior and posterior hypothalamus is likewise seen in the work on temperature regulation (808): the anterior hypothalamus controls the heat release through cutaneous vasodilatation and relaxation of the muscles, whereas the posterior hypothalamus is involved in the conservation and production of heat through generalized sympathetic discharges including vasoconstriction (except for vasodilatation in the muscles; 4), increased muscle tone (397, 443), and shivering (Al-A3).f Ranson (807) observed that lesions in the posterior hypothalamus cause somnolence and suggested that it was due to the loss of the "downward" sympathetic discharges. However, later work established the existence of diffuse excitatory discharges to the cerebral cortex, indicated by the appearance of grouped potentials in the EEG in animals with posterior hypothalamic lesions (565, 759) and by the diffuse cortical excitation following the direct (743, 744) or reflexly induced (71, 353) excitation of the posterior hypothalamus of the anesthetized animal.): **For further details see the recent work of Hunsperger et al. (502, 503). tFall in body temperature of decerebrate cats is associated with shivering but the muscle activity fails to influence the rate of heat loss. Apparently, the hypothalamically controlled sympathetic discharges are necessary to maintain body temperature (56). Numbers on this and following pages preceded by A refer to items in a supplementary bibliography contained in an appendix to this book. ^In lightly anesthetized animals sensory stimuli increase arousal according to the sequence: acoustic < proprioceptive < nociceptive (71, A4). Proprioceptive discharges induced by passive movements involve stimulation of stretch receptors and also of Pacinian corpuscles and joint receptors. The study of stimulation of muscle afferents (790, 791, 792) suggests that impulses conducted through the fast-conducting nerve fibers (group I) do not produce arousal, but those belonging to groups II and III showing higher thresholds and lower conduction rates elicit desynchronization and arousal but no signs of pain. Since according to Sherrington (892) proprioceptors are located in "muscles and their accessory organs (tendons, joints, blood vessels, etc.)," it may be said that proprioceptive stimuli activate the ascending reticular formation (including the hypothalamus) and induce diffuse cortical excitation and arousal (see also 327, 384, 790, 839).

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Moreover, it was shown that humoral or reflex stimulation fails to produce a generalized cortical excitation in animals with bilateral lesions in the posterior hypothalamus (588) or with this structure relatively inexcitable due to anesthesia (334). 2. Arousal from Reticular Formation and Related Structures Ranson's work showing that the somnolence produced by hypothalamic lesions was not permanent suggested that additional mechanisms exist which play a role in the maintenance of wakefulness. Bremer's (99) finding that transection of the brain stem at the collicular level but not below the medulla oblongata leads to permanent sleep potentials in the cortex implied that a structure between these two levels is involved in maintaining wakefulness. The extensive investigations of Moruzzi and Magoun and their collaborators (303, 521, 523, 665, 666, 667, 668, 738) showed that stimulation of the reticular formation from the pons to the thalamus elicits arousal (desynchronization of cortical potentials) and that this action is retained after the classical long-afferent systems have been interrupted through lesions in the lateral parts of the brain stem.* Moreover, destruction of the reticular formation leads to coma in spite of the integrity of the specific afferent systems (305, 634, 635). Similar arousal reactions are evoked from various parts of the neocortex (sensori-motor, temporal, and occipital areas, 303), and particularly from the association areas, the visceral brain (gyrus cinguli, orbital gyrus, entorhinal area, 549, 906), and the cerebellum (865);f also from subcortical structures such as the pallidum (437), the caudate nucleus (894), and the medial thalamus (435, 724, 884). Behaviorally the cortically induced arousal is characterized by the arrest of ongoing activity followed by searching movements directed toward the contralateral side as in the Pavlovian "orienting reflex" (275). Arousal may also be elicited through various sensory receptors (33, 100, 719, 828). In this case the reticular formation is activated through afferent collaterals from the medial lemniscus (918). Even the presence of man is sufficient to cause arousal in the EEC of the rabbit (718). As the electromyogram shows, increased muscular activity accompanies the period of cortical desynchronization (719). *The important finding that cortical arousal is accompanied by synchronized potentials (frequency 4—7/sec) in the hippocampus whereas cortical synchronization is associated with irregular hippocampal potentials is beyond the scope of this book (409). fThe ergotropic response elicited from the anterior lobe of the cerebellum consists of pupillary dilatation, exophthalmos, rise in blood pressure, increase in muscle tone, relaxation of the bladder, and cortical desynchronization, whereas a trophotropic reaction (miosis, fall in blood pressure, enophthalmos, contraction of the bladder, and cortical synchronization) occurs on stimulation of the posterior lobe (1009).

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Arousal, accompanied by increased sympathetic and gamma discharges, results from stimulation of the motor cortex (399), the mesencephalic tegmentum, the caudate nucleus, and the bulbar reticular formation (402, 895), provided that high frequencies of stimulation are applied.* It should be added that changes in the internal environment, such as hypercapnia,f anoxia, and asphyxia, likewise induce arousal. The excitation (directly and reflexly via the chemoreceptors of the sino-aortic area) seems to involve the brain stem as a whole —the respiratory and vasomotor centers in the medulla oblongata as well as the reticular formation (202, 500) and the posterior hypothalamus (333). Somatic discharges reinforced by enhanced gamma activity (877) are also increased. That lobeline induces sham rage in decorticate cats provided that the chemoreceptors of the carotid sinus are intact (76) speaks likewise for the reflex arousal of the ergotropic system via these receptors. The diffuse cortical excitation resulting from stimulation of the posterior hypothalamus or the reticular formation parallels in general the degree of downward discharges which activate the sympathetic and somatic nervous systems at the same time. This is evident from experiments involving different intensities of stimulation and various levels of anesthesia. It occurs also in conditions in which the hypothalamic balance is altered through intrahypothalamic injection of drugs or through baroreceptor reflexes (338). Similarly, this parallelism persists when the reticular formation is released from the action of the bulbar inhibitory area through bilateral coagulations at the level of the Xth nucleus (85) (see p. 30). Then, stimulation of the reticular formation leads to an increase in cortical desynchronization and in sympathetic and somatic discharges (see also 499). These findings are confirmed in systematic studies involving cortical potentials, sympathetic discharges in the long ciliary and splanchnic nerves, and sweat secretion from the foot pads. In different states of vigilance occurring "spontaneously" it is seen that as the degree of desynchronization increases the sympathetic discharges are augmented, whereas the appearance of large, slow cortical potentials (spindles) is accompanied by a decline in sympathetic activity. Moreover, stimulation of the reticular formation or of afferent nerves shows the same threshold "Recent work (403) indicates that the increased discharges from the muscle spindles which follow stimulation of the reticular formation or of the pyramidal tracts are not solely the work of the gamma fibers but that fast conducting alpha fibers are also involved. This is understandable since anatomical work has established evidence for the innervation of the polar portions of the muscle spindles by alpha and gamma fibers.

t See also the increase in desynchronization of the EEG with decreasing respiratory volume which is due to the increased CO2 pressure in the alveolar air (2).

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for cortical and sympathetic effects and a parallelism between these phenomena with increasing intensity of stimulation (89). 3. On the Psychophysiology of Arousal The extensive psychophysiological literature in which arousal and various forms of mental activity are correlated with autonomic and EEG effects cannot be reviewed (see 232). Suffice it to mention a few data which clearly show that arousal in man is an ergotropic reaction. It involves a sympathetic discharge, although the various effectors may respond in different degrees (607). Muscle tension is increased and greater desynchronization appears in the EEG. Whether the arousal is due to sensory stimuli or to mental tasks is immaterial for these effects. In some experiments the parallelism between muscle tension and certain autonomic indicators is striking during various mental efforts (198, 674) and a similar relation appears to exist between sympathetic responsiveness and cortical excitation leading to a decrease or blocking of the alpha and an increase in the beta potentials (188, 191). There are no significant differences between the ergotropic syndrome occurring in association with a willed movement — Darrow, (187) showed that voluntary movements are accompanied by increased palmar conductance (sweating) in the aroused subject — and that seen during a mental effort. As Sherrington (893) pointed out: the motor act is "the cradle of the mind." Apparently in both instances somatic and autonomic discharges from the cortex are involved. Their intimate relation is evident from the fact that stimulation of the pyramidal tract at the medullary level elicits generalized sympathetic discharges (610). The influence of the state of arousal goes even farther. The sensory threshold is lowered (232) and since afferent stimuli of all modalities cause arousal, this change in threshold must contribute further to maintaining and/or increasing this state. Direct stimulation of the posterior hypothalamus, excitation of this structure via nociceptive reflexes (367, 368), and, under special conditions, stimulation of the reticular formation (311) enhance the effect of optical and acoustical stimuli on the specific cerebral projection areas. These processes seem to account for the changes in sensory threshold and perception at different states of arousal. In addition, sensori-motor integration is improved. This is indicated by a shortening of the reaction time with increasing arousal in response to sensory stimulation and by the increased speed in the performance of complex motor tasks under these conditions (232). Here again, recordings of the EEG, EMG, and sympathetic indicators disclose that arousal increases motor action, sympathetic discharges, and the alpha frequency of the EEG (232). It is believed that the facilitation of

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cortically induced responses of the motor area (743) through hypothalamic excitation is involved in the effect that arousal exerts on motor acts. To summarize the data presented thus far on the ergotropic system, it may be said that it is activated from neocortex and limbic cortex, from subcortical structures, and from the brain stem and spinal cord. When supraspinal mechanisms are involved, cortical desynchronization and behavioral alertness, indicated by an increase in sensory sensitivity and speed of action and also by improvement of muscular coordination, occur at the same time. 4. The Trophotropic Supraspinal System Conversely, trophotropic reactions associated with synchronous cortical potentials and sleep* have been induced from widely different areas of the brain. The trophotropic effects resulting from electrical stimulation or heating of the anterior hypothalamus were accompanied by increased cortical synchronization (47, 263). Low-frequency stimulation of the thalamus lateral to the centrum medianum which elicited behavioral sleep in Hess's work was shown to be associated with synchronization of cortical potentials (12). Stimulation of the intralaminar nuclei of the thalamus produced behavioral sleep with corresponding increase in the slow (delta) potentials in the EEC (491, A5). Recruiting responses f evoked from this area were accompanied by a reversible decrease in the movements elicited from the motor cortex (408). Pyramidal discharges following stimulation of the motor area were likewise inhibited during recruiting responses arising from medial thalamic nuclei (802). Cortical synchronization and sleep or somnolence were also obtained from the caudate nucleus j (440, 894, 950) and the hippocampus (516). In unanesthetized animals low-frequency stimulation of the caudate nucleus produced increased sleepiness and muscular relaxation. Animals which had been trained to press a bar (for food reward) ceased to do so during the stimulation period. Obviously, the state of alertness was reduced and the trophotropic system was activated (127). Simultaneous recordings of gamma motor activity and cortical poten*In natural sleep, miosis increases with intensification of cortical synchronization (68). fTwo types of recruiting responses which are elicitable by an electrical shock have been used. Either a single shock is applied (to the reticular thalamic nuclei or to the caudate nucleus) resulting in a "spindle," a burst of rhythmic waves as seen in natural or barbiturate sleep; or repetitive shocks are administered (6— 12/sec) which induce the waxing and waning of large negative cortical waves. Both phenomena are present in the whole cortex but appear in various parts after different latent periods (524). I Concerning the spread of current to the internal capsule see Laursen (612) and Horvathetal. (490).

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tials show that cortical spindle bursts which occur spontaneously are associated with a decrease in gamma discharges (Fig. 1-2). This relation is also found when a recruiting response or spindle is evoked from the centrum medianum or the caudate nucleus, and often a striking cor-

Fig. 1-2. Correlation between inhibition of muscle-spindle discharges and an induced EEC spindle burst. Upper three records are EEGs of the right globus pallidus (R. GP.), posterior sigmoid gyrus (R. POST. SIG.), and lateral gyrus (R. LAT.). Graph indicates continuous change of frequency of single-unit discharges from left soleus muscle spindle. The scale of abscissa (time in sec.) is adjusted to the time of the upper EEG records. Single pulses (5v., 10 m.s.) are applied every 3 sec. to the right caudate nucleus. Arrows indicate the position in time of the shocks. Inhibition of musclespindle discharges occurs only when a well-developed spindle burst is induced, even though shocks applied remain constant. (From Kongo, Shimazu, & Kubota. A supraspinal inhibitory action on the gamma motor system. In: Symposium on Muscle Receptors, Hong Kong, Hong Kong U. Press, 1961, p. 61.)

relation is seen between the magnitude of the produced spindle and the decrease in the gamma activity. Similar effects are obtained from the anterior lobe of the cerebellum, the globus pallidus, and the bulbar inhibitory system (402, 487,488). Stimulation of the medial bulbar reticular formation inhibits cortically and reflexly initiated movements (670). This area is also involved in the

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transmission of inhibitory somatic effects from the gyrus cinguli,* the septum, and the intralaminar thalamic nuclei to the spinal cord (476, 755). However, as will be discussed later, a more laterally located bulbar center seems to send tonic inhibitory (synchronizing) impulses to the cortex (85). Obviously, the anatomical identification and delimitation of the bulbar inhibitory areas remain to be done (A47). An increase in the tone of the trophotropic system manifests itself not only in behavior and in the EEG but also in the activity of parasympathetic nerves. Thus, bursts of slow potentials in the cortex were shown to be accompanied by increased discharges in the short ciliary nerves (89). MacLean and Ploog (660) produced grooming reactions and penile erection in the monkey from the hippocampus, the septum, the gyrus cinguli, and anterior and medial parts of the thalamus. Other parasympathetic symptoms, such as a drop in heart rate, were also found. It is interesting that hippocampal after-discharges were accompanied by quietude and somnolence, signifying that a trophotropic syndrome had been produced. Parmeggiani (769) showed that weak hippocampal stimulation tends to produce trophotropic symptoms whereas higher intensities cause ergotropic effects to predominate. Trophotropic reactions involving cortex and subcortex may also be elicited through visceral and cutaneous receptors. Thus, afferent vagal stimulation may result in cortical synchronization and corresponding changes in hippocampal potentials (162).f Stroking the back of the cat induces parasympathetic symptoms, cortical synchronization, and inhibition of the gamma system (264). Low-frequency stimulation of cutaneous nerves produces similar effects and even sleep, but these phenomena could not be evoked in the fully aroused animal (789). Heating of the whole organism or of an area of the skin causes synchronization likewise (761). An increase in the pressure in the sino-aortic area either by mechanical means (87) or through the injection of drugs (747) such as noradrenaline or adrenaline leads to a decrease in the state of arousal, while grouped potentials appear in the EEG.| These changes which, as previously men*In its rostral portion this area causes on stimulation inhibition of the cardiovascular sympathetic tone and, in unanesthetized animals, suppression of movements and decrease in respiration. From experiments with electrolytic lesions it is concluded that these effects are transmitted to the bulbar inhibitory area via the anterior hypothalamus (646). Increase in blood pressure and respiration, and facilitation of reflexly or cortically induced movements and arousal, which have also been reported (546, 547), are perhaps due to the closeness of a sympathetic area in the subcallosal region (646). t There is, however, good evidence that the vagus also contains afferent fibers which activate the ergotropic system and induce desynchronization. Blocking the vagi may result in high-voltage slow potentials in the EEG and in behavioral sleep (776). | Consequently in the analyzed records the amplitude of potentials of low frequen cy is greatly increased (Fig. 1-3).

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tioned, are associated with trophotropic effects do not occur after sinoaortic denervation (Fig. 1-3). Pressure on the larynx leads also to trophotropic symptoms in the unanesthetized rabbit. Synchronization of cortical potentials, slowing of respiration, somnolence, and, occasionally, a slight decrease in blood pressure and heart rate occur (816). It is believed that these effects are mediated by the bulbar inhibitory area which receives impulses from the IXth and Xth nerves (85).

Fig. 1-3. Continuous record from a chronic electrode-implanted cat. All four leads are monitoring the EEC, the implanted depth electrodes being placed in the forebrain synchronizing zone bilaterally. Stimulation bilaterally induces an alert animal to become drowsy and to go to sleep. The EEC shows synchronous waves and sleep patterns coincident with behavioral sleep; the animal can be easily aroused and put back to sleep at the investigator's will. (From Clemente & Sterman. Cortical synchronization and sleep patterns in acute restrained and chronic behaving cats induced by basal forebrain stimulation. EEC clin. Neurophysiol. Suppl. 24:183, Elsevier, Amsterdam, 1963.)

5. On the Separability of Trophotropic and Ergotropic Effects More recently, sleep and cortical synchronization were induced with great regularity in the cat through bilateral stimulation at the base of the brain rostral to the optic chiasma (926; Fig. 1-4). Slow-frequency stimulation was likewise successful in producing behavioral and electroencephalographic sleep in various species when applied to the reticular formation in midbrain, pons, and medulla oblongata (279, 491, 661, 662, 737). Apparently the effect of stimulation depends not only on the struc-

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ture but also on the form of stimulation: sleep as well as arousal may be produced from the caudate nucleus, the intralaminar nuclei of the thalamus, and various parts of the reticular formation in the brain stem by low and high frequency or by low and high intensity stimulation respectively (156, 408, 491, 492, 505, 729, 738, 797, 951).* Similarly, low-fre-

Fig. 1-4. Frequency analysis of the potentials of the motor cortex. Cat, 2.25 kg. Top. The effect of 4 gamma/kg noradrenaline i.v. The amplitudes of the control and experimental periods were averaged for each frequency (abscissa) and the numbers obtained in the experimental periods were expressed in percentages of the controls (ordinate). Note that in the normal animal the amplitude of the potentials at low frequencies is increased and that of the high frequencies is diminished after administration of noradrenaline (solid line). After sino-aortic denervation (broken line), the effect of noradrenaline is reversed. Bottom. The effect of 4-5 gamma/kg adrenaline i.v. on the frequency analysis of the cortex of the cat before (solid line) and after (broken line) denervation of the sino-aortic area. The graph shows an increase in the amplitude at low frequencies after adrenaline, an effect which is absent after sino-aortic denervation. This graph is based on experiments on 5 cats. The greater amplitude of potentials of low frequencies after noradrenaline or adrenaline indicates increased cortical synchronization. This effect is abolished or reversed after sino-aortic denervation. (From Nakao, Ballin, & Gellhorn. The role of the sino-aortic receptors in the action of adrenaline, noradrenaline and acetylcholine on the cerebral cortex. EEC clin. Neurophysiol. 8:415, Elsevier, Amsterdam, 1956.) *Stimulation of the amygdala usually results in activation (281), but arrest reactions and ergotropic as well as trophotropic syndromes have also been reported. These actions are accounted for by the connections of the amygdala with septum and

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quency stimulation of the posterior hypothalamus inhibits and highfrequency stimulation increases tonic sympathetic discharges (62). In man similar effects have been obtained on stimulation of fornix and the reticular thalamic system. High-frequency stimuli caused arousal and low-frequency stimuli induced somnolence on excitation of the fornix (493,963). In studies in which the thalamo-reticular relations were further analyzed under these conditions it was found that bilateral coagulation of the posterior commissure and pretectum abolished the desynchronizing cortical and also the excitatory sympathetic effects of reticular thalamic stimulation at high frequencies (873, 874), although cortical arousal occurred spontaneously or on stimulation of the mesencephalic reticular formation directly or via reflexes. This work suggests that thalamically induced arousal takes place via the reticular formation. The synchronizing effect of low-frequency stimulation was not interfered with by the lesion. Moreover, surgical separation of the two hemispheres through sections of the corpus callosum and the anterior and posterior commissures abolished the recruiting response in the contralateral cortex on lowfrequency thalamic stimulation but did not interfere with contralateral cortical desynchronization in response to high-frequency stimulation of the reticular thalamic system. Apparently different structures are involved in the production of ergotropic and trophotropic effects via the diffuse thalamic system. This conclusion is supported by the following observations: 1. that in spite of considerable overlap the sites from which recruiting responses and desynchronization can be elicited are not the same (875); 2. that lesions involving the oral pole of the thalamus inhibit thalamically induced recruiting responses but do not alter cortical desynchronization of the thalamic origin (981). Similarly, it was shown that caudate stimulation evokes facilitatory and inhibitory effects on cortical potentials which had been evoked through stimulation of various specific sensory afferent systems. Lesions in the mesencephalic reticular formation abolish the facilitatory effect, but the inhibitory action is retained or even increased (209). Finally, by using evoked visual potentials as indicators, facilitatory and inhibitory ascending effects have been demonstrated with chemical stimulation anterior hypothalamus and also with posterior hypothalamus and reticular formation. However, it has not yet been possible to determine the exact conditions for the production of either the ergotropic or the trophotropic syndrome. The great complexity of the subcortical connections of the amygdala is evident from anatomical and physiological studies (385, 966). Perhaps experiments with lesions, as in Schlag's work (875), may be useful. Recently Birzis (73) succeeded in producing trophotropic effects (slow cortical potentials and reduced activity) in unanesthetized rats with lowintensity stimulation of the limbic cortex whereas EEC and behavioral arousal resulted from stimulation of the same sites with higher intensities.

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(acetylcholine) of the dorsal and ventral parts of the pontine reticular formation respectively. If the same sites are stimulated electrically, the dorsal reticular formation retains its facilitatory action, but the ventral part loses its inhibitory effect unless the central gray (below the inferior colliculi) is destroyed (208). Although no attempt is made to interpret in detail the underlying mechanism, these experiments likewise support the contention of the anatomical separability of the ascending facilitatory and inhibitory systems. See also Cordeau et al. (173). The fact that stimulation of cutaneous nerves produces trophotropic effects with currents of low frequency or intensity whereas ergotropic effects prevail when currents of high frequency or intensity are applied, made it possible to determine the central areas involved in these fundamentally different actions. Pompeiano & Swett (792) found that stimuli which elicit cortical synchronization in the normal animal predominantly affect brain stem units in the medulla oblongata and the caudal part of the pons whereas stimuli producing desynchronization chiefly excited the units in pons and mesencephalon. Apparently the ergotropic and trophotropic effects resulting from appropriate stimulation of cutaneous nerves are mediated by the facilitatory and inhibitory areas of the reticular formation respectively. 6. The Behavior of Single Neurons in Evoked States of Synchronization and Desynchronization of the Cerebral Cortex Purpura and collaborators (800, 803) have begun the difficult task of investigating in terms of single neuron functions different states of cortical activity induced by stimulation of the thalamic reticular system at low and high frequencies. When a recruiting response was evoked, recordings through intracellular microelectrodes showed a small, shortlatency, excitatory (negative) postsynaptic potential with a spike discharge followed by a prolonged, inhibitory (positive) postsynaptic potential. During the inhibitory phase spontaneous spikes were absent. It is this phase which corresponds to the individual waves of the recruiting response recorded from the surface of the cortex with macroelectrodes. By changing the frequency of stimulation it was possible to produce alternately inhibitory potentials accompanied by a cessation of spike discharges (in response to low frequency of stimulation) and excitatory potentials associated with high-frequency spikes (on high-frequency stimulation). Similar results were obtained by Krupp & Monnier (602) who found in anesthetized rabbits that the average frequency of discharge declines in single neurons of the motor cortex when thalamic reticular nuclei are stimulated with low-frequency pulses whereas the opposite effect occurs

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with stimuli of high frequency (Fig. 1-5). Moreover, the majority of reacting neurons is inhibited in the former instance but activated in the latter.* These important investigations support the interpretation that synchronization is, to a large extent, an inhibitory phenomenon and that in the transition from synchronization to desynchronization following ap-

Fig. 1-5. Stimulation of the midbrain reticular system at low frequency (6/sec) synchronizes the motor cortex (macrogram) and inhibits the discharge of a cortical motor neuron, whereas stimulation at high frequency (150/sec) desynchronizes the motor cortex and activates the discharge of the same cortical unit. (From Monnier, Hosli, & Krupp. Moderating and activating systems in medio-central thalamus and reticular formation. EEC clin. Neurophysiol. Suppl. 24:110, Elsevier, Amsterdam, 1963.)

propriate stimulation of intralaminar nuclei a "blockade of inhibition and the development of sustained excitatory synaptic drives" are involved (803). These authors look upon the thalamic reticular system as a "labile system of excitatory and inhibitory interneurons exquisitely sensitive to variations in the frequency of impulses in internuclear pathways arising "Kawamura & Sawyer's finding (559) that the slow d.c. potentials are negative on spontaneous or induced arousal and positive during sleep and following the administration of barbiturates is compatible with this interpretation. See also Gaspers (152), who relates these changes in d.c. potentials to "variations in the unit activity of the brain stem reticular formation."

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in the midline thalamus."* It should, however, be remembered that inhibitory and excitatory effects obtained from similar sites of the caudate and intralaminar thalamic nuclei with different frequencies of stimulation could be separated by appropriate lesions. This clearly shows that neurons causing excitatory and inhibitory actions or, to use more specific terms, ergotropic and trophotropic effects, although intermingled in various subcortical structures (caudate nucleus, thalamus, hypothalamus, and reticular formation) and also in the limbic brain, are anatomically and physiologically different entities. Further insight into the nature of desynchronization and synchronization has been gained by the beautiful work of Verzeano (970, 972), who has used up to four microelectrodes simultaneously in thalamus and cortex in order to study the patterns of excitation and inhibition in response to various stimuli and during sleep and wakefulness. His studies revealed that the transition from desynchronization to synchronization, regardless of its causes, is accompanied by similar changes. Excitatory and inhibitory processes are involved. Excitation is evident from the increase in the frequency of discharge of individual neurons, the increase in the total number of neurons activated per unit of time, and from the enhanced speed of propagation of activity through neuronal networks. However, this activity which follows certain patterns has an inhibitory action on "neighbouring neurons, which are not involved in it, and the increased periods of silence which occur in the intervals between successive passages of the propagating activity through the neuronal field suggest that, in the transition from wakefulness to sleep, an enhanced inhibitory process develops, periodically, during the passage of the propagating activity in its immediate vicinity and, after its passage, in its wake." It is obviously this inhibitory action which accounts for the reduced state of consciousness and the lessened responsiveness to environmental stimuli seen during spontaneous and experimentally induced periods of synchronization. 7. Brain Stem and Ergotropic and Trophotropic Balance The data presented in the preceding sections need to be supplemented by some insight into the factors which determine the balance between the ergotropic and trophotropic systems. For this purpose the state of arousal indicated by the EEC will be described in animals in which the brain stem has been sectioned at various levels. *It is interesting to note that during progressively diminishing states of arousal indicated by a decrease in the diameter of the pupil and in the frequency of cortical potentials, thalamic single neurons show a decrease in frequency and also a grouping of the spikes whereas the latter phenomenon is not found in the reticular formation (873).

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Whereas the normal cat shows cortical desynchronization for 20-50 per cent of the total recording time, an animal with the brain stem transected at the intracollicular level (Bremer's cerveau isole; 99) shows continuous sleep* and such a state persists also when the section is made in the rostral part of the pons (59). In contrast, the midpontine transection (rostral to the exit of the Vth nerves) shows an increase in the period of wakefulness to 70 and even 90 per cent of the total time (60). These observations suggest that in the cerveau isole and in the rostropontine preparation sleep prevails because important parts of the ascending reticular system have been eliminated. Under these conditions the synchronizing tonic action of cortical and subcortical structures (thalamus, anterior hypothalamus, caudate, etc.) dominates. The almost continually prevailing desynchronization of the midpontine catf shows that the balance is shifted in favor of the desynchronizing reticular formation. The fact that the period of wakefulness is much longer in this preparation than in the normal animal indicates that caudal to the section a powerful tonic synchronizing mechanism exists which accounts for the longer duration of sleep in the normal organism than in the midpontine cat.j That this interpretation is correct is shown not only by the synchronizing effects resulting from stimulation of the medulla oblongata and involving the nucleus of the solitary tract and the nucleus reticularis ventralis (661), but also by the following ingenious experiment performed on cats with section of the spinal cord at Ci (663). Minute quantities of barbiturate, which are ineffective on intravenous application, were injected via the vertebral arteries in some cases and via the carotid arteries in others. In the former case the area of distribution of the drug was confined to the medulla oblongata and the caudal portion of the pons, and in the latter to the midbrain, the diencephalon and the telencephalon. The vertebral injection caused temporary desyn chronization of the EEC, indicating the inactivation of the tonic inhibi« tory (synchronizing) action originating in the lower brain stem. The intracarotid injection had the opposite effect since it increased synchronization, obviously through lessening of the tonic activity of the mesencephalic portion of the ascending reticular system.§ * However, the sleep-wakefulness cycle reappears in chronic preparations after ten or more days following the operation (61, 974, A6) and particularly when the lesion has been produced in stages ( 6 ) fThe Vth nerves were destroyed in both rostropontine and midpontine preparations. | Recent work indicates that the caudal parts of the pons are chiefly responsib the inhibition of cortical activity. Inhibition involves the nucleus reticularis caudalis whereas the nucleus reticularis pontis oralis exerts the activating effect (142). §Bonvallet & Allen (85) present further evidence for assuming that the synchronizing bulbar mechanism originates in an inhibitory center closely associated with the nucleus of the tractus solitarius, since its tonic activity is lessened after the sectioning of the IXth and Xth nerves. See also A59.

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Finally, cooling the floor of the IVth ventricle affords an elegant demonstration of the inhibitory function of the bulbar deactivation "center." If during the sleeping phase seen in the encephale isole* the bulbar section of the brain stem is cooled, cortical synchronization is converted into desynchronization, while autonomic (pupillary dilatation) and behavioral changes (for example, eye movements) indicate arousal (67). These effects are reversible and show that reduction in the activity of the bulbar area releases the ergotropic system. III. RECIPROCAL RELATIONS AND RELATED PROBLEMS Since the conditions of stimulation which lead to the appearance of trophotropic and ergotropic syndromes have been described for spinal and supraspinal preparations, it behooves us now to consider two problems : the mutual relations of the two systems and the mechanisms which account for the fact that somatic discharges are associated with an activation of the sympathetic but not of the parasympathetic division of the autonomic nervous system. 1. Reciprocal Ergotropic-Trophotropic Relations at the Spinal and Medullary Levels Numerous investigations have shown the validity of the principle of reciprocity for autonomic reflexes. Thus, stimulation of the depressor nerve causes a slowing of the heart rate which is due not only to an increased activity of the vagus but also to a diminished action of the accelerator nerve. Action potential studies disclose that similar changes underlie the slowing of the heart rate resulting from an increase in the pressure in the carotid sinus (111, 410, 512). Increased baroreceptor activity leads also to a decrease in pupillary size associated with relaxation of the nictitating membrane (189), the former indicating increased trophotropic, the latter diminished ergotropic, discharges (see 329 for the literature). Reciprocal relations between splanchnic and vagal discharges occur spontaneously and following reflex excitation via cutaneous nerves (594). That reciprocal relations are not confined to the autonomic efferents is shown by the fact that increased sino-aortic pressure causes parasympathetic excitation and inhibition of shivering (956). 2. Reciprocity at the Hypothalamic Level Lesions in the posterior hypothalamus which, as already mentioned, diminish hypothalamic-cortical discharges and cause somnolence lead to an increased parasympathetic reactivity of the anterior hypothalamus. *The spinal cord is transected below the medulla oblongata.

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Conversely, lesions in the anterior hypothalamus cause a release of the sympathetic division of the hypothalamus. Moreover, states of increased reactivity of the posterior hypothalamus are associated with a lessened responsiveness of the anterior hypothalamus and vice versa (338, 372). Furthermore, the pressor effect on stimulation of the posterior hypothalamus (or following nociceptive stimuli) is accompanied by a rise in pulse rate, although an even smaller rise in blood pressure induced by the injection of noradrenaline elicits a slowing of the heart rate (338). In the former case the excitation of the sympathetic centers inhibits the parasympathetic reflex (119) whereas in the latter case only the parasympathetic reflex (slowing of the heart rate due to an increase in intrasinusal pressure) is involved. The inhibition of the trophotropic system which accompanies the excitation of the ergotropic division of the hypothalamus finds a characteristic expression also in a post-stimulatory rebound phenomenon. A marked fall in pulse rate (often associated with an abrupt fall in blood pressure) follows hypothalamically induced ergotropic effects and increases in magnitude within certain limits as the preceding hypothalamic stimulation is intensified (339). Conversely, the heating of the anterior hypothalamus which elicits trophotropic symptoms is followed by an ergotropic rebound indicated by a sudden increase in the excretion of noradrenaline and adrenaline (25). Reciprocal inhibition at the hypothalamic level is exemplified also by the observation that from a small area of the anterior hypothalamus (behind and below the anterior commissure) a fall in blood pressure and heart rate is produced in the vagotomized, atropinized cat, thus indicating inhibition of the sympathetic tone as the cause of trophotropic symptoms (178, 297). The reduction of the pressor response to carotid occlusion following stimulation of the anterior hypothalamus (826) is caused likewise by reciprocal inhibition of the ergotropic system. Similar effects may be produced through reflexes. Thus, stroking the skin induces not only trophotropic discharges but also muscular relaxation and cessation of crying. The latter effect, present in an infant without cerebral hemispheres (241), suggests that reciprocal inhibition of ergotropic reactions mediated by hypothalamus and reticular formation is involved. Autonomic-somatic correlations were clarified considerably by von Euler & Soderberg (263), who studied in cats and rabbits the influence of moderate heating of the anterior hypothalamus, known to produce parasympathetic effects. Recording the EEC and also the activity of the muscle spindles, they observed not only cutaneous vasodilation but also synchronization of cortical potentials (as in sleep) and at the same time an inhibition in the muscle spindle discharge. As in the experiments

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involving the caudate nucleus which were reported earlier, reduced rates of discharge from the muscle spindles and cortical synchronization appeared at the same time (123, 262). Moreover, the more marked the period of synchronization was, the lower was the gamma frequency (263, 488). If it is borne in mind that stimulation of the anterior hypothalamus by raised temperature or electrical currents inhibits sympathetic hypothalamic functions and shivering (669, 928), which may be elicited from the posterior hypothalamus, it follows that the trophotropic syndrome is due to the excitation of the parasympathetic from the anterior hypothalamus and to reciprocal inhibition of sympathetic and somatic effects (involving alpha and gamma motoneurons) in the posterior hypothalamus. The quantitative relations existing between the reduction in gamma discharges and the reduction in cortical excitation suggest that when proprioceptive discharges are lessened, the degree of hypothalamic-cortical activation is likewise diminished. This is in fact the case, since the elimination of proprioceptive impulses through paralysis of the neuromuscular junction with curare and similar drugs leads to lessened sympathetic reactivity of the posterior hypothalamus, to cortical synchronization, and also to a reduction in hypothalamic-cortical discharges in response to nociceptive stimuli (340). At the same time, parasympathetic symptoms and sleep supervene (474), indicating that if the animal is in the proper condition, the reduction in proprioceptive impulses causes a lessened activity of the posterior hypothalamus and indirectly, through a lessened reciprocal inhibition, a release of the anterior hypothalamus so that the balance is shifted to the trophotropic side. The beneficial effect of muscular relaxation in neurotic conditions seems to be based on this mechanism. In spite of the importance which we attach to these processes in the normal organism, it should not be overlooked that the inhibition of the posterior hypothalamus through stimulation of the anterior hypothalamus takes place in animals in which proprioceptive impulses from the skeletal muscles have been eliminated. Thus the heating of the anterior hypothalamus produces cortical synchronization in cats with spinal transection below the medulla oblongata (263), and reciprocal relations between the two divisions of the hypothalamus are demonstrable in curarized animals (338). Conversely, it has been shown that the stimulation of the posterior hypothalamus leads not only to sympathetic discharges, cortical desynchronization, and overt movements (mediated by alpha motoneurons) but also to an increase in the frequency of the gamma system (402). Since the excitability of the posterior hypothalamus increases with increasing proprioceptive activity (71), other conditions remaining un-

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changed, it must be assumed that the gamma discharges enhance ergotropic excitation.* Closely related to these phenomena is the observation that on acoustic stimulation, which leads to cortical desynchronization, the reticular formation shows, following an initial excitation, a second burst of activity after a latent period of several hundred milliseconds. This activation which tends to prolong the cortical excitation in the unanesthetized animal is absent after immobilization. It is thought to be due to increased discharges from the muscle spindles (154) associated with the motor reaction induced by a loud noise. Studies on the action of Chlorpromazine support the assumption that the gamma system plays an important role in increasing muscle tone on stimulation of central sympathetic structures. Decerebrate rigidity is abolished by the administration of Chlorpromazine, and this effect is accompanied by inhibition of the gamma discharges in the anterior spinal roots. Moreover, these discharges as well as those recorded from the muscle spindles (in preparations with intact anterior roots) fail to respond to stimulation of the reticular formation, although the drug exerts no action on the isolated muscle spindle itself (444). These effects account for the flaccidity of muscles, while the lethargic behavior after administration of Chlorpromazine appears to be due to lessened excitability of the posterior hypothalamus and diminished cortical discharges from posterior hypothalamus (357) and the centrum medianum of the thalamus (571). The ergotropic effect of stimulation of the posterior hypothalamus is further enhanced by reciprocal inhibition of the anterior hypothalamus whereby not only its parasympathetic action but also its inhibitory influence on the gamma system is eliminated. Again it should be said that the autonomic and cortical excitatory actions (desynchronization) persist in the curarized animal. Apparently the shift from sleep to arousal and vice versa in these experiments can be accomplished by a change in the balance between anterior and posterior hypothalamus (including reticular formation) without the aid of afferent discharges, but in the intact organism it may be triggered and reinforced by proprioceptive impulses and numerous other factors.! 3. Reciprocal Relations between Extrahypothalamic Ergotropic and Trophotropic Systems Since ergotropic and trophotropic reactions are controlled by numerous sites in cortical and subcortical areas and brain stem other than the **See also Malmo (673), who postulated a general increase in activation with increasing muscle tension. fThe excitatory effect of sensory stimuli on the gamma neurons persists in animals in which the arousal reaction has been abolished through extensive cortical injury (123).

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Autonomic-Somatic Integrations

hypothalamus, the question whether reciprocal relations obtain for these excitatory and inhibitory systems remains to be investigated. Moruzzi & Magoun (738) and Jasper et al. (526) have observed that the recruiting response elicited by low-frequency stimulation of the intralaminar thalamic nuclei is diminished or abolished by high-frequency stimulation of the reticular formation. This antagonism was confirmed by Tokizane et al. (950, 951) under widely different physiological and pharmacological conditions. In these investigations the cortical spindle induced by a single shock to the caudate nucleus served as an indicator of the reactivity of the inhibitory (trophotropic) system, whereas the high-frequency stimulation of the posterior hypothalamus or of the reticular formation was used to test the ergotropic excitatory system. It was found that stimulation of the posterior hypothalamus or of the reticular formation raised pari passu the caudate spindle threshold. Similar effects appeared during spontaneous periods of arousal (Fig. 1-6), on nociceptive or acoustic stimulation, and in hypercapnia induced by inhalation of 5 to 10 per cent CO-2 or following i.v. administration of Metrazol (950, 951, Fig. 1-7). Conversely, the caudate threshold was lowered when the reactivity of the posterior hypothalamus or of the reticular formation was lessened as, for instance, following lesions in the posterior hypothalamus or on administration of barbiturates of Chlorpromazine (see also 867). This work was confirmed in experiments on unanesthetized animals in which, in addition, the caudate threshold was found to be lower in the sleepy than in the aroused animal regardless of whether the arousal was due to stimulation of a sense organ, the reticu-

Fig. 1-6. Change of the induced spindle threshold (caudate stimulation with a single shock) during a spontaneous cortical arousal reaction. Curarized cat. A: drowsy state; B: state of arousal; 1: left anterior sigmoid gyrus; 2: left marginal gyrus; 3: left middle suprasylvian gyrus. 100/xv., 1 sec. Note that during arousal ( B ) the spindle is greatly reduced although the intensity of stimulation is more than doubled. (From Tokizane, Kawakami, & Gellhorn. On the relation between the activating and the recruiting systems. Arch, internat. physiol. & biochem. 65:415, 1957.)

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Fig. 1-7. Effect of inhalation of 10 per cent CO2 for 3 min. (between upward-pointing arrows) on the threshold of the caudate nucleus before and after bilateral injection of 0.025 cc Pentothal (40 mg/cc) into the posterior hypothalamus (between the tenth and twelfth min., indicated by P and downward-pointing arrow). The upper and lower part of the figure are continuous. Abscissa: time in min.; ordinate: threshold in v. Between 0 and 3, 15 and 18, 24!£ and 2752, and 48?2 and 51% min. (indicated by arrows), 10 per cent CO2 was inhaled. The horizontal bars indicate the appearance of the arousal reaction in the EGG. The broken lines indicate that the caudate threshold was higher than 80 v. The experiment shows that CO2-induced arousal causes a marked increase in the spindle threshold and that this effect is inhibited reversibly by Pentothal. (From Tokizane, Kawakami, & Gellhorn. On the relation between the activating and the recruiting systems. Arch, internat. physiol. & biochem. 65:415, 1957.)

lar formation, the globus pallidus, or the centrum medianum of the thalamus (126,128).* "The caudate threshold is lowered with lowered body temperature in the normal animal, but this effect is absent in cats with bilateral posterior hypothalamic lesions (557). Apparently the reduced excitability and activity of the posterior hypothalamus at low temperatures account for the change in threshold in the normal animal under these conditions.

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Autonomic-Somatic Integrations

Reciprocal relations have been shown to exist also between the reticular formation and the intralaminar thalamic nuclei, which on lowfrequency stimulation elicit a recruiting response in the cortex. The threshold of this response decreases after intracollicular decerebration, indicating that the elimination of a major part of the ascending facilitatory reticular formation releases the thalamic recruiting system (722). Conversely, bilateral coagulation of the medial thalamic nuclei leaves the excitatory system relatively unopposed: the slow potentials disappear from the EEC of the unanesthetized rabbit and motor hyperreactivity results (491). The lower threshold of the thalamic recruiting response in the resting as compared with the aroused cat likewise indicates a reciprocal relation between the thalamic trophotropic system and the reticular formation (1005).* Similarly, thalamically induced spindle and recruiting responses increase in anoxia as the reactivity of the ergotropic system declines (748). Lesions in the basal forebrain and preoptic areas, which on stimulation produce cortical synchronization and sleep, cause an increase in ergotropic functions — general bodily activity is intensified — and (reciprocally) a decrease in trophotropic reactivity indicated by a lesser cortical synchronization on feeding (927). Rebound phenomena such as behavioral arousal following a thalamically elicited recruiting response (724) are likewise indicative of the reciprocity between the ergotropic and the trophotropic systems. Pharmacological studies illustrate likewise the antagonism between the thalamic recruiting and the mesencephalic excitatory reticular systems. By employing low-frequency stimulation for the thalamus and high-frequency for the reticular formation it could be shown that excitatory drugs such as amphetamine, lysergic acid, or cocaine facilitate the excitatory action of the reticular formation and inhibit the recruiting effect of the thalamic nuclei whereas the moderating drugs Chlorpromazine, reserpine, and morphine exert the opposite effects (722). Fundamental studies by Bonvallet & Allen (85) have furnished evidence for reciprocal relations between the mesencephalic ergotropic system and a bulbar inhibitory area. Whereas Magoun's inhibitory area (670), located in the ventromedial part of the bulbar reticular formation, modulates the intensity of somatic discharges of spinal and supraspinal origin, another inhibitory area is located more laterally and involves the cephalic part of the nucleus of the tractus solitarius and the region between this nucleus and the floor of the IVth ventricle. When coagulated bilaterally, the mesencephalic reticular formation is released as indicated * Whether the powerful inhibitory area located in the medulla oblongata undergoes corresponding changes in different states of alertness and under the influence of drugs seems not to be known as yet.

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by an increase in the spontaneously occurring periods of cortical desynchronization. These excitatory actions coincide with periods of enhanced sympathetic and decreased parasympathetic discharges. The former, recorded from the cervical sympathetic trunk, and the latter, monitored from the short ciliary nerves, are accompanied by a period of cortical desynchronization. Moreover, stimulation of the reticular formation with brief stimuli (or reflexly, through cutaneous or acoustic receptors) shows after coagulation of the bulbar inhibitory area a prolongation of the cortical arousal, sympathetic and somatic excitation, and parasympathetic inhibition (Fig. 1-8). The experiments described in this section have shown through the determination of the threshold of various intracerebral structures such as the caudate nuclei, the intralaminar thalamic nuclei, and various parts of the brain stem that the centrally evoked trophotropic and ergotropic

Fig. 1-8. Prolongation of cortical activation and short ciliary nerve inhibition, produced by short mesencephalic reticular stimulation, following localized bilateral bulbar coagulations. Cat encephale isole, Flaxedil, EEC. Direct and integrated recordings of short ciliary nerve activity (SCN.). Reticular stimulation, 3 v., 400 m.s. ( R . ) . (From Bonvallet & Allen. Prolonged spontaneous and evoked reticular activation following discrete bulbar lesions. EEC clin. Neurophysiol. 15:973, Elsevier, Amsterdam, 1963.)

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activities are reciprocally related. A similar relation seems to hold for the bulbar inhibitory area and the ergotropic division of hypothalamus and reticular formation. But even under more physiological conditions, in the intact organism without lesions in the brain stem or stimulation of intracerebral structures, the validity of the principle of reciprocity between the ergotropic and trophotropic action has been established. It requires the recording of the EEC, of the action potentials in reciprocally related autonomic nerves (sympathetic and parasympathetic nerves to the eye), and of the tone of the skeletal muscles. Then, spontaneous variations in arousal are found to be associated with ergotropictrophotropic reciprocity: as arousal increases, sympathetic discharges in various parts of the body are increased while the parasympathetic activity of the short ciliary nerves reflecting the state of the Edinger-Westphal nucleus is diminished and the pupils (normal and sympathectomized) are dilated. Similar results are obtained on stimulation of peripheral receptors. It should be stressed that the threshold of the effects on the autonomic and somatic (activity of the muscles) systems and the EEC (desynchronization) is the same (89). The ergotropic system acts as a unit. (A46) Whereas the inhibition of the Edinger-Westphal nucleus accounts for the diminution in trophotropic discharges to the eye and illustrates ergotropic-trophotropic reciprocity during ergotropic excitation, the following experiments exemplify this phenomenon for trophotropic excitation. That increased baroreceptor discharges augment parasympathetic discharges and inhibit sympathetic activity was mentioned earlier. These effects are demonstrable at supraspinal levels (344) and appear in the form of interesting behavioral changes if this action is studied in decorticate cats. In such animals, showing spontaneous attacks of sham rage after "release" of the posterior hypothalamus by decortication, the main action of increased baroreceptor discharges consists not in evoking a trophotropic action but in reducing the ergotropic syndrome of sham rage (58). Since earlier work (344) showed that an increase in baroreceptor discharges enhances the trophotropic activity of the anterior hypothalamus, it may be said that reciprocal changes in the trophotropic and ergotropic systems at the hypothalamic level underlie these behavioral changes. A similar effect and shift in ergotropic-trophotropic balance are seen when the trophotropic system is activated via cutaneous reflexes: in the rabbit pressure of the skin leads to a hypnosis-like state in which cortical synchronization is associated with a diminution in motor and sympathetic discharges (for example, lessened sweat secretion; 603). Reduction in muscle tone and in sympathetic activity has likewise been observed in man under these conditions (934).

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Another example of the reciprocal relation between the ergotropic and trophotropic systems and the validity of this principle for the human brain is based on the following observation. Habituation to a sensory stimulus which manifests itself in the loss of the blocking of the alpha potentials in the EEC on repetition of the same stimulus is related to the sleep-wakefulness balance, since the more rapid the habituation the earlier sleep occurs in man (325). From animal studies (155, 890) it is known that habituation depends on the reticular formation and not on the specific afferent systems which continue to be responsive when the arousal effect of the same stimulus is lost. Apparently the greater the reduction in the activity of the reticular formation the greater is the release of the trophotropic system. Moreover, stimulation of the septum (a part of the trophotropic system) enhanced habituation in response to sensory or reticular stimuli (251), thus illustrating directly the applicability of the reciprocity principle for habituation. 4. Medullary Lesions and Hypothalamic Ergotropic and Trophotropic Effects It was emphasized that somatic and autonomic effects change in a parallel manner on stimulation of spinal and supraspinal sites which activate the ergotropic system. This statement remains valid for the downward discharge after certain lesions have been made in the medulla oblongata (949). If stimulation of a point in the hypothalamus yields an ergotropic response (increase in blood pressure, respiration, and knee jerk), this effect is increased for sympathetic and somatic actions after a lesion is placed in the medial part of the medulla which destroys the inhibitory bulbar area of Magoun & Rhines (670). Conversely, a lesion in the lateral part of the medulla interrupting the facilitatory bulbar system reduces or abolishes the sympathetic and somatic effects of an ergotropic point in the hypothalamus.* Even a reversal may take place under these circumstances: instead of an increase in respiration, blood pressure, and knee jerk, the respiratory record may show an apnea, the sympathetic circulatory response may be replaced by a fall in blood pressure, and facilitation of knee jerk is absent. IV. CONCLUDING REMARKS

Afferent corticopetal and efferent somatic and autonomic discharges characterize the ergotropic and trophotropic syndromes. As the ergotropic effect is induced, cortical desynchronization and increased sympathetic and somatic activity occur, whereas on activation of the tropho"It should be recalled that lesions in the pretectal area and posterior commissure abolish the arousal response in the EEC as well as the dilatation of the pupil in response to high-frequency stimulation of the thalamic reticular system (875).

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tropic system cortical synchronization is combined with parasympathetic discharges and inhibition of somatic activity. In either case this triad is an integrated whole, since the upward and downward discharges undergo parallel changes when the intensity of stimulation is altered. Similar alterations in integrated responses occur when the excitability of the diffuse ("unspecific") nervous system responsible for the ergotropic and trophotropic triads varies spontaneously or as the result of lesions, drug actions, changes in the internal environment, and similar factors. Reciprocal relations exist between anterior and posterior hypothalamus, caudate and reticular formation (or posterior hypothalamus), and intralaminar thalamic nuclei and the mesencephalic or pontine reticular formation, provided that the first-named structure of each pair is activated by stimuli of proper parameters (low frequency and/or intensity ). Reciprocal inhibition is apparent from the fact that with increasing activity of the ergotropic system the threshold of the synchronizing action of caudate nucleus or thalamus increases and vice versa, regardless of whether the state of activity of the ergotropic system changes spontaneously (as from sleep to wakefulness) or is altered experimentally. Autonomic reactions produced by hypothalamic or reflex stimuli likewise disclose reciprocal relations between anterior and posterior hypothalamus. Thus, a state of sympathetic hyperactivity of the posterior hypothalamus is associated with a lessened parasympathetic responsiveness of the anterior hypothalamus and vice versa (338). Since the ergotropic and trophotropic systems are tonically innervated, the elimination of a part of one system leads to a release of the antagonistic system, indicated by behavioral and electroencephalographic effects. Whether the separation of the anterior from the posterior hypothalamus induces sleeplessness and, finally, death by exhaustion (749) is still controversial (534), but lesions in the anterior hypothalamus lead to increased emotional reactivity, the animals becoming very aggressive (150). Similarly, coagulation of the intralaminar thalamic nuclei (98) or damage to the caudate nuclei (197) causes motor hyperactivity which is related to the size of the lesion, and increased degrees of desynchronization occur after elimination of the thalamic (491) or bulbar (85, 279, 663) inhibitory systems. Conversely, lesions in the posterior hypothalamus are accompanied by somnolence (807), and procedures such as the separation of the mammillary bodies from the tegmentum, which seem to lower the activity of the ergotropic division of the hypothalamus, produce sleep (749). Our analysis suggests that the intimate relation between the activity of the ergotropic system and that of the gamma impulses (and between trophotropic discharges and inhibition of the gamma system) contributes effectively to the maintenance of reciprocal inhibition between the two

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systems. That reciprocity persists under conditions in which the gamma system cannot operate does not lessen its physiological importance. It just illustrates the well-known fact that duplication of physiological function is not uncommon (55). The relatively easy manipulation of the muscle tone (see various forms of relaxation therapy, 517, 879) furnishes a means of altering the intensity of the ergotropic discharge and, thereby, the balance between the excitatory and inhibitory systems. Relaxation manifesting itself in the skeletal muscles seems, on the basis of the experimental work cited earlier, to be due to a diminution in extrapyramidal alpha and gamma impulses of diencephalic and mesencephalic origin and, consequently, lessened afferent discharges from the muscle spindles. It should be added that the gamma discharges affect flexors and extensors in a similar (and not a reciprocal) manner (247). In spite of the great influence of the gamma system on the muscle tone and the activity of muscle spindles, experiments have shown that the ergotropic and trophotropic systems still control the muscle tone after deafferentation. Thus, decerebrate rigidity, which persists in the deafferented leg after removal of the cerebellum, is inhibited on stimulation of Magoun's bulbo-reticular inhibitory center, whereas stimulation of the pontine (facilitatory) reticular formation increases the tone of the flaccid deafferented leg in a decerebrate cat (939). Similarly, it has been found that the baroreceptors and chemoreceptors, which profoundly influence the state of excitation and the balance between the ergotropic and trophotropic systems, are not indispensable for their normal function and the maintenance of reciprocal relations. It seems to follow that although various receptors activate either the ergotropic or the trophotropic system and contribute to the reciprocal relation of these systems, the typical cortical, autonomic, and somatic patterns which may be elicited at various levels of the nervous system and the maintenance of reciprocal relations between ergotropic and trophotropic reactions are independent of exteroceptive, proprioceptive, and interoceptive reflexes. In an attempt to evaluate the physiological significance of the reciprocal relations existing between the ergotropic and trophotropic systems it seems useful to distinguish between tonic and phasic alterations. Tonic changes tend to be of a global character, affecting the systems as a whole, whereas phasic changes may modify the tonic state in limited areas. As we have seen, tonic changes result from "spontaneous" shifts in the balance between the two systems, as in the sleep-wakefulness cycle, and are reinforced by somatic reflexes involving the gamma system. They are likewise induced by lesions in subcortical structures and brain stem, changes in the internal environment, anesthetics, etc. Phasic reflexes are superimposed on a given state of ergotropic-trophotropic balance.

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Thus, stimulation of somatic nerves may cause sympathetic effects such as contraction of the nictitating membrane, rise in blood pressure, and dilatation of the pupil, singly or in various combinations (338). The combinations of tonic and phasic discharges result in numerous patterns of autonomic activity through which the widely different local demands of the tissues during rest, exercise, food intake, etc. can be met in a given state of central autonomic balance. The reciprocal behavior of the ergotropic and trophotropic systems ensures the smooth transition from trophotropic to ergotropic responses and the gradation of the responses of each of these systems following increasing degrees of excitation. This should not obscure the fact that two fundamentally different systems are involved. That in the physiological experiment different frequencies of stimulation induce trophotropic and ergotropic effects from the same site does not contradict this statement. As mentioned earlier, specific lesions eliminate the ergotropic effect without altering the trophotropic action and vice versa. Obviously, two different paths are utilized by the two systems, although their neurons may be closely intermingled in certain structures. The discussion of numerous related problems had to be omitted. In spite of fascinating results obtained in microphysiological studies on single neurons in arousal and sleep (186, 272, 523), it has been possible only in some special conditions (602, 800, 803, 970, 971, 972) to evaluate macroscopic events such as changes in synchronization, frequency, and amplitude of the EEC in microphysiological terms. While the establishment of such an interpretation is an important goal of research, it should not be forgotten that the state of the excitatory and inhibitory systems and their balance with which we were primarily concerned are important determinants of behavior. As we have seen, large parts of the brain constitute the ergotropic and trophotropic systems. We stressed what these parts have in common, but the differences are also bound to be of significance. Although our knowledge is scanty, the thalamic and bulbar synchronizing areas are known to differ. Thus, the frequency of the induced slow potentials follows the frequency of stimulation of the thalamic but not of the medullary synchronizing area. Furthermore, the maximal synchronizing effect lies in the frontal cortex for thalamic and in the parieto-occipital area for medullary stimuli (521, 662, 875). There are likewise differences in the tendency of various inhibitory areas to produce behavioral sleep which may or may not outlast the period of stimulation, and corresponding data could be cited for various parts of the excitatory system (139, 719, 952). Moreover, the rostral and caudal sections of the reticular formation differ in that the thalamic portion is said to be insensitive to adrenaline which excites the caudal part (522), whereas Chlorpromazine is more effective on the thalamic than on the

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mesencephalic reticular formation (571). Decreasing states of arousal are associated with a diminution of thalamic but not of mesencephalic reticular neurons (286, 370, 873). What these differences mean in behavioral terms remains to be investigated. They seem to reflect the fact that the state of alertness is the conditio sine qua non for numerous mental activities, such as attention, perception, and emotion, which require different types of interactions between the cerebral cortex and specific parts of the excitatory and inhibitory systems.* For the more limited purposes of this book it seems of importance to stress the ergotropic and trophotropic character of excitatory and inhibitory cerebral systems, their control of cortical excitability and of peripheral autonomic and somatic functions, their reciprocal relation (and the mechanism involved), their modifiability by drugs and through reflexes and as a result of cortical excitation, and the parallelism between upward and downward discharges in a variety of conditions. These data furnish the blueprint of the physiological patterns of activity of the ergotropic and trophotropic systems and thereby establish the basis for judging deviations which occur in special physiological conditions and also pathological states. V. SUMMARY

A survey of ergotropic reactions characterized by the association of increased sympathetic and motor responsiveness and of trophotropic reactions based on the combination of parasympathetic discharges and inhibition of the motor system at various levels of the central nervous system discloses that: 1. Ergotropic effects may be elicited in the spinal or anesthetized animal through cold or nociceptive stimuli regardless of whether the latter act on the skin, afferent somatic nerves, or the viscera. Trophotropic effects occur on stimulation of the vestibular apparatus and of cutaneous sense organs. Warmth and stimulation of pressure receptors, particularly in the form of stroking the skin, are effective. 2. A rise in the sino-aortic pressure produces trophotropic symptoms whereas a fall in this pressure evokes the ergotropic syndrome. The tone of the striated muscles and the activity of the gamma system are lessened as the intrasinusal pressure is increased and vice versa. 3. Anoxia, hypercapnia, and asphyxia activate, at least in their initial phases, the ergotropic system. Increased discharges from the sino-aortic chemoreceptors contribute to this effect not only by stimulating sympathetic centers but also by increasing the activity of the gamma neurons. ''Concerning the anatomical interrelations between the various structures which constitute the ergotropic and trophotropic systems see 284, 476, 566, 752, 774, 870, 875.

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4. In the intact organism changes in the EEG and in behavior are observed when the ergotropic and trophotropic systems are activated through reflexes or through stimulation of supraspinal structures. Depending on the parameters of stimulation, activation and inhibition may be produced ranging from deep sleep to wakefulness and even convulsions. Nevertheless, two states can be distinguished sharply: the alert state, characterized by a generalized sympathetic (or sympatheticoadrenal) discharge, increased tone of the muscles, and cortical desynchronization, and the drowsy condition or state of sleep, associated with parasympathetic discharges (pupillary constriction, salivation, etc.), a lessened sympathetic tone, cortical synchronization, and loss of muscle tone. The state of alertness is the result of the balance between the excitatory system — consisting chiefly of the ascending facilitatory system of Magoun, the posterior hypothalamus, certain parts of the limbic system, and the intralaminar nuclei of the thalamus — and the inhibitory system — comprising a portion of the medulla oblongata, the anterior hypothalamus, septum, and caudate nucleus and anatomically related structures. To what extent the two systems are anatomically distinct is uncertain; while well separated in some parts, in others differentiation can be made satisfactorily at present only on functional grounds. Thus, stimulation of the medial thalamic nuclei, reticular formation, and caudate nucleus, for instance, elicits a trophotropic syndrome with low and an ergotropic syndrome with high frequency. However, there is evidence to suggest that even where only functional distinction is presently possible, two distinct systems of neurons are intermingled. 5. The two systems are tonically innervated and show a reciprocal relationship. Even the partial elimination of one system released the antagonistic system. These reciprocal relations persist in preparations in which, due to spinal section at GI, the effects on the skeletal muscles have been eliminated. It is suggested that the discharges via the gamma system are important but not indispensable for the maintenance of reciprocity between the ergotropic and trophotropic systems and for the regulation of cortical synchronization. 6. It is emphasized that ergotropic and trophotropic symptoms are sharply separated under most physiological conditions and do not appear in a mixed form at the same time — again an expression of reciprocal relations. 7. There is a parallelism between the intensity of the upward discharge which determines the degree of cortical excitation and that of the autonomic-somatic downward discharge. 8. If through a change in the frequency or intensity of stimulation of parts of the cerebral ergotropic or trophotropic systems or through the

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administration of appropriate drugs cortical synchronization is converted into desynchronization, the downward discharge is changed correspondingly: parasympathetic effects change into sympathetic action and somatic inhibition is replaced by activation of the striated muscles through alpha and, indirectly, also through the gamma fibers.

II

Physiological Analysis ofErgotropic a Trophotropic Imbalances; Application to Vario States of Consciousness

IN THE first chapter it was stressed that ergotropic and trophotropic reactions do not occur at the same time. They are reciprocally related, since with the increasing activity of one system the responsiveness of the antagonistic system declines progressively. It was further shown that the autonomic-somatic downward discharges are associated with characteristic upward discharges which determine the degree of synchronization of cortical potentials. States of altered excitability of the central autonomic nervous system were found to induce parallel changes in autonomic and cortical activity. Thus, arousal is related to the activity of the ergotropic system and, particularly, to cortical desynchronization of the whole cortex whereas in sleep trophotropic discharges are combined with synchronization of cortical potentials. We intend to show in this chapter that important deviations from these patterns occur in experimentally induced and also in "spontaneously" occurring alterations in the state of consciousness. Since we believe that the difference between physiological and pathological conditions is often not qualitative but only quantitative, it seemed to us of interest to determine under what physiological conditions the above-mentioned principles do not hold and to utilize this information for the interpretation of various experimental and clinical phenomena. I. DEVIATIONS IN AUTONOMIC NERVOUS FUNCTIONS FROM THE PRINCIPLE OF RECIPROCITY

1. Observations on Reflexes and Hypothalamic Stimulation Several observations suggest that under the influence of strong stimuli or in states of heightened central excitability reflexes may show increased parasympathetic and sympathetic discharges at the same time. Babkin (43) reports that stimulation of afferent fibers of the sciatic nerve in40

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creases salivary secretion via chorda tympani and sympathetic nerves. Penile erection involves the excitation of the lumbar sympathetic as well as the excitation of the sacral parasympathetic in the dog (742). The Aschner reflex, elicited by pressure on the eyeball which in man results in a fall in heart rate and often also in a fall in blood pressure, was shown in experiments on the dog to induce parasympathetic and sympathetic excitation. Thus, slowing of the heart rate was found to occur in combination with gastrointestinal inhibition (due to sympathetic excitation, 880, 881) or associated with a rise in blood pressure. Since the slowing of the heart rate persisted in sympathectomized dogs whereas the pressor effect was abolished (69, 70) the former was not due to a pressor reflex but resulted from centrally increased parasympathetic discharges. This interpretation holds likewise for experiments showing that cerebral anemia induced by vertical posture led to an increase in heart rate in the normal but to a slowing of the pulse rate in the sympathectomized animal (473). One gets the impression from these and similar experiments that it is the intensity of the stimulus (or the degree of the central excitatory state as in the sexual reflexes) which is responsible for the simultaneity of sympathetic and parasympathetic discharges under these conditions. Experiments on hypothalamic and sciatic stimulation give similar results. Weak hypothalamic stimuli produce a parasympathetic action on the gut (increased activity), whereas stronger stimuli elicit a sympathetically induced inhibition (691). Moreover, low-frequency hypothalamic stimulation causes parasympathetic effects on blood pressure and heart rate, where.as with higher frequency sympathetic cardiovascular actions prevail (427). Such results are obtained also with stimulation of the central end of the sciatic nerve at different frequencies (338). Pressor responses resulting from reflex or central stimulation are converted into depressor reaction through certain lesions of the brain stem (418) and through administration of barbiturates (416, 417). These experiments seem to indicate that when through certain procedures the sympathetic responses are eliminated, parasympathetic reactions are revealed. Apparently, the stimuli evoke sympathetic and parasympathetic reactions in the normal animal, with the former dominating.* 2. Changes in Internal Environment (329) If experimental animals are subjected to varying degrees of anoxia, asphyxia and hypercapnia signs of sympathetic excitation and sympathet*A hypothalamic stimulus which evokes a generalized sympathetic reaction may secondarily, as the result of a pressor effect with consequent increased baroreceptor discharges, reduce the heart rate and increase the activity of the gut via parasympathetic nerves (342). Although both branches of the autonomic system are in a state of heightened activity, the mechanism is fundamentally different from that under discussion and need not be considered further.

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ico-adrenal discharges are commonly seen. Parasympathetic symptoms come into prominence when those changes in the internal environment are severe or extended for relatively long periods. Thus, mild degrees of anoxia or asphyxia lead to acceleration of the heart rate whereas severe forms (inhalation of nitrogen) cause a slowing of the heart. Since after bilateral vagotomy the heart rate increases in anoxia (629), it is concluded that anoxia (and asphyxia induced by clamping the trachea) cause parasympathetic and sympathetic discharges on the heart. The following facts are in agreement with this interpretation: 1. The action potentials of the accelerator and other sympathetic nerves are augmented in asphyxia and this increased activity persists while the blood pressure falls (227, 561). 2. After atropinization anoxia also produces tachycardia in those instances in which it had elicited a slowing of the heart before the administration of the drug (227). The study of the blood pressure yields similar data. Asphyxia and inhalation of carbon dioxide induce a rise in blood pressure in normal but a fall in sympathectomized animals (44). In the early phase of asphyxia, while the blood pressure and heart rate rise and the nictitating membranes contract, indicating strong sympathetic discharges, the sympathetic reactivity is increased and the parasympathetic responsiveness is lessened. In the late phase of asphyxia, however, when parasympathetic symptoms become dominant (fall in blood pressure and heart rate), sympathetic and parasympathetic reactivity are augmented (338, 347). In the first instance a state of reciprocal innervation exists: the sympathetic activity is increased and the parasympathetic activity is diminished. As the asphyxia continues, this state passes over into one in which both branches of the autonomic system are hyperactive and show an increased responsiveness to stimulation. Asphyxia of the medulla oblongata, induced by raising the intracranial pressure (183), causes the blood pressure to rise but the heart rate to diminish. This diminution is not a reflex slowing, since it persists when the blood pressure is kept constant (240). It is suggested that anemia chiefly affecting the medulla oblongata causes increased excitation in both divisions of the autonomic nervous system. These findings seem to be applicable to man. Severe anoxia is accompanied by a marked rise in the minute volume of the heart. In most instances, particularly when the response is relatively small, it is increased after atropinization (643), suggesting that trophotropic and ergotropic discharges are involved. Hypoglycemia is known to call forth a generalized sympathetico-adrenal discharge (see 329 for the literature). Whereas in the earlier stages the heart rate is increased, during insulin coma (470) it is lowered, suggesting that as in asphyxia a phase of sympathetic dominance passes

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over into one of sympathetic and parasympathetic hyperactivity, with dominance of the latter. This interpretation is supported by the finding that hypoglycemia causes a slowing of the heart rate in sympathectomized cats (234). Moreover, gastric acidity controlled by the vagus is increased in normal man (482) and experimental animal during insulin hypoglycemia, this effect being abolished by vagotomy (304). When the anterior hypothalamus is heated, two fundamentally different types of response are obtained. On moderate heating trophotropic symptoms (cortical synchronization, vasodilatation, and inhibition of the gamma system) prevail, whereas an ergotropic syndrome (cortical desynchronization, arousal, and increased gamma discharges) appears as the hypothalamic temperature is raised to fever levels (263). It is assumed that in fever the parasympathetic and sympathetic systems are activated, the latter dominating (783). The sympathetic effects consist of cardiovascular symptoms, increased secretion of adrenaline (103, 148), and rise in body temperature — this rise being reduced by sympathectomy but increased by anterior hypothalamic lesions which release the ergotropic division of the hypothalamus (64). Trophotropic effects are shown by the increased secretion of insulin via the vagus (329, 606), the fall in blood pressure, and leucopenia (481) in the early phase of experimental fever while ergotropic symptoms prevail later. The wave-like pattern of the temperature (810) suggests likewise the interaction of parasympathetic and sympathetic discharges. 3. Further Examples Many more conditions could be cited which illustrate the simultaneous activity of both branches of the autonomic nervous system. It may suffice to mention emotional excitement and certain centrally acting drugs (see 329 for the literature). It is important, however, to point out that some experiments described in this section disclose physiological and other rather pathological reactions. Thus, the trophotropic syndrome elicited by a moderate rise in the hypothalamic temperature is obviously a physiological reaction, since the autonomic and somatic changes contribute to a release of heat and a reduction in metabolic activity. On the contrary, the activation of both branches of the autonomic system through higher hypothalamic temperatures creates fever because the excessive sympathetic activity which then occurs cannot be balanced by parasympathetic discharges. Similarly, the activation of vagal and sympathetic nerves on heart and circulation in prolonged asphyxia seems to aggravate the fall in blood pressure.* It has also been reported that moderate pain induces sympathetic car*The writer is not aware of a study in which the survival time in anoxia in normal and vagotomized animals has been compared.

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diovascular reactions, whereas severe pain and injury are accompanied by a fall in blood pressure (990), suggesting that in the latter condition sympathetic and parasympathetic discharges are involved, the parasympathetic effects being dominant, as in prolonged asphyxia. Experimentally induced convulsions are likewise characterized by simultaneous sympathetic and parasympathetic discharges. The former are indicated by contraction of nictitating membrane, secretion of sweat, rise in blood pressure, and dilatation of the pupil whose parasympathetic innervation has been interfered with by sectioning of the oculomotor nerve. The sympathetic system is dominant most of the time but powerful parasympathetic discharges interrupt its activity. This is seen in the sympathectomized pupil whose dilatation (due to inhibition of parasympathetic discharges) is interrupted by phases of constriction. Moreover, convulsions are frequently accompanied by a marked fall in the blood pressure, which is followed by a prolonged pressor phase (362, 689). Apparently sympathetic and parasympathetic discharges are in constant rivalry. It is suggested that excessive excitation of the sympathetic and parasympathetic centers, as in fever, prolonged asphyxia, and convulsions and states of severe pain, interferes with the principle of reciprocal relations which regulates the activity of the trophotropic and ergotropic systems under strictly physiological conditions, and contributes thereby to the creation of a pathological state. Although several examples were given for pathological states produced by stimuli of great intensity or occurring in conditions of heightened excitability, no hard and fast rules allow one to separate physiological and pathological states. Thus certain parasympathetic reactions have been found to be present on eliciting a sympathetic syndrome even if mild stimuli are used: a contraction of the bladder occurs on stimulation of the sympathetic division of the hypothalamus in response to weaker currents than are required to inhibit the gut or raise the blood pressure (343), and a similar reaction is seen on sensory (tactile, acoustic) arousal (880). If one bears in mind the role of the hypothalamus in emotions, sex drive, hunger and satiety, etc., one would expect that its activity involves numerous visceral discharge patterns which would not fit into the strait jacket of ergotropic or trophotropic syndromes but would mirror the diversity of the hypothalamic-cortical discharges associated with its various functions. It is also believed that not all conditions involving simultaneous activation of both branches of the autonomic system are maladaptive and potential sources of pathology. Emotional excitement, cold, hormones, and certain drugs have been found to stimulate the sympathetico-adrenal and

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the vago-insulin systems (329).* Consequently, glucose and insulin concentrations in the blood are increased. This reaction may contribute to homeostasis through increased utilization of glucose (913) in states in which the metabolism is augmented. 4. The Ergotropic and Trophotropic Systems and Deprivation of Sleep A discussion of the physiological changes occurring after prolonged experimental deprivation of sleep seems to throw light on borderline states between physiology and pathology which are associated with symptoms of increased ergotropic and trophotropic discharges. A number of investigators (77, 676, 993) reported results to be expected after a long vigil: with increasing duration of wakefulness the performance of various skilled tasks declines, reaction time increases, and, with serial tasks involving near-threshold acoustic stimulation (beep test), lapses of attention occur which seem to coincide with characteristic changes in the EEC —the absence of alpha potentials and their replacement by slower (theta) potentials of low amplitude.f Sleep-deprived subjects are unable to maintain alpha potentials for more than 10 seconds (836). The tendency toward brain potentials of slower frequency suggests, in the light of extensive work on the ascending diffuse excitatory system involving hypothalamus and reticular formation, that the activity of this ergotropic system is lessened. In support of this interpretation are the findings that the body temperature falls (745), that the palmar sweating as well as the response of the sweat glands to pain declines (41), and that the symptoms of sleep deprivation can be alleviated to a considerable degree by drugs such as amphetamine (961) which increase the activity of the ergotropic system. In addition, the fall in heart rate (77) and the vasodilation indicated by an increase in finger volume (993) suggest a lessening of the activity of the ergotropic and/or an increase of the trophotropic system. That these various symptoms are interrelated is shown by the observations that lapses in attention coincide with slowing of the potentials in the EEG and that "a sleep-deprived subject, presented with a signal during a period of vasodilation, is likely to delay or fail to respond. If a signal is presented during a period of vasoconstriction, the response is likely to be brisk" (993). The lessened frequency of the potentials in the EEG and the diminished activity and responsiveness of the sympathetic system to various "Concerning experiments in which cold and immobilization caused hyperglycemia in normal animals but hypoglycemia in monkeys with posterior hypothalamic or extensive limbic lesions, see 787 and 788. fThe theta potentials are frequently very small (993) and may not appear distinctly in the EEG.

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stimuli in a prolonged vigil seem to be the expression of the lowered intensity of upward and downward discharges from hypothalamus and reticular formation. How far the cortical balance is shifted is evident from the observation that stimuli (mental work, startle) which block alpha potentials under control conditions produce them in the EEC during (34) or after a period of sleep deprivation (836). It seems that the stimuli act in a similar manner in the normal and in the sleep-deprived subject in that they increase the frequency of the cortical potentials — from the theta range to the alpha frequency in the sleepless state and from the alpha frequency to the faster beta potentials of low amplitude (blocking the alpha potentials) when applied in the normal rested state. There is, however, another group of observations which seems to contradict this picture. Tyler (961) noted that sleep deprivation was associated with an increase in the frequency of the brain potentials. Others found little change in the performance of various tasks in spite of prolonged wakefulness. This paradox was solved by recognizing that two states are in rivalry in sleep deprivation, the trophotropic system tending to produce sleep and the ergotropic system tending to maintain wakefulness. The more frequently incentives of various kinds to stay awake are applied —they vary from the application of painful stimuli as the subject's attention lapses (676) to informing him of the quality of his performance (992, 993) — the more signs of increased activity of the ergotropic system appear.* The tension of the striated muscles is often a good indicator: Wilkinson (992) found that sleep deprivation may result either in a lower performance or in an increased muscle tension during the test (see also 673). Studies on animals are in agreement with this interpretation. Sleepdeprived rats need fewer trials for mastery and perform better in the maze than the control group (622). The greater reactivity of the ergotropic system in the experimental group is indicated by the increased aggressiveness of the rats in which the daily period of sleep had been shortened. Moreover, in conditioned rats (bar-pressing for food) the heart rate increases with increasing duration of sleep deprivation (856). If we bear in mind the overpowering tendency of the sleep mechanism to supervene after a prolonged vigil unless a continuous effort is made to counteract sleep, it seems that sleeplessness furnishes a good illustration of the effects of the simultaneous or quickly alternating activity of the trophotropic and ergotropic systems. The previous examples of asphyxia, fever, and convulsions were based on physiological experiments but not on physiological conditions. Since in sleep deprivation the internal environment is virtually unchanged and no excessive excitation *See also the increased excretion of adrenaline and noradrenaline under conditions of muscular work after sleep deprivation (434).

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takes place, we deal with physiological rather than pathological processes. On the other hand, by prolonging the vigil (up to 220 hours!) various degrees of abnormal phenomena may be produced. They involve the state of awareness — the subject felt "things appeared as if he were looking through a fog" (651). Moreover, hallucinations, illusions (inanimate objects were mistaken for persons), temporal disorientation, cognitive disturbances (735), and feelings of depersonalization (79) were noted. A heightened reactivity to LSD (79) and a tendency for the subjects to become "more irritable-paranoid" with increasing sleep deprivation occurred. The nearly simultaneous activation of the ergotropic and trophotropic systems which may be related to these psychological disturbances is reflected in the observation that in prolonged vigil the subject is "sleeping while awake."* The hypothesis that nearly simultaneous upward and downward discharges of the ergotropic and trophotropic systems contribute to abnormal cortical phenomena and behavioral disturbances will be further tested in Chapter IV, in which the mechanisms underlying experimental and clinical neuroses will be discussed (A56). II. DOMINANCE OF THE TROPHOTROPIC SYSTEM 1. The "Tuning" of the Hypothalamus

Since it was shown in the preceding pages that a weakening of the reciprocity of the trophotropic and ergotropic systems leads to pathological reactions in peripheral organs and also to central disturbances as indicated by behavior, the question arises as to whether an intensification of this reciprocity may likewise be of pathological significance. Such conditions are produced by shifting the central autonomic balance. Systematic studies (329, 341, 346, 372) have shown that the balance between the trophotropic and ergotropic systems at the hypothalamic level can be changed by lesions or stimulation confined to one division of the hypothalamus or through reflexes. Thus stimulation of the posterior hypothalamus increases sympathetic and diminishes parasympathetic discharges, and these effects are reversed when the anterior hypothalamus is stimulated. Conversely, lesions in the posterior hypothalamus increase parasympathetic and decrease sympathetic activity, whereas reverse effects result from lesions in the anterior hypothalamus. Conse*Johnson, Syle, & Dement (536) found in a 17-year-old subject after sleep deprivation of 236-246 hours dominant delta potentials in the EEC but a very high level of ergotropic activity as indicated in skin resistance, heart rate, and skin temperature. The paradox, in the authors' opinion, that the "sleep-deprived subject is at a high level of arousal judged by autonomic measures, but at a low level of arousal judged by EEC and behavior" seems to me to be resolved by assuming that hypothalamic functions are released as the result of cortical depression.

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quently, conditions are created by these and similar procedures in which the reciprocal relations between the parasympathetic and the sympathetic divisions of the hypothalamus are greatly exaggerated or, to express it differently, in which the difference between the active and the inhibited divisions is much greater than under control conditions. The physiological significance of such states is apparent if the reactivity of the hypothalamus is tested. Thus if, through stimulation of the posterior hypothalamus, the activity of the sympathetic system is increased, its responsiveness to direct (hypothalamic) or indirect (via reflexes involving, for instance, afferent nociceptive fibers) stimulation is likewise augmented, whereas that of the anterior (parasympathetic) division of the hypothalamus is reduced. Conversely, states of increased parasympathetic activity are associated with an increased responsiveness of the parasympathetic system, whereas that of the sympathetic system is reduced. It is apparently immaterial whether a certain shift in autonomic balance is produced by central stimulation or lesions, by stimulation of afferent somatic nerves, or by changes in the rate of discharge of the sino-aortic baroreceptors. It may be said, then, that a state of increased ergotropic discharges (sympathetic or ergotropic "tuning") is associated with increased reactivity and enhanced upward and downward discharges of the ergotropic system, whereas a state of increased trophotropic discharges (parasympathetic or trophotropic "tuning") is accompanied by increased reactivity and enhanced upward and downward discharges of the trophotropic system. Moreover, in the sympathetically tuned nervous system the trophotropic system is more inhibited than in the balanced control condition. Similarly, the ergotropic system is more inhibited in the parasympathetically tuned organism than in the control condition. These concepts and experimental findings were applied to some problems of psychosomatic medicine by Gellhorn & Loofbourrow (370), who related hypertension, gastric ulcer, asthma, etc. to disturbances in the trophotropic-ergotropic balance. In this chapter we confine ourselves to the study of the state of parasympathetic tuning as the basis of certain disturbances in consciousness. In the physiological experiment this state of imbalance was induced either by increasing reflexly (via the baroreceptors) parasympathetic discharges (87, 747) or by reducing the activity of the sympathetic division of the hypothalamus (through lesions or intrahypothalamic injection of Pentothal, 357). In both instances the EEG pattern is shifted toward synchronization. Testing the autonomic system through appropriate central or reflex stimuli under these conditions discloses the following effects: 1. A diminished sympathetic responsiveness shown, for instance, by a

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lessened contraction of the nictitating membrane on stimulation of the posterior hypothalamus. 2. An increased parasympathetic reactivity illustrated by slowing of the pulse and fall in blood pressure on stimulation of the sciatic nerve with low-frequency currents of threshold intensity. 3. A parasympathetic reaction in response to a stimulus which in the control test exerts a strong sympathetic action. Instead of a rise in blood pressure and heart rate a decrease in both functions occurs (reversal). 2. Autonomic Balance in Sensory Deprivation The principles illustrated in these acute physiological experiments contribute to the understanding of behavioral disturbances in man and animals in which central or peripheral factors or a combination of both lead to an imbalance between the trophotropic and ergotropic systems. Since afferent impulses greatly contribute to the tone of the reticular formation (918), the intensity of the hypothalamic-cortical discharges (71, 337, 353, 588), and the sympathetic reactivity of the hypothalamus (340), one would expect that elimination of the major senses would shift the balance toward the trophotropic side. The lesser general activity and the increased duration of sleep in animals deprived of the organs of smell, vision, and hearing (420) seem to be the behavioral expression of this shift in balance. Assuming that the autonomic balance is shifted, one would expect on stimulation an alteration in the reactivity of the autonomic system analogous to that seen in the "tuning" experiment described above: a nociceptive stimulus which causes increased sympathetic discharges and arousal, i.e., ergotropic activation, in normal animals would not only produce parasympathetic effects in the experimental animals but also alter central discharges as if the trophotropic system in general or the anterior hypothalamus in particular had been stimulated. Nociceptive stimuli inducing ergotropic effects in the normal cat have, indeed, been found to exert trophotropic actions in cats which are blind, deaf, and anosmic. "When a cat was placed in the pen, sleep occurred more quickly after a strong noxious stimulus than when the cat was not so stimulated" (420). 3. Narcolepsy A state of autonomic imbalance with dominance of the trophotropic system seems to be present also in narcolepsy. If this assumption is correct the investigation should disclose that: 1. Signs of this imbalance differentiate the narcoleptic from the control group. 2. Conditions which promote sleep in the normal person are more effective in the narcoleptic.

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3. Reversal phenomena involving the autonomic system occur in narcolepsy. 4. Narcoleptics benefit from procedures tending to shift the autonomic balance to the ergotropic side. From Kleitman's (577) review of the literature the following data may be cited. Heart rate, basal metabolism (reflecting the state of the tone of the skeletal muscles, 246), and body temperature "are likely to be somewhat lower than normal in narcolepsy." Vagotonia has been reported in one investigation to be common in narcolepsy. These findings suggest, on the basis of increased downward discharges, a slight dominance of the trophotropic system. The tendency to fall asleep after breakfast indicates a greatly increased susceptibility to the postprandial shift in autonomic balance. The occurrence of sleep on hyperventilation which is associated with a lessened tone of the ergotropic system is explainable on similar grounds, as is the appearance of the "dream phase" shortly after the onset of sleep rather than after approximately ninety minutes (813, A53). Emotional excitement, particularly laughter but also orgasm, may precipitate a cataplectic attack (sleep and loss in muscle tone). Although little is known about the physiology of laughter, certainly it is associated with increased muscular activity. Orgasm produces, in addition to enhanced parasympathetic and sympathetic discharges, an increased tone of the skeletal muscles. It may therefore be said that in both forms of emotional excitation the heightened activity of the striated muscles is due to increased discharges of the gamma system originating in the diencephalic and mesencephalic parts of the brain stem.* Whereas this action is part of the ergotropic activity elicited by the emotions in the normal organism, the sudden loss in muscle tone which results from laughter and orgasm in narcoleptics seems to be a reversal phenomenon in the trophotropically tuned nervous system. Under these circumstances ergotropic stimuli induce trophotropic actions, including inhibition of the gamma system and, thereby, loss in muscle tone. These reversal phenomena are not confined to the downward discharges, but alter the upward discharges as well. This explains the precipitation of sleep through emotional excitement and also the appearance (instead of the disappearance) of the alpha potentials in the EEC of narcoleptics when the eyes are opened. Physiological experiments on "tuning" (329) showed that the reversal phenomena occur in response to strong, short stimuli in the parasympathetically tuned nervous system. This explains why sudden emotions are particularly effective in producing a cataplectic attack. On the other hand, stimuli which act gradually and for a prolonged period on the "See Chapter I.

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ergotropic system are likely to intensify ergotropic discharges and to restore, at least temporarily, the autonomic balance. This mechanism accounts for the therapeutic effects of amphetamine (577). The action of insulin-induced hypoglycemia, known to stimulate the ergotropic system, must be explained in a similar manner. This procedure relieves drowsiness in narcoleptics and accelerates the potentials in the EEC. Both effects are reversed on restoring the blood sugar by the injection of glucose (908a). In principle, narcolepsy might arise as the result of a centrally or reflexly induced imbalance between the ergotropic and trophotropic systems. It is interesting that as in the physiological "tuning" experiments described earlier a shift in autonomic imbalance accounting for the trophotropic dominance is due in some narcoleptics to a hyperactivity of the baroreceptors of the sino-aortic area. In such cases denervation of the carotid sinus or removal of tumors pressing on this structure effect a cure (see 577). In other instances the imbalance seems to be of central origin. This interpretation is supported by the finding that sleep-like episodes occur also in functional ("vegetative dystonia") and organic diseases of the diencephalon (845,846). Vizioli (975) utilizes physiological experiments in which the cerebral cortex is inhibited (694) and the tone of the muscles is lessened through stimulation of the cingulum (546), as the basis for a physiological interpretation of the narcoleptic attack. A shift in balance with dominance of the trophotropic system would, indeed, be produced by such a stimulation, since it seems to act on the ventromedial nucleus of the hypothalamus (546), which inhibits its sympathetic division (988). It will be the task of clinical and, particularly, surgical studies to differentiate between narcolepsy arising from excessive afferent impulses (involving baroreceptors) and those cases in which a functional or organic disturbance is located in the diencephalon or in the limbic brain. The experimental and clinical experiences described suggest that states of increased reactivity of the trophotropic system may result from several causes. Increased discharges from the baroreceptors, reduction in the impulses which reach reticular formation and hypothalamus via collaterals from the specific afferent systems, or a central autonomic imbalance with or without changes in the afferent input seem to be involved. The central imbalance may be the result of increased activity of the trophotropic or of lessened activity of the ergotropic system. The moderate heating of the anterior hypothalamus (263) illustrates in the physiological experiment the former mechanism, whereas the release of the anterior hypothalamus seen after lesions in the posterior hypothalamus represents a model for the latter mechanism (372).

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The deviations from the norm in the mutual relationship between the ergotropic and the trophotropic systems which have been described thus far seem to be explainable on a physiological basis by the following considerations: 1. Increasing frequency or intensity of stimulation applied to subcortical nuclei, various parts of the brain stem, and afferent nerves leads from trophotropic to ergotropic activation and finally to an activation of both systems. The first stage involves responses which are restricted to the trophotropic system. Thus, stroking of the skin or low-frequency stimulation of cutaneous receptors (790) elicits parasympathetic effects and cortical synchronization and sleep. Under similar conditions reciprocal innervation is illustrated by the increased arousal threshold. In the second stage, involving stimuli of moderate intensity or frequency, arousal (cortical desynchronization) and sympathetic discharges are induced, the latter accompanied by signs of reciprocal inhibition. The contraction of the sympathetically innervated nictitating membrane and the dilatation of the sympathectomized pupil, indicating sympathetic excitation and parasympathetic inhibition respectively, may suffice as an example. Finally, stimuli of great intensity lead to sympathetic and parasympathetic discharges. The presence in asphyxia of slowing of the heart rate in combination with increased action potentials in sympathetic nerves, and the alterations in cardiovascular functions seen in asphyxia following vagotomy or sympathectomy support this interpretation. 2. In certain experimental conditions trophotropic effects appear in response to stimuli which induce ergotropic actions in the control test. These conditions (characterized by a shift in balance of the ergotropic and trophotropic systems in favor of the latter) result from reflexly increased trophotropic discharges due to enhanced baroreceptor activity, or from the release of the trophotropic system in states of diminished activity of the ergotropic system. The first group of data shows that the trophotropic system has a lower threshold than the ergotropic system and that with increasing stimulation the ergotropic excitation grows more rapidly than the trophotropic excitation. Within a wide range reciprocal relations persist, but when the excitation surpasses a critical value it spreads to the trophotropic system. Under these conditions the ergotropic reactions may remain dominant* or the dominance may pass over to the trophotropic system. * Dominance refers to that part of the autonomic discharge which determines the action on the target organ. Thus, if prolonged asphyxia causes slowing of the heart before but acceleration after vagotomy, sympathetic and parasympathetic discharges are involved in the action of asphyxia in the normal organism with dominance of the latter.

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The second group of data shows that even at an intermediate intensity of stimulation, i.e., above the threshold for the ergotropic system when stimulation causes an ergotropic action in the normal organism, trophotropic neurons are potentially excitable. Obviously, this excitation can manifest itself only when the reciprocal inhibition which accompanies sympathetic excitation is lessened or absent. Thus, it has been found that asphyxia which produces a rise in blood pressure and heart rate when the excitability of the ergotropic system is high will induce predominantly a fall in blood pressure and heart rate when the central sympathetic excitability is low (347). Similarly, if through increased baroreceptor discharges the trophotropic system is in a state of increased responsiveness while the sympathetic system is inhibited, a trophotropic response pattern appears on stimulating the sympathetic division of the hypothalamus or nociceptive receptors. The work discussed above shows that this reversal is not confined to the peripheral components of the trophotropic system but also fundamentally alters the EEC and behavior. This mechanism accounts for the observations that noxious stimuli in blind, deaf, and anosmic animals and emotional excitement in narcoleptics may induce sleep. It seems noteworthy that these abnormal reactions (reversal), in contrast to those discussed in the first section of this chapter, are not the result of unphysiological excessive stimulation but are due rather to a shift in the ergotropic-trophotropic balance. IV. DISSOCIATIONS BETWEEN THE UPWARD AND DOWNWARD DISCHARGES OF THE ERGOTROPIC SYSTEM

1. Mental Activity and the Striated Muscles It was stressed in Chapter I that in numerous conditions involving reflex and direct excitation of the ergotropic system and also under the influence of drug action there is a parallelism between the central and peripheral effects: as the central excitation increases, producing and enhancing arousal, the sympathetic and somatic discharges are augmented, and vice versa. The physiological changes occurring during voluntary muscular work illustrate this relationship and its adaptive value. The sympathetic discharges elicited during such activity are said to maintain adequate circulation through heart and brain, increase the blood flow through the working muscles, and delay fatigue (329) while enhanced impulses from hypothalamus and reticular formation increase the cortically induced contractions (338, 743) and the feedback from the muscles to the brain stem (340), which in turn further enhances the cortical excitation. These data raise the question of the relationship between upward and downward discharges in various forms of mental activity. Extensive studies have shown that mental activity is accompanied by

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cortical arousal (blocking of alpha potentials), sympathetic discharges indicated by numerous reactions (an increased psychogalvanic reflex, for example), and also by increased tone of the skeletal muscles. That the latter, within limits, improves mental performance (919) seems explainable through the feedback mechanism referred to above. A simple test in arithmetic raises the basal metabolism by about 11 to 17 per cent while action potentials of the striated muscles (245) and the blood flow through the forearm muscles (390) increase. In general, the metabolic and muscular response is not related to the difficulty of the problem or the intelligence of the experimental subject but to his emotional responsiveness. Mental tasks involving frustration lead to abrupt increases in muscle activity (396). Moreover, mental work carried out with some emotional excitement may considerably increase metabolism and muscle activity, whereas the same person in a contemplative attitude (induced through hypnotic suggestion, 244) may perform an identical task without any change in EMG and O2 consumption. It is suggested that discharges from hypothalamus and reticular formation (402) over the gamma system, which occur also in man during mental effort (768), are responsible for the associated increased muscle tone and metabolism. 2. The Yoga Trance and the Significance of Muscular Relaxation It appears from these data that increased muscle tone, although commonly associated with intellectual activity, is no prerequisite for mental work. Observations on yogi are pertinent to this problem. Das & Gastaut's (194) study of Indians who had practiced the yoga trance for years showed progressive changes in cortical excitation as the subjects passed through the various stages of fixation of attention, meditation, and ecstasy. While the EMG records showed no activity over several hours during these phases, there was an acceleration of the heart rate during ecstasy, and following the trance, a slowing (rebound) below the control level took place before the pre-experimental state was reached. The EEG changes were startling. The alpha frequency increased by 1-3/sec and decreased in amplitude while faster potentials (15-30/sec) appeared. In the ecstatic phase peak values of 40-45/sec and an amplitude of 30-50 microvolts were recorded. The return to the norm was preceded, as in the pulse records, by a rebound during which the alpha frequency slowed to 7/sec. Clearly, in trained subjects unusual degrees of mental concentration and corresponding levels of cortical excitation may be attained during complete muscular relaxation. On the other hand, it is common experience that muscular relaxation is conducive to sleep.* If the proprioceptive discharges which contribute *See the discussion of pertinent experiments by Gellhorn (340) and by Hodes (474) in Chapter I.

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to the tone of the ergotropic system are absent, the central autonomic balance shifts to the trophotropic side and sleep supervenes. However, this shift may but does not necessarily occur since receptors other than proprioceptors and cortical processes may maintain wakefulness. Thus, stimulation of numerous cortical sites has been shown to activate the reticular formation and, thereby, to arouse a sleeping animal (884), these procedures being effective in the curarized animal (885) and in the encephale isole in which proprioceptive influences from almost all skeletal muscles are excluded (102). Perhaps it is not superfluous to add a personal experience. After a severe coronary attack many years ago I learned to relax quickly, particularly after dinner. My legs feel heavy then and I often go to sleep in a few minutes. More recently, after working at my desk for three to four hours in the morning I feel the need of an interruption. If in this state of fatigue I lie down on a reclining chair in the sun, I relax almost immediately and since I do not feel mentally tired at all, I pursue the problem which has occupied my mind during the past several hours with much greater success than during the last half hour before resting. I often have the impression that in this relaxed state I recall particularly well many details of the work I have studied in the preceding hours. Even in writing a book or preparing a paper on a neurophysiological topic, thought and emotional processes are mixed. The latter — consciously or unconsciously — are likely to be aroused in the writer's mind through questioning himself as to the correctness of his arguments, the clarity of his writing, and the worthwhileness of the whole task. I would like to suggest that the reduction in the proprioceptive activation of the hypothalamus and the reticular formation in the relaxed state creates favorable conditions for the cortical thought processes to go on without interference while an adequate state of awareness is maintained through corticofugal impulses impinging on the reticular formation. Otto Loewi's story that he had elaborated in his sleep the experimental design which led to the discovery of the neurohumors seems interpretable on a similar basis. There are relations between this state of relaxation, which is compatible with mental alertness, and sleep paralysis. I have often found that in the state of relaxation a great effort is necessary to move arm or leg slowly although a quick movement is carried out easily. Moreover, even gross movements of one extremity do not alter the feeling of heaviness and, apparently, the state of relaxation in the remainder of the body. In my experience the facial muscles never participate in the relaxation. 3. Paradoxical Sleep Until recently sleep appeared to be characterized neurophysiologically by an increasing degree of activity of the trophotropic system which mani-

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fests itself cortically by a decrease in frequency and an increase in amplitude of the EEC and by a decrease in respiration, heart rate, and muscle tone. The shift in autonomic balance to the parasympathetic side is obvious from the miosis of the pupils, the relaxation of the nictitating membranes, and the increase in skin resistance. The important work of Dement (206) and Jouvet et al. (538, 539, 542, 543) and the experiments by Dement & Kleitman (207) on man have established an additional "paradoxical phase" (p.p.) which seems to be related to dreaming. Stage 4, characterized by large slow delta potentials in the EEC, is followed by a phase showing fast potentials of low amplitude in the EEC, disappearance of muscle potentials in the neck, increased but more superficial respiration, slowing of the heart rate, and rapid movements of the eyes. The designation "paradoxical" seems justified, since desynchronization of the EEC (denoting excitation) is combined with complete muscular relaxation and markedly increased arousal threshold as determined by either sensory or reticular stimulation. In this state subarousal acoustic stimulation evokes large slow waves and spindles in the EEC, suggesting that the p.p. represents the deepest sleep level. For our purpose it may suffice: 1. To present further evidence for the assumption that the cortex is in a state of excitation during the p.p. while the downward discharge is greatly diminished. 2. To characterize the autonomic-somatic discharges in more detail. 3. To indicate the neurophysiological mechanism underlying this phase. What is the nature of the cortical activity during the p.p.? Bremer suggested that the record, which appears flat, might be the result of desynchronization and depression of the cortex (101). Since it is well known that cortical desynchronization as in arousal is accompanied by a lesser responsiveness of the trophotropic system (see Chapter I), the question arises as to the threshold of the latter during the p.p. Low-frequency stimulation at near-threshold intensities of the medial thalamic nuclei and also of the reticular formation — corresponding experiments involving low-frequency caudate stimulation have not yet been performed — results in a typical recruiting response when carried out in light sleep, but this effect is absent during the p.p. (843). Since it has been shown that the trophotropic system is reciprocally inhibited with increasing activation of the ergotropic system, which leads to diffuse cortical excitation and arousal in the normal organism, it follows that the EEG in the p.p. behaves as if the reticular formation had been stimulated. Conversely, the reduction in the state of excitation of the ergotropic system induced by the injection of barbiturate during the p.p. lessens the inhibition of the trophotropic system and makes a low-frequency thalamic stimulus effective: a recruit-

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ing response appears in the EEC in response to a stimulus which did not alter cortical potentials before the administration of the drug. The heightened cortical excitation during the p.p. is evident from threshold determinations of the motor cortex. Its threshold is almost the same as during the waking state whereas that of the reticular formation progressively increases (477, A7). A state of increased cortical excitation during the p.p. may be inferred also from the study of the activity of single neurons. The rate of discharge of neurons of the visual cortex is smaller in light sleep (high voltage, slow activity in the EEC) than in the p.p. (272). Similar changes occur in the neurons of the motor area. The pyramidal discharges increase as the fast activity of the p.p. appears, and may be higher than in the aroused animal (32). The evoked potentials of the auditory cortex in response to acoustic stimulation (935) and those of the sensori-motor cortex to stimulation of a thalamic relay nucleus during sleep and wakefulness are greatest in deep sleep (p.p.) and least in light sleep (784). Moreover, the cortical response to dromic and antidromic impulses is significantly increased during the p.p.* In contrast to these data showing a high degree of diffuse cortical excitation and increased responsiveness of specific projection areas during the p.p., the downward discharge does not show increased sympatheticsomatic activity but rather the reverse. The complete relaxation of the neck muscles, which is the most characteristic mark of the p.p., is associated with a decrease in heart rate (543), a marked miosis (68), and a fall in blood pressure (144; Fig. 2-1, A8), while in the corresponding dream stage in human sleep the skin resistance is increased reversibly (438). Inhibition of muscle tone (A48) and the described autonomic changes indicate that the cortical excitation is combined with enhanced trophotropic and/or diminished ergotropic discharges.! Moreover, these central and peripheral manifestations of the p.p. are interrelated: the arousal threshold rises with falling blood pressure! If, however, the blood pressure is lowered to a similar degree during light sleep by vagal stimulation or through the administration of vasodilator drugs, no p.p. ensues (843). It follows that the trophotropic discharge which occurs in the p.p. is part and parcel of the central discharge which determines this phase of sleep, although the trophotropic discharge by itself cannot produce the p.p. Accompanying *The failure of individual neurons to respond to sensory stimuli during the high degree of activation which characterizes the p.p. is not attributed to a lessened excitability but to occlusion, as seen in spinal reflexes. t There is, however, a notable exception: the p.p. is associated with increased sympathetic discharges to the eye as indicated by pupillary dilation and retraction of the nictitating membrane (475). This is obviously related to the activity of the eye muscles.

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the fall in blood pressure but occasionally occurring while it remains unchanged is an increase in cerebral circulation during the p.p. (552, 553). It is a further indication of the shift in balance to the trophotropic side. Jouvet's fundamental studies have shown that in contrast to light sleep which shows slow, high-voltage potentials and depends on the integrity of the cortex, the p.p. is the result of a discharge from the caudal pontine part of the reticular formation.* Destruction of the caudal nuclei of the

Fig. 2-1. EEG, EMG, and BP patterns during sleep. Records obtained at a very slow paper speed. The BP does not change at the onset of sleep and during light sleep, whereas it falls markedly during deep sleep characterized by desynchronization of EEG and inhibition of tone of cervical muscles (EMG). (From Rossi. Sleep inducing mechanisms in the brain stem. EEG clin. Neurophysiol. Suppl. 24:118, Elsevier, Amsterdam, 1963.)

pons abolishes (but see A9) the p.p., whereas stimulation of this area produces it. The upward discharge also involves the visual system. Lowfrequency stimulation elicits groups of monophasic potentials in the lateral geniculate bodies similar to the potentials which appear during the spontaneously occurring p.p. in synchrony with discharges in the pontine reticular formation (75, 112). This discharge also involves the oculomotor nucleus and accounts for the eye movements seen in the p.p., which is closely related to dreaming (206). The EEG changes of the p.p. still occur after lesions in the mesencephalic portion of the reticular formation provided the interpeduncular region, hypothalamus, and septum are intact so that the pontine impulses can reach the limbic brain (538, 542; Fig. 2-2). The importance of hypo°That light sleep depends on the cortex and the p.p. on the pontine reticular formation holds true for man, as observations on patients with appropriate lesions have shown (543).

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thalamic-limbic relations has also been stressed by Faure & Bensch (278) who succeeded in eliciting the p.p. in the rabbit by stimulation of the hypothalamus, and impedance patterns (74) suggest that during this phase the hypothalamic circulation is increased as in the waking state. (For further investigations of p.p., the influence of reserpine on this state, and the role of neurohumors, see A10, All.)

Fig. 2-2. Schematic representation of the neural structures responsible for RPS (Rhombencephalic Phase of Sleep, or paradoxical phase, as it is called in this book). Dots ( 8 ) : nucleus reticularis pontis caudalis, whose destruction suppresses RPS. Black: an ascending part of the limbic midbrain circuit, with the "limbic midbrain area" of Nauta and Kuypers. 1,2,5,6: lesions of the septum, subthalamic region, interpeduncular region, and medial part of the anterior pontine tegmentum; these lesions suppress, totally or in part, the fast cortical activity and the theta hippocampal rhythm during RPS. 3 and 4: lesions interrupting the ascending reticular activating system at the mesencephalic level; these lesions, which suppress cortical arousal, do not eliminate the possibility of a fast cortical activity during RPS. Black area posterior to area 8: ponto-bulbar inhibitory reticular formation, which is probably responsible for the total atony during RPS. (From Jouvet & Jouvet. A study of the neurophysiological mechanisms of dreaming. EEG clin. Neurophysiol. Suppl. 24:143, Elsevier, Amsterdam, 1963.)

In the yoga trance and the p.p. of sleep, cortical excitation coincides with muscular relaxation. Both states exemplify a marked deviation from the common ergotropic pattern. There are, however, important differences: the desynchronization of the cortex seems to be due to the activation of a cortico-reticular-cortical loop in the yoga state but to pontine reticular discharges to the limbic brain and, indirectly, to the neocortex in the p.p. Moreover, the autonomic discharge is predominantly sympathetic in the yoga state but parasympathetic in the p.p. 4. Depression of Cortical and Release of Ergotropic Functions The various forms of dissociation between the upward and downward discharges of the ergotropic system which have been discussed in the

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preceding sections have the fact in common that increased cortical activity (desynchronization) has been, found to be associated with signs of lessened tone of the striated muscle. A deviation more frequently seen in physiological experiments is of the reverse type: a lessened cortical function is associated with increased ergotropic discharges. It results from changes in internal environment to which the cerebral cortex is more sensitive than brain stem and spinal cord. Thus, anoxia produced by the inhalation of OL> and N^ mixtures or by lowered barometric pressure, asphyxia in its milder form induced by administration of gas mixtures low in O2 but high in CO^, and hypoglycemia reduce cortical activity long before comatose or convulsive symptoms appear. This is indicated by a diminution in frequency of cortical potentials and in sensory function paralleling the alterations in the EEC (364), a decline in muscular coordination, and inferior performance in various psychophysiological tests (associations, etc., 369). At the same time sympathetic and sympatheticoadrenal discharges are enhanced, as disclosed by cardiovascular changes, sweating, etc. These findings are interpreted as being due to a release of subcortical centers controlling the activity of the sympathetic system from the cerebral cortex, and a similar explanation is frequently given for the increased sympathetico-adrenal discharges accompanying ether and chloroform anesthesia. Since medullary and spinal reflexes are less sensitive to the action of certain drugs than brain stem and, particularly, cerebral cortex, stimulation of nociceptive receptors induces sympathetic and sympatheticoadrenal discharges in deeply barbiturized animals without altering the cortical synchronization. Lesions in the posterior hypothalamus abolishing the desynchronization in response to noxious stimuli (588) lend themselves also to the demonstration of a dissociation between cortical and subcortical ergotropic actions, since under these conditions the reflex response of the sympathetico-adrenal system remains intact. Cortical depression associated with release of ergotropic functions is seen in man in various forms of loss of consciousness due to hypoglycemia or cerebral lesions. When consciousness is lost in hypoglycemia, muscular spasms, clonic twitchings associated with sweating, increased heart rate, and exophthalamus occur (470). The subcortical release is evident from the appearance of convulsive discharges in amygdala and hippocampus and from the spread of the spikes to the hypothalamus and other subcortical structures but not to the cerebral cortex (953). This state of the amygdala and its propagation to the hypothalamus may contribute to the increased sympathetic discharges which lead to an increased adrenaline content of the blood in hypoglycemia (969). Deep coma due to cerebral lesions may cause a release of sympathetic discharges; in most cases cardiovascular, respiratory, pupillary, and spinal reactivity (flexor

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reflex) are retained in response to noxious stimuli, although cerebral responses are absent (539). V. DISSOCIATION BETWEEN RETICULAR AND HYPOTHALAMIC UPWARD DISCHARGES

1. Hypnosis Seemingly contradictory symptoms characterize the state of hypnosis. Consciousness is greatly restricted and in deep hypnosis there is "a selective constriction of awareness which excludes all but the hypnotist as a source of stimulation" (984). The resemblance to sleep has been pointed out by Pavlov and others. The observation that suggestions are made effective through monotony seems to support this contention since monotony, internal inhibition, and sleep are interrelated (772) and repeated exposure to the same sound or light leads not only to drowsiness but also to increasing degrees of susceptibility to hypnosis (193). The "tendency toward protracted immobility" in the absence of suggestions is compatible with the interpretation that hypnosis is a sleep-like state. But it must also be borne in mind that although the hypnotized subject seems asleep, he shows a "waking" EEC and even improved recognition of visual objects (579). One is reminded of the action of atropine and eserine which alter EEC and wakefulness in opposite manners (95). Although most recent investigators point out that the EEC in hypnosis is that found in the waking state, it is not unlikely that more subtle electroencephalographic changes occur which do not appear in the standard EEC. Thus, according to Darrow et al. (190) the temporal relations between the activities recorded from different parts of the cortex are altered and are in part similar to those seen in sleep. Posthypnotic suggestions may produce symptoms not unlike those resulting from lesions in the angular and supramarginal gyri (936). In the application of hypnosis to cases with intractable pain the reaction to pain is altered as if a leucotomy had been performed (842). It is suggested, therefore, that at least some cortical functions are depressed in hypnosis. This agrees with the observation that drugs which reduce consciousness (barbiturates, scopolamine) facilitate hypnosis. In sharp contrast to these findings are observations on the autonomic nervous system. Recent extensive experiments have clearly shown that hypnosis is accompanied by a large and reversible increase in palmar conductance (760). There are additional signs of increased autonomic reactivity in hypnosis, particularly on suggesting emotional excitement, which may produce marked cardiovascular reactions; but even the mere suggestion of an increased heart rate may result in tachycardia without a change in

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respiration, arousal, or evidence of fear. Secretory and motor changes in gastrointestinal functions have frequently been elicited in hypnosis and the suggestion in hypnosis of heat and cold has been shown to call forth vasodilation and vasoconstriction respectively, while that of pain and burn may elicit blisters in the skin (see 50, 577 for the literature). The susceptibility of the emotional state and the ergotropic and trophotropic systems to the effect of suggestions with or without hypnosis is apparent from the fact that placebo injections elicit disturbances involving both branches of the autonomic system (palpitation, vomiting, diffuse skin rash, etc., 997) and also the classical signs of hypothalamically induced secretion of ACTH (eosinopenia, lymphopenia, increased excretion of 17-ketosteroids); the degree of these actions parallels that of the anxiety which is present (166). The hypnotic suggestion of hyperesthesia and anesthesia is likewise paralleled by corresponding changes in autonomic reactivity (65, 160). Moreover, the suggestion of a delicious meal or of various emotions in hypnosis produces marked changes in gastric secretion (509), whereas severe cardiovascular changes may result from the suggestion of a fainting spell (805). Shor (898) comes, on the basis of critical and experimental studies, to the conclusion that the diminution of the autonomic and somatic response to nociceptive stimuli in hypnotic analgesia is the result of "eliminating the incidental anxiety component of the total pain experience." A further dramatic illustration of this relationship is the finding that the hypnotic suggestion of quantitative changes in sensory and auditory perceptions produced in one experimental subject changes in mood varying from "catatonic apathy to wild maniacal excitement, thought and motor behavior" (293). Obviously, autonomic and emotional hyperreactivity is combined with a restriction of awareness in hypnosis, whereas under physiological conditions (sleep-wakefulness cycle) awareness and autonomic (ergotropic) reactivity run parallel. Bearing in mind that awareness is generally attributed to the activity of the ascending impulses of the reticular formation (particularly of its mesencephalic part), and that autonomic and emotional responsiveness is related to the excitatory state of the hypothalamic system, we may say that in hypnosis the former shows a decreased and the latter an increased state of activity. Is such an interpretation tenable from the physiological point of view or, to express it differently, are conditions known in which the two systems behave in a fundamentally different manner? The following observations favor an affirmative answer: 1. Behavioral studies on rats have shown that as the orienting reflex, which is a function of the reticular formation, increases, the emotional reactivity diminishes (924).

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2. During "spreading depression" of the cortex induced by KC1 the hypothalamic activity diminishes, whereas that of the reticular formation increases (762, 983).* Since "monotony is believed by many hypnotists to have the ability in itself to bring hypnosis about" (984) and since repeated (monotonous) stimuli result in habituation which is thought to be due to a lessened activity of the reticular formation (890), it is suggested that hypnosis is accompanied by a diminution in the rate of discharge of the diffuse ascending reticular system of Magoun and at the same time, as in the two examples just cited, by a release of the hypothalamic system. Such a release may result from the lessened cortical activity (as in "sham rage") and/or from a reduction in inhibitory impulses which originate in the reticular formation and impinge upon the posterior hypothalamus (284).f The next problem concerns the mechanism by which, in this setting of the brain, verbal stimuli elicit the sensory, motor, and autonomic effects commonly seen in hypnosis. Here two sets of observations are helpful: 1. That "procedures for inducing hypnosis require the focusing of attention upon the experimenter's verbal stimuli with obliteration of irrelevant stimuli" (453). 2. That most if not all effects seen in the hypnotic trance can be evoked in adequately motivated subjects through appropriate suggestions in the waking state (51, 52). This holds true for motor tasks involving increased endurance (648), sensory phenomena such as anesthesia (53), autonomic effects, and more complex expressions of hypnotic behavior. It is therefore probable that the mechanisms underlying the shifting of attention in the physiological experiment are involved in the events elicited by the verbal suggestions of the experimenter under control conditions and in hypnosis.| This problem has been investigated by Hagbarth and Hernandez-Peon and their collaborators (424, 446, 448, 454, 456). Following the lead given by Adrian's observation (8) that the alpha potentials in the EEG which are blocked on opening the eyes reappear under certain conditions if the attention is concentrated on an acoustic event, they studied systematically the effect of attention on the transmission of afferent impulses to the brain. In unanesthetized cats with chronically implanted electrodes, photic potentials recorded from the visual cortex or the lateral geniculate body are reversibly diminished if the attention of the animal is shifted to an*See also the biochemical evidence of a differentiation between hypothalamus and reticular formation: on intravenous injection of LSD this drug is concentrated in the hypothalamus but not in the reticular formation (A51). fGuze (419) likewise assumes that emotional reactivity is increased in hypnosis while cortical control is lessened. tNote also the resemblance between the effects of hypnotically induced anesthesia and inattention to sensory stimuli.

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other significant sensory event — a sound or a smell. Photic potentials recorded from the optic tract disappear while the cat looks at a rat. The application of a noxious stimulus has a similar effect. Potentials appearing in the lateral column of the spinal cord in response to slight cutaneous shocks disappear during eating or sniffing which is elicited by an odor. Auditory potentials in the dorsal cochlear nucleus are reduced by visual, olfactory, or somatic stimuli. That attention is primarily involved is suggested by the loss of sensory response in habituation as the stimulus becomes meaningless through repetition and, conversely, by the reappearance of the response when the stimulus gains significance through conditioning. With such reappearance the sensory response becomes greater than in the control test (315, 455). Attention seems, therefore, to involve the blocking out of biologically insignificant afferent impulses while accentuating the effect of those impulses which lead to sensory events to which the animal responds. The blocking of impulses takes place in the synapses at various levels of the afferent systems. It is elicited also by stimulation of the reticular formation and sensori-motor cortex and is abolished by barbiturate anesthesia and lesions in the reticular formation (456). These findings seem valid for man: the photic response recorded in the visual cortex is intensified during maximal attention and diminished during habituation, attention to other sensory events, and mental activity (449). Moreover, barbiturate anesthesia, presumably by abolishing the inhibitory action of the reticular formation on afferent synapses, enhances the cortical response to afferent stimuli (423). This work and some related observations support the hypothesis that the sensory changes which may occur on hypnotic suggestion are based on the centrally induced inhibition and facilitation of afferent impulses presumably involving the reticular formation. Thus, tactile and nociceptive reflexes are lessened during suggested anesthesia and increased during suggested hyperesthesia, although there is no evidence for a change in the excitability of the motoneurons (453). Furthermore, verbal suggestions (without hypnosis) that the intensity of a light has been altered induce in sensitive subjects corresponding changes in evoked potentials of the visual cortex although the stimulus is kept constant.* Whether the reduction of autonomic reflexes (882) in the anesthetic state of the hypnotized subject is to be explained in a similar manner remains to be investigated. The significance of these investigations is increased by the observation (in one case) that hysterical anesthesia seems to involve the same mechanism (452). From the physiological point of view the chief characteristic of the * Unfortunately these results were not confirmed by Halliday & Mason (425). See also A49.

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hypnotic state seems to be the combination of an increased reactivity of the hypothalamic system, including increased hypothalamic-cortical discharges, with a lessened activity of the ascending reticular system of Magoun.* The focusing of attention consists (a) of the elimination of the irrelevant stimuli through the centrifugal action of the reticular formation on synapses of the afferent systems and (b) of the interaction with hypothalamic-cortical discharges of those afferent impulses to which the organism responds. This interaction is thought to underlie perception (336, 367, 368). That it takes place in hypnosis in a neocortex subjected to subnormal reticular discharges may account for the wide range of autonomic and somatic changes which are induced in hypnosis, and for the preponderance of emotional phenomena. VI. DISCUSSION AND CONCLUSIONS

The deviations from the common pattern of activation of the ergotropic and trophotropic systems discussed in this chapter may be divided into several groups. The first is characterized by an alteration or breakdown of the reciprocity principle. Even under certain strictly physiological conditions simultaneous ergotropic and trophotropic discharges do occur, as in states of heightened excitation, for example. They are also demonstrable in asphyxia, hypoglycemia, and other conditions involving gross changes in the internal environment, and also in convulsions. The physiological basis of this phenomenon lies in the fact that stimuli acting on central autonomic structures or on receptors of the somatic system evoke ergotropic and trophotropic reactions even with moderate intensities, but due to the principle of reciprocal inhibition the excitatory processes manifest themselves in only one system. With increasing intensity of excitation, however, both systems discharge, although the action of one system may be masked by the dominance of the other. Fever exemplifies the breakdown of the reciprocity principle, since both sympathetic and parasympathetic reactions are evoked. Sleep deprivation is another condition with simultaneous or nearly simultaneous ergotropic *It will be shown in Chapter III that conditioning is likewise associated with an increased reactivity of the hypothalamic system while that of the mesencephalic reticular formation is somewhat reduced. These findings support Pavlov's statement that suggestion is a typical conditional reflex in man (772) and are in agreement with experiments in which not only sensory stimuli (conditional stimuli) but also verbal commands were shown to elicit responses not subject to voluntary control (496). The gradual transition of a classical conditional reflex into a similar but verbally induced reaction leaves little room for a fundamental separation of the two processes. There is, however, good reason to assume that due to the prolonged application of monotonous stimuli under conditions of suggestive verbal stimulation (with or without hypnosis) the reduction in the rate of reticulo-cortical discharges is greater than in the typical conditional reflex. (For a discussion of the relation of conditional reflex to hypnosis see 862.)

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and trophotropic discharges. In both conditions the state of consciousness is greatly altered. It is suggested that the nearly simultaneous discharges of the two systems on the cerebral cortex contribute to the pathology of consciousness seen in fever and prolonged deprivation of sleep. The second group comprises ergotropic-trophotropic imbalances. The quantitative changes in the excitability of either the trophotropic or the ergotropic system do not interfere with the principle of reciprocity; nevertheless, they produce alterations in consciousness. Earlier work on the hypothalamus (338) showed that a state of heightened excitation of the trophotropic division leads to increased inhibition of the ergotropic division. At the same time parasympathetic reactivity is increased and sympathetic reactivity is lessened. This shift in reactivity may produce a reversal phenomenon in the state of parasympathetic "tuning," in that a stimulus acting on the sympathetic system in the control test evokes a parasympathetic effect in the state of heightened trophotropic responsiveness. Our discussion shows that a state of parasympathetic "tuning" exists in animals whose major sense organs have been eliminated and also in patients with narcolepsy. The shift in autonomic balance in the first case is due to the reduction of the central sympathetic tone to which the sensory receptors contribute, whereas in the latter a central autonomic imbalance and/or increased discharges from the baroreceptors are involved. The occurrence of sleep in response to noxious stimuli in the anosmic, blind, and deaf animal and the precipitation of a cataplectic attack as the result of emotional excitement in narcoleptics are interpreted as reversal phenomena. Apparently, the reversal affects not only the peripheral (autonomic) components of the ergotropic and trophotropic systems as shown in our earlier work (338, 346), but the central (corticopetal) actions as well. The parallelism between the intensity of central and peripheral discharges of the two systems stressed in Chapter I for various experimental conditions is still valid under conditions of trophotropic reversal.* The chief characteristics of the third group are listed in Table 1. States of increased cortical activity (desynchronization) may be associated with a loss instead of a rise in muscle tone. Thus, in the yoga trance cortical and sympathetic discharges are enhanced while the tone of the striated muscles is diminished. This is related to numerous physiological observations reported in the first chapter, in which it was shown that increased muscle tone and proprioceptive discharges, although reinforcing the central and peripheral activity of the ergotropic system, are not necessary for maintaining the parallelism between sympathetic discharge and cortical ^States of increased activity of the ergotropic system are not considered in this chapter, since in those states the state of consciousness is not altered. It should be mentioned, however, that in sympathotonia sympathetic downward and ergotropic upward discharges (the latter being indicated by an increase in the alpha frequency of the EEC, 36) are augmented.

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excitation. In the p.p. of sleep cortical excitation is associated with a strong preponderance of trophotropic discharges, since inhibition of muscle tone is combined with a fall in blood pressure, a slowing of the heart, and an increase in skin resistance. As Jouvet points out, the cortex in the p.p. is excited through the rhombencephalon via the hypothalamus and the limbic system. The facial movements intimately related to the emotions (351) and the emotional aspects of dreams which occur at this stage are likewise accounted for by hypothalamic-limbic activity. Table 1. Patterns of Ergotropic and Trophotropic Discharges Physiological or Clinical State Sleep

Cortex

Synchronization Wakefulness . Desynchronization Yoga trance . . Desynchronization Paradoxical sleep Desynchronization

Peripheral Discharges

Muscle Tone

Trophotropic excitation Ergotropic excitation Ergotropic excitation

Inhibited

Trophotropic excitation

Inhibited

Increased Inhibited

Patterns of Discharge Typical

Atypical

Alterations in cortico-diencephalic discharges seem to be involved in the cephalic state of sleep and in the excited but outwardly resting state of the yoga trance. In the former they are diminished and lead to a dominance of the trophotropic system; in the latter they are increased and cause an activation of the ergotropic system without participation of the striated muscles. As a working hypothesis the suggestion is made that a functional dissociation between the hypothalamic and the mesencephalic divisions of the diffuse excitatory ascending system takes place in hypnosis. Under the influence of monotonous stimuli, the activity of the reticular formation declines whereas that of the hypothalamus increases. The mechanism of focusing attention, which involves hypothalamic-cortical upward and reticular downward discharges, is discussed. It is believed that the changes which occur under the influence of suggestions with and without hypnosis involve this mechanism and that the particular setting of the nervous system in hypnosis, the dissociation between certain functions of hypothalamus and reticular formation, accounts for the quantitative and qualitative characteristics of the autonomic and somatic responses seen in this condition. The analysis of different states of consciousness presented in this chapter is admittedly incomplete; though it emphasized in the various syn-

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dromes those features which appeared to be characteristic of the particular state, it neglected others. Consequently, the classification that was adopted is somewhat arbitrary. Paradoxical sleep, for instance, was shown to be a state in which a dissociation exists between the increased upward and the decreased downward discharges of the ergotropic system. On the other hand, the fact that we are dealing with "deep" sleep, the waking threshold being higher than in light sleep, is proof that in addition to the ergotropic system the trophotropic system is also in a state of heightened activity. Thus, paradoxical sleep shares certain characteristics with the state of sleep deprivation. Moreover, it would not be difficult to show certain similarities between the functions of the ergotropic system in paradoxical sleep and in hypnosis, but here again the discussion stressed the important differentiating features — the essentiality of loss in muscle tone in the case of paradoxical sleep in contrast to its variability in states of hypnosis. Obviously, the states of consciousness analyzed in this work are interrelated and the final classification based on physiological principles requires further investigation. VII. APPENDIX. PROBLEMS OF HOMEOSTASIS

Since the trophotropic and ergotropic systems are tonically innervated and antagonistic in their action on autonomically innervated organs, striated muscles, and the cerebral cortex, they would seem to be eminently suited to serve homeostatic purposes. Nevertheless, states of increased activity of the ergotropic system are associated with increased inhibition of the trophotropic system and vice versa. Instead of preventing excessive excitation of one or the other system by calling into action the antagonistic system, the organism maintains the reciprocity principle under these conditions and biologically purposeful actions prevail (as in reciprocal spinal reflexes). The value of this arrangement was apparent when we compared these physiological states with the pathological conditions in which both systems were activated at the same time (see also Chapter IV). One could argue that the reciprocity principle contributes to an increase in the effectiveness of the sympathetico-adrenal system, whose homeostatic function has generally been recognized since Cannon's work (145), and that the enhanced sympathetico-adrenal discharges tend also to minimize cortical dysfunction in cold, anoxia, and hypoglycemia. These and important associated mechanisms consisting of the central effects of the neurohumors thus liberated and of the increased hypothalamic and reticular upward discharges serve homeostatic ends by preventing too low levels of cerebral excitability. On the other hand, it is highly probable that specific processes exist in the brain which limit cortical excitation. That the bulbar synchronizing mechanism exerts such a homeostatic action is apparent from the following experiments. If the reticular forma-

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tion is briefly stimulated twice at an interval of several seconds, the second stimulus is less effective in eliciting a galvanic reflex (sweat secretion) than the first, and this action is reflected also in the EEC, in which the desynchronizing action of these stimuli was found to decline on repetition, thus paralleling the autonomic reaction (80). Since repeated stimuli remain equally effective on the cortex if this experiment is performed after a prebulbar section of the brain stem, it is concluded that the reticular stimulation calls forth increased ascending discharges from the bulbar synchronizing system which dampen the responsiveness of the ergotropic system. Moreover, experiments of Bonvallet & Bloch (86) show that this synchronizing mechanism is brought into action whenever reticular stimulation is prolonged or increased progressively. Under these circumstances the desynchronization is replaced by cortical synchronous potentials during the period of stimulation. The records showing that the fast cortical potentials decrease in frequency before spindles and slow waves appear suggest that first the reticular formation is inhibited and only hereafter is the synchronizing system called into action. If, however, the test is repeated after a prebulbar section or the injection of novocaine into the bulb, procedures which eliminate the bulbar inhibitory mechanism, the desynchronization persists through prolonged periods of stimulation and increases with increasing intensities. Apparently the bulbar inhibitory system fulfills a homeostatic function under these conditions and prevents excessive arousal.* The homeostatic control of cortical excitation is not based solely on indirect bulbar-reticular mechanisms but depends also on the cerebral cortex itself, as the important work of Hugelin & Bonvallet (498, 499) has shown. These authors, using in the encephale isole the facilitation of a monosynaptic reflex induced by stimulation of the reticular formation as an indicator of cortico-mesencephalic relations, found that 1. in the anesthetized preparation or following decortication the wellknown facilitatory effect of reticular stimulation on the amplitude of the masseter reflex persists indefinitely, as was expected from the work of Rhines & Magoun (829); 2. in the unanesthetized preparation this facilitation is very brief and followed by a period of inhibition which reduces the amplitude of the reflex to the prestimulatory or even lower levels. Cooling of the cortex eliminates this inhibition reversibly, suggesting that cortical excitation gives rise to impulses inhibiting the reticular formation. Appropriate experiments have traced the inhibitory paths to the tegmentum. Further work showed that the intensity of the corticofugal inhibitory impulses is diminished when the cortical tone is lessened and that these *It would be of interest to determine whether the intensity and duration of convulsions are greater in animals with bulbar lesions or prebulbar transection than in control animals.

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regulations are independent of bulbar mechanisms. Apparently a negative feedback mechanism exists between the neocortex and the reticular formation: reticular excitation leads to cortical excitation which, in turn, induces corticofugal impulses that inhibit the reticular formation via extrapyramidal fibers. That the maintenance of cortical excitability is even more complicated is evident from the fact that numerous cortical sites give rise to facilitatory impulses impinging on the reticular formation (884) which obviously oppose this inhibitory system. This work, brilliantly conceived and executed by these French researchers, has clearly disclosed homeostatic controls whereby the excitation of the ergotropic system is effectively limited. Although this mechanism is capable of eliminating the effects of stimulation of the reticular formation within a few seconds, it raises the question whether the homeostatic control is evoked under strictly physiological conditions. The state of wakefulness is easily maintained in men and animals for many hours, and yet in the work of Bonvallet, Bloch, and Hugelin and of Dell (204) synchronization of cortical potentials occurs within seconds after the onset of reticular stimulation! This suggests that the electrical stimulation of the reticular formation produces abnormal degrees of excitation in spite of the relatively low voltage used in the tests. We assume, therefore, that the described homeostatic process is of greater pathophysiological than physiological significance. Since repeated stimulation of autonomic centers in the hypothalamus tends to increase considerably the intensity of ergotropic discharges (344, 348) and summation processes appear to play an important role in the causation of hypothalamic imbalance and psychosomatic diseases (see 370, Chapters 13-15), it is thought that these recently discovered inhibitory mechanisms may, at least to a moderate extent, counteract the development of certain pathological conditions.

Ill

The Role of the Ergotropic and- Trophotropic Systems in Conditioning

THE concept of the ergotropic and trophotropic systems was developed by W. R. Hess (463) on the basis of stimulation experiments involving the diencephalon. The distribution of these systems throughout the brain and their general characteristics were discussed in Chapter I, and an attempt was made in Chapter II to deal with their relation to various states of consciousness. In this chapter the role of the ergotropic and trophotropic systems in conditioning will be described. The basis for this undertaking lies in the symptomatic prominence of ergotropic emotional reactions in classical conditioning experiments in which either salivary or flexor reflexes serve as unconditional reflexes, and also in Pavlov's (771) emphasis on the intimate relation between internal inhibition and sleep. The recent neurophysiological work on conditioning — see the symposia on learning and related topics edited by Delafresnaye (199), Furness (310), and Jasper (527), and the reviews of John (530), Morrell (733), and Thomas (940) — represents a wealth of material for such a theoretical study. I. SOME CHARACTERISTICS OF THE CONDITIONAL RESPONSE By contrast with the inborn unconditional reflexes (u.r.) the conditional reflexes (c.r.) are acquired through repetitive combined presentation of a conditional stimulus (c.s.) with an unconditional stimulus (u.s.). Thus a sound will produce salivation after it has been presented an adequate number of times with a morsel of food. A nociceptive stimulus resulting in a flexor reflex may also be used in combination with a c.s. On this basis a light or sound may induce a flexor reflex. This principle has been applied to other forms of learning, commonly referred to as instrumental conditioning. In this work the animal carries out a certain action, i.e., learning a specific response (766). It is motivated by a strong drive: to get food or water or to avoid pain. By reinforcing a c.s. with the u.s. a stable conditioned response is established which may persist for months or years. In contrast to the positively reinforced c.s. a negative c.s. is one which has 71

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never been reinforced. Thus a sound of 500/sec reinforced by the u.s. elicits a c.r. whereas another sound (1,000/sec, for instance) which has never been reinforced, fails to do so. These important results have been obtained with a wide variety of c.r. in many species including man in numerous forms of classical and instrumental conditioning. Whereas Pavlov looked upon the conditioning process as a cortical phenomenon, subsequent studies (110, 937, 946, 958, and others) have clearly demonstrated conditioning in decorticate animals provided that the rhinencephalon is intact (861). However, monkeys with medial and basal frontal lesions require more trials to acquire conditional avoidance responses and show more rapid extinction of c.r. than animals with posterior lesions in the neocortex (796). Moreover, sensory differentiation between different odors and patterns of sound indicated in the normal animal by positive and negative c.r. is abolished by rhinencephalic-temporal lesions (16, 17) and destruction of the auditory cortex, respectively (387, A12). Similarly, Kliiver (582) showed that after the removal of the geniculatestriate system, positive c.r. in response to optical stimuli are retained but differentiation between positive and negative c.s. cannot be achieved any more.* Since cooling of the cortical visual areas temporarily abolishes conditional motor responses to optic stimuli while acoustic stimuli remain effective (850), it follows that cortex and subcortical structures contribute to the full range of conditioned activity. Before the integration of cortical and subcortical processes is discussed, a brief survey of some electrophysiological data related to the formation of the c.r. will be presented, f II. ELECTROENCEPHALOGRAPHIC CHANGES DURING CONDITIONING An animal reacts behaviorally and through its EEC in a characteristic manner when a sound (later to be used as a c.s.) is presented for the first time. It is aroused and orients itself toward the stimulus (orientation: "What is it?" reaction). At the same time desynchronization appears diffusely in cortical leads. If the stimulus is applied again and again, behavioral and EEG effects disappear.! This phenomenon of habituation (890) occurs in a similar manner in thalamus, hypothalamus, and the mesencephalic reticular formation. It is present after removal of the auditory cortex and most other parts of the neocortex, but it is abolished through lesions in the lower (pontine) brain stem (451). Since these procedures do not interfere with the reactivity of the specific auditory system ''Concerning the mechanisms which account for the impairment of c.r. after frontal lesions and, particularly, for the loss of inhibition (380) see 844. fThe role of the limbic cortex in conditioning is discussed on p. 89. JThe validity of these findings for man is indicated by the decreased responsiveness of the EEG in man to sensory stimulation under conditions of habituation (545, A13).

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and the responsiveness of the latter is retained during habituation, it may be said that habituation to sensory stimuli is chiefly due to a progressive change in the function of the ascending reticular activating system. Barbiturates as well as Chlorpromazine (451, 545) eliminate habituation. In cats the cortical state of excitation is reduced by Chlorpromazine before diencephalic or mesencephalic potentials are altered (357), and the threshold of arousal induced by electrical stimulation of the cortex is raised with doses that are ineffective on the brain stem (548). These cortical changes may play a significant role in habituation. Habituation has been studied mainly in acute experiments but similar phenomena are seen in chronic experiments in which stimuli (later to be used in conditioning) are applied for days until the animals cease to react to them. As Fig. 3-1 indicates, there is no response to the sensory stimulus either in the EEC or in behavior at the end of this "familiarization period," but if this stimulus is followed after a certain interval by a u.s. (shock), the animal becomes "highly agitated, cringes and cries out, and may attack the

Fig. 3-1. Diagrammatic illustration of the conditioning process. (From John. Discussion. In: The Central Nervous System and Behavior, New York, Macy, 1959, p. 335.)

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cage floor, which is going to hurt him subsequently, but he does not jump across the partition" (529) until the u.s. is applied. This overt conditional emotional response is gradually lessened as the animal learns the avoidance response, jumps across the partition, and escapes thereby the u.s. Morrell's experiments (730) neatly illustrate the reorganization of central patterns of activity wrought by conditioning. A steady light causing alpha blocking in the visual cortex or a light flickering at an appropriate frequency inducing "photic driving" of the potentials serves as u.s. while a steady sound preceding and overlapping the u.s. is chosen as c.s. The c.s. alone is repeatedly applied until it appears to be "ignored," as indicated by behavior and by lack of significant change in brain potentials. Then conditioning is carried out by reinforcing the c.s. each time with the u.s. Soon the steady sound becomes a meaningful symbol signifying an imminent light stimulus. If the c.s. is followed by a steady light during the training period, after sufficient reinforcement the c.s. alone is adequate to produce alpha blocking. Thus a "cross-modality" linkage is established so that an auditory stimulus leads to a "visual" response (Fig. 3-2). Even more striking is the finding that in animals in which a flickering light is the u.s., the same c.s. (steady sound) leads to rhythmic potentials of the visual cortex at the flicker frequency.

Fig. 3-2. Conditional blocking of alpha rhythm in a normal subject. A indicates the lack of cortical response to a tone stimulus of 1,024 c/sec (thin black line on signal channel) before conditioning. B is the response to bright light (thick black line on signal channel) before conditioning. C is the first paired trial, showing no response to the tone but prompt blocking when the light appears. D is the ninth trial and demonstrates the fully developed conditional alpha blocking. The alpha desynchronization in the EEC (lines 1 and 3) occurs in response to the tone, considerably before the light stimulus is presented. An EMG, recorded via surface electrodes from the right forearm (line 2), was used to measure visuomotor reaction time; there is an EKG artifact in that channel. (From Morrell. Some electrical events involved in the formation of temporary connections. In: Reticular Formation of the Brain, Boston, Little, Brown, 1958, p. 547.)

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Similarly, it was found that the sensori-motor cortex is the ultimate site of the conditioning effect when an acoustic c.s. is paired with an electrical shock to the foot as a u.s. (973). The validity of these findings for man is evident from the study of Gastaut et al. (326), in which conditioning with an optic stimulus as a u.s. leads to blocking of the alpha potentials in the occipital area, while contralateral rolandic blocking accompanies the c.r. which is based on a sensory c.s. in combination with passive or active movements of the hand (u.s.). The extensive experiments of John & Killam (531, 532) have added valuable information on the behavior of subcortical areas during various phases of conditioning. A flicker frequency of 10/sec serves as the c.s., and a shock (u.s.) applied in a double-grill box elicits an avoidance reaction. Before conditioning is begun the animal is exposed to the nonreinforced visual stimulus for a number of days. During this period of habituation the widespread cortical and subcortical responses involving the auditory and visual systems disappear gradually, but they reappear on the first day of training under the influences of reinforcement with the u.s. Then the phase of "contraction" follows as the c.r. develops progressively: as a 100 per cent conditioned response is achieved the "labeled" (flicker) response is present in the visual system, the amygdala, and the anterior ventral nucleus of the thalamus, but it disappears from the auditory cortex, the reticular formation, the septum, and the hippocampus (see also 619,1011).* Galambos & Sheatz (315) and Hearst et al. (439) find in cats and monkeys that after the period of habituation the reinforcement of the c.s. (click, flash) with a u.s. (shock, puff of air) increases the cortical and subcortical response. Moreover, this response is reduced when in a conditioned animal the c.s. is applied repeatedly without reinforcement, thereby paralleling the reduction or extinction of the c.r. (A14). It is of particular interest that the conditional response of the cortex to a click is retained after the specific afferent path has been eliminated through bilateral section of the brachium of the inferior colliculi. The experiments suggest that in the operated animals the conditioned auditory response is mediated by extralemniscal afferents whose relation to the reticular formation and the hypothalamus remains to be determined (see also 314). The adequacy of the operative procedure is apparent from the fact that the operated animals subjected to barbiturate anesthesia fail to respond to the click whereas before surgery they give a positive reaction.! Recording of single-unit discharges in cortical and subcortical areas dur°John & Killam (532) studied the appearance of the "labeled" response in various cerebral structures during differential conditioning and showed a relation between the intensity of this response and the correctness of the c.r. If the animal committed an error, the labeled response was diminished. The discussion of this remarkable finding is, unfortunately, beyond the scope of this book (A15). fBarbiturates eliminate functionally the multisynaptic conduction involving the reticular formation and hypothalamus (306, 334).

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ing the conditioning process in which a click serves as a c.s. and an intermittent light as a u.s. discloses that after habituation has made the c.s. ineffective, its combination with the intermittent light leads to increased discharges (731). Again an early phase with widespread responses in neocortex and limbic brain associated with discharges from units in the recticular formation precedes the final phase in which reticular formation and hippocampus fail to respond to the c.s., whereas the conditioned response appears in the visual cortex and the nucleus ventralis anterior of the thalamus. It should be added that d.c. potentials of the cerebral cortex are altered by conditioning. Acoustic stimulation previously reinforced by an electrical shock was found to have a greater effect on cortical d.c. potentials than unreinforced c.s. (153). For the theory of conditioning presented in this chapter it is important that the increase in the magnitude of the evoked potentials seen during conditioning is related to the emotional state and alertness of the experimental animal (381). III. CORTICO-CORTICAL CONDITIONING

Although in contrast to Pavlov we do not look upon conditioning as a cortical process, the study of the cortical process in various types of conditioning is of considerable interest. Rusinoff (855) showed that a sensory stimulus (light or sound) which causes no motor discharges elicits movements if at the same time the motor cortex is subjected to an anodal polarization. Apparently impulses do reach the motor cortex in this case and if it is made hyperexcitable by anodal polarization, their arrival may be revealed by an overt movement. Morrell (732) observed that even minutes after the polarization, a sensory stimulus which had previously been paired with the cortical polarization evokes a conditioned motor response whereas nonpaired stimuli are ineffective. Obviously, positive and negative c.r. are demonstrable in these cortico-cortical phenomena. Similar effects are obtained when an electrical shock applied to any site of the ipsilateral or contralateral cortex is used as a c.s. instead of a light or a sound. These conditioned stimuli evoke, during anodal polarization of the motor area, not only a motor response but also an increase in the rate of discharge in single neurons of the motor area. This discharge consists of two phases showing a short and long latent period respectively. Circumsection of the cortex, thus preventing impulses induced by the c.s. (shock) from reaching the motor cortex via transcortical paths, abolishes the long latency response, whereas subcortical undercutting eliminates the short latency response. Even in this simplified model of a cortico-cortical conditioned reaction subcortical impulses play an essential part in establishing the conditioned response.

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If stimulation of a cortical site in the parietal-occipital area (c.s.) is paired with that of the ipsilateral or contralateral motor cortex (u.s.), a c.r. is formed. A movement duplicating that resulting from application of the u.s. occurs in response to the c.s. Apparently no sensory excitation in the meninges is involved, since the extirpation of the Gasserian ganglion does not alter the results. It was also found that the c.s. continues to elicit a c.r. in the contralateral motor area after sectioning of the corpus callosum and the anterior and posterior commissures (222, 226). Further observations from Doty's laboratory illustrate the relative importance of intracortical and subcortical processes in conditioning. If stimulation of the parieto-occipital site serving as c.s. is paired with a shock to the foot until c.r. are established, the subsequent undercutting or sectioning of intracortical fibers has significantly different effects on the loss and reacquisition of the c.r. The loss in conditioning is greater and relearning takes place to a lesser degree after elimination of subcortical as compared with intracortical connections (858). The cortico-cortical conditioning experiments, although useless to the organism, are of great value for a physiological analysis of the conditioning process under relatively simple conditions. They clearly establish that the temporary connection between the processes induced by the c.s. and the u.s. is based on the state of heightened excitation of the "unconditioned" area. * Furthermore, they show that impulses via subcortical pathways are of greater importance than those involving cortico-cortical links. These investigations raise the question of the cause of this marked difference. Behavioral observations provide the clue: in cortico-cortical conditioning experiments motivational factors are absent —the animals continue to eat while the c.s. elicits rather violent movements. If stimulation of the tail is substituted for that of the motor cortex as u.s. and the shock is avoidable by pressing a lever, the threshold for the c.s. is lowered (222). Apparently, motivational factors enhance conditioning. This conclusion is confirmed by experiments in which stimulation of "widely distributed" cortical and subcortical sites serving as c.s. in an avoidance c.r. was effective at lower intensities than were required to elicit a movement from the motor cortex (224). This work seems to indicate that the linkage between the sites activated by the c.s. and the u.s. is brought about by the following factors listed in order of their increasing physiological significance: 1. intracortical conduction, 2. subcortical excitatory processes without involvement of motivational factors, and **The mechanism underlying these phenomena is similar in principle to that which accounts for the tendency of central excitatory processes to flow into stretched muscles: their spinal neurons are in a state of heightened excitability due to proprioceptive impulses (664).

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3. subcortical links reinforced by activation of motivational systems. It is suggested that the cortico-thalamic (233) and cortico-hypothalamic circuits (337, 743, 744) account for the processes listed under 2 and 3 respectively. IV. THE ROLE OF SUBCORTICAL STRUCTURES

Although it is realized that marked differences in experimental procedures, sites of recording, and parameters of stimulation make it hazardous to attempt to arrive at general electrophysiological characteristics of the conditioning processes, a few tentative conclusions may be drawn: 1. The changes in activity of cortical and subcortical structures which occur during conditioning in response to the c.s. consist of a reversible increase in the electrical potentials recorded in the afferent system activated by the c.s. (314, 315). 2. There is a fundamental shift in subcortical activity as the conditioned response develops. In the early phase desynchronization is widespread in cortex and subcortex and seems to be due to the activation of the reticular formation. As mastery is achieved the reticular formation becomes inactive and the cortical desynchronization is confined to the area activated by the u.s. Discharges are increased in the diffuse thalamic system (see also 326 and 1012), the lateral hypothalamus (315), and amygdala but diminished in hippocampus and septum (531). 3. Even in cortico-cortical conditioning the subcortical component is of greater importance for the "closure" of the c.r. than are cortico-cortical paths (A50). It is of paramount interest to determine the nature of this subcortical component, but before reviewing the role of the hypothalamic system in conditioning, some facts which distinguish it from the reticular formation should be mentioned. From our previous discussion it is apparent that on the basis of behavioral criteria we differentiate orientation, habituation, and conditioning. Orientation is due to the increased activity of the reticular formation and results in diffuse cortical desynchronization and appropriate movements of the animal toward the stimulus. Habituation, the loss of this reaction, is thought to be due to the progressive diminution in the activity of the reticular formation. This leads gradually to a lessened diffuse sensory response of the cortex, characterized by an increase in the latent period and a decrease in the duration of alpha blocking reaction. Habituation may in part be due also to a decline in cortico-reticular impulses. At this stage another (nonhabituated) stimulus evokes a typical orienting response behaviorally and electrographically. This is seen in the habituated animal before and after conditioning. After conditioning the new (nonhabituated) stimulus temporarily abolishes the c.r. (Pavlov's external inhibition). This phenomenon is stressed because it shows the antagonism between conditional and orientation responses. It suggests

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that the mesencephalic part of the reticular formation which controls the orientation reaction is inhibited during conditioning. One of the fundamental differences between the reticular formation involved in the orientation reflex, and the hypothalamic system, activated in motivational and emotional processes, lies in the fact that only the former is sensitive to habituation. Thus, experiments on aviators (81) have shown on the basis of autonomic indicators (excretion of adrenaline and noradrenaline) that emotional excitement (parachuting) does not lose in physiological effectiveness on repetition. This statement is thought to apply not only to autonomic downward discharges but also to those intracerebral processes which underlie the emotions, since the ergotropic system acts as a unit. In this respect it is of great interest to point out that c.r. remain stable in spite of many repetitions (provided that adequate time intervals are observed).* This stability is seen even in those forms of c.r. which require only a single reinforcement (66). These and other observations such as the emotional behavior of the experimental animal during conditioning, the persistence of fear during months of conditioning although no u.s. are used in this period (298), the gross disturbances seen in experimental neuroses which are often produced by slight temporal changes in the relation between c.s. and u.s., and the feeling of tension reported by the human subject in similar setups, suggest a fundamental role of the emotions in conditioning. The study of the hypothalamic system under these conditions substantiates this suggestion. V. INFLUENCE OF HYPOTHALAMIC AND RETICULAR LESIONS ON CONDITIONING

Cardo (150) showed on rats that mesencephalic reticular lesions do not interfere at all with defensive or alimentary c.r. which had been established preoperatively, but that such lesions prevent the acquisition of conditioned defensive reflexes and delay the acquisition of conditioned alimentary reflexes. The reduction in the orienting reaction (exploratory activity) through the lesion seems to be related to this effect. Amphetamine, which in the normal animal and also in rats with large hypothalamic lesions increases exploratory activity and enhances c.r. and u.r., fails to be effective in animals with reticular lesions. If such lesions are carried out by stages and sufficient time is allowed for recovery, large reticular lesions do not interfere with the acquisition or retention of various types of c.r. in cats (164, 225) and dogs (598). Studies by Thompson et al. (948) on rats show likewise that mesencephalic lesions involving extensive bilateral damage to the lateral tegmentum, the central grey, or the superior colliculus do not alter the retention of pre*If, on the contrary, nonreinforced c.s. are repeated in quick succession, extinction results.

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operatively acquired visual c.r. (see also 652). The work of Chow & Randall (164) also agrees, showing that extensive lesions in the reticular formation made in several stages in cats do not interfere with the learning and retention of avoidance c.r. or with conditioning involving visual discrimination tests. Furthermore, the injection of Chlorpromazine into the mesencephalic reticular formation leaves avoidance c.r. unchanged while spontaneous activity is reduced (83, A50). In an extensive study Sprague et al. (915) compared the effects of lesions in the lateral mesencephalon with those involving the medial part and extended his observations over months following the operations. They noted that cats with medial lesions recover after some weeks from their somnolence, are easily aroused, and show in general excessive emotional reactions. Such cats acquire c.r. slowly, but in cats in which the emotional disturbance is absent conditioning is easily accomplished. We do not know what factors determine the emotional state in animals with bilateral lesions confined to the reticular formation, but since, barring excessive emotional reactivity, various types of conditioning involving avoidance reaction and the defensive flexor reflex may reach the 100 per cent level in a few days, it seems to follow that the elimination of the mesencephalic reticular formation does not abolish conditioning. Cats with lateral lesions in the midbrain also have defects in conditioning, but for entirely different reasons. They show excessive exploratory activity —the reticular formation is intact! — and difficulty in directing attention to any sensory stimulus. Affective reactions to appropriate stimuli are lacking. This is illustrated in unilaterally operated animals by the observation that stroking elicits signs of pleasure only on the side ipsilateral to the lesion, but not on the side contralateral to it, and conditioned reactions are distributed in a similar manner. Apparently, the medial lemnisci contribute important impulses to the hypothalamic system. If they are sectioned, emotional reactions as well as c.r. are absent but c.r. can be developed by supplying additional sensory stimuli or by utilizing emotional factors (food) in directing the animal's attention to the c.s. These observations emphasize again the significance of the emotional processes and, therefore, of the hypothalamic system in conditioning. They suggest that appropriate lesions in the hypothalamus rather than in the reticular formation interfere with various types of c.r., a suggestion supported by the following data. Alimentary c.r. which are retained in rats with large mesencephalic lesions are abolished in animals in which the intermediate hypothalamus (at the level of the ventromedial nucleus) is destroyed bilaterally.* Retraining is without effect. Cardo (150) believes that neither the anorexia nor the hypoactivity which occur postoperatively is the cause of this failure, since the anorexia is only a temporary phe*For anatomical details of feeding and satiety areas see 726.

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nomenon and the hypoactivity may be eliminated by amphetamine but the c.r. are not restored. As far as the posterior hypothalamus is concerned, Doty et al. (225) noted that large lesions may abolish conditioned defensive reflexes in cats. Systematic studies on the role of the hypothalamus in avoidance conditioning of rats to photic stimuli (831, 947) showed that lesions in the anterior hypothalamus (medial or lateral) and in the medial part of the posterior hypothalamus are without effect* but that the posterolateral lesions lead to a loss of c.r. and, in most instances, to an inability to re-establish them. On the basis of further studies involving lesions in the limbic system, the pretectum, the thalamus, and also the nucleus ruber and the substantia nigra,f Thompson, Rich, & Langer (948) come to the conclusion that "the avoidance conditioned response is elicited and maintained by the convergence of two descending pathways, upon the hypothalamomesencephalic area, one involving a specific input related to changes in the external environment (sensory system) and the second involving a nonspecific input related to changes in the internal environment (motivational system)." | Moreover, bilateral lesions in the lateral hypothala are accompanied by a permanent or a temporary loss of avoidance c.r. in rabbits. The emotional reactivity is reduced at the same time, but the u.r. remains unchanged (46). Since reciprocal relations exist between the ventromedial hypothalamic nucleus and the ergotropic division of the hypothalamus, the activity of the latter is increased following ventromedial lesions. As expected, not only emotional reactivity but also the conditioning process is intensified (45, 960).§ Similar relations known to exist between the septum and the posterior hypothalamus account for the enhancement of conditioning in animals with septal lesions (955)4 * Lesions in the mammillary bodies are compatible with the retention of preoperatively learned avoidance reactions (184, 786, 945). In Cardo's work (150) the lesions comprised the mammillary bodies and the posteromedial hypothalamus, and the c.r. were retained. t Bilateral lesions in nucleus ruber and substantia nigra abolish visual c.r. $ Pavlygina's experiments (773) show that in states of heightened hypothalamic excitation induced by electrical polarization, sensory stimuli elicit cardiac and respiratory effects in habituated animals. Apparently the same processes are involved in guiding sensory impulses to the hypothalamus as were shown to be operative in cortico-cortical conditioning. § Important as emotional reactivity and hypothalamic responsiveness are for conditioning (see also 897), the significance of genetic factors should not be forgotten. Through selective breeding, strains of rats have been obtained which show marked differences in the speed of acquisition of an avoidance c.r. although their emotional reactivity is similar (105). IfThese results seem to be in disagreement with Cardo's work on rats in which anterior hypothalamic lesions impaired conditioning. Apparently the lesions resulted in extreme changes in excitability: the animals were too wild to be conditionable (see also 941). It is a common experience that marked increases (induced, for in-

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It is this interaction between sensory c.s. and hypothalamic discharges which seems to underlie the closure of the c.r. and which is believed to play an important role in perception and emotion (336). The heightened excitability of the posterior hypothalamus in insulin hypoglycemia and the increased hypothalamic-cortical discharges which accompany such a state (370) were thought to be responsible for the restitution of previously inhibited c.r. and also for the acceleration in the conditioning process when insulin was injected in partially conditioned rats (330, 371). Although increased hypothalamic discharges seem to be a conditio sine qua non for the establishment of c.r., the specific site within the hypothalamus varies. The feeding and satiety areas at the level of the ventromedial nucleus are involved in alimentary conditioning, but the posterolateral hypothalamus in avoidance reactions, in correspondence with the fact that the feeding is integrated in the former (20, 727) and the fight and flight reactions in the latter (see 370 for the literature). Reciprocal relations existing not only between the anterior and posterior hypothalamus but also between the ventromedial nucleus (closely associated with the control of satiety) and the posterolateral nuclei (988) account for the fact that conditions which intensify avoidance reactions inhibit alimentary c.r. and vice versa (636). VI. CONVULSIONS AND CONDITIONED REFLEXES Experiments involving a markedly different methodological approach confirm the assumption that not the reticular formation but structures rostral to it are essential to the conditioning process. In Zuckermann's study (1018) generalized convulsions resulting from cortical stimulation abolish c.r. (blink reflex) for many minutes whereas convulsions initiated by stimulation of the mesencephalic reticular formation even enhance c.r. in the postconvulsive period. On the other hand, brain stem reflexes (righting reflex) were absent for long periods following reticular convulsions. It is, however, not the elimination of cortical functions which accounts for the deleterious effect of the seizure on the c.r.: focal convulsions interfere with persistence of the c.r. in the postconvulsive period only if the stimulus is applied to the projection area of the c.s., whereas this effect is absent following focal paroxysmal discharges in the projection area of the u.s. The relation of these findings to Doty's (222) and Morrell's (732) experiments discussed earlier needs to be clarified. Although Zuckermann's work does not permit one to localize precisely the site of the stance, by injections of noradrenaline or amphetamine, 708) and decreases (produced, for example, by Chlorpromazine injection, 1016) in emotionality impair conditioning. Only within relatively narrow limits is it demonstrable that conditioning improves with the increasing reactivity of the ergotropic division of the hypothalamus (754, A16).

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closure of the c.r., it is compatible with our assumption that the hypothalamic system is involved. VII. HYPOTHALAMIC STIMULATION AND CONDITIONAL REFLEXES In order to gain some understanding of the role of the anterior and posterior divisions of the hypothalamus for conditioning it is necessary to resort to stimulation experiments which permit one to alter hypothalamic functions and balance gradually and reversibly. In conditioned monkeys in which a light served as c.s. and a shock to the forelimb as u.s., Sheer (891) demonstrated that presentation of the c.s. together with stimulation of the anterior hypothalamus (between optic chiasma and anterior commissure) or of the septum prevents conditioning. Even when, under these conditions, c.s. and u.s. are paired for hundreds of times, conditioning does not take place, whereas it occurs readily during stimulation of the posterior hypothalamus. Since stimulation of the posterior hypothalamus did not alter the rate of conditioning, although distinct autonomic and cortical changes occurred, its possible facilitatory action was tested in a delayed c.r. in which the response had just become negative. Under these circumstances the excitation of the sympathetic division of the hypothalamus restores the c.r. Similarly, it was observed in a bar-pressing alimentary conditioning experiment that posterior hypothalamic stimulation produces a higher response rate than is evoked by excitation of the anterior hypothalamus. Lissak and collaborators (253, 406, 637) have given numerous examples for facilitation and inhibition of c.r. Stimulation of the septal area and the anterior hypothalamus exerted an inhibitory action: it furthered extinction of alimentary c.r., whereas excitation of the posterior hypothalamus tended to restore the extinguished reflexes. Moreover, the effect of hypothalamic stimulation parallels the state of conditioning. When the defensive c.r. is well established, stimulation of the posterior hypothalamus elicits sympathetic and somatic discharges of a greatly increased magnitude, whereas with progressive extinction of the response the effectiveness of stimulation declines pari passu. Similar variations in autonomic reactions occurred on stimulation of the posterior hypothalamus in different states of excitability (338). The experiments support the interpretation that the establishment of a defensive c.r. involves a state of increased excitability of the posterior hypothalamus whereas this excitability declines as extinction progresses. The observations of Matsumoto et al. (692) that on stimulation of the parasympathetic and sympathetic hypothalamic zones c.r. are inhibited and accelerated respectively are in agreement with the work of the Hungarian workers. It should be added that stimulation of the same hypothalamic site reinforces avoidance as well as approach c.r. (113, A17).

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The intimate relation between hypothalamus and conditional state is further illustrated by the observation that in the conditioned animal the stimulation of a facilitating hypothalamic site by itself may induce a complete alimentary or defensive conditioned reaction.* This observation has been confirmed by Andersson & Wyrwicka (26) on goats in which the stimulation of the hypothalamic drinking area elicits the conditioned motor pattern as well as the act of drinking. Similarly, pressing a bar for food may result from stimulation of the hypothalamic feeding area (711). Such effects occur even in the satiated animal (406, 1004). They are not due to a general activation of the animal but are specifically related to the stimulated hypothalamic area: for example, only the food-getting reaction is elicited from the feeding area! Whereas the studies involving the defensive reflex illustrate the dependence of this conditional reaction on the balance between the anterior and posterior hypothalamus, those on stimulation of the hypothalamic feeding area in satiated animals show that its threshold increases with increasing satiation, indicating thereby that afferent inhibitory impulses, presumably from the gastrointestinal tract, modify the excitability of specific hypothalamic areas and, thereby, conditioned behavior. The close relation between hypothalamic feeding and satiety areas and conditional responses is further illustrated by the fact that after the stimulation of the satiety area which prevents eating the conditional alimentary reflex is intensified (1004). Apparently a rebound discharge from the feeding area follows the excitation of the satiety area and accounts for the appearance and intensification of the conditional feeding reflex. VIII. CONDITIONING, SELF-STIMULATION, AND SPREADING DEPRESSION

Space does not permit a discussion of the relation of the hypothalamus to motivation as disclosed by Olds' ingenious experiments on self-stimulation (763) and related data. Obviously motivational forces and conditioning are intimately interwoven. As Olds & Margules (765) point out, the hypothalamic feeding center is also a very effective self-stimulation area, and its increased reactivity in hunger leads to an enhancement of selfstimulation. Moreover, food intake as well as self-stimulation of the lateral hypothalamus is inhibited by stimulation of the ventromedial hypothalamus (satiety area), and both functions are released by lesions in this area *Stimulation of the mesencephalic reticular formation with subthreshold currents (no overt movements) likewise elicited conditional alimentary reflexes in previously conditioned animals (259, 959). Similar results were obtained with the conditional blink reflex (1018). It is suggested that reticular stimulation, although too weak to produce a strong orientation reaction which would inhibit the c.r., activates the hypothalamus indirectly (see 752 and 917 for anatomical and physiological evidence for reticulo-hypothalamic relations) and thereby elicit a c.r.

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(479). Since in the conditioned animal these hypothalamic areas control the food intake and the associated learned behavior, it seems to follow that motivation (measured by the rate of self-stimulation), hunger, and conditional alimentary reflexes are quantitatively determined by the excitability of the lateral and medial feeding and satiety areas of the hypothalamus. The pursuit of these studies by Olds (762) and by Bures and his collaborators (133, 983) has greatly increased our knowledge of the neurological basis of these phenomena. Olds established the lateral hypothalamus as an area of maximal selfstimulation and the dorsomedial tegmentum as one of minimal self-stimulation. In addition, he stimulated these areas in a setup which allowed the animal to eliminate this stimulation through bar-pressing. If this procedure is applied to the hypothalamus, the animals react minimally and receive, therefore, a maximum number of stimuli. On the contrary, the animals learn to escape from the stimulation through bar-pressing if the electrodes are placed in the tegmentum. In this experimental setup Olds, Bures, and their collaborators applied KC1 on the cerebral cortex to produce a depression of cortical functions which gradually spreads over the whole cortex (680), and utilized this effect for a further analysis of the role of cortex, hypothalamus, and reticular formation in c.r. of varying degrees of complexity and in self-stimulation tests. The experiments showed that the spreading depression (S.D.) which leads to a reversible loss of cortical potentials does not alter the limbic cortex but reduces the activity in midline thalamic nuclei and the hypothalamus (983). The specific afferent neurons are not affected. The behavioral changes are as follows: 1. There is a loss or marked reduction in c.r. during the spreading depression, the effect increasing with increasing complexity of the conditional reaction. 2. The orientation reaction is retained and habituation to repeated acoustic stimulf is preserved and even more marked during S.D. than in the control period. 3. The hypothalamic self-stimulation is abolished during S.D. 4. All effects are reversible. For an interpretation of these findings important data are available about the activity of single neurons in hypothalamus and in the mesencephalic and ponto-bulbar reticular formation. They show that the discharge rate of hypothalamic neurons markedly declines during S.D., whereas that of the units recorded in the reticular formation is increased (Fig. 3-3). The reader will remember that lesions in the posterior hypothalamus cause a loss in c.r. and that stimulation of this division accelerates conditioning. Moreover, emotionality measured by the reactivity of the auto-

Fig. 3-3. Influence of spreading depression on hypothalamic and reticular activity. Top. Decrease of unit activity in a hypothalamic unit during homolateral cortical spreading depression. Above: steady potential change of cortical spreading depression, negativity downwards; below: discharge frequency (impulses/min). Arrow indicates application of 1 per cent KCl on the homolateral neocortex. Bottom. Repeated short increase of activity of a tegmental reticular unit accompanying both the homolateral and the contralateral cortical slow potentials. The same description as in the top figure. First arrow: application of KCl to the right hemisphere; second arrow: application of KCl to the left hemisphere. (From Buresova, Bures, Fifkova, & Riidiger. The use of spreading cortical depression in analyzing the mechanisms of operant behavior. In: Central and Peripheral Mechanisms of Motor Functions, Prague, Cz. Acad. Sci., 1963, p. 152.)

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nomic nervous system — the increase in heart rate and palmar sweat secretion serving as indicators — parallels in man the rate of acquisition of c.r. (854). It therefore seems reasonable to link the abolishment of instrumental conditioning during S.D. to the decline in hypothalamic activity and to interpret the loss of self-stimulation on the same basis. It was stressed earlier that the orienting reflex and conditioning are reciprocally related and that the former involves activation of the reticular formation. In agreement with these data are the observations that during S.D. and accompanying the disappearance of previously established c.r. the orienting reaction is preserved and the firing rate of the reticular formation increased. Moreover, the augmented rate of neuronal firing in the reticular formation corresponds to the enhanced habituation to monotonous acoustic stimuli seen during S.D. (982). The idea that the antagonistic behavior of reticular and hypothalamic neurons in S.D. is due to an inhibition of the hypothalamus through the reticular formation (762) is disproved experimentally: S.D. still exerts this typical effect when hypothalamus and reticular formation are separated by transection of the brain stem (135, A18). IX. HYPOTHALAMIC-CORTICAL AND THALAMO-CORTICAL DISCHARGES IN CONDITIONING

These investigations raise the question as to the mechanism by which changes in hypothalamic reactivity influence conditioning and hypothalamic-cortical relations in general. Murphy & Gellhorn (744) have shown that a facilitatory influence is exerted from the neocortex on the hypothalamus and the latter, in turn, increases excitatory discharges on the whole cortex with increasing excitation of its sympathetic division (see also 353). This positive feedback circuit is interrupted when through application of KC1 a S.D. of the neocortex is induced. At the same time the reticular formation is released as it is when cortical excitability is reduced —for instance, on cooling of the cerebral mantle (498). On the other hand, it is assumed that a state of increased excitation of the ergotropic division of the hypothalamus develops as conditioning comes into being. The increased downward discharges manifest themselves in sympathetically innervated organs and also in increased motor activity (920), whereas enhanced upward discharges seem to account for cortical desynchronization and the heightened response of the specific afferent system to the c.s. Such an interpretation is experimentally well founded since an enhanced response of sensory projection areas to optic and acoustic stimuli is, indeed, demonstrable through simultaneous stimulation of the sympathetic division of the hypothalamus (367, 368).* This facilitation occurs even with very weak hypothalamic stimuli which do not alter the EEG *In contrast, most authors note that stimulation of the reticular formation causes a decrease of cortical potentials evoked by stimulation of sense organs (see 739 for the literature, and A58).

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per se and manifests itself not only in the specific projection area but also, as seen in the conditioned animal, in the association areas. Increased hypothalamic activity is of great influence on the motor system as well. It augments cortically and reflexly induced movements (743) and enhances pyramidal discharges (338). The striking movements seen in a conditioned avoidance test in a deafferentated leg, although the leg is not used purposively in the freely moving monkey (583), are believed to be based on this mechanism. The specific patterns of movements which are elicited in the conditioned animal on presentation of the c.s. may be transmitted from the hypothalamus to the region of the nucleus ruber and the substantia nigra as lesion experiments suggest (948). Since hypothalamic-cortical discharges pass at least in part through the reticular thalamic nuclei, their role remains to be evaluated. Gastaut et al. (326) assume that the confinement of the conditional reaction to the cortical area activated by the u.s. as the result of conditioning is due to the excitation of the thalamic reticular system which, in contrast to the mesencephalic reticular formation, causes a more localized cortical desynchronization (521). The important role of the medial thalamus for conditioning is evident from the abolishment of a frequency-specific conditioned cortical response after bilateral lesions in the centrum medianum (1011). Furthermore, it was found that animals which have completely recuperated from unilateral lesions of the reticular thalamic nuclei show, under the influence of S.D., that formation of c.r. as well as retention of previously established conditional reactions is unilaterally impaired (134). In view of the fact that the medial thalamus is an important relay station for the transmission of impulses from the reticular formation and hypothalamus to the cortex, and close functional relations exist between medial thalamus and lateral hypothalamus (653), these findings do not contradict our assumption that hypothalamic-cortical discharges are primarily involved in the conditioning process. The increased emotionality during conditioning, the effects of lesions and stimulation of the hypothalamus on c.r., the reciprocal relation existing between orienting reaction and c.r. reflected in reciprocal relations between potentials in reticular formation and hypothalamus under the influence of S.D., and the hypothalamically induced facilitation of evoked sensory cortical potentials are but a few of the arguments which favor the hypothesis that an increased hypothalamic activity is essential for the establishment of c.r. It is assumed that these enhanced hypothalamic impulses reach the cortex at least in part via the reticular thalamic nuclei, and that thalamo-cortical discharges altered by increased hypothalamic discharges play a dominant role in complex (instrumental) c.r. * Thompson et al. (948) found that the posterior nucleus of the thalamus participates in visual avoidance reactions.

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X. LIMBIC BRAIN AND CONDITIONING

Whereas, as previously stated, removal of the neocortex interferes only with the complex forms of conditioning (differentiation, etc.), the elimination of neocortex and paleocortex alters the character of c.r. profoundly. Dogs so operated react to the c.s. (sound) "with a general disorderly movement" which cannot be differentiated or extinguished (66). The extensive work of recent years dealing with stimulation and removal of various parts of the limbic cortex must be viewed in the light of the anatomical (752) and physiological (657, 658) work through which the affinity between hypothalamus and limbic cortex has been established. The finding (952) that hypothalamic stimulation causes a greater degree of desynchronization in the limbic than in the neocortex, whereas the inverse relation holds for the effects of reticular stimulation, is a further illustration of this fact. One would, therefore, expect the limbic cortex to be of greater importance for conditioning than the neocortex. Spreading depression induced by injection of KC1 into the hippocampus was found, indeed, to impair conditioning more than when spreading depression was initiated from the neocortex (131). This result agrees with the work of Kaada, Rasmussen, & Kveim (550) showing that hippocampal lesions impair maze-learning and retention, particularly when combined with lesions in the gyrus cinguli.* It should be added that during hippocampal seizures autonomic and somatic c.r. of varying degrees of complexity are abolished. Since the convulsive discharges do not invade the neocortex — the cortical response to the acoustic c.s. remains unchanged during the hippocampal seizure — the effect seems to be due to alterations in the limbic-hypothalamic relationship. It is of interest that if the convulsions do not involve the contralateral limbic cortex, the c.r. are retained (292). Apparently, massive convulsive discharges leading to a functional ablation of the hippocampus (656) are necessary to eliminate c.r. Unfortunately, discordant results have also been reported. They suggest that factors such as the difficulty of the learning process employed (573), the size and location of the lesion (572), and the species used account for quantitative and even qualitative differences (513) in the experimental results. Nevertheless, the finding that, as c.r. are established, frequency and amplitude of hippocampal potentials increase in response to the c.s. (407, 859) suggests that the hippocampus plays a significant role in conditioning (see 556, 637, 1014, A19). Since the reciprocal behavior of conditioning and orienting reaction was mentioned earlier it should be added that the orienting reaction becomes hyperactive in animals with hippocampal lesions (555). Ablation of the amygdala causes delay in the acquisition of c.r., whereas "See also 831 and 1006.

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extinction becomes more rapid (98, 489, 581). These studies suggest that the amygdala exerts a facilitatory effect on c.r., Sheer (891) finding, indeed, in the monkey an acceleration in the acquisition of defensive c.r. with stimulation of the amygdala. Moreover, the excretion of adrenal corticosteroids is lessened in animals with partial amygdalectomy in response to a conditional avoidance stimulus (686), but here again the reports are far from uniform (see 299 and 508).* There are many reasons for the discrepancies in the results concerning the role of the hippocampus and amygdala in conditioning. Sympathetic and parasympathetic actions are elicited from different parts of the amygdala (592, 593) via the hypothalamus (864). Thus, the hypothalamically induced attack response is facilitated or inhibited by simultaneous stimulation of different parts of the amygdala (242), and the activity of these areas is altered in turn from hypothalamus and brain stem.f In addition, they play a role in memory processes and may affect c.r. of varying degrees of complexity in a different manner (120). Obviously, the state of our knowledge concerning the influence of hippocampus and amygdala on c.r. is rather unsatisfactory. There is, however, one area of the limbic brain through which c.r. are modified in a consistent manner: it is the subcallosal cortex located just below the genu of the corpus callosum. On stimulation it produces inhibition of respiration and of cortically or reflexly induced movements (547). Lesions in this area do not interfere with an active avoidance reaction in which the animal avoids the shock (u.s.) after it has been paired with the c.s. (buzzer) a number of times, but they abolish the passive avoidance response through which the normal animal learns to refrain from entering the food compartment after it has been shocked twice in it while eating (693). These investigations were confirmed and extended by Kaada et al. (551) who showed also that similar effects are produced by lesions in the anterior hypothalamus. From Kaada's earlier work (546, 547) it is inferred that the inhibitory action of the subcallosal cortex is mediated by impulses reaching the ventromedial hypothalamic nuclei via the septum and the anterior hypothalamus. It is suggested that the inhibition of the sympathetic division of the hypothalamus through the ventromedial nuclei (988) and the reduction of hypothalamic-cortical discharges which accompanies a reduction in "Morrell et al. (734) showed that epileptic foci in the amygdala greatly impaired conditioning. The effect seems to be through the discharging lesion and may be mediated through action on the septum and the preoptic area which has been shown to delay conditioning (575). tSee also 580 for functional and 385 for anatomical relations between amygdala and hypothalamus and 727a for a brilliant discussion of limbic-hypothalamic interaction as the basis of motivated behavior. For further studies of the influence of the limbic system on c.r., see A20, A21.

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activity of the posterior hypothalamus (357) are the basis of the inhibitory behavior exhibited in the conditional passive avoidance reaction. If the passive avoidance reaction is caused by inhibition of the ergotropic system in the posterior hypothalamus, it seems not unreasonable to expect that limbic areas which facilitate sympathetic and somatic responses are involved in the execution of the active but not of the passive avoidance reaction. Such an area is located in the anterior part of the cingulate gyrus from which facilitation of cortically and reflexly induced movements, increased discharges of the gamma system, rise in blood pressure, and pupillary dilatation have been elicited (547). McCleary (693) showed, indeed, that after ablation of this area the active avoidance behavior is impaired but the passive avoidance response remains normal.* Lesions in the cingulate gyrus cause a delay or a deficiency in the acquisition of the active avoidance reactions, whereas this reaction is established faster in animals with subcallosal lesions than in unoperated controls (Fig. 3-4). It is of considerable interest that the different physiological bases of the active and passive avoidance reactions are reflected in the behavior of animals with lesions in the amygdala. Lesions involving mainly the lateral nucleus (from which the syndrome of flight is elicited on stimulation) show impairment of the active but not of the passive avoidance c.r., whereas the reverse effect appears when the medial parts of the amygdala are involved (965). The projection of the medial nucleus to the septum accounts for the fact that on stimulation similar trophotropic symptoms are evoked from both structures while the ergotropic system is inhibited. The elimination or weakening of these trophotropic mechanisms seems to cause an impairment of the passive avoidance c.r. regardless of whether the lesions involve the subcallosal gyrus, the anterior hypothalamus, or the medial sections of the amygdala (A22). XI. OBSERVATIONS ON HORMONAL SECRETION AND CONDITIONING

If conditioning involves primarily an activation of the hypothalamus it is likely, in view of the intimate relations existing between hypothalamus and pituitary, that certain secretions from the anterior pituitary will be increased during conditioning. Moreover, one would expect that feedback processes which lessen hypothalamically induced pituitary secretion when the hormone level in the blood is high would manifest themselves in characteristic alterations in conditioned behavior. "The tendency of animals with hippocampal lesions to perseveration may likewise lead to an impairment in passive avoidance reactions (514) while the acquisition of an active avoidance response is enhanced.

Fig. 3-4. Top. Midsagittal drawing of the cat brain, showing two areas on the mesial cortex from which Kaada (546) obtained, respectively, inhibitory and facilitatory motor effects. The shaded area is the corpus callosum. MF: mesial frontal cortex; S: septal area; MI: massa intermedia of the thalamus. Bottom. Trials to criterion (c.s., buzzer, evokes active avoidance response in 90 per cent of the trials) on the active avoidance test for normal controls and operated animals. The figure shows that animals with subcallosal lesions are at least as efficient in reaching the criterion as are the unoperated controls. Animals with cingulate lesions are deficient in acquiring the active avoidance reaction. (From McCleary. Response specificity in the behavioral effects of limbic system lesions in the cat. J. comp. physiol. Psychol. 54:605, 1961.)

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1. The Adrenal Cortex Numerous investigators * have shown that stimulation of the tuberomammillary area leads to an increase in the secretion of ACTH indicated by lymphopenia, eosinopenia, reduction in the ascorbic acid content of the adrenal gland, and an increase in adrenal weight and in the concentration of the adrenal cortical hormones in the blood. Similar effects produced by various forms of stress (trauma, emotional excitement, violent exercise, etc.) in the normal organism are absent in animals with lesions in the median eminence of the hypothalamus. Moreover, stimulation of the posterior hypothalamus and of the mesencephalic reticular formation increases the secretion of ACTH (254, 930), and lesions in the median eminence cause a diminution in the secretion of adrenocortical hormones (316). From these investigations it is inferred that direct stimulation of a well-defined area in the hypothalamus or its activation in various forms of stress leads to an increased release of ACTH from the anterior pituitary. On the other hand, feedback mechanisms regulate the release of ACTH through hypothalamus and pituitary. Thus, adrenalectomy increases the release of ACTH whereas administration of corticoids diminishes it. That the hypothalamus plays a role in the feedback is apparent from the fact that the injection of cortisone acetate into the caudal hypothalamus (but not into other neural structures) lowers the corticosteroid concentration in the blood (256) and that hypothalamic implantation of hydrocortisone crystals produces atrophy of the adrenal glands (196). These data raise the question of the role of the trophotropic system in conditioning and steroid secretion. Since, as was mentioned earlier, activation of this system prevents conditioning and facilitates extinction of c.r., one would expect that it would also lead to an inhibition of steroid secretion. Such effects have, indeed, been obtained on stimulation of the septum, the anterior hypothalamus, and the dorsal tegmentum at the level of the superior colliculi (254). It should be added that the limbic brain, whose influence on c.r. was discussed earlier, modifies the secretion of ACTH: stimulation of the anterior cingulate cortex (889) and of the amygdala enhances it, and stimulation of the hippocampus inhibits it (252, 685). The effect of these procedures on ACTH parallels, to a certain degree, that on conditioned avoidance reflexes (A23). It is therefore to be expected that at physiological levels the degree of adrenocortical secretion would reflect the state of excitation of the sympathetic division of the hypothalamus and, indirectly, that of the hypothalamic balance. With greater degrees of the secretion the negative feedback mechanism would go into action, thereby limiting the hypothalamic excitation. Finally, internal or external factors that cause an excessive *For the literature see 428, 707, and 932.

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excitation would result in pathological conditions which could no longer be prevented by these homeostatic controls. The first phase is illustrated by the study of the adrenal steroids during conditioning. Using the plasma 17-hydrocorticosteroid level as an indicator, Mason et al. (687, 688) found in the monkey that conditioned avoidance reactions of several types are associated with significant increases in the steroid secretion. The greater the emotional strain, i.e., the more frequently the animal has to press a lever to avoid the shock, the greater is the steroid secretion (686). Experiments on rats involving avoidance conditioning give similar results when eosinopenia is chosen as indicator of increased secretion of ACTH (391). If a monkey is conditioned to press a bar to obtain food in a setup in which nociceptive stimuli are not used, conditioning takes place but there is no change in the steroid secretion. That hypothalamic excitation and hypothalamic-cortical discharges occur under these conditions was discussed earlier. The experiment illustrates the well-known fact that higher degrees of excitation are necessary to produce neuronal plus hormonal discharges than neuronal alone.* Nevertheless, under appropriate conditions a c.s. may evoke a maximal ACTH secretion. These experiments show that the more extensive the emotions set up during conditioning the greater the hypothalamically controlled secretion of ACTH. In addition, they suggest that the secretion is a measure of this central excitability. Its relation to conditioning is apparent from the fact that in a group of animals the magnitude of the resting adrenocortical secretion and the ease with which conditioning could be established were found to run parallel (Fig. 3-5; 82). These relations are further illustrated by Endroczi & Lissak's work (253) on "goal directed motor activity" (gma). In this work unrestrained cats learned, in response to a c.s. (reinforced by a shock to the grid in the floor of the cage), to jump to a shelf from which they could reach a morsel of food. These tests were carried out at intervals of two minutes during which the frequency of the gma to the shelf was determined. To Lissak (639) this number signifies the "driving force." While not disagreeing with this interpretation, we believe that gma is the result of hypothalamic-somatic discharges which, under appropriate conditions, are reduced through the feedback action of the adrenal steroids. In agreement with our interpretation, posterior hypothalamic stimulation increases and anterior hypothalamic or septal stimulation decreases corticoid secretion and gma. Moreover, c.r. and gma reappear following stimulation of the posterior hypothalamus in animals in which the c.r. has been inhibited through lack of reinforcement (extinction). These observations show that the gma is This statement apparently holds true for sympathetic-adrenomedullary (345) as well as for hypothalamic-hypophyseal relations.

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directly related to the activity of the ergotropic and inversely to the activity of the trophotropic system. Apparently feedback processes do not take place to a significant degree under these circumstances. The second level is easy to demonstrate by experimental injection of ACTH. In man, this lessens palmar sweating (654), presumably through inhibition of diencephalic sympathetic centers. In cats and dogs (641), ACTH administration accelerates the extinction of alimentary and avoidance c.r. On the basis of these data it is suggested that the inhibitory influence of ACTH on conditioning is associated with its inhibitory action on central sympathetic centers.

Fig. 3-5. Correlation between avoidance conditioned reflex activity and adrenocortical secretion. White columns: adrenocortical secretion (mg/100 gm body weight/ hour); black columns: avoidance conditioned reflex activity. (From Bohus, Endroczi, & Lissak. Correlations between avoiding conditioned reflex activity and pituitaryadrenocortical function in the rat. Acta physiol. hung. 24:79, 1963.)

The study of cortical limbic functions in active and passive avoidance c.r. has led to the conclusion that active avoidance c.r. involve increased ergotropic activity whereas passive avoidance c.r. are accompanied by an inhibition of this activity. If, as we believe, these changes are prerequisites for the formation and the magnitude of the c.r., one must expect that inhibition of the ergotropic system at the hypothalamic level through ACTH-induced high corticosteroid levels in the blood would modify active and passive avoidance c.r. in opposite ways. This is, indeed, the case. The active avoidance c.r. is inhibited, as described above, but the passive avoidance c.r. is actually enhanced (617). The third level, at which, due to excessive excitation, the adrenocortical feedback mechanism fails to restore physiological conditions, is reached particularly under the influence of strong nociceptive stimuli which act too

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fast to be compensated for by hormonal action. It is illustrated by the common experience (see 219, for instance) that conditioning is impaired when the intensity of the u.s. is too strong. That under such circumstances the c.r. may be blocked for prolonged periods is evident from the work of Lissak, Endroczi, & Medgyesi (640). After having established a conditioned alimentary reflex in dogs, they twice applied simultaneously with the c.s. a nociceptive stimulus and determined the disturbance of the c.r. on subsequent days. It was found that the c.r. was inhibited for 1 to 15 days* and that the hydrocortisone level in the venous blood paralleled the duration of the inhibition (Table 2). A similar experiment was performed Table 2. Relation between the Duration of the Inhibition of Conditional Reflexes and the Secretion of Adrenal Corticosteroids Inhibition of c.r. in Days

No.

1 2 3 4 5 6 7 8 9 10 11

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

1 1 1 1 1 4 6 8 10 12 14

Hydrocortisone *

2.00 1.92 3.26 5.50 3.50 9.60 4.30 8.30 8.00 12.00 13.60

Corticosterone*

0.81 0.58 1.68 2.00 1.80 2.20 0.69 0.81 1.10 1.50 0.91

Ratio

2.3:1 3.3:1 1.8:1 2.7:1 1.9:1 4.3:1 6.2:1 10.0:1 8.0:1 8.0:1 14.9:1

Source: Lissak, Endroczi, & Medgyesi, 640. **In Mg/g adrenal/kg body weight/hr.

on rats. Here again the inhibition of the c.r. was reflected in a reaction involving the secretion of ACTH. Under the influence of a standard stress procedure the lowering of the ascorbic acid content of the adrenal cortex increased with increased duration of the inhibition of the c.r. (258). Both sets of experiments show that the individual differences in the inhibition of the c.r. are related to the amount of the corticosteroids liberated in certain stressful situations. They seem to indicate that the inhibition of c.r. depends on the intensity of hypothalamic excitation as reflected in the corticoid output. Since marked qualitative changes — absolute and relative increase in the secretion of hydrocortisone — occur at the same time, it is likely that this hormone, which is known to increase cerebral excitability (1001), to produce euphoria (707), and to prolong anxiety (780), contributes to the behavioral disturbances. It may therefore be said that at "low" levels the adrenocorticosteroids *The procedure used by these authors is that which is frequently used for the production of experimental neurosis (see Chapter IV).

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provide an indicator of the activity of the sympathetic division of the hypothalamus; at intermediate levels they contribute through intrahypothalamic action to homeostasis; at high levels this mechanism fails and the qualitative changes in the hormonal secretion may aggravate the central disturbance even further. Obviously, the state of the organism resulting from the injection of ACTH is fundamentally different from that seen when this hormone is liberated through intracerebral processes, although the concentration of the corticoids in the blood may be the same in both instances. Thus, central stimulation is associated with emotional excitation which seems to facilitate conditioning, whereas the injection of ACTH tends to inhibit conditioning and to facilitate extinction. The liberated ACTH is an indicator of the excitation of the ergotropic system, whereas the injected ACTH inhibits this system either directly or, as Lissak (639) suggests, via the hippocampus. Since this inhibition leads to a release of the trophotropic system involving anterior hypothalamus and septum, it is understandable that the injection of ACTH produces effects similar to those resulting from the stimulation of the parasympathetic division of the hypothalamus, although the level of the corticosteroids is increased on injection of ACTH and lowered on stimulation of the anterior hypothalamus.* 2. The Adrenal Medulla f In view of the many data supporting the assumption that hypothalamic sympathetic discharges are associated with the establishment of c.r., the role of adrenomedullary secretion must be considered. In Mason's experiments on monkeys in which conditioning was accompanied by increased secretion of ACTH, the concentration of nor adrenaline but not of adrenaline was significantly increased. Since the threshold of adrenomedullary secretion is higher than that of the sympathetic discharge which leads to the liberation of noradrenaline, it is understandable that adrenodemedullation frequently fails to influence conditioning and that optimal parameters for stimulation in avoidance learning must be chosen in order to show that the controls acquire the c.r. faster than the demedullated animals (618; see also 141). Striking differences appear between unoperated control groups and sympathectomized animals when very strong nociceptive stimuli are used as u.s.: the c.r. are acquired by the control animals very quickly and persist after cessation of reinforcement, whereas after sympathectomy the rate of avoidance learning is slower and extinction occurs when the c.s. are not reinforced (1002). Moreover, the emotional re"There is likewise a fundamental difference regarding the restitution of previously inhibited c.r. between central discharges leading to the liberation of adrenaline and the injection of this neurohumor (331). f See Chapter VII.

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actions are diminished in the operated animals. Under these conditions the liberation of noradrenaline and the adrenomedullary secretion contributes to the excitatory state of the hypothalamus (848, 916). However, the adrenal medulla and the increased sympathetic discharges are not indispensable for conditioning, since a perfect score in avoidance learning can be achieved by sympathectomized dogs. XII. SOME OBSERVATIONS ON DRUGS, NEUROHUMORS, AND CONDITIONING

Only a brief comment can be made on the action of some psychoactive drugs and their relation to conditioning. Our purpose is not to discuss the extensive literature but to determine to what degree if any the concept that the hypothalamus plays a decisive role in conditioning is supported by studies on drugs. Several authors have shown that doses of Chlorpromazine (CPZ) which do not alter the u.r. inhibit or abolish the c.r., particularly if conditioned avoidance reactions are chosen.* Similarly, the conditional flexor reflex is abolished by a dose of CPZ which has little effect on cortically induced flexion (857). Such "specific" effects were seen also in man when conditional vasoconstriction in the fingers was studied (996). Moreover, the extinction of previously established c.r. through lack of reinforcement is facilitated by this drug (7, 457). The changes in EEC in man and experimental animals in response to even large doses of CPZ are slight (569). In a quantitative study Martin & Eades (683) found that atropine (0.2 mg/kg), pentobarbital (4 mg/kg), and CPZ (10 mg/kg) raised the threshold of the mesencephalic reticular formation for producing a desynchronization of the EEG to the same degree. However, several authors (91, 357, 682, and others) obtained clear evidence of slowing of the EEG and reduced activation in response to sensory and reticular stimulation, particularly of its rostral parts. Moreover, Hiebel et al. (465) showed that the activation of the EEC by adrenaline was lessened or even reversed by CPZ. Whereas adrenaline produced desynchronization in the control animals, it elicited synchronization and slowing of the pulse after administration of CPZ. Since adrenaline and noradrenaline in addition to their direct central excitatory actions are known to inhibit the posterior hypothalamus and hypothalamic-cortical discharges via the carotid sinuses (87, 747), it is inferred that the action of the catecholamines is due to the balance between central activation of the diffuse excitatory ascending system and its reflex inhibition through the baroreceptors. If lesions are made at various levels of the brain stem, it is found that the *For the literature see the reviews by Domino (220), Herz (457), and Wikler (991).

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ability of adrenaline to activate the EEC and also to evoke excitatory potentials in the posterior hypothalamus (793) disappears when the brain stem is transected "at about the posterior border of the diencephalon'' (848). This suggests that the action of CPZ to block the excitatory action of adrenaline takes place at the hypothalamus and possibly other diencephalic structures. The following data support this conclusion. The viciousness in rats resulting from septal lesions and consequent release of the posterior hypothalamus is combated more successfully with CPZ than with Pentothal (869). Several authors stress the effectiveness of this drug in lessening aggressiveness, and Bovet (90) illustrates this fact by comparing the action of CPZ on grouped and isolated mice which had been injected with toxic doses of amphetamine. This drug is ten times as toxic to mice kept in groups as to isolated mice, but CPZ reduces the toxicity of amphetamine in grouped animals to normal levels, whereas the toxicity for isolated animals remains unchanged. The mutual excitation of amphetamine-excited rats kept in a small space accounts for the increased toxicity of this drug in grouped animals and for the effectiveness of CPZ to reduce it. Both sham rage and sympathetic reactions elicited in decorticate animals are greatly reduced with minimal doses of CPZ (195). Tokizane et al. (951) report that moderate doses of CPZ shift the ergotropic-trophotropic balance to the trophotropic side, as indicated by the lowering of the caudate-induced spindle threshold. Similar effects were obtained on stimulation of the diffuse thalamic system with low frequency: the drug caused an increase in the recruiting response (718, 722). Under the influence of CPZ the hypothalamic potentials show an increase in the amplitude of the integrated potentials at the low-frequency range which is characteristic for states of lessened excitability, and the ability of nociceptive stimuli to elicit a diffuse excitation of the cortex is diminished (357). Killam et al. (570), who emphasize the ineffectiveness of CPZ on the mesencephalic reticular formation, show that the drug raises the threshold of the diencephalic (thalamic) section of this system.* It seems to follow from these and numerous other investigations that an important site of action of CPZ is the posterior hypothalamus. Sympathetic downward and hypothalamic-cortical discharges as well as behavioral reactions (aggressiveness, sham rage) are lessened under conditions in which the mesencephalic reticular formation does not show significant changes. **See also Kreindler et al. (599), who found a marked increase in the convulsive threshold of the cortex after doses of CPZ which did not alter the convulsive seizure induced by reticular stimulation. Similarly, Gellhorn & Ballin (357) found that the slowing of cortical potentials after CPZ preceded that of hypothalamic potentials. The sensitivity to this drug decreases from cortex to reticular formation with the hypothalamus in an intermediate position.

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It was pointed out earlier that hypothalamic changes result from stimulation and lesions in the limbic brain. Such changes may likewise be involved in the action of CPZ, since it evokes convulsive potentials in amygdala, hippocampus, and related structures (795). These discharges do not spread to the neocortex, but they lead to functional changes in the relation between the visceral brain and the hypothalamus and thereby contribute to alterations in the function of the latter. The occurrence of seizures confined to amygdala and/or hippocampus in hypoglycemia (953) is probably of great importance for the development of increased reactivity of the sympathetic system in this condition. The thesis of this chapter, the significance of the hypothalamic balance for conditioning, is supported by the investigations on the action of CPZ in general and its effect on conditioning in particular. The drug causes a diminution or inhibition of the c.r., and these processes are associated with a decline in hypothalamic sympathetic reactivity and hypothalamic-cortical discharges while the excitability of the mesencephalic reticular formation and of lower parts of the brain stem and spinal cord is still unchanged. This gradient in reactivity is believed to be responsible also for the specific effect of the drug on the c.r., which occurs without a significant change in the u.r. It was mentioned earlier that an antagonism exists between alimentary and defensive c.r. This phenomenon likewise appears when the action of CPZ is studied on both types of c.r. In Ray's experiments (812) sounds of different pitch served as c.s. for the two c.r. and two levers, identical in construction, furnished food and prevented the administration of shock respectively. Here again it was found that CPZ rather selectively impaired the defensive but not the alimentary c.r. (see also 442). Similar results were obtained with small doses of reserpine (533, 986). This drug has a certain action on the central nervous system in common with CPZ: it does not depress the mesencephalic reticular formation (834), but leads to a diencephalic shift in the trophotropic-ergotropic balance in favor of the former system. This shift is indicated by the lowering of the recruiting threshold on thalamic stimulation (722) and by the inhibition of shivering (928). Like CPZ, reserpine induces convulsive discharges in the amygdala and related areas (570), and both drugs are very effective in reducing the rate of self-stimulation when injected into the hypothalamus (764). The autonomic downward discharges are likewise shifted in the trophotropic direction. In addition, reserpine but not CPZ lowers the noradrenaline content of the hypothalamus (485, 486; see also 174 on the action of reserpine on serotonin). Numerous studies on the influence of neurohumors on c.r. cannot yet be interpreted satisfactorily. Several authors (see 977a) have reported that 5-hydroxytryptophan (5-HTP), a precursor of serotonin, depresses various

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types of c.r. Since the cholinesterase concentration in the brain decreases on administration of 5-HTP and the inhibition of c.r. induced by 5-HTP can be reduced or prevented by atropine, the action of 5-HTP on c.r. might be attributed to an increase in the acetylcholine concentration in the brain. Further investigations disclosed antagonistic relations between 5HTP and noradrenaline: 5-HTP decreases not only the conditioning score but also the noradrenaline content of the brain, whereas dopa, the precursor of noradrenaline, exerts the opposite effect (695). Moreover, adrenaline enhances cortical conditioning* (blocking of alpha potentials, 480), whereas the inhibition of c.r. seen during cortical spreading depression is associated with a decline of hypothalamic potentials (see p. 86) and also with a decrease in the noradrenaline concentration of the hypothalamus (221, A24, A25). These data are of interest if it is remembered that the posterior hypothalamus in contrast to the anterior hypothalamus and the septum shows a high concentration of noradrenaline (976), whereas the concentration of cholinesterase identified by Koelle's histological method (589) is highest in the nuclei of the anterior hypothalamus (5) and in the septum (11), which are intimately related to the trophotropic system. It should be stressed, however, that the interpretation of these experiments is uncertain. As will be shown in Chapter IX, arousal as well as sleep involves cholinergic transmission. Nevertheless, that adrenergic transmission plays a role in emotional arousal has recently been supported experimentally (see p. 241). It remains to be seen whether or not this idea may be applicable to the problem of neurohumoral transmission in conditioning in which emotional arousal is of paramount importance. XIII. REINFORCED CONDITIONAL STIMULI AND THE ERGOTROPIC SYSTEM

From behavioral observations and numerous groups of experiments discussed in the preceding pages it is apparent that with the learning of a conditioned response the c.s. exerts effects as if the sympathetic division of the hypothalamus had been stimulated. In man and experimental animals the c.r. is accompanied by various sympathetic discharges, such as the psychogalvanic reflex, increase in heart rate, cutaneous vasoconstriction, and pupillary dilatation. Russian investigators (see 782) showed that these sympathetic and associated respiratory discharges occur earlier than the somatic (defensive) c.r. in response to the c.s. This holds particularly for avoidance c.r. (912). Even in cortico-cortical c.r. — the stimulation of *There are, however, reports in the literature which are difficult to reconcile with these findings. Ricci & Zamparo (830) report that c.r. and associated cortical desynchronization in response to the c.s. are lost by atropine and restored by eserine (see also 132 and 859).

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sites in the visual and motor cortex serving as c.s. and u.s. respectively — the motor response is accompanied by increased sympathetic activity. It has been shown in Chapter I that the sympathetic or, as we prefer to call it, the ergotropic syndrome is characterized by sympathetic and somatic discharges and also by cortical excitation. That the latter occurs with conditioning, particularly in the projection area of the u.s., has been discussed. The analysis of the somatic discharge resulting from stimulation of the ergotropic system at various central levels or from reflexes has shown that alpha motoneurons are facilitated by discharges via the gamma system which are easily distinguished from those involving the alpha neurons by the lesser amplitude of the gamma potentials (recorded from the proximal end of the sectioned anterior lumbar roots). It is therefore of considerable interest to determine whether the gamma system is activated during the conditioning. In curarized cats the gamma system discharges remain constant on exposure to the c.s. (sound) after repeated nonreinforced presentations (habituation), but after a few pairings with a u.s. (shock) the rate of discharge is accelerated, an effect which does not take place when a different nonreinforced sound is used. This conditioning effect is readily abolished by lack of reinforcement (extinction). All effects are reversible and occur before any overt signs of motor conditioning appear (122). The extension of this work to chronic animals permitted a further evaluation of alpha and gamma activation in conditioning. After a defensive c.r. had been established a final test was carried out with recording of alpha and gamma activity from the ventral lumbar roots. It disclosed a greater sensitivity of the gamma than of the alpha system. The gamma discharge preceded that of the alpha fibers during conditioning, and after a c.r. had been established it showed a shorter latency. During extinction the latent periods increased but the gamma discharges persisted for some time after the c.r. had been abolished (Fig. 3-6). The c.r. develops, therefore, on a "background of proprioceptive activity, mediated by the gamma-efferent system" (121). The short latent periods point to the subcortical origin of the gamma discharges (in agreement with our assumption about the role of the hypothalamus in conditioning), whereas the long latency of the alpha system suggests that the motor impulses of the c.r. originate in the cerebral cortex. As pointed out in Chapter I, the significance of the gamma discharge for the conditioning process is not limited to its facilitating influence on spinal neurons through which the conditional movement is mediated. The increased proprioceptive discharge heightens hypothalamic activity and hypothalamic-cortical discharges which, in turn, further increase the activity of alpha and gamma neurons and thereby enhance conditioning. This interpretation, particularly regarding the significance of gamma activity

Fig. 3-6. Extinction and re-establishment of alpha-fiber conditioned response. At the beginning of the extinction trials ( A ) , the c.s. elicits acceleration of the tonically discharging gamma unit and initiates high-amplitude alpha discharge. Onset of c.s. is indicated by artifact on the trace and duration of c.s. by bar at bottom of figure. After repeated unreinforced presentations of the c.s., alpha discharge was abolished, leaving only the gamma-fiber acceleration (B). When the first u.s. reinforcement was given ( C ) , alpha potentials appeared during the 0.5-sec. shock period, but not during the c.s. period preceding the shock. On the next trial, a feeble alpha-fiber discharge occurred during the c.s. period preceding the second reinforcement ( D ) . After 5 reinforcements the alpha-fiber response to the c.s. alone ( E ) had been re-established. (From Buchwald, Beatty, & Eldred. Conditioned responses of gamma and alpha motoneurons in the cat trained to conditioned avoidance. Exp. Neurol. 4:91, Academic Press, New York, 1961.)

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for conditioning, is supported by further studies on the role of proprioception in c.r. (124, 125). In cats the importance of proprioceptive impulses is so great that deafferentation (but not cutaneous anesthesia) prevents the development of c.r. in the denervated limb. Similarly, attempts to develop c.r. in a curarized limb are unsuccessful although c.r. may develop in the cortex of the brain and in the pupil at the same time (A26-A28). The occurrence of sympathetic discharges, cortical desynchronization, and activation of the gamma system in response to the c.s. indicates that this stimulus activates the ergotropic system, probably via the sympathetic division of the hypothalamus. If, as Pavlov has shown, nonreinforced c.s. inhibit c.r., one would expect that the mechanism underlying the Pavlovian internal inhibition would be associated with the release of a reciprocal innervation pattern mediated by the trophotropic system which, at the hypothalamic level, is represented by the anterior hypothalamus. Its activation leads to the appearance of slow waves in the EEC, parasympathetic discharges, and an inhibition of the gamma system. XIV. INTERNAL INHIBITION AND THE TROPHOTROPIC SYSTEM Systematic studies by numerous authors (see 447, 530, 733, 849, and 985 for the literature) have shown that internal inhibition is associated with a period of synchronization in the EEC. Thus, if a delayed c.r. was formed in man in which a light (u.s.), causing the blocking of the alpha potentials in the EEC, was paired with a sound (c.s.), a period of alpha potentials appeared in the EEG in the interval between the onset of the c.s. and the u.s. (515). Other forms of internal inhibition (for example, extinction and loss of differentiation through lack of reinforcement) not only resulted in the disappearance of the c.r. (blocking) but also induced a period of synchronization (326) which, like the excitatory phenomena characterizing the establishment of the c.r,, is chiefly localized in the projection area of the unconditioned analyzer. In animal experiments it was found that by increasing the interval between the c.s. and the u.s. (delayed c.r.) the duration of the period of synchronization is increased (386). Similar phenomena were seen when conditional "trace" reflexes were established (1010). It may therefore be said that cortical synchronization is associated with various forms of internal inhibition in c.r. of widely different types (alimentary, defensive, and instrumental). If we take into consideration that in Pavlovian internal inhibition a tendency to sleep occurs, it may be said that this state is associated with an activation of the trophotropic system (A29). * This interpretation is sup°That parasympathetic discharges take place under these conditions is not improbable because (1) the heart rate rises distinctly in response to the positive but only minimally or not at all to the negative c.s.; (2) in the monkey in which the positive c.s. elicits bar-pressing and tachycardia a reduction in the time of exposure

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ported by the fact that like other phenomena depending on the trophotropic system the cortical effects of internal inhibition are intensified when the activity of the ergotropic system is lessened: in delayed c.r. the period of synchronization increased when the animals had been deprived of sleep. Lessening of the intensity of the u.s. which activates the ergotropic system had a similar effect. The observation that arousal is associated with a negative shift in the slow cortical d.c. response, whereas a positive shift accompanies the onset of sleep (152), makes it desirable to use these potentials as additional indicators of the state of the ergotropic-trophotropic balance in conditioning. Although this area of research is still in its infancy, the pioneering work of Rowland and his collaborators (851, 853) has established the following facts: 1. After habituation c.s. evoke during the formation of c.r. a period of desynchronization which is associated with a progressively increasing negative d.c. shift. 2. Nonreinforced c.s. causing extinction elicit a period of synchronization which may be associated with positive d.c. potentials in experiments in which the c.r. was based on a u.s. involving nociception. In further studies on cats trained to perform alimentary c.r., flashes or clicks were used as c.s. Only one of the c.s. was reinforced, but the response to each type of c.s. was determined. Then the reinforcement was shifted from one modality to the other. In this experiment of "reciprocal reversal" it was shown that the cortical response to the reinforced c.s. consisted of a slow potential shift and desynchronization, whereas following lack of reinforcement first the slow potential and then the desynchronization disappeared. They were replaced by a period of synchronization. However, no reversal in the slow cortical d.c. potential occurred (Fig. 3-7).° It was mentioned that reduction in the intensity of the u.s. creates conditions which are favorable for the demonstration of synchronous cortical discharges in delayed c.r. A reduction in the hunger drive produces similar effects on conditioned alimentary reflexes. When, due to repeated presentation of the c.s., reinforced each time by a morsel of food, the animal became satiated, the EEC changes consisted of a diminution followed by a disappearance or reversal of the d.c. shift in response to the c.s. With further satiation the period of desynchronization was replaced by highvoltage slow activity (synchronization) (Fig. 3-8; 853). to this stimulus induces a slowing of the heart rate while the bar-pressing is abolished (714a). "Pickenhain (782) reports Russian extinction experiments in which repeated nonreinforced application of the c.s. was followed by a slowing of the heart rate, whereas before extinction this c.s. had elicited a pulse acceleration.

Fig. 3-7. A. Selected trials from a consecutive series in a single session showing loss of conditioned baseline shift with satiety in cat cortex (1-13) and subsequent development of stimulus-bound high-voltage slow activity (15, 16). Recording from ectosylvian cortex referred to frontal bone with chronically implanted nonpolarizing electrodes. Signal line indicates conditioned stimulus lasting 10 seconds and consisting of 2/sec. interruptions of ambient light. Unconditioned stimulus: 20 g. milk-fish food homogenate delivered at termination of c.s. Trials 1-9 showed shifts varying little from those of selected trials 3 and 9. On trial 12 cat refused half and, on trial 13, all of its feeding. B (on facing page). Samples selected over weeks during two discrimination reversals, recorded as for A. Upper tracing characteristic of the shift acquired to the intermittent light (c.s.) as a result of reinforcement with food ( R ) . Middle tracing taken during extinction (E) of light and when the reinforced signal was auditory. Lower tracing shows restoration of shift with second reversal restoring reinforcement of light. Redrawn by Dr. Rowland from experiments of Rowland and Goldstone. (From Rowland & Goldstone. Appetitively conditioned and drive-related bioelectric baseline shift in cat cortex. EEC clin. Neurophysiol. 15:474, Elsevier, Amsterdam, 1963.)

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It is probable that certain drives such as hunger and thirst are associated with increased discharges of the ergotropic system, since the organism is in a state of heightened arousal. Animals deprived of water show a low amplitude of cortical potentials, whereas high-voltage synchronous discharges characterize the satiated rat (925).* Hunger results from stimulation of the lateral hypothalamus, which is part of the ergotropic system, and satiation follows excitation of the hypothalamus close to the ventromedial nucleus which inhibits rage. It may therefore be said that a shift in the trophotropic-ergotropic balance to the trophotropic side results from satiation as well as from lack of reinforcement and enhances the trophotropic response (synchronization) to a c.s. (see also 1003). Behaviorally also these two states are closely related. The tendency to fall asleep in the state of satiety is well known, and that sleep follows repetitive nonreinforced c.s. was stressed by Pavlov. This sleep is preceded in the rabbit by various phases in the EEC similar to those seen when the animal falls °See also Chapter X.

Fig. 3-8. Baseline shifts, conditioning and satiety. Baseline shifts from occipital bone placement in chronically implanted cat referred to a left visual cortex lead shown by other recording combinations to be unreactive. Shifts appeared during the successive presentation of 30 g. milk-fish food homogenate feedings to, and immediately after, satiation. Feeding pattern shown by horizontal line. On sixth tracing continuous rapid feeding begins to break up into smaller segments. On seventh, food is left behind and a diphasic shift appears. On the last two tracings the dashed horizontal line is an arbitrary baseline; the cat attended the feeder but took no food, and shifts are now in positive direction. Vertical line shows time of feeding. (From Rowland. Personal communication.)

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asleep naturally. At the same time the muscle tone is diminished so that the animals cannot stand unassisted (393), a phenomenon which seems to be due to the loss of activity in the gamma system referred to above. This interpretation is supported by experiments in which the rat whose lateral hypothalamus was stimulated could stop the current (and the aversive reaction) by bar-pressing. Experiments involving variations in frequency and pulse duration of the stimulus showed that with increasing stimulation (expressed in microcoulombs) the latency of the bar-pressing reaction decreased and the amplitude of the d.c. shifts increased (852). Obviously, the magnitude of the d.c. shift is determined in these experiments by the magnitude of the hypothalamic excitation. The finding that the negative shift in d.c. potential is associated with a pressor phase* and the restoration of the d.c. baseline with a depressor phase (rebound) agrees with our explanation that a reversible shift in the ergotropic activity underlies these changes in the slow cortical potentials. In view of the importance of subcortical structures for the sleep-wakefulness cycle and for conditioning, it is of interest that the discussed shifts in d.c. potentials occur also in the hypothalamus. The slow-wave phase of sleep is associated with a shift to the positive side, whereas on alerting these potentials become negative (559). The chief data on which this discussion is based are summarized in Table 3. Table 3. Ergotropic and Trophotropic Action and Conditioning A. Comparison of Ergotropic and Trophotropic Action with That Produced by c.s. Stimulation of the trophotropic system (for instance, of the anterior hypothalamus by raising its temperature) induces cortical synchronization, parasympathetic discharges, inhibition of the gamma system, and loss in muscle tone. These symptoms are likewise produced by c.s. under conditions of internal inhibition. Stimulation of the ergotropic system (for instance, of the posterolateral hypothalamus) produces cortical desynchronization and increased discharges of the sympathetic and gamma systems. These effects result likewise from the stimulation of reinforced c.s. B. Reciprocal Relations between the Ergotropic and Trophotropic Systems and Conditioning Reduction in the activity of the ergotropic system through lesions, drugs, etc. leads to the dominance of the trophotropic system indicated by behavior (somnolence), cortical synchronization, and increased reactivity of the parasympathetic system. Reduction in the intensity of the u.s. and/or reduction in the state of arousal through sleep deprivation enhances trophotropic reactions (synchronization) in delayed c.r. in response to the c.s. Lessened hunger drive likewise causes the appearance of trophotropic effects in response to c.s. in alimentary c.r. The behavioral and neurophysiological changes are thought to be due to a shift in the trophotropic-ergotropic balance to the trophotropic side. This is a release phenomenon, since the two systems are reciprocally related. "The negative d.c. shift precedes the pressor phase and is, therefore, not due to circulatory changes (852).

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XV. ERGOTROPIC-TROPHOTROPIC BALANCE AND CONDITIONING Several examples have been cited of the quantitative and qualitative alterations of the conditioning process as the result of changes in ergotropic-trophotropic balance. Thus, sleep deprivation, satiation, decrease in the intensity of the u.s., and progressive postponement in the application of the u.s. in delayed c.r. tend to shift the balance to the trophotropic side and to increase trophotropic symptoms in response to nonreinforced c.s. The study of habituation further illustrates the importance of the ergotropic-trophotropic balance for the action of sensory stimuli. Whereas a neutral nonreinforced stimulus at first evokes an orienting reaction and cortical desynchronization, it later (during habituation) produces a period of synchronization which is said to be due to a cortically induced inhibition, of the reticular formation (540). Here again the weakening of the ergotropic division manifests itself behaviorally in a tendency toward sleep and electrographically in the appearance of slow potentials of large amplitude in the EEC (see also 1011). On the other hand, if a c.s. which has been paired with a u.s. (mild shock) a few times is applied repeatedly without further reinforcement, habituation is greatly delayed. The arousal threshold remains constant for many stimuli until extinction at last takes place (93). This striking effect seems due to the shift in the trophotropic-ergotropic balance to the ergotropic side as the result of conditioning. It was shown in Chapter I that different states and, degrees of wakefulness are obtained when the brain stem is sectioned at various levels between the rostral border of the diencephalon and the spinal cord. Through these procedures states may be produced in which the trophotropic system is virtually unopposed by the ergotropic system and vice versa. Thus wakefulness is minimal in the cerveau isole (intracollicular section of the brain stem) and maximal in the midpontine preparation, whereas the normal cat occupies an intermediate position. In these preparations Meulders (703) found that the habituation times* are 30 minutes, 3 hours, and 24 hours for the cerveau isole, the normal cat, and the midpontine preparation respectively. It follows that the ergotropic-trophotropic balance profoundly influences conditioning as well as sensory habituation. The concept of "tuning" seems particularly applicable to the following experiments, which give a dramatic illustration of the "setting" of the central nervous system for its response to various types of stimuli closely related to the conditioning process. A novel, neutral stimulus does not produce any or produces only minimal changes in the EEC when presented in an environment in which the animal has previously been fed. However, *The time required until the response to the rhythmically applied sensory stimulus disappears.

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if applied in another environment, in which the animal has been subjected to painful stimulation, the stimulus elicits a marked desynchronizing effect on the EEC and even a jerking movement of the leg similar to that seen when a nociceptive stimulus was administered (29). In the "pain environment" the animal is, according to our interpretation, in a state of "sympathetic tuning." The ergotropic system discharges at a higher rate, as indicated by cortical desynchronization, whereas the trophotropic system is reciprocally inhibited. The neutral stimulus therefore acts chiefly on the ergotropic system. It was shown in Chapter I that from the hypothalamus and the "unspecific" thalamic nuclei ergotropic and trophotropic effects may be produced by different intensities and frequencies of stimulation. This suggests that even at a given frequency of stimulation both systems are activated, although the overt response is confined to the system which shows the greater reactivity in the normal organism. If this is the case, the effect of stimulation should be a function of the state of the ergotropic-trophotropic balance. It is suggested that this mechanism accounts for the following fascinating observation of Lissak (639) and Kopa et al. (596). Cats were conditioned to escape a shock applied to the grid in the floor by jumping onto a ledge. With a conditioned animal, if the centrum medianum was stimulated in the grid situation, the cat jumped onto the ledge. Stimulation in the ledge situation, however, induced relaxation and even sleep! Obviously, the animals were in different states of ergotropic-trophotropic balance in the two experimental situations. In the grid situation a state of ergotropic "tuning" prevailed and the animals responded behaviorally and in the EEC as if the posterior hypothalamus had been stimulated. In the ledge situation the animals were quiet (trophotropic "tuning") and sensitive to the trophotropic component of the stimulus. Consequently, they relaxed or fell asleep (Fig. 3-9; see also 28). XVI. CONCLUDING REMARKS AND SUMMARY

Repeated pairings of unrelated cortical stimuli lead to cortico-cortical conditioning particularly if the second stimulus causes a focal increase in excitability. The "attraction" of the excitation induced by the c.s. to the area involved in the u.s. is based on this phenomenon. It is present at all levels of the central nervous system, even in the isolated spinal cord (827). Some forms of conditioning, such as the cortico-cortical reflexes, are without any biological significance, as Doty (223) points out, and others are even paradoxical as illustrated in the experiments of Clemente et al. (168) and Kawamura & Sawyer (558), who use a sound as a c.s. and the stimulation of the basal forebrain as a u.s. with the result that the sound produces the behavioral and EEC changes of sleep instead of arousing the animal.

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Fig. 3-9. Cinematographic recording (24 shots/sec) of the dual behavioral effect produced by stimulating the region of the centrum medianum (3 v., 100/sec). A: stimulation on the grid floor of the cage (where the animal received shocks during the establishment of the conditional reflex) elicits the characteristic avoidance response; B: stimulation on the bench (where the animal never received shocks) elicits a relaxing effect. Numbers along the top denote the order of the picture selected and copied graphically from the film. Numbers below the pictures show the actual time in sec. after the application of stimulation. Note the different time courses of the two effects. (From Kopa, Szabo, & Grastyan. A dual behavioural effect from stimulating the same thalamic point with identical stimulus parameters in different conditional reflex situations. Acta physiol. hung. 21:207, 1962.)

These experiments show that c.r. can be built on the basis of a centrally evoked trophotropic syndrome (A30, A31). However, the bulk of the work on conditioning since Pavlov has been carried out under highly motivated circumstances. This is done by using food (or water) in the hungry (or thirsty) animal or painful stimuli as u.s. They act on the ergotropic division of the hypothalamic system, as indicated by the fact that nociceptive stimuli, for instance, fail to activate the cerebral cortex after lesions in the posterior hypothalamus. If the hypothalamus is highly excited, it "attracts" the sensory impulses induced by the c.s. An interaction of hypothalamic and sensory discharges takes place, which increases the cortical sensory response and also enhances discharges from the motor cortex and the extrapyramidal neurons in the diencephalon and mesencephalon. The sensory facilitation is related in some fashion to the symbolic significance the c.s. acquires in conditioning, whereas the facilitation of the motor system leads to an augmented activity of alpha and gamma motoneurons which underlies the conditioned motor response. It is noteworthy that nociceptive stimuli produce such a degree of excitation that conditioning results even when c.s. and u.s. are presented at random intervals (140). The state of emotional excitement and its significance for the condition-

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ing process are reflected in the fact that hypothalamic stimulation per se may evoke the previously learned c.r. Furthermore, the total environment becomes part of the c.s. The placing of the animal in a stock in which it had been injected with morphine on other days suffices to elicit salivation, retching, and vomiting (578), and similar observations involving a learned avoidance reaction have been made by Miller (711, A32). These phenomena seem to be adequate to eliminate the "temporal paradox" of conditioning (223). It has been argued that post-tetanic potentiation, which may last for minutes, could account for the facilitatory phenomena accompanying conditioning, except for the fact that an opposite temporal sequence is involved in the two experimental sets: tetanic stimulation of a neuronal system A, which shares with a neuronal system B a group of interneurons, leads to an increased responsiveness of the B neurons; but in conditioning it is "the response of the antecedent stimulus, the c.s., which is altered, and the u.s., which bears the temporal relation of 'B' in the foregoing paradigm, remains unchanged" (223). However, this problem is eliminated if we consider the fact that the experimental situation (in an avoidance c.r., for instance) causes a central ergotropic excitation as if the nociceptive (u.s.) had been applied, arid it is under these circumstances that the c.s. elicits the learned reaction (A33). The discussion of the relation between the ergotropic-trophotropic balance in general and the hypothalamic balance in particular for the conditioning process forms the core of this chapter and cannot be repeated here. Suffice it to say that with the acquisition of c.r. the c.s. exerts ergotropic effects which are replaced by trophotropic effects as conditioning is abolished by extinction and other forms of internal inhibition. Experiments involving stimulation and lesions of the hypothalamus, the influence of spreading depression, neurohumors, and psychoactive drugs are compatible with the concept that conditioning is accelerated when the ergotropic/ trophotropic quotient increases but delayed or abolished as the quotient decreases. However, the concept of ergotropic-trophotropic balance and its significance for conditioning should be applied with caution. Since both systems fulfill important functions in the conditioning process, it is understandable that the effect of a shift in balance depends on the state of excitability and tone of each system. Thus, animals with a low score for an avoidance c.r. and good differentiation (group I) show an improvement in conditioning on treatment with adrenaline, whereas cats with good avoidance c.r. and poor differentiation (group II) increase their score on treatment with Chlorpromazine (671). The following explanation is suggested: in group I the trophotropic system and in group II the ergotropic system is highly active. Therefore, they will undergo relatively small changes when the balance is altered in contradistinction to greater incre-

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mental changes which will affect the less active systems. Consequently, a shift to the ergotropic side through adrenaline raises conditioning without interfering with differentiation in group I, whereas a shift to the trophotropic side through Chlorpromazine improves differentiation without interfering with the high score of conditioning.* The importance of the ergotropic-trophotropic balance or, more specifically, of the hypothalamic balance is further illustrated by the comparison of active and passive avoidance reactions under similar conditions. Experimentally it has been shown that active and certain forms of passive avoidance reactions are reciprocally related: conditions (for instance, limbic lesions) which impair passive avoidance reactions (inhibition of movements acquired as the result of conditioning) improve, i.e., accelerate, active avoidance learning and vice versa. The reason is that passive avoidance reactions are apparently based on a limbically induced inhibition of the posterior hypothalamus via septum and ventromedial hypothalamic nucleus, whereas active avoidance involves excitation of the posterior hypothalamus. The inference that active c.r. are associated with an increase of the ergotropic-trophotropic quotient whereas passive c.r. are accompanied by a decrease of this quotient may have still further implications. It is not unlikely that the ergotropic-trophotropic balance modifies "voluntary" actions. At any rate, rats running a maze show cortical desynchronization, but at the point of choice the running is temporarily inhibited and at this time the EEC is synchronized (1013). Although the importance of the ergotropic-trophotropic systems and the importance of the role of the hypothalamus in conditioning have been emphasized throughout this book, it must be pointed out that these structures are only reinforcing agents, since c.r. may be produced in the isolated spinal cord. The biological significance of such c.r. is, however, nil by contrast with those forms of learning which are accomplished in the animal on the basis of powerful drives (such as hunger, thirst, escape from pain). One would expect that the more sophisticated forms of learning, including creativity in man, would still be linked with the hypothalamic system, because even the highest forms of intellectual endeavor are not achieved in an emotional vacuum. Our discussion was chiefly confined to the factors which are indispensable for the formation of simple conditional reflexes. The significance of certain parts of the cortex, such as the frontal lobe, for special (delayed) c.r. and the role of the hippocampus in the storage of information and in recall were thought to be beyond the scope of this book. Closer to our main problem are observations concerning fundamental differences between *The reader is reminded that the rate of acquisition of c.r. is related to the excitability of the ergotropic system, whereas differentiation involves prominently the trophotropic system.

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avoidance and escape c.r. Hyperglycemia is said to occur during the early escape phase but not during the avoidance c.r., and trained rats retain the avoidance c.r. after hypothalamic lesions which abolish their responsiveness to the unconditional noxious stimulus (468). Does this result indicate that the formation of the c.r. requires the integrity of the hypothalamus but that its persistence is due to thalamic influences? The reticular formation is of importance for the development of the orienting reflex, for habituation in response to sensory stimuli, and for the maintenance of a high level of excitability of the hypothalamus; but the site of closure of the c.r. is thought to be rostral to it (hypothalamus and medial nuclei of the thalamus). Both limbic cortex and mesencephalic afferent paths (involving the reticular formation and the lemnisci) seem to modulate hypothalamic reactivity (242, 284, 750, 957) and may thereby modify conditioning. However, limbic-hypothalamic relations are poorly understood and the influence of hippocampus and amygdala, for instance, on c.r. is still controversial. That in certain areas of this research contradictory results have been reported is not surprising. Uniformity in details of electrical potentials in various cerebral areas is hardly to be expected if widely different species are used in conditioning procedures varying from the Pavlovian reflex to highly complex forms of instrumental conditioning. Lesion experiments are complicated by the fact that no criteria have been established to determine the optimum postoperative interval. Age (564) and genetic influences (171, 574) have hardly been taken into consideration. Factors which reduce avoidance reactions may not inhibit alimentary c.r. and vice versa (299). To this must be added the important fact that the hypothalamic system is labile: it is easily altered by afferent impulses, hormones and neurohumors, and previous experience. This lability makes it eminently suitable for conditioning and makes the exploration of conditioning and related phenomena hazardous and fascinating.

IV

The Physiology of Experimental Neurosis and of States of Anxiety

IT is the task of this chapter to apply the knowledge gained from the study of c.r. to characteristic pathological deviations in the learning process and behavior which, since Pavlov's work (771, 772,773), have been designated as experimental neurosis. We are chiefly concerned with the ergotropic and trophotropic systems and specifically with their relations in neurotic states. Studies of the symptoms occurring in preneurotic conditions and in neurosis and of the causes leading to their development as well as of the nature of the therapeutic procedures will be utilized for this purpose. Pavlov's great merit in having opened up this important area of research with its vast clinical applications is not lessened by the frank statement that his interpretations were made in terms of popular psychology. More recently, attempts have been made to interpret c.r. and experimental neurosis on the basis of modern learning theory (see 501 and 1000 for the literature), but it is admitted in these important studies that they deal with " 'hypothetical constructs' for which no neurological or physiological equivalent is necessarily postulated." Although this theoretical framework has a definitive place in investigations of behavior, it does not replace but rather supplements the study of the physiological mechanisms involved. We therefore propose to discuss experimental neurosis by making use of those concepts of modern neurophysiology which were found helpful in understanding the physiological foundations of c.r. Moreover, it has already been shown in Chapter II that such an analysis can be carried out with some measure of success on pathological states of consciousness. The application of this procedure to the problems of experimental neurosis should enhance our understanding of the pathology of emotional behavior; the significance of such understanding for the neuroses and psychoses is obvious. To anticipate the results discussed in this section, it may be said that there is a resemblance between the trophotropic-ergotropic relations found in certain abnormal forms of consciousness and those linked with pathological states of emotional behavior. The meaning of this resemblance 116

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is not yet clear, but further study along these avenues of investigation seems promising. I. PHYSIOLOGY OF EXPERIMENTAL NEUROSIS

1. The Production of Experimental Neurosis Following Pavlov's work, experimental neurosis has been produced in numerous species ranging from rats to monkeys while the animals were either restricted in a harness, as in Pavlov's experiments, or moving freely. The major conditioning procedures which lead to the development of experimental neurosis may be divided into several groups and involve 1. Application of very strong pain stimuli, sometimes applied inadvertently as u.s., while in other experiments conditional nociceptive stimulation produces similar results if the intensity, duration, or number of stimuli per test period becomes too great (537, 625); 2. "Overstraining" conditional inhibitions by increasing the duration of the negative c.s. (771, 772) or by applying these stimuli at brief intervals (1 min.) as often as 20 times in each experimental session (22); 3. Too fine a discrimination between positive and negative c.s. or too rapid temporal alternation between these stimuli (772); 4. Monotonous repetition at regular intervals of positive c.s. reinforced by electrical shocks (22, 623, 624, 625); 5. Administration of an electric shock (or air blast) during the conditioned feeding reflex (213, 322, 690, 1000). As we have seen in Chapter III, the conditioned animal shows a coordinated and meaningful behavior. If, for instance, a sensory stimulus (sound of a certain pitch) has become the symbol for food through adequate reinforcement of the u.s., this originally neutral stimulus elicits salivation because the pitch has acquired meaning as a harbinger of food. A different pitch, not reinforced by a subsequent u.s., remains meaningless or neutral ("negative" c.s.), and no c.r. to this stimulus develops. As long as the pitches are sufficiently different, the animal responds consistently to the meaningful but not to the meaningless stimulus and remains in good mental health. As the difference between the pitches is progressively reduced, however, errors in response progressively increase and neurotic behavior develops. Under these conditions previously acquired c.r. (differentiated c.r. as well as simple c.r. in response to the positive c.s.) are lost either permanently or for weeks or months. It is not necessary, though, to apply procedures which involve a clash between positive and negative c.r. in order to produce neurosis. Massive nociceptive stimuli and even a few very loud sounds may have the same effect and, as mentioned above, this also holds true for the excessive application of negative (nonreinforced) c.s. In the latter case it is often not

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necessary to administer numerous negative c.s. but rather to prolong their duration. Then even a few stimuli may elicit an experimental neurosis. The impression gained from experiments involving extreme differentiation that a clash between antagonistic systems underlies the production of experimental neuroses is strengthened by observations on antagonistic reflexes. The salivary c.r. and the nociceptive defense c.r. are such reflexes, since, as was mentioned earlier, intracerebral stimuli act upon them in opposite manners (638). If, after the establishment of an alimentary reflex, an electric shock is applied a few times shortly after the positive c.s., i.e., at the time when salivation occurs and the c.r. is reinforced by a morsel of food, an experimental neurosis results. Subsequently the animal refuses to eat or to approach the feeding box. This procedure was effective in many species (monkey, cat, dog, pig) classically or instrumentally conditioned (623, 690), even after a mild air blast to the face was substituted for the nociceptive stimulus. Another famous experiment from Pavlov's laboratory seems to belong to this group. A salivary c.r. is formed in a dog in response to a nociceptive c.s. After the c.r. has been established it is possible to gradually increase the intensity of the shock and still evoke a salivary response, although in the nonconditioned animal such stimulus would evoke a generalized sympathetic discharge, vocalization, and extensive defensive movements. If, however, the intensity of the stimulus becomes too great or is applied to cutaneous sites other than the site originally used in the conditioning experiment, the behavior changes suddenly. A generalized excitation occurs and the c.r. disappears. Finally, in the work of Liddell, Anderson, and their collaborators (22, 623, 624, 625) a c.s. followed by a mild shock administered at regular intervals (7 min.) for adequate periods of time produces an experimental neurosis with great regularity in sheep and goats. It is evident from this brief survey that seemingly quite different procedures induce experimental neurosis in experimental animals. The Pavlovian concept of the "overstraining" of the excitatory or inhibitory conditional processes as the cause of experimental neuroses is as unsatisfactory from the physiological point of view as the assumption that neurosis results from "conflict or collision between the excitatory and inhibitory conditional reflexes [when] excitatory and the inhibitory stimuli were made similar in their physical properties" (321). Obviously, an understanding of the neurophysiological mechanisms underlying experimental neurosis is gained neither through the characterization of the stimuli that effect it nor by vague psychological terms such as "conflict or collision." It is therefore proposed to describe the behavior of neurotic animals, the symptoms of experimental neurosis, the predisposing factors, and the characteristics of

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preneurotic states that are likely to reveal data which are of crucial importance for the development of a neurophysiological theory. 2. Conditioned Responses during Experimental Neurosis and Related States The experimental neurosis appears in an excitatory and an inhibitory form. In the former the general activity is increased and the animal shows numerous signs of anxiety, such as whining, trembling, and hyperventilation. The responsiveness to minimal sensory stimuli is enhanced. Thus, Anderson & Parmenter (22) emphasize hyperirritability to touch as the first symptom of experimental neurosis, whereas neurotic rats "freeze" at the slightest noise and retain this proneness to inhibition of movements for many weeks (322). On the bench the formerly quiet dog shows an increased intertrial activity and howling. In more severe disturbances it is difficult to bring the animal into the experimental room. It attempts to escape, is aggressive, and refuses to eat, particularly in the experimental laboratory. Even outside the laboratory the "emotional" disturbances persist and lead to alterations in the social behavior of the neurotic animal (shyness, etc., 628). In contrast to these phenomena the inhibitory form of the experimental neurosis is characterized by lessened activity and sleep-like states. Whereas animals showing the excitatory form of neurosis seem to suffer from insomnia, prolonged periods of drowsiness occur in the inhibitory form. Cataleptic states with rigidity are also observed. These observations raise the question whether the form of neurosis is determined by the experimental procedure which induced the behavioral disturbances or whether it is related to individual characteristics ("person," constitution) of the animals. There are some data in the literature which suggest that certain procedures are more likely to produce the excitatory than the inhibitory form of experimental neurosis. When animals are subjected to neurosis-producing stimuli under conditions which limit the freedom of movement, inhibitory forms of neurosis prevail (620). Nevertheless, this external factor is of only secondary importance, since most investigations show that the individual type determines the form of neurosis regardless of the method applied. According to Gantt (319), "the pattern of breakdown in a given individual remains relatively constant" and different patterns appear in different dogs subjected to the same procedures. Of the four personality types which Pavlov distinguishes in dogs on the basis of behavioral characteristics and responsiveness to positive and negative c.s., two are prone to develop experimental neurosis. Both have an "unbalanced" nervous system with a predominance of excitatory proc-

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esses in the choleric animal and a predominance of inhibitory processes in the melancholic type. The choleric tends to develop the excitatory, the melancholic the inhibitory, form of experimental neurosis, but it would be unwise to assume a too rigid classification. Even highly excitable dogs may show the tendency to fall asleep when subjected to neurosis-producing procedures (319). Thus, an excitatory neurotic dog showing greatly increased intertrial activity and violent behavior in response to a slight noise and to a positive c.s. (and other stimuli) responded after a rest period of one month to the resumption of testing on the bench with a state of "pseudo-decerebrate rigidity" and almost complete lack of any movement (22). Moreover, animals which were inhibited in the experimental situation showed in the cage aggressive and agitated behavior which in some instances resembled manic excitement (620). These observations suggest that the neurotic state as produced in the physiological experiment varies from a deeply inhibited to a highly excited condition and that probably intermediary mixed states likewise occur. At first these changes are reversible following a prolonged rest period. Thereafter, the application of a few c.s. is often sufficient to evoke the neurotic state again. If these tests are continued, severe and irreversible behavioral changes occur during which c.r. and often even u.r. (feeding) are abolished, so that a hungry animal will refuse to eat in the experimental room from the food box at which it had received a shock or an air blast. Some further comments on the reversible neurotic state are necessary. Pavlov observed certain abnormal responses during this state. He interpreted them as indicators of hypnotic stages because they may be seen during the transition from wakefulness to sleep and consist of quantitative alterations in the responsiveness of the c.r. to varying intensities of the c.s. Whereas in the normal organism the c.r. increases with increasingo inteno sity of the stimulus (318), the following deviations occur during the reversible stage of neurosis: I. a phase of equalization during which c.s. of different intensities elicit equal responses; II. a paradoxical phase during which a weak c.s. evokes a stronger c.r. than a more intense stimulus; III. an ultraparadoxical phase during which the negative but not the positive c.s. produces a c.r. In favorable circumstances the transition from phase I to II and III (or in the reverse order as the animal recovers from the neurotic state) may be seen in the same animal. Procedures which are likely to produce experimental neurosis may evoke these "hypnotic" stages. Thus Pavlov (772) mentions an experiment in which the rapid alternation of positive and negative c.s. had led to a complete loss of c.r. which persisted for weeks. In the subsequent recovery the animal passed from the paradoxical phase

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to that of equalization and finally to the normal response to c.s. Furthermore, animals which had lost their c.r. during the famous flood in Pavlov's laboratory and then recovered showed the tendency to develop a paradoxical phase. Often a relatively slight increase in the intensity of the c.s. or of its duration is sufficient to produce this effect. The physiological basis of these phases, which Pavlov thought were due to a spreading of cortical inhibition, is by no means clear. A physiological theory of the experimental neurosis should provide an explanation of the mechanism underlying these remarkable phenomena which characterize the preneurotic state of the experimental animal and which have also been observed in man during hypnosis (781), in states of anxiety, and in depressions (13). 3. General Symptomatology of the Experimental Neurosis The neurotic state and also the preneurotic condition during which paradoxical and related responses to c.s. occur are characterized not only by changes in c.r. but also by disturbances in autonomic and associated somatic functions (respiration, licking movements, etc.). Hyperpnea was frequently noted by Pavlov in neurotic states and Liddell (625) calls attention to the fact that mere standing on the bench for an hour increased the respiratory rate from 5 to 135/min. Gantt (319) recorded numerous types of irregularity in respiration in his neurotic dogs which persisted for years and were present also outside the experimental laboratory. An increase in heart rate occurs in response to the c.s. in the normal animal. These cardiac (as well as the respiratory) changes are more marked in excitable than in placid dogs and increase greatly during experimental neurosis (320). They may be present at rest (tachycardia) and persist in response to the c.s. for years after the motor and salivary components of the c.r. have disappeared. In the experimental laboratory neurotic animals showed numerous autonomic disturbances such as profuse salivation (236, 319), retching and vomiting (235, 620), and frequent urination and defecation. Gantt (320) observed that erection and ejaculation occurred in the neurotic dog in response to c.s. and, like other autonomic disturbances, persisted for years. Parasympathetic reactions such as slowing of the heart rate (associated with slowing of respiration) on petting are more marked in the neurotic than in the normal dog, and Gantt (321) mentions that the mere presence of a person reduces the heart rate of a neurotic dog from 140-180 to 6070/min and inhibits "the marked respiratory changes usually evoked by an anxiety-producing stimulus." The combination of the autonomic changes with vocalization, trembling, etc. justifies the assumption that, psychologically speaking, the neurotic animals are emotionally disturbed. These effects are not the result of the

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restriction of movements since they are observed also in freely moving animals (213, 690, 964, and others). It is of great interest to add that autonomic reactions are not only magnified in experimental neurosis but also altered qualitatively. The dilatation of the stomach vessels which accompanies feeding and precedes secretion is abolished or reversed in experimental neurosis (Kurtsin, 605). This author reports further that sham feeding which elicits gastric secretion and vasodilatation in the Pavlov pouch — reactions which are abolished by vagotomy —may evoke vasoconstriction in the neurotic state. Moreover, whereas blood pressure and heart rate rise and fall in response to the positive and negative c.s. respectively in the normal animal, these vascular reactions are often reversed in experimental neurosis. If neurosis-producing stimuli of lesser intensity are applied, the behavioral disturbance, including the disappearance of c.r., may last only a few days. Such cases' recovering spontaneously may be regarded as examples of the preneurotic state and not of experimental neurosis which continues for months or years and requires special procedures for cure. However, the difference between the two conditions is only quantitative. Even in the preneurotic states parasympathetic phenomena such as vomiting and diarrhea and associated somatic discharges (licking) are common (518), and three shocks applied inadvertently during conditioning resulted temporarily in "struggling, vomiting, defecation and penile erections" when the dog was placed in the stock (237). In experiments on man (798) a light was followed by a cold or warm stimulus to the skin in a certain order whereby a c.r. resulting in vasoconstriction or vasodilatation respectively was established. If this order was changed, nausea and rise in blood pressure associated with restlessness and confusion appeared. It may therefore be said that the preneurotic and neurotic experimental states are characterized by behavioral disturbances, alterations in c.r., and the occurrence of parasympathetic and sympathetic symptoms. 4. The Hypothalamic System in Experimental Neurosis and Related Conditions From the experiments described above and numerous reports in the literature it is obvious that severe emotional excitement is associated with the precipitation of a neurosis in the experimental animal. The form and intensity of the neurosis depend not only on the stimuli used but also on the reactivity of the animal. The marked differences in this respect among various dogs induced Pavlov to distinguish stable from unstable animals and to relate their degree of proneness to experimental neurosis to their temperaments. Even such procedures as the application of a shock during the conditioned feeding reflex, which are in general very effective in producing experimental neurosis, may fail with certain animals (758).

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External and internal factors which modify emotionality alter the susceptibility to experimental neurosis. Thus, paradoxical responses to c.s. of different intensities and loss of differentiation persisting for days appeared in a dog as it was placed near a dog in estrus (319). Internal secretions exert profound effects. Experimental neurosis is prevented by thyroidectomy, and thyroxin injections may restore a neurosis which has been abolished by thyroidectomy (627). Not only gross changes in the function of glands of internal secretions and in the internal environment which are likely to alter cerebral excitability modify the susceptibility to experimental neurosis-producing stimuli, but more subtle, "psychological" situations are likewise effective. Animals subjected to a life-threatening situation (as, for instance, during the flood which inundated Pavlov's laboratory) became neurotic and remained very susceptible to similar neurosis-producing stimuli after they had been cured. Furthermore, a kid separated from the mother is more prone to experimental neurosis than the twin in which this relationship was undisturbed (626). The role of repeated emotions in precipitating and maintaining the neurotic state has been emphasized by still other experimenters. Anderson & Parmenter (22) stress, in addition, a "chronic imbalance of internal secretions, and Gantt (317) and Wolpe (1000) emphasize the role of anxiety and frustration. Although man's understanding of animal behavior in situations of conflict is somewhat furthered by these psychological terms, it is still necessary to attempt a physiological interpretation. It has been shown elsewhere (Gellhorn & Loofbourrow, 370) that emotions are based on the activation of the hypothalamic system. This concept takes into consideration the fact that the hypothalamus is the "nodal point in a vast neural mechanism extending from the medial wall of the cerebral hemisphere caudalward to the lower boundary of the mesencephalon" (750). This accounts for the fact that emotions may be aroused not only reflexly but also from the limbic system. Moreover, the hypothalamus may be excited from the neocortex, and hypothalamic excitation activates in turn the neocortex and the limbic brain. On this anatomical and physiological basis it is understandable that the hypothalamus is greatly excited by stimuli which have been shown to elicit experimental .neurosis. This excitation will take place reflexly in the case of massive painful stimulation (504) but probably involves cortico-hypothalamic circuits when difficult sensory discriminations are used. Before we discuss hypothalamic activity in experimental neurosis in detail, some general remarks on hypothalamic-cortical relations in experimental neurosis are in order. The loss of c.r. or, in milder forms, the decrease in differentiation and the appearance of a paradoxical response to c.s. as well as the explosive character and decreased duration of the c.r.

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(see Pickenhain, 781) have been interpreted by Pavlov and others as the result of a decline in cortical activity and a release of subcortical structures. On the contrary, it seems to this writer that conditions leading to experimental neurosis are associated with an excitement of the hypothalamus which takes place via reflexes under the influence of nociceptive stimulation and through cortico-hypothalamic discharges in situations of conflict, but there is no evidence that the neurosis is due to a release from cortical inhibition. This excitation of the hypothalamic system manifests itself in fear and anxiety and in ergotropic and trophotropic symptoms. Its magnitude is apparent from the fact that increased sympathetic discharges may persist in the experimental animal for years after cessation of experimentation. It is therefore suggested that the loss in c.r., and particularly the loss of differentiation between positive and negative c.r., occurs not because the activity of cortical neurons is weakened (inhibited) but because the excessive random excitation of the whole cortex and the hypothalamus prevents the orderly specific interaction between cortical and subcortical neurons which is the basis of conditioning and normal behavior (370). The statement that strong hypothalamic discharges play an essential role in the genesis of the experimental neurosis is a natural sequel to the findings that the hypothalamic system is deeply involved in the formation of c.r. and that the c.r. undergo such striking changes during development of neurosis. For a physiological theory of the experimental neurosis a further analysis is necessary which should explain: 1. The mechanism through which various neurosis-producing procedures act on the central nervous system, 2. The processes accounting for the phenomena of equalization and the paradoxical responses to c.s. of different intensities, 3. The physiological basis of inhibitory and excitatory forms of experimental neurosis, and 4. The principles underlying the therapy of experimental neurosis. In spite of our inadequate knowledge, an attempt will be made in the following pages to outline a physiological theory of the experimental neurosis. 5. Physiological Mechanism Underlying Neurosis-Producing Procedures That emotional excitement (anxiety) is related to experimental neurosis is stressed by all students of this behavioral disturbance. The important role of autonomic processes in the emotions in general and in experimental neurosis in particular raises the question whether fundamental differences exist between the pattern of activity of the involuntary nervous system seen in animals with normal c.r. and in those which are in a neurotic state. From our description of the symptoms accompanying c.r. in the normal or-

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ganism, it is obvious that ergotropic discharges, involving the sympathetic system and increased tone of striated muscles, are elicited by the c.s. However, these discharges are of a limited nature. The excitatory effect (desynchronization) on the cortex is confined to the projection area of the u.s.; there are no generalized movements and no significant somatic or autonomic discharges during the intertrial period. Moreover, on presentation of the negative c.s. the trophotropic system is activated: parasympathetic symptoms appear, together with synchronous activity in the cerebral cortex and lessening of the tone of the striated muscles, indicating the integrative activity of the trophotropic system. In contradistinction to these findings the symptoms in the neurotic state are characterized not only by the greater intensity of somatic and autonomic discharges but also by the simultaneous appearance of activity in ergotropic and trophotropic systems. Licking, retching, vomiting, and diarrhea are seen even in the reversible preneurotic conditions (518; Fig. 4-1). Recovery from this state or cure of the experimental neurosis by drugs bring about a return of a moderate ergotropic response to the c.s.: the simultaneous activation of the ergotropic and trophotropic systems has disappeared. The study of the EEG supports this interpretation, since delta potentials of low frequency and high amplitude occur together with beta waves of high frequency and low amplitude in the neurotic state (931,1014), seem-

Fig. 4-1. The development of conflict-induced behavior. Abscissa: number of feeding cycles (the time taken for the cat to finish eating one food pellet, to release the signal by means of the switch, to move back to the foodbox, to open it, and to begin to eat the next food pellet); mark for every tenth feeding cycle. Ordinate: duration of each feeding cycle in sec. The occurrences of the various displacement activities are marked below each graph; the symbols like plus signs, etc. mean extra manipulations of the switch, once, twice, three times, etc. (From Jacobsen & Skaarup. Experimental induction of conflict-behaviour in cats: its use in pharmacological investigations. Acta pharmacol. et toxicol. 11:117, 1955.)

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ingly due to a nearly simultaneous activation of the ergotropic and trophotropic systems. These data suggest that neurosis-producing stimuli evoke an excitation which spreads from the ergotropic to the trophotropic system or heightens the excitability of both systems to such a degree that on rather mild stimulation or "spontaneously" both systems discharge. Massive pain and insulin hypoglycemia leading to repeated comas have been used to elicit experimental neurosis (504, 838). The physiological analysis shows that mild nociceptive stimuli call forth ergotropic reactions whereas with strong pain (and/or heightened central reactivity) trophotropic symptoms, such as fall in blood pressure and heart rate, including fainting, appear at the same time. Similarly, hypoglycemia activates the ergotropic and trophotropic systems. Symptoms involving the latter system are observed particularly in the deep coma (bradycardia), although increased gastric secretion occurs at an early phase.* Since Pavlov's time many authors have used his method to produce experimental neurosis by attempting a differentiation between the positive and negative c.s. which goes beyond the capacity of the animal. Wolpe (1000) emphasizes this procedure in his analysis, and believes that its effectiveness in producing neurosis is due to an "ambivalent stimulus situation" which he defines as one "to which opposing responses tend to be elicited in more or less equal measure." The data presented in this and the preceding chapter permit one to utilize this idea in physiological terms. Whereas Pavlov stresses the excitatory and inhibitory effects of positive and negative c.s. respectively and believes that the "clash" of these effects on the "cortical analyser" causes the neurosis, we assume that it is the simultaneous or nearly simultaneous activation of the ergotropic and trophotropic systems which is responsible for the disturbed behavior. This activation is bound to alter the relation of the hypothalamus to limbic and neocortex, to change neuronal and endocrine discharges within the hypothalamus itself, and to alter feedback processes (for instance, via the gamma system). The close association between the positive c.r. and the ergotropic system and between the negative c.r. and the trophotropic system discussed earlier, and the finding that these systems are activated chiefly from the diencephalon and the brain stem suggest that the primary disturbance in experimental neurosis is linked with these systems in general and with the hypothalamic system in particular. The early appearance of autonomic symptoms in experimental neurosis and their persistence after the somatic "In view of the apparent significance of emotional excitement for the development of experimental neurosis, it is of interest to mention that hypothalamic stimulation leads in the anesthetized cat to sympathetico-adrenal and vago-insulin discharges and that similar effects are produced in rats by fear induced .by firecrackers (360).

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disturbances have been eliminated, their quantitative and qualitative alterations, and their unadaptive character provide ample evidence for the severity of these functional changes. Moreover, it was shown in Chapter I that whenever the autonomic downward discharges are altered, corresponding changes in the upward discharges to the cortex occur. It is therefore not unlikely that these qualitative and quantitative changes affecting the ergotropic and trophotropic systems at the hypothalamic level have a profound influence on cortical activity in general and on the frontal lobe, whose relation to the hypothalamus is well established (979), in particular. The alleviation of experimental neurosis through frontal lobotomy (621) illustrates this point. Sherrington (892) showed the significance of the reciprocity principle for the performance of movements and coordinated action. This principle is valid for autonomic reflexes and central autonomic processes (see 338) and also determines autonomic-somatic relations. Thus, trophotropic discharges are associated with decreased gamma discharges and lessened muscle tone whereas these phenomena are augmented when the ergotropic system is activated. The disturbance in the reciprocity principle seen in experimental neurosis alters these effects: sleep-like conditions may appear in which the tone of the skeletal muscles is greatly increased ("pseudo-decerebrate" rigidity, 22). It seems to follow that the simultaneous activation of the ergotropic and trophotropic systems under the conditions of excessive conditioned differentiation leads to disturbances in autonomic functions and autonomic-somatic relations and to alterations in synchronizing and desynchronizing effects on the cortex. These effects appear to be the result of a loss of reciprocal relations between trophotropic and ergotropic systems. These disturbances seem to underlie the experimental neurosis produced by several other procedures: 1. The rapid alternation of positive and negative c.s., 2. The application of a nociceptive stimulus during eating induced by a c.s., 3. The use of a painful c.s. which is gradually increased during the development of a conditional alimentary reflex until it exceeds a certain intensity. It must be assumed that the "rapid alternation" procedure leads to an interaction between the ergotropic and trophotropic discharges because there is a tendency for the negative c.s. to exert an inhibitory action during the post-stimulatory period, since the positive c.s. are less effective in it than after a longer interval (319). The method listed under 2 above involves the interaction between an ergotropic nociceptive action and a trophotropic reflex (eating). The increased secretory and motor activity of the gastrointestinal tract and the cortical synchronization (169) asso-

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elated with food intake; the dependence of satiation on the ventromedial nucleus of the hypothalamus (106), which is known to inhibit the sympathetic hypothalamic division (988); and the well-known relaxation of the striated muscles during, and the increasing drowsiness after, a meal are adequate proof of trophotropic action during eating and, consequently, justify our assumption that intensive trophotropic and ergotropic discharges are called forth by procedure 2 above. These antagonistic systems are also involved in 3 above, except that as long as moderate intensities for the positive c.s. are used and this stimulus is applied to one cutaneous site only, the ergotropic flexor reflex is inhibited through the conditioned alimentary trophotropic reflex. If the c.s. is intensified and/or is not confined to one site, it evokes a strong nociceptive reflex which occurs at the height of the trophotropic alimentary reflex. Here again the simultaneous ergotropic and trophotropic excitation is accompanied by neurotic disturbances. A word of caution must be inserted here. As was mentioned earlier, some types of dogs develop experimental neurosis under certain conditions while others having a "stable" nervous system fail to do so. Novakova (758) could not produce experimental neurosis in dogs or cats subjected to an electrical shock during the conditioned alimentary reflex, a procedure which has been very effective in the hands of numerous investigators. Moreover, Asratyan (39) developed antagonistic reflexes by reinforcing the same c.s. with food in some and with a shock in other trials or by reinforcing this stimulus simultaneously with food and shock. Animals thus trained showed in response to the c.s. salivation and a defensive reflex but no experimental neurosis! Apparently the simultaneous occurrence of trophotropic and ergotropic discharges by itself is not sufficient to elicit an experimental neurosis unless the intensity of the stimuli and/or the reactivity of the hypothalamic system pass beyond a critical level. Thus, Anderson & Parmenter (22) noted in their neurosis studies based on difficult differentiations that "in certain sheep and dogs the inability to solve the problem did not seem to 'bother' them, and it was consequently not followed by any observable deleterious effect upon behavior." If, however, in sufficiently excitable animals stimuli are applied which lead to strong ergotropic and trophotropic discharges, experimental neurosis results which is psychologically characterized by a state of anxiety. This syndrome is at the base of the behavioral disturbance in experimental and clinical neuroses according to Wolpe (1000) and others (see Broadhurst, 104). Investigations by Yerkes & Dodson (1007) and Broadhurst (104), who studied the learning of brightness discrimination involving tasks of varying difficulty under different degrees of motivation (hunger), further elucidated the problem of experimental neurosis. These authors found that

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there is an optimal drive level beyond which discrimination declines. This optimum lies at progressively lower levels for tasks of increasing difficulty. Since, as Broadhurst points out, the animal has not previously experienced the working mechanism of this principle, it is likely to try harder: as the discrimination difficulties mount, the drive level increases and it is at this increased drive level that general responses (struggling, agitated behavior, etc.), suppressed during the earlier training, reappear. It should not be forgotten, however, that the increased drive level (due to hunger or punishment for wrong responses) is associated with an increased activity of the ergotropic system, particularly at the hypothalamic level, since hypothalamus elicits the behavioral characteristics of hunger (106, 712) and nociceptive stimulation activates the posterior division of the hypothalamus (71, 353). In the light of these findings the agitated behavior in Broadhurst's experiments appears to be due to an increased excitation of the ergotropic division of the hypothalamus rather than to a "regression" to an earlier phase of training. This state of excitation of the hypothalamus predisposes to experimental neurosis. Similarly, previous severe emotional disturbances (induced by the flood in Pavlov's laboratory and by accidental intercanine fights in Gantt's work) leave the hypothalamic system in a state of heightened excitability in which trophotropic and ergotropic systems are easily aroused simultaneously. There are other procedures such as Liddell's "rigid time schedule" which induce experimental neurosis, although neither massive pain nor simultaneous activation of the ergotropic and trophotropic systems seems to be involved. Nevertheless, the underlying mechanism appears to be similar. The monotonous prolonged stimulation creates a rising emotional excitement during which both divisions of the hypothalamic system are activated. 6. Pavlov's Phasic (Hypnotic) Phenomena Quantitative and qualitative changes in the response to c.s. characterize the preneurotic state and also (according to Pavlov) transitional stages between wakefulness and sleep. Under these conditions the animal may react to weak and strong c.s. to a similar degree (phase I, "equalization") and then may progress to the "paradoxical" phase II (response to the weak c.s. being greater than that to the strong one), and, finally, to phase III ("ultraparadoxical"), in which only negative c.s. are able to elicit a c.r. Pavlov explains these changes by alterations in the "top capability" of the cortical cells (see 595). Stimuli beyond a certain intensity exceed the top capability and evoke an inhibitory effect, and factors such as drowsiness, age, and neurosis which lower the top capability thereby predispose the organism to inhibitory reactions. Similar effects result from an increase in

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cortical excitability. The action of large doses of caffeine (and also hunger) in inducing phases I and II in c.r. was thought by Pavlov to be due to such cortical changes. The fact that in drowsiness and experimental neurosis (particularly in its inhibitory form) trophotropic symptoms predominate suggests that the lowering of the "top capability" is due to a shift in ergotropic/trophotropic balance toward the trophotropic side. A similar change in this balance may occur with increasing age since it is associated with a decline in sympathetic reactivity in man and animals (753, 860, 902). It was shown in Chapter III that c.s. act on ergotropic and trophotropic systems, but that at the normal balance the action of the positive c.s. on the trophotropic system is absent due to the reciprocal inhibition existing between the two systems. In states of imbalance, however, leading to a dominance of the trophotropic system (for instance, in drowsiness), the action of the positive c.s. is lessened on the ergotropic but enhanced on the trophotropic system. Consequently, conditioning is less effective, while internal inhibition is intensified. Such a shift in balance would account for phase I if we assume that the threshold for excitation of the ergotropic system remains lower in Pavlov's transitional stages than that for the trophotropic system. Under these conditions a threshold stimulation would evoke a c.r. by acting on the ergotropic system only. At a certain higher intensity, however, the stimulus affecting the excitatory ergotropic and the inhibitory trophotropic systems would, through algebraic summation of these processes, produce a degree of excitation similar to that produced by threshold stimulation and thereby elicit the phenomenon of equalization. With the more marked shift to the trophotropic side associated with an increased reactivity of the inhibitory system and/or with a stronger stimulus, one would expect phase II: a weak positive c.s. would evoke a c.r., but a strong stimulus would fail to do so, since the inhibitory trophotropic effect would build up faster than the excitatory effect.* The effect of hunger, attributed by Pavlov to hunger's influence on increasing cortical excitability, seems to be explainable within our theoretical framework, since the hunger drive depends on the activity of the lateral hypothalamus. Moreover Briigger's (117) work on the "Fresstrieb" has shown its intimate connection with the somatic and sympathetic components of the ergotropic system. In an organism in a highly intense state of hunger, a strong c.s.f is likely to raise the excitability of the ergotropic system to such a degree that the reciprocal innervation is interfered with and the excitation overflows into the trophotropic system, thereby establishing the conditions for the occurrence of phases I and II. *An explanation of the ultraparadoxical phase is not attempted because the evidence for this rare phenomenon is not very convincing. tSee also Konorski's book (595), p. 105.

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7. The Physiological Basis of the Excitatory and the Inhibitory Form of Experimental Neurosis The excitatory form of neurosis occurs chiefly in animals which are aggressive and develop strong c.r. easily but differentiation with difficulty (type I). On the contrary, the inhibitory form of neurosis is found in anxious animals whose central nervous system seems "weak," since c.r. are difficult to establish and rather unstable (Pavlov's type IV). If we bear in mind the dependence of the formation of c.r. on the ergotropic system and that of the negative c.r. (through which differentiation is accomplished) on the trophotropic system, it seems probable that types I and IV, in contrast to the stable animals which have a lesser tendency to develop neurosis, suffer from an autonomic-somatic imbalance. High emotional reactivity and ease in conditioning indicate predominance of the ergotropic system in type I, whereas anxious behavior and easy extinction of c.r. in type IV point to a dominance of the trophotropic system. Under the influence of the neurosis-producing procedures which have been shown to act on both systems, these original imbalances are retained but amplified, leading in type I to hyperemotionality, restlessness, and sensory hyperreactivity and in type IV to a hypnotic, cataleptic state. In both types, however, the symptoms indicate that ergotropic and trophotropic systems are activated. The physiological model which illustrates, in principle, the changes which result from the application of stimuli in widely different states of central imbalance is Gellhorn's study on hypothalamic tuning (338, 346, 347). In this work it was shown that in a state of dominance of either the ergotropic or the trophotropic division (induced reflexly via the baroreceptors or by lesions or stimulation of the anterior or posterior division of the hypothalamus) the effects of stimuli acting on these systems are greatly altered. Trophotropic dominance is associated with increased parasympathetic reactivity and ergotropic dominance with increased sympathetic reactivity. Moreover, stimuli which produce sympathetic effects in the normal organism enhance parasympathetic discharges in the state of parasympathetic "tuning." These changes affect not only the autonomic discharges but the somatic and cortical (synchronization and desynchronization) effects'as well. It must therefore be assumed that in experimental neurosis the synchronization and desynchronization actions are enhanced and that the former are dominant in the inhibitory form and the latter in the excitatory form of the experimental neurosis. The dominance of the ergotropic system in the excitatory form of experimental neurosis is evident from the greatly increased susceptibility of the animals to minimal sensory (touch) stimuli (22) and the explosive character of the ergotropic responses which follow them.* It is also apparent *The responsiveness to nociceptive stimuli is likewise increased (601).

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from the EEC in which the basic pattern is increased in frequency and decreased in amplitude, as if the brain had been subjected to strong sensory stimuli (1013). In cats in which a continuous sound was used as the c.s. and an intermittent light as the u.s., the c.s. evoked the photic pattern not only in the occipital cortex as in normal cats but also in fronto-temporal areas. On the other hand, during a period of somnolence in the same neurotic animal, the fast EEC potentials seen during rest in the agitated cat were replaced by slow potentials and the conditioned photic rhythmical potentials were absent (1012). Jouvet (537) likewise observed the occurrence of large slow patterns in the EEG during the catatonic phase of experimental neurosis which persisted in spite of the fact that the c.s. were reinforced by electrical shocks. When in a conditioned animal a strong electrical shock is used as a u.s. in conjunction with a sound (c.s.) and this procedure is applied several times in one minute, the c.r. is lost and a sleep-like behavior results. Under these conditions the desynchronized potentials seen in the normal animal in cortex and reticular formation in response to the c.s. are replaced by synchronous potentials of high amplitude (540). Shifts in trophotropic-ergotropic balance in the inhibitory form of experimental neurosis, and changes in reactivity similar to those seen in parasympathetic and sympathetic tuning states are further illustrated by the following findings. Excitatory (noxious) stimuli prolong the inhibitory neurosis, whereas they induce sleep in a non-neurotic animal in which the trophotropic-ergotropic balance has been shifted to the trophotropic side by the elimination of the olfactory, acoustic, and optic receptors (see p. 49). Apparently in both instances the increased reactivity of the trophotropic system is responsible for these striking effects. Another study shows that at least in the initial stages of the experimental neurosis c.r. may be restored by stimulation of the reticular formation (259). Moreover, instead of eliciting excitement as in the normal animal this stimulation leads to "complete rest" in the neurotic dog. Although no interpretation can be given at this time these observations and particularly the reversal in the action of the reticular formation suggest that further investigations of the balance of the ergotropic-trophotropic system will be of value for our understanding of the physiology of experimental neurosis. For this reason studies of the following topics are recommended: 1. The incidence of excitatory and inhibitory types of experimental neurosis in normal animals and in others with lesions in the septal or anterior hypothalamic area. It is expected that the operated animals would show a lesser percentage of inhibitory experimental neurosis or none at all, due to the preponderance of the ergotropic system in the lesioned animals. 2. The behavior of animals with small lesions in the posterior hypothalamus which do not interfere with the conditioning process. Such animals

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should show mainly the inhibitory type of experimental neurosis after neurosis-producing procedures have been applied. II. PHYSIOLOGICAL DIFFERENTIATION BETWEEN ACUTE FEAR, SUBACUTE FEAR, AND CHRONIC ANXIETY*

The analysis of the effect of the neurosis-producing procedures has shown that experimental neurosis is accompanied by increased ergotropic and trophotropic discharges. It is believed that the central (cortical) component of these discharges is responsible for the behavioral disturbances, provided that the tone of the ergotropic system, particularly at the hypothalamic level, is great enough. Since the chief clinical syndrome seen in experimental and clinical neuroses is that of anxiety (22, 319, 1000), it seems probable that anxiety is the result of such changes in the ergotropic and trophotropic systems. For this reason an attempt is made to analyze anxiety and related emotional states from the physiological point of view. 1. Physiological Basis of Acute Fear Let us discuss first the physiological basis of the clinical symptoms which underlie acute fear. In acute fear blood pressure and heart rate may drop suddenly (for instance, at the sight of blood or due to severe pain), the tone of the striated muscles decreases, and the person faints (vasodepressor syncope), particularly if he was in an upright position. In other cases vagal discharges may play a prominent role (260). The loss of sympathetic vasomotor tone and/or the increase in vagal activity lead to a shift in the ergotropic-trophotropic balance to the trophotropic side. This change is aided by the loss in muscle tone, since the tone of the striated muscles counteracts circulatory collapse not only through its action on the venous return to the heart but also through the stimulating action of proprioceptive impulses on the ergotropic centers in the brain stem (see Chapter V). Even in the acute state of fear leading to a fall in blood pressure and fainting, sympathetic symptoms are present, such as sweating, pupillary dilatation, and increased blood flow through the muscles. They are probably secondary reactions resulting from the fall in blood pressure and its action on the activity of the baroreceptors of the sino-aortic area. 2. Subacute States of Fear In order to gain further insight into the physiological basis of fear, various emotional states have been induced in experimental subjects in the laboratory and correlated with changes in several physiological indicators. The emotions thus evoked were less intense but more prolonged than those described as acute fear. They led not only to characteristic alterations °For a more complete survey of the literature see 352.

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in cardiovascular functions but also to changes in the rate of excretion of noradrenaline and adrenaline. Two types of emotional reaction appeared: one designated as fear,* or "anger-in," during which the subject was "irritated, annoyed, or mad at himself"; the other characterized as aggression, or "anger-out," in which the subject was "angry at the experimenter, or the situation" but not at himself. It is assumed that in "anger-in" the emotional state is closely related to that of acute fear but that the compensatory action of the ergotropic system in "anger-in" is more effective. The observation that in subacute fear periods showing lack of tone in facial and skeletal muscles alternate with phases of marked tone leading to trembling in face and legs suggests that some ergotropic reactions, probably enhanced via the gamma system, may also occur under these conditions. Moreover, signs of sympathetic excitation such as an increase in the frequency of "spontaneous" activations of the sweat glands have been reported in anger-in as well as in anger-out (902). It may therefore be assumed that a gradual transition takes place between the anger-in and the anger-out states, although the trophotropic system is prominent in anger-in and the ergotropic system dominates in anger-out. Investigations of the influence of different emotional states on the reactivity to Mecholyl and on the resistance to centrifugal force bear out this assumption. Before we discuss the circulatory effects on man in different emotional states, the action of this drug (and other hypotensive agents) on the experimental animal (cat) at various states of hypothalamic reactivity will be summarized. If the sympathetic division of the hypothalamus is activated by subthreshold electrical stimuli, intrahypothalamic injection of Metrazol, or other procedures, the hypotensive action of Mecholyl is lessened and followed by an overshooting of the blood pressure. On the contrary, the lowering of the excitability of the sympathetic hypothalamus enhances and prolongs the hypotensive action of the drug and no overshooting of the blood pressure occurs. Apparently the state of the ergotropic division of the hypothalamus determines, other conditions being equal, the circulatory response to Mecholyl. This drug is, therefore, a semiquantitative indicator of the central activity of the sympathetic system. But we may go even further. Since reciprocal relations exist between anterior and posterior hypothalamus, a lesion in the anterior hypothalamus leads to a release of the posterior hypothalamus. This release acts as if the posterior hypothalamus had been stimulated: the hypotensive action of Mecholyl is diminished (338, 372, 375, 814). The balance between the ergotropic and trophotropic divisions of the hypothalamus is reflected in the responsiveness of the organism to the circulatory action of Mecholyl. Experiments on human subjects showed that the hypotensive action of *In this discussion the term "anxiety" is reserved for the intensive pathological emotional changes described in the following section.

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Mecholyl was small and brief in anger-out but marked and prolonged in anger-in (309). When somewhat smaller doses of Mecholyl were used (170), the tests revealed even greater differences in vascular reactivity in different emotional states. As Fig. 4-2 shows, Mecholyl elicited a hypertensive effect in an aggressive mood (anger-out) and a hypotensive action in an anxious state (anger-in), whereas intermediate emotional states were accompanied by an intermediate or mixed vascular response. Tests made on the same person in different emotional states showed that the vascular effect of Mecholyl varied with the emotional condition (Fig. 4-3). Our interpretation that the ergotropic-trophotropic balance is shifted to the ergotropic side in anger-out and to the trophotropic side in anger-in is supported further by experiments in which the resistance to blackout is studied on the human centrifuge in different emotional states. The g-tolerance, which is related to sympathetic discharges opposing the lowering of the blood pressure in the head, was found to be greater in subjects responding to Mecholyl with a hypertensive reaction than in those in which the drug lowered the blood pressure (170).

Fig. 4-2. The change in systolic blood pressure following the injection of 5 mg. Mecholyl is indicated across the upper horizontal row and the lower two rows contain the psychiatric ratings. (From Cohen & Silverman. Psychophysiological investigation of vascular-response variability, J. Psychosom. Res. 3:185, Pergamon Press, New York, 1959.)

There is another group of data, concerning the excretion of noradrenaline and adrenaline in different emotional states, which seems to strengthen this interpretation. The following experiments performed on the anesthetized cat may serve as a background. If contractions of the normal and the denervated nictitating membrane (n.n.m. and d.n.m. respectively) are recorded, it is found that the former is a good indicator of central ergotropic activity whereas the latter depends on adrenomedullary secretion,

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Fig. 4-3. The systolic (solid line) and diastolic (broken line) blood pressure change following the injection of Mecholyl during two separate experiments (on right and left side of double vertical center line). The affect state associated with each vascular response is also charted. The pre-Mecholyl control blood pressure is charted to the left of the lines indicating the change following Mecholyl. The central horizontal line in each patient's record signifies the control level. The scale provides for a deviation of plus or minus 15 mm of mercury. In the cases where the change exceeded this it is noted (subject 4, experiment II; subject 2, experiment I). The tests show that the blood pressure response to Mecholyl depends on the emotional state. (From Cohen & Silverman. Psychophysiological investigation of vascular-response variability, J. Psychosom. Res. 3:185, Pergamon Press, New York, 1959.)

since its response is abolished by adrenodemedullation (376). Although with increasing intensity of stimulation of the ergotropic system neurogenic and hormonal responses increase (345), experimental conditions are known in which the normal but not the denervated n.m. reacts and vice versa. Thus, low intensities of stimulation of the posterior hypothalamus cause a graded response of the n.n.m. without evoking a reaction of the d.n.m. whereas in the postasphyxial state — immediately following the readmission of air —the d.n.m. but not the n.n.m. contracts. If vascular reactions induced by Mecholyl or histamine are studied at the same time, it is found that in conditions in which the contraction of the n.n.m. is increased the hypotensive action of Mecholyl is lessened and the secondary

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overshooting of the blood pressure is enhanced. On the contrary, in conditions leading to a contraction of the d.n.m. the hypotensive action of Mecholyl is greater than under control conditions. In order to utilize these findings for the interpretation of the relation between emotional states and excretion of catecholamines, it should be borne in mind that in man the excretion of adrenaline is chiefly of adrenomedullary origin (265), whereas that of noradrenaline is due to its liberation from the endings of sympathetic and particularly vasomotor nerves (266). Thus, tilting a subject from the recumbent to the 75 degree head-up position increases chiefly the excretion of noradrenaline, and this effect is greatly reduced by ganglion-blocking agents (929). On the other hand, adrenalectomy virtually abolishes the excretion of adrenaline in man but does not alter that of noradrenaline (267). The relations between catecholamine excretion, vascular reactivity to Mecholyl, gravitational action in the human centrifuge, and emotional state were investigated by Cohen & Silverman (170). In anger-in, in which the compensatory ergotropic reaction to Mecholyl and centrifugation is small, the excretion of noradrenaline is low and that of adrenaline is high; in an aggressive mood the type of excretion is reversed while the compensatory ergotropic action is large. Different degrees of centrifugation evoke parallel changes in the excretion of noradrenaline but not in that of adrenaline, which is more related to the state of fear regardless of the circulatory stress which is involved in the test (394). These findings apply not only to interindividual differences but also to intraindividual changes observed when the subjects were tested in different emotional states (see also 903). Even the prestress levels of noradrenaline and adrenaline reflect the emotional and vascular reactivity under stress. It is the passive fear (anger-in) which is associated with adrenaline excretion while the active (aggressive) attitude enhances the liberation of noradrenaline.* However, it is not assumed that the excitation of different sites in the posterior hypothalamus is responsible for the enhanced secretion of the two neurohumors t — the complexity of autonomic symptoms in any emotion argues against such an interpretation. It is rather thought that in anger-in a trophotropic fear reaction evokes secondarily an adrenomedullary secretion, whereas in anger-out the autonomic activity is chiefly confined to the ergotropic system. Injection or secretion of adrenaline has been shown to evoke either excitatory effects on the ergotropic system in the brain stem or an inhibitory action via the baroreceptors (87, 372, 848). The fact that with increasing excretion of adrenaline the compensatory action against Mecholyl and centrifugation is weakened indicates °See also von Euler & Lundberg's (269) study of flight stress in airplane pilots and passengers, showing increased excretion of noradrenaline and adrenaline respectively. fFor a discussion of this problem see Gellhorn (349).

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that in anger-in the adrenomedullary secretion tends to aggravate rather than to antagonize the physiological effects of the initial state of fear. 3. Anxiety Since anxiety is a chronic state of fear, one would expect that the trophotropic discharges which characterize fear would be prominent in anxiety, but this is not the case. As in experimental neurosis, fear and signs of trophotropic discharges develop on the basis of a greatly increased ergotropic activity which is responsible for an increased reactivity of the ergotropic system indicated by vasoconstriction, rise in blood pressure and heart rate (palpitation), and the reaction of the psychogalvanic reflex and, particularly, of the striated muscles to unspecific stimuli (pain, strong sounds). Stresses associated with specific experiences of the patient are highly effective in producing marked ergotropic discharges. The state of ergotropic activation tends to be increased further by the fact that the sympathetic response is less adaptable in anxiety states than in control conditions, as experiments with repeated stimulation show. A high degree of arousal in anxiety, corresponding to the increased ergotropic downward discharges, is seen in the EEC. The frequency of the potentials is increased and the photic driving response is positively correlated to the emotional state: by determining the response to flashes presented at rates of 15 and 10/sec, it was found that the response ratio is highest in anxiety states and lowest in depressions, while normals occupy an intermediate position. The concentration in the blood of steroids of adrenocortical origin and/or corticotropin is augmented in anxiety. In view of the dependence of the rate of secretion of the adrenocortical hormones on ACTH and, indirectly, on the ergotropic division of the hypothalamus, these findings and the parallelism between 17-ketosteroid excretion and intensity of ergotropic activity strongly support the assumption that powerful ergotropic discharges prevail in anxiety. Various reports indicate that trophotropic discharges are likewise increased under these'conditions. Nausea, vomiting, and dizziness may occur. The EEG shows also more slow potentials than are seen in the controls. The simultaneous presence of an increase in the potentials of low and high frequencies and a decrease in those in the alpha range suggests that the trophotropic and ergotropic systems are activated at the same time. It follows from these considerations that a fundamental difference exists between fear and chronic anxiety. Acute fear is associated with a brief trophotropic discharge leading to cardiovascular collapse, loss in muscle tone, nausea, and slowing of the

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potentials in the EEC. A subacute condition of fear produced in the laboratory by various stresses, including mental tests, is accompanied by an increased excretion of adrenaline (but not of noradrenaline) while the muscle tone is not grossly affected. The greater sensitivity to Mecholyl and centrifugation in this state of fear as compared with that seen in an aggressive state (resentment) appears to be the result of a shift in the trophotropic-ergotropic balance to the trophotropic side. Reciprocity between ergotropic and trophotropic discharges is preserved and restitution of physiological and psychological functions is effected by procedures which tend to restore ergotropic activity. Chronic anxiety, on the contrary, develops on the basis of excessive ergotropic discharges which spill over into the trophotropic system. Reciprocal relations between the ergotropic and trophotropic systems are lost. As the following section shows, procedures which lower ergotropic activity tend to cure experimental and clinical neuroses. III. PHYSIOLOGICAL CONSIDERATIONS CONCERNING THE THERAPY OF NEUROSES

1. Experimental Neurosis It is easily understandable that drugs such as bromide (772) and other sedatives exert some beneficial effect since they reduce the reactivity of the ergotropic system. The elimination of the neurosis by thyroidectomy and its reappearance on the injection of thyroxin are likewise explainable on this basis (627). In the light of the feedback action of increased circulating concentrations of adrenal steroids on the posterior hypothalamus and adjacent areas (mammillary bodies and the posterior part of the tuber cinereum, 428), it is believed that the cure of experimental neurosis by the administration of cortin (628) and of ACTH (716) involves an inhibition of the posterior hypothalamus. The physiological antagonism between trophotropic alimentary and ergotropic defensive reflexes may be utilized to restore the ergotropictrophotropic balance. Masserman (690) observed a reduction in anxiety and phobic reactions of cats fed outside the experimental room before their exposure to the neurosis-producing situation and similar favorable effects of feeding were reported by Farber (276) in rats which had developed certain compulsory motor acts. The feeding by the human hand (690, 1000) in nonexperimental rooms and the gradual transition to rooms increasingly resembling the experimental room helped to eliminate the symptoms of experimental neurosis and to restore normal feeding habits. One gets the impression from Masserman's report* that gentling the neu*"If the animal in the experimental situation was gently brought to the foodbox by an experimenter it trusted, hand-fed by him, and then patiently retrained to take

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rotic animal would likewise contribute to restoring health. It does not seem necessary to "explain" this effect as "transference," since proper cutaneous stimuli induce pleasurable reactions apparently related to activation of the trophotropic system.* These as well as the feeding experiments tend to cure the experimental neurosis by shifting the balance to the trophotropic side and reciprocally inhibiting the ergotropic system. Clemente et al. (168) have shown that a very effective physiological and behavioral activation of the trophotropic system can be evoked by bilateral stimulation of the basal forebrain. Under this condition grouped potentials appear in the cortex which are accompanied by parasympathetic symptoms, loss of muscle tone, and sleep. It would be most interesting to determine the responsiveness of this forebrain area in experimental neurosis and the therapeutic effect of repeated stimulations on this clinical state. It has also been shown that the pairing of a sound (c.s.) with the stimulation of this area (u.s.) leads to a c.r.: the sound evokes sleep. This observation suggests that neocortical impulses which are conveyed to the basal forebrain area might be utilized in the psychotherapy of neuroses. 2. Clinical Neurosis Under the leadership of Wolpe (1000; see also 804) these principles have been applied with considerable success to a large number of neurotics. As the title of his book indicates, Wolpe gives prominence to the principle of reciprocal inhibition as a therapeutic procedure. Unquestionably this principle is operative if, as in animal experiments discussed earlier, a weak anxiety-producing stimulus is tolerated when it is presented during eating, and if on repetition of this procedure the stimulus can be gradually increased without evoking any disturbances. Rachman & Costello (see 804) discuss not only the famous case of Watson but two other cases of phobia in which the application of this principle was very effective therapeutically, while Clark (165) shows that improvement observed during this desensitization period manifests itself objectively in a progressive increase in skin resistance which is inversely related to the tone of the ergotropic system. Other procedures listed by Wolpe which were applied to the majority of patients are: 1. The elicitation of assertive, sexual, and relaxation responses which the food directly from the box, it gradually resumed normal feeding responses on signal and, despite residua of neurotic behavior, the anxiety, phobic, and regressive reactions gradually disappeared. This technic likewise partook of some of the elements of 'transference,' since the animal apparently utilized the security it had previously associated with the experimenter in resolving the fear component in its fearhunger motivational conflict. Conversely, if the animal had always feared the experimenter or had grown to distrust him, the technic was ineffectual." "See p. 16.

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in his opinion represent procedures of increasing "parasympathetic ascendance"; 2. Inhalation of 50-70 per cent CO2 in a single deep breath; and 3. "Interview-induced emotional responses."* Assertive responses are established by increasing the patient's motivation to express his resentment. He learns "to behave assertively in progressively more exacting circumstances and reports a growing feeling of ease in all relevant situations" (Wolpe's book, 1000, p. 115). Before this "feeling of ease" is attained, the patient learns to react to the situational stimuli with resentment rather than with anxiety. As we interpret their data, Funkenstein (309) and Cohen & Silverman (170) have clearly shown that resentment is characterized by strong ergotropic activity including secretion of noradrenaline.f The very strong sympathetic reactivity to a Mecholyl-induced hypotension and the gradual transition between resentment and ragej (with its marked somatic discharges ) leave little doubt that resentment is characterized not by a "parasympathetic-dominated response pattern" (1000) but, on the contrary, by intensive ergotropic discharges. Under the influence of psychotherapy the patient progresses from this stage to that of assertive responsiveness which to the writer represents an attitude reflecting a mood but not an emotional state. The chief difference between mood and emotion seems to lie in the fact that the emotion involves hormonal secretion and therefore tends to persist relatively long in contrast to the former. My state of assertive responsiveness may be boosted or lost almost instantaneously by a favorable or unfavorable statement about me by a person whose judgment I value highly. My resentment or rage, however, can neither be aroused nor turned off so easily, since the humoral response has a higher threshold (see Chapter VII) and lasts longer than the neurogenic discharge. If this is the case and if we bear in mind that self-assertiveness presupposes a high degree of vigilance and probably some increased tone in the striated muscles, self-assertiveness seems to be based on the cortical discharges (and feedback activities) which accom*Wolpe (1000) mentions two further procedures (p. 73), which are not discussed since they have not yet been tried adequately. I In addition, some parasympathetic discharges (of reflex origin?) are probably augmented in this emotional state, since increased vasodilatation and secretion are reported in the mucosa of the gastrointestinal tract and the nose (483, 999). Unfortunately, these findings are difficult to evaluate because the term anxiety is used differently by different authors. This may explain why Holmes et al. (483) contrast fear (and disgust) with anxiety, resentment, and feelings of frustration but do not note distinct differences in the action of anxiety and resentment on the nasal mucosa. t Anger is certainly due to a strong ergotropic discharge with sympathetic effects on pupil, sweat gland, blood pressure, etc. If, as Wolpe mentioned, anger is associated with a slowing of the heart rate, the slowing probably results from a reflexly induced activation of the sino-aortic baroreceptors but not from central parasympathetic discharges.

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pany a state of physiological balance of the hypothalamic system in which the ergotropic division is slightly dominant. Under these conditions the reciprocal relation between the ergotropic and trophotropic systems should be restored and the trophotropic fear component of the anxiety complex should be lessened or disappear. The gradual decline in anxiety through these psychotherapeutic procedures is further aided by "interview-induced emotional responses" (1000). Their purpose is to create an atmosphere of trust which is "anxiety inhibiting." Then a feeling of security probably develops, comparable to that seen in the experimental animal on petting, which leads to muscular relaxation, purring, cortical synchronization, and sleep. This syndrome, which may be elicited by stimulation of the anterior hypothalamus or the limbic brain (656), is the expression of an excitation of the trophotropic system. It may also result from a release of the trophotropic system following the bilateral ablation of the amygdala. Under these conditions fear and aggression are lessened and pleasure reactions are enhanced (580). The attainment of this state is obviously a desirable psychotherapeutic goal in clinical neuroses. Cortico-hypothalamic impulses of neocortical and limbic origin are thought to play an important role in producing such a shift in ergotropic-trophotropic balance and in restoring, thereby, normal behavior. Jacobson's method of muscular relaxation is discussed on p. 35. It aids the restitution of autonomic balance by reducing the action of proprioceptive impulses on the ergotropic division of the hypothalamic system. Meduna's (699) success in the treatment of neuroses with 30 per cent CO2 was interpreted as being due to a reduction in the reactivity of the sympathetic division of the hypothalamus (333). Wolpe applies this method in the modified form of La Verne (613) in which only a single deep inhalation of 70 per cent COL> is taken (and, in some instances, repeated two or three times after some interval). In such circumstances it is unlikely that the "narcotic" effect of CO^ is involved. The symptoms (rapid breathing, sensory excitation) suggest rather a strong excitation of the central nervous system which is followed by •! prolonged period of "relaxation," the physiological basis of which has not been investigated. From this brief and rather incomplete survey it is evident that the principle of reciprocal inhibition was applied to a limited extent only and that in most instances anxiety was lessened or eliminated by psychotherapy and muscular relaxation (including CO^), i.e., procedures which lead to a gradual diminution in the activity of the ergotropic system and thereby to a restitution of reciprocal relations between the ergotropic and trophotropic systems at the hypothalamic level. Wolpe's belief that neurosis is a learned emotional reaction and can be unlearned is supported by his clinical and experimental experiences. The physiological model of this learn-

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ing process is the experiment showing that an emotional reaction can be conditioned. If stimulation of the posterior hypothalamus is the u.s. and is combined with a sensory stimulus as a c.s., aggressiveness (746) and numerous autonomic reactions may be conditioned (10, 48, 896). Ban & Shinoda (49) showed also that these c.r. may be abolished by lack of reinforcement.* Although Pavlov and other investigators noted that experimental neurosis may be reversible, it was often necessary to interrupt the experiments for prolonged periods and in numerous instances the neurosis persisted for years. The intensity of hypothalamic excitation, the loss of reciprocal relations between the ergotropic and trophotropic systems, and the influence of both factors on hypothalamic-cortical relations seem to account for the severity and persistence of the disturbances of behavior. Moreover, the reader is reminded of the peculiar vicious cycle which develops in subacute states of fear and possibly also in anxiety as "compensatory" adrenomedullary secretion tends to weaken the activity of the ergotropic system (see pp. 137-138) and intensify the state of fear.f IV. CONDITIONING PROCESSES IN ABNORMAL MENTAL STATES The analysis of the therapeutic principles which are effective in the treatment of human neuroses seems to show that in spite of the great differences in the complexity of the symptoms at the human and animal level the basic disturbance is similar; cure is effected by the reduction of the activity of the ergotropic system and by the restitution of reciprocal relations between the ergotropic and the trophotropic systems. The studies by Alexander (13,14,15) furnish valuable quantitative data on conditioning in normal, neurotic, and psychotic persons with and without the addition of psychotropic drugs and contribute to a further analysis of the physiological basis of neurosis and related conditions. In this work c.r. were recorded in which sounds of different frequencies served as positive and negative c.s. while a shock to a finger was chosen as u.s. The effects of these stimuli on the EEC and particularly on the palmar skin resistance (psychogalvanic reflex, PGR) in different clinical conditions (anxiety, various forms of depression) may be compared with those seen in normal persons. In anxiety states signs of an "excitatory generalization" occur. In normal persons only the positive but not the negative (nonreinforced) c.s. evokes a PGR. In phobic states, however, even a negative c.s. elicits this reflex, which appears in a biphasic form not seen in normal subjects: a response occurring shortly after the onset of the negative c.s. is followed in the fifth second —that is, at the time when during the acquisition of the c.r. the 'This phenomenon is not seen in experimental neurosis. fSee Wolpe (1000) and Broadhurst (104) for the interpretation of these phenomena from the point of view of the theory of learning.

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positive c.s. had been reinforced (General Time Reflex, GTR) — by a second response (Fig. 4-4). Apparently the reciprocal innervation which permits the activation of the trophotropic system and the inhibition of the ergotropic system in response to the negative c.s. is abolished in this state. The generalization of excitation is basically similar to that seen in the excitatory form of experimental neurosis (although it is much stronger in the

Fig. 4-4. Effect of a nonreinforced conditional stimulus in a neurotic patient. Male, age 24, suffering from psychoneurosis, phobic reaction with obsessive features. Polygraphic recording illustrating a psychogalvanic reflex response to the inhibitory tone (CR — ) occurring 2 sec. after the onset of the tone, and an additional psychogalvanic reflex response beginning 0.8 sec. after the end of the tone, interpreted as a generalized time reflex (GTR) patterned after the response to the excitatory tone and its reinforcing stimulus. (From Alexander. Effects of psychotropic drugs on conditional responses in man. In: Neuro-Psychopharmacology, 2:97, Elsevier, Amsterdam, 1961.)

latter). Depressed patients, on the other hand, show minimal or no response to either the positive or the negative c.s. If the response to the positive c.s. is present, the PGR is weak and/or delayed and the alerting response of the cortex is absent. In its place a hypersynchronous period may appear in response to the positive c.s. instead of the blocking of the alpha potentials (desynchronization) which characterizes the normal response (Fig. 4-5). This paradoxical response is likewise seen in the normal person after administration of meprobamate or a phenothiazine preparation. It is suggested that in clinical depression and in the drug-induced state a shift in the ergotropic-trophotropic balance has taken place as in the inhibitory form of experimental neurosis.

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Fig. 4-5. Effect of a conditional stimulus on a depressed patient. Male, aged 19. depression, manic-depressive type. Fifteenth presentation of the excitatory tone. Note marked hypersynchronous sinusoidal buildup beginning 1.5 sec. after the onset of the tone and outlasting the tone and the reinforcing shock by 4.5 sec. Note also the absence of conditional PGR response to the tone and an adequate but delayed PGR response of 5,000 ohms to the shock. (From Alexander. Effects of psychotropic drugs on conditional responses in man. In: Neuro-Psychopharmacology, 2:101, Elsevier, Amsterdam, 1961.)

Marked changes in reflex action were seen when meprobamate or benactyzine were given singly or in combination to neurotic patients. Meprobamate administered in excitatory states induced an increase in skin resistance and lessened or abolished the signs of excitatory generalization (GTR). These results were to be expected in view of the lessened tone of the skeletal muscles (due to the action of the drug) which, in turn, reduces the central tone of the ergotropic system. At the same time the differentiation between the action of positive and negative c.s. was improved. More surprising is the fact that in depressive states this drug in response to positive c.s. will restore or improve the PGR and abolish the paradoxical synchronization effect in the EEC. In some instances these effects may even be replaced by a slight alerting reaction (13). Since meprobamate reduces rather than increases the ergotropic discharges, the reappearance of the ergotropic effects to positive c.s. can only mean that excessive ergotropic activity flows over into the trophotropic system and produces trophotropic effects in depressive states, and that its reduction to normal levels is associated with the restitution of the reciprocal inhibition of the trophotropic system and the restoration of the excitatory action of the ergotropic system. The reader will remember that the appearance of experimental neurosis as the result of excessive pain or of simultaneous trophotropic and ergotropic stimulation applied while the ergotropic activity of the

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hypothalamic system was at a high level was assumed to be due to such an overflow. Equally interesting are the effects of benactyzine per se or in combination with meprobamate. This drug has been found to be very effective in antagonizing the behavioral effects of preneurotic states. Cats which had been trained to open a food box to a c.s. were exposed to an air blast while they attempted to eat. This caused a marked lengthening of the "feeding cycle" and numerous "displacement" activities indicative of disturbed behavior (518). If continued or intensified this procedure led to experimental neurosis as discussed earlier. At the preneurotic stage benactyzine restores normal behavior (Fig. 4-6): in spite of the air blast feeding is practically undisturbed and the abnormal activities cease (519). Although it is impossible to give a simple classification of this drug, some further characteristics seen in normal animals must be listed. Benactyzine reduces signs of tension in conditioned rats (520), yet it increases the frequency of c.r. in partially conditioned animals and restores c.r. abolished by lack of reinforcement. The seemingly contrary effects — improvement and restitution of c.r. on one hand, and diminution of the motor

Fig. 4-6. The effect of saline and benactyzine on the neurotic behavior of the cat induced by repeated air blasts. Plus signs, etc. mean 1, 2, or 3 extra manipulations of the switch during the corresponding feeding cycle. "A 1.0 mg" indicates a dose of 1 mg. benactyzine hydrochloride 1 hr. before the experiment. "Saline" indicates the injection of 1 ml. saline 1 hr. before the experiment. The experiment shows that benactyzine shortens the feeding cycle and greatly reduces displacement activities. (From Jacobsen & Skaarup. Experimental induction of conflict-behaviour in cats: the effect of some anticholinergic compounds. Acta pharmacol. et toxicol. 11:125, 1955.)

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and autonomic symptoms of emotional excitement on the other — are found again in Alexander's conditioning studies on neuropsychiatric patients. Benactyzine increased the skin resistance (i.e., reduced the sympathetic tone in at least one area) while it improved differentiation of c.r. In combination with meprobamate this drug was particularly effective in restoring paradoxical and ultraparadoxical c.r. to normality, in improving differentiation of c.r., and in eliminating the generalization of excitatory effects. The improved differentiation (measured by the psychogalvanic reflex in response to positive and negative c.s.) was based on a reduction of the conditioned psychogalvanic reflex to the negative c.s. and on its increase in response to the positive c.s. Although many details need further clarification, it is of great interest to point out that experimental neurosis and clinical phobic and depressive states show an alteration in the trophotropic-ergotropic balance. Measured by the action of the c.s. on the PGR and the cortical alerting response, the over-all balance is shifted to the ergotropic side in the phobic, and to the trophotropic side in the depressive, state. This is indicated by the increased c.r. to positive c.s. and the generalization of excitatory effects in the phobic state and, conversely, by the reduced effects of these c.s. and the reversal of their action on the EEC (synchronization instead of desynchronization) in the depressive. Such shift in balance may also be attained by the administration of drugs to normal persons. It is important to add that experimental neurosis as well as abnormal clinical states seems to be characterized by simultaneous trophotropic and ergotropic discharges and loss of reciprocal innervation. This was pointed out for anxiety states earlier and seems to hold also for depressions which show in addition to trophotropic reactions in response to positive c.s. (13) signs of increased activity of the ergotropic system, since muscle tone (987) and secretion of corticosteroids (780) are increased, phenomena which are regulated by the sympathetic division of the hypothalamus. Even physical pain, which enhances primarily the tone of the ergotropic system, will in severe and chronic conditions lead to an overflow of the excitation into the trophotropic system. Alexander observed in some cases of this kind a hypersynchronous trophotropic response of the cortex to a positive c.s. Under these circumstances procedures which keep the excitatory level of the ergotropic system within certain limits so that the spread of excitation to the trophotropic system is avoided tend to restore reciprocal relations between the actions of the positive and negative c.s. These changes, indicated by alterations in conditioned behavior, may be accompanied by clinical improvement or cure.* "See also Selbach (886) who attempts to relate the action of psychoactive drugs to the responsiveness of the ergotropic and trophotropic systems.

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The widely different procedures which have been used to produce experimental neurosis have one feature in common: they lead to a breakdown in the reciprocity of the relations which exist under physiological conditions between the ergotropic and trophotropic systems in general and the ergotropic and trophotropic divisions of the hypothalamic system in particular. This disturbance seems due either to excessive excitation of the ergotropic system (following severe electrical shocks, for instance) or to the gradual buildup of such an excitation during the conditioning process. It is believed that in such circumstances the excitation spreads from the ergotropic to the trophotropic system, a spread indicated by the appearance of marked trophotropic symptoms such as excessive salivation, urination, defecation, erection, and vomiting. The more or less simultaneous corticopetal discharges of these physiologically antagonistic systems appear to be responsible for the behavioral disturbances, provided that the tone of the ergotropic system is high. This high tone is important, because trophotropic and ergotropic reflexes may occur simultaneously in the normal organism without inducing cerebral disturbances. It is suggested that the simultaneous activation of these antagonistic systems (due to nociceptive stimulation during a conditioned alimentary reflex or through presentation of too highly differentiated c.s.) induces likewise a breakdown of the reciprocity principle and thereby experimental neurosis. The quantitative changes in the response to positive and negative c.s. seen in preneurotic stages involving Pavlov's equalization and paradoxical phases, and the qualitative changes (reversal of autonomic reactions) seen in experimental neurosis seem to be due to a relative predominance of the trophotropic system. The reversibility of the preneurotic symptoms, with the disappearance of the abnormal trophotropic discharges (vomiting), and the demonstration in the physiological experiment that a shift in the trophotropic-ergotropic balance is accompanied by a reversal of autonomic reactions, support this interpretation. That trophotropic and ergotropic discharges are present at the same time in experimental neurosis is reflected in the EEC as well as in peripheral organs: increased muscle tone, an ergotropic symptom, may be combined with a sleep-like condition in the form of "pseudo-decerebrate" rigidity, and potentials of small amplitude and increased frequency indicative of increased excitation of the ergotropic system may appear in the EEC together with periods of large slow potentials which denote depression of cortical functions and occur in association with increased trophotropic discharges. Whether experimental neurosis appears in the excitatory or inhibitory type is largely determined by inherent characteristics (ergotropic-trophotropic balance), although external factors are of some influence.

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The chief psychological disturbance in clinical (and probably in experimental ) neurosis is anxiety. Its production is thought to involve intensive ergotropic discharges in the hypothalamic system overflowing into its trophotropic division. It is believed that the emotional disturbance results from the simultaneous action of the trophotropic and ergotropic systems on the cerebral cortex, whereas reciprocal relations between these systems prevail under physiological conditions. Recovery or cure of experimental neurosis is effected by procedures which reduce hypothalamic excitability to a level at which the abovementioned overflow does not occur. Reciprocal relations between the ergotropic and trophotropic systems are thereby restored. Experimental data suggest that these mechanisms account also for the clinical improvement induced by various procedures in human neurosis and in depressive states. There is a fundamental difference between states of fear (acute and subacute) and the chronic anxiety of experimental or clinical neuroses. In the states of fear the trophotropic-ergotropic balance is shifted to the trophotropic side and the tone of the ergotropic system is low, but reciprocity between trophotropic and ergotropic reactions is preserved. Chronic anxiety develops on the basis of such intensive ergotropic discharges that reciprocity between trophotropic and ergotropic reactions is lost. It is therefore understandable that in fear increased ergotropic activity tends to restore trophotropic-ergotropic balance and to end the fear, whereas in anxiety a reduction of ergotropic activity is necessary to restore ergotropic-trophotropic reciprocity and to cure the anxiety.

V

Aspects of Reticulo-Somatic Interactions

THE preceding chapters have dealt chiefly with the general characteristics of the ergotropic and trophotropic systems and their mutual relations. Thus in Chapter I the ergotropic syndrome was contrasted with the trophotropic syndrome; the existence of reciprocal relations between the two systems was derived from experiments in which the threshold of one system was determined at different levels of activity of the other system and also from the effect of diencephalic and brain stem lesions on the reactivity of these systems. Their role in the learning process was analyzed in Chapter III and interference with the principle of reciprocity was discussed in Chapters II and IV; such interference resulted in disturbances of consciousness (Chapter II) and severe alterations of behavior (Chapter IV). These data will be supplemented in the present chapter by a discussion of the mechanisms linking the visceral and somatic components that constitute the ergotropic system and by an attempt to evaluate further the physiological, psychological, and pathological significance of this linkage. The first group of experiments deals with the influence of the hypothalamic system on movements, the second analyzes the interrelation between hypothalamic and sensory functions. I. EFFECT OF THE RETICULAR FORMATION ON THE

MOTOR SYSTEM 1. Facilitation of Movements through the Reticulo-Hypothalamic System The first question to be investigated concerns the influence of the activation of the autonomic system on the intensity and general characteristics of movements. The term "autonomic" is not used in the older sense of a structure providing only efferent mechanisms to smooth muscles and glands (611), but takes into consideration that afferent as well-as efferent impulses originate from the diencephalon and brain stem and that the afferent impulses influence neocortex and limbic cortex (728, 744, 952).* Specifically, we confine our discussion to the influence of the excitation *For anatomical references see 510, 750, and 752.

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of the hypothalamus and reticular formation on movements. In view of the close relation between emotional excitement and excitation of the sympathetic division of the hypothalamus, this discussion should provide some insight into the physiological mechanisms whereby a person physically in desperate straits is able greatly to increase his muscular strength and endurance. The survival value of these reactions is obvious. It has been found that cortically or reflexly induced movements can be greatly enhanced by stimulation of the hypothalamus or the reticular formation.* If stimulation of a site in the motor cortex is combined with a near-threshold stimulation of the hypothalamus, which by itself produces sympathetic but no somatic effects, the movements of the extremities are increased. They appear with a shorter latent period and with increased magnitude and may involve joints not activated when the cortical site was stimulated alone. The facilitatory effect appears also in the form of after-discharges (rhythmic pawing movements), and movements may be seen even in experiments in which cortical and hypothalamic subthreshold stimuli are combined. Unilateral hypothalamic stimulation exerts a facilitatory effect on the ipsilateral and contralateral motor cortex. Although the strongest facilitatory effects are obtained from the sympathetic division of the hypothalamus, the elimination of the cervical sympathetics and the ligation of the adrenal veins do not interfere with this action of hypothalamic stimulation. This effect seems to be due, at least in part, to the action of hypothalamic impulses impinging on the motor cortex, since the movements resulting from the facilitatory effect of subthreshold hypothalamic stimulation can be duplicated by increasing the cortical but not by intensifying the hypothalamic stimulus. In the latter case a different type of movement, showing bilaterality and prominence of a strong postural component, appears instead of the phasic movements involving the various joints in sequence which are seen on stimulation of the motor cortex with and without subthreshold stimulation of the hypothalamus (743). Moreover, Dr. Koella recorded pyramidal action potentials above the transection of the pyramidal tracts in my laboratory and found that their frequency increased when the hypothalamus was stimulated directly or reflexly via nociceptive impulses (see 338). That sciatic stimulation increases discharges of the pyramidal tract also has been reported by Purpura et al. (801). Such discharges may likewise be evoked by auditory stimuli (137) which are known to elicit responses in hypothalamus and reticular formation (665), and Bruner et al. (118) implicate the median thalamic nuclei in this action, f Furthermore, the *Jasper (521) showed that stimulation of the intralaminar thalamic nuclei likewise facilitates cortically induced movements. t However, the subcortical structures involved in the activation of the motor cortex following hypothalamic and sensory stimulation may not be the same (see also 510 and 774).

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intensity of pyramidal discharges declines markedly as the animal passes from wakefulness to synchronized sleep (32). It seems to follow that sensory impulses as well as the ergotropic state of activity of hypothalamus and reticular formation enhance discharges from the motor cortex. Strong hypothalamic-cortical discharges are thought to account for the temporary restoration of ejaculatory speech which occurs in aphasia under conditions of emotional excitement (995). The increased strength and endurance seen in emotional states is related also to the facilitatory effects of hypothalamic-reticular excitation on the spinal cord. Stimulation of the hypothalamus and various parts of the reticular formation greatly enhances cortically as well as reflexly induced movements (829). Moreover, spinal reflexes are increased when, after the removal of the motor cortex, the pyramidal tracts are stimulated. Though this experiment clearly proves the importance of the spinal cord as a site of facilitation, it does not invalidate the evidence cited earlier in favor of a cortical facilitation under the impact of increased hypothalamic activity. Finally, it must be remembered that stimulation of sympathetic nerves delays fatigue in the isolated muscle. This phenomenon, originally described by Orbeli and confirmed in numerous papers from Asher's laboratory (see 604), suggests that the liberation of noradrenaline from the sympathetic nerve endings counteracts fatigue and contributes to muscular endurance in the emotional state. The motor endplates are sensitized to acetylcholine in the presence of noradrenaline, and this improved neuromuscular transmission seems to play a major role in the Orbeli effect (506). 2. Pain and Movements The most familiar action of nociceptive stimulation is the elicitation of the flexor reflex which "tends to protect the threatened part by escape or defence" (Sherrington, 893). This author, who studied nociceptive reflexes extensively in the spinal animal, called them "prepotent" because they "prevail over reflexes of other species when in competition for the use of the final common path." In addition to the spinal effects, nociceptive stimuli also elicit responses with a greater latent period. These are protective in character but variable in pattern and are thought to be mediated via the cerebrum (422•). Since the discussion in the preceding section has shown that various sensory impulses and particularly nociceptive stimuli increase pyramidal discharges, one would expect that under these conditions the responsiveness of the motor cortex would be enhanced. Experiments showed that the injection of a hypertonic NaCl solution, or the faradization of a muscle used for the excitation of nociceptive nerves, caused the pupils to dilate and the nictitating membrane (n.m.) to contract in the anesthetized cat.

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While these autonomic changes (which accompany the perception of pain in the waking animal) took place, the responsiveness of the motor cortex was greatly increased. The enhanced excitatory effect appeared not only as intensification and more rapid development of the movements than were seen under control conditions but also in a spread to other joints not activated in the control test. Movements appeared even ipsilateral to the side of cortical stimulation (377). That this facilitatory action of nociceptive stimuli involves supraspinal structures in part is apparent if one compares it with that seen in the spinal animal. In the latter the flexor reflex is augmented by ipsilateral and diminished by contralateral nociceptive stimuli, whereas the action of cortically induced movements is increased regardless of whether the nociceptive stimuli are applied on the left or right-side. The similarity of the action on the motor cortex of nociceptive stimulation to that produced by hypothalamic stimuli is obvious. It is believed that in both instances the hypothalamic or nociceptive stimuli enhance the degree of excitation of the motor area and that this interaction as well as similar processes taking place at the spinal level accounts for the increased movements. From these experiments it may be concluded that nociceptive as well as hypothalamic stimulation activates the ergotropic system —the EEG shows desynchronization, strong sympathetic discharges are evoked,* and the somatic discharges are greatly increased, presumably involving the gamma system at cortical and hypothalamic levels (399, 402). Darwin (192) pointed out in 1873 that pain increases the effort to escape and Cannon (145) showed that pain and emotional excitement augment sympathetic discharges and adrenomedullary secretion. The results are a redistribution of blood and an increase in the blood-sugar level favorable to prolonged muscular activity as well as an acceleration of blood clotting which is of obvious survival value. There are, however, more severe painful states in which a different behavior prevails. If, for instance, a leg is fractured, the severe pain will evoke the above-mentioned ergotropic symptoms but at the same time strong inhibitory phenomena occur. What is the nature of this "inhibition" which apparently makes volitional movements in a fractured limb impossible? Hess (459) made a few simple but pertinent observations on the behavior of his dog after it had fractured a hindleg. Running up and down stairs on three legs and carrying out complex and intensive movements apparently did not lead to any spread of innervation into the injured leg. This activity did not elicit any signs of discomfort, although the fractured leg was very sensitive to touch. In addition, the muscles of the broken leg * Nociceptive stimuli greatly increase the size of the low-resistance area of the skin of the hand and face. The sympathetic discharges to the sweat glands which account for this effect are obviously widespread, since ischemic pain of the foot may alter the skin resistance in the contralateral hand (943).

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did not show shivering on exposure to cold and the supporting reflex was absent when the dog, several weeks after injury, attempted to urinate and lifted the opposite (healthy) leg. Hess suggests that reflex inhibition of the injured leg prevents voluntary impulses or reflex stimuli from impinging on it and thereby secures immobilization. It is obvious that the flexor reflex is highly active upon nociceptive stimulation and secures the withdrawal of the injured leg. This effect makes it possible for the dog to "neglect" the injured leg during running. Apparently non-nociceptive reflexes of cutaneous or proprioceptive origin cannot be elicited in a "painful" leg. Thus, in the cat the knee jerk is inhibited when nociceptive impulses leading to pupillary dilatation and vocalization are produced in the hamstring muscles through injection of hypertonic NaCl solution (942), and in man the triceps reflex disappears under the influence of ischemic pain* in this muscle (378). Thalamic pain in man has been shown to abolish associated movements which are evoked under control conditions through strong proprioceptive discharges (351). As mentioned earlier, the supporting reflex and shivering are likewise inhibited by pain. The former is elicited through cutaneous and proprioceptive impulses, whereas the latter is a reflex which involves proprioceptive discharges (779) and is controlled by supraspinal centers, particularly in the hypothalamus. Heating of its anterior division inhibits shivering by inhibiting the gamma system whereas stimulation of the posterior hypothalamus intensifies it (263, 443). It follows from this brief survey that a great variety of reflexes are blocked in the painful region. This effect is not related to the type of receptors or the complexity of the nervous organization of the various reflexes. It affects equally spinal and supraspinal reflexes, associated movements initiated by volitional impulses, and probably willed movements. The cause of this inhibition seems to lie in the prepotency of the flexor reflex emphasized by Sherrington. It does not allow other reflexes to occupy the final common path while strong nociceptive impulses prevail. At the same time the antagonists are reciprocally inhibited and block thereby any reflex action involving this group of muscles. Under these circumstances impulses associated with volitional acts are likewise prevented from inducing movements in the pain-afflicted area. Thus, through a simple law of the physiology of the spinal cord, reflexly induced and volitional movements are abolished in the painful area. It is assumed, however, that the activation of the hypothalamus through nociceptive stimuli is not disturbed by local pain and it seems probable that the pain-induced facilitation of the motor apparatus is retained in areas outside that from which the pain originates. This assumption, however, has not yet been tested experimentally. 'Ischemia by itself as applied in these experiments does not reduce the reflex.

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3. Facilitation of Convulsive Discharges The mechanisms which were shown to increase the discharges from motor cortex and spinal cord when the diffuse ascending system is activated at mesencephalic or diencephalic levels account also for the intensification and spread of focal convulsive discharges and the precipitation of convulsions. Emotional excitement (see 908 for the literature) as well as various sensory stimuli may induce convulsive discharges in certain cortical areas not seen in the EEC under control conditions. The administration of a convulsant such as Metrazol (in a subconvulsive dose) is often used in conjunction with a photic stimulus to precipitate a convulsive discharge for diagnostic purposes. Experimentally it was first shown by Amantea (19; see also 736) that sensory stimuli elicit localized convulsive movements or generalized convulsions after strychninization of the motor cortex. Recording of pyramidal activity or of single units in the pyramidal tracts under these conditions shows that sensory stimuli accelerate the high-frequency bursts which characterize convulsive pyramidal discharges (9). When convulsants such as picrotoxin are administered intravenously in subconvulsive doses, nociceptive or hypothalamic stimuli evoke or intensify convulsive discharges in hypothalamus and, diffusely, in the cerebral cortex (354, 355). This facilitation of convulsive discharges through direct or reflexly induced activation of hypothalamus and reticular formation involves increased discharges from the diffuse ascending systems which augment the activity of the motor cortex and of other cortical areas. Through the motor cortex the pyramidal discharges are enhanced. In addition, the reticular formation enhances the reflex excitability of spinal neurons (665) and thereby further augments the responsiveness of the motoneurons at the spinal level. The importance of the discharge from the hypothalamus or the reticular formation for the enhancement or the precipitation of convulsions is evident from the following observations: 1. Injection of nembutal into the posterior hypothalamus or bilateral coagulation of this area reduces or abolishes cortically induced strychnine spikes (337). Reduction in excitability of the posterior hypothalamus by curare has a similar effect (340). 2. Stimulation of the hypothalamus or the reticular formation in animals injected with subconvulsive doses of picrotoxin or Metrazol precipitates convulsive discharges in motor and sensory cortical areas (see Fig. 5-1). These discharges are associated with similar convulsive spikes in various parts of the diffuse ascending excitatory system (centrum medianum, posterior hypothalamus, and mesencephalic part of the reticular formation). 3. A photic stimulus elicits diffuse cortical and subcortical convulsive discharges (involving hypothalamus, reticular formation, and centrum medianum) after an epileptogenic focus has been created in the mesence-

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Fig. 5-1. Precipitation of convulsions by stimulation of the reticular formation in a cat injected with Metrazol. Metrazol (20 mg/kg i.v.) had been injected 48 min. earlier. A: control; B: 2 min. after stimulation (1.9 v., 100 c/sec for 10 sec.); C: 2 min. after B; 1: anterior sigmoid gyrus; 2: posterior sigmoid gyrus; 3: posterior hypothalamus; 4: reticular formation (midbrain). 200/uv., 5 sec. (From Gellhorn, Ballin, & Kawakami. Studies on experimental convulsions with emphasis on the role of the hypothalamus and the reticular formation. Epilepsia 1:238, Elsevier, Amsterdam, 1959.)

phalic tegmentum by penicillin, although no convulsive spikes were present before the stimulation (40). 4. A convulsive focus created in the posterior hypothalamus causes diffuse synchronous spikes to appear in cortex and subcortical diencephalic structures in deep asphyxia (359). * Studies by Buser et al. (138) contribute further to the understanding of the mechanism by which visual or acoustic stimuli accentuate or precipitate convulsions. These stimuli increase, in the chloralosed cat, pyramidal as well as extrapyramidal discharges — the latter indicated by increased potentials in the anterior roots of the spinal cord which persist after pyramidotomy. From various operative procedures leading to partial or complete isolation of the visual and acoustic cortical projection areas, it is concluded that the cortico-cortical transmission between motor and sensory areas is of less importance than a cortico-subcortico-cortical circuit which involves the centrum medianum and mesencephalic reticular formation.! It is interesting to point out that investigations of cortico-cortical conditioning (see p. 76) led to similar conclusions. II. INTERRELATIONS BETWEEN THE SENSORY AND THE RETICULAR SYSTEMS

Since numerous examples of the action of the sensory stimuli on the hypothalamic system and the reticular formation have been given in Chapter I, only a brief resume and some supplementary comments are necessary here. It will be remembered that ergotropic and trophotropic *For further details see 358. tThe role of the hypothalamus was not investigated.

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systems are reciprocally related and in a state of tonic activity, the latter being dependent chiefly on changes in internal environment and on afferent impulses. Sensory impulses of all modalities have been found to excite the ergotropic system, but they do so to very different degrees. In the cat nociceptive, proprioceptive, acoustic, and optic stimuli show a decreasing effect on the arousal and activation of the sympathetic division of the hypothalamus (71, 332; Fig. 5-2). Olfactory stimuli are likewise powerful stimulators of the arousal reaction. The mere blowing of air into the nose elicits this effect in the cerveau isole in which participation of the Vth nerve is excluded through intracollicular transection. Optic stimuli do not produce arousal in this preparation (33). Most important for the maintenance of wakefulness are impulses from the Vth nerve. The bilateral removal of the Gasserian ganglion produces in the cat with spinal transection at Ci (encephale isole) a sleep pattern in the electrocorticogram, but this change in the EEG does not follow the

Fig. 5-2. Effect of different afferent impulses on activation of hypothalamus and cortex. "Moderately light" cat, 24 hr. after Dial-urethane. 1: left lateral mammillary nucleus; 2: left sensori-motor area; 3: left primary auditory area; 4: left optic area. A: partially generalized cortical response with activation of posterior hypothalamus in response to proprioceptive stimulation; excitation in lateral mammillary nucleus, sensori-motor, and optic areas and no excitation in auditory area. B: generalized cortical response with activation of posterior hypothalamus in response to nociceptive stimulation. C: specific response of auditory cortex to acoustic stimuli indicated in bottom line. (From Bernhaut, Gellhorn, & Rasmussen. Experimental contributions to the problem of consciousness. J. Neurophysiol. 16:21, 1953.)

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Fig. 5-3. The importance of afferent impulses, particularly from the Vth nerve, for the activity of the EEC in the encephale isole. A: 1 hr. 45 min. after section of the spinal cord and immediately after section of the VHIth nerves; B: 2hr. 45 min. after A and 1 hr. 30 min. after section of the vagi; C: 15 min. after removal of right Gasserion ganglion. Note: cortical synchronization followed by arousal through olfactory stimulation; D: 1 hr. after removal of left Gasserion ganglion. Arrow shows arousal through mechanical stimulation of the reticular formation. (From Roger, Rossi, & Zirondoli. Le role des afferences des nerfs craniens dans le maintien de 1'etat vigile de la preparation "encephale isole," EEG clin. Neurophysiol. 8:8, Elsevier, Amsterdam, 1956.)

removal of other somatic or visceral afferent nerves (837; Fig. 5-3). However, afferent as well as cortically induced discharges are capable of temporarily producing a general arousal in cats deprived of the Vth nerve ganglia. Afferent impulses originating in the viscera contribute likewise to the tone of the ergotropic system. Thus, stimulation of the central end of sectioned visceral nerves (vagi, splanchnics) leads to a diffuse cortical desynchronization (1017), and blocking the vagi with direct currents induces cortical synchronization and behavioral sleep in waking cats (776). Recording of single unit activity in the reticular formation has shown that afferent stimuli "drive" these units, but no unit responds to all sensory modalities, and marked differences exist in the spatial distribution of exci-

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tation induced by different afferent nerves (872). The latter phenomenon is probably related to the relative effectiveness of various sensory modalities to produce arousal. It may be said that the state of arousal is influenced by the impulses impinging on the reticular formation through exteroceptors, interoceptors, and proprioceptors. The trophotropic system is also activated by afferent impulses. Stimulation of the vagi elicits synchronization of cortical potentials. This effect appears with a considerable latent period whereas the excitatory, desynchronizing action is immediate (88). As was mentioned earlier, low-frequency stimulation of cutaneous afferent nerves produces synchronization and also behavioral sleep. In such conditions units in the medulla oblongata and pons are activated, whereas stimulation of cutaneous nerves with higher intensities and frequencies inducing arousal drive reticular units chiefly in pons and midbrain (791). These investigations suggest that afferent impulses contribute to the tone and reactivity of the trophotropic division of the reticular formation. Feedback mechanisms have an important influence on the tone and reactivity of the reticular system. Thus, activation of the reticular formation at the hypothalamic and midbrain level leads to increased discharges of the alpha and gamma neurons in the spinal cord and thereby to enhanced proprioceptive activity, which in turn is essential for the maintenance of the tonic activity of the ergotropic system.* There is also evidence that stimulation of sympathetic fibers in the skin lowers the threshold of cutaneous receptors and induces activity in these receptors without mechanical stimulation. An adrenaline-like neurohumor is liberated under these conditions (644). Tactile, visual, auditory, and nociceptive stimuli may lead reflexly to increased afferent discharges from the skin,f provided that they are preceded by efferent spikes which are apparently of sympathetic origin. These responses fail to appear in the sympathectomized skin (163). It seems to follow that ergotropic discharges cause the liberation of neurohumors from the endings of the sympathetic nerves and thereby activate somatic receptors. This feedback is thought to play a part in arousal. It is commonly assumed that afferent and particularly proprioceptive impulses play an indispensable part in the genesis of willed movements (see 335 and 351 for the literature). In flaccid frogs which are in the socalled hypnotic state sympathetic discharges regularly precede the occurrence of "voluntary" movements. These important observations of Chernet*See p. 26 about the role of proprioception in hypothalamic reactivity and wakefulness. tThis includes skin innervated by cutaneous branches of the Vth nerve whose importance for the maintenance of arousal was stressed earlier.

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ski (163) suggest that willed movements require the integration of sympathetic and somatic (sensory and motor) activity. In view of the marked facilitation of motor cortex functions through impulses from the sympathetic division of the hypothalamus, it appears not unlikely that this mechanism plays a role in the causation of voluntary movements in higher organisms, whereas in lower forms such as amphibia the peripheral sympathetic-sensory link is primarily involved. Numerous special problems of considerable physiological and psychological significance involve the reticulo-sensory relations. The effect of hypothalamic excitation on the subcortical and cortical action of specific (visual, auditory) afferent impulses and its importance for perception (see p. 13) and also the inhibition of somatic afferent discharges resulting from reticular stimulation and its role in "attention" (see p. 63) were briefly mentioned earlier. The detailed discussion of these and related problems (such as the state of wakefulness and its influence on the action of afferent impulses on the cortex) is beyond the scope of this book. However, two questions in this area will be dealt with: first, the role of afferent impulses in the development of the emotions in general and empathy in particular; and second, the influence of the emotions on perception. III. THE CONTRIBUTION OF AFFERENT IMPULSES TO THE EMOTIONS

Some years ago, in reading Nietzsche's Menschliches Allzumenschliches (756), I was struck by the following assertion: "He who always wears the mask of a friendly man must at last gain a power over friendliness of disposition, without which the expression itself of friendliness is not to be gained — and finally friendliness of disposition gains the ascendancy over him — he is benevolent." This statement prompted me to find out whether it is supportable on physiological grounds. Emotions are expressed through tonic and phasic changes in the striated muscles. The former appear as alterations in posture, the latter as contractions of the facial muscles. The following discussion attempts to evaluate the significance of these patterns of innervation for the formation of the emotions. 1. Posture and Mood* Our starting point is the fact (see p. 10) that proprioceptive impulses increase the excitability of the sympathetic division of the hypothalamus and the intensity of hypothalamic-cortical discharges and that, conversely, loss in muscle tone lessens these symptoms of ergotropic activity and favors a shift in ergotropic-trophotropic balance. It may therefore be said that *This and the following two sections are reproduced from my Motion & Emotion. Psychol. Rev. 71:463-467, 1964, with the permission of the American Psychological Association.

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different settings of the hypothalamic balance may be produced by different types and intensities of afferent stimulation. Considering the latter first, we know that the loss in muscle tone which accompanies sadness and similar moods (576) is associated with characteristic postures which are diametrically opposed to those seen in a happy mood. The low intensity of proprioceptive impulses prevailing in a state of sadness would seem to contribute to the shift in hypothalamic balance to the parasympathetic side and to its maintenance, and a corresponding statement would apply to the role of increased proprioceptive discharges and the state of sympathetic hypothalamic dominance in some forms of the happy state. Although a specific stimulus, mostly in the form of symbols (words seen or heard), appears to be the direct cause of mood or emotion, the setting of the hypothalamic balance through the total quantity of proprioceptive impulses impinging on the hypothalamus per unit of time is of considerable importance. If on receiving the news of a great loss one would make up one's mind to strut back and forth with chest expanded, this posture would interfere with the development of a sad mood appropriate to the occasion. Conversely, sitting with hunched shoulders as if one had just heard of a tragedy would hardly allow one to experience the uplifting effect of listening to a great Mozart quartet. This close relation between bodily posture and mood, recognized in the German language by the word Haltung, which means external carriage (posture) as well as the inner attitude, permitted Kretschmer (600) to make the terse statement: "Die innere Haltung ist von der Aussenhaltung induzierbar und umgekehrt."* Our interpretation of the relation between posture, mood, and emotional responsiveness is supported by experiments using hypnosis. In numerous tests it has been impossible to induce a certain feeling which is unrelated to the directly suggested motor attitude. If, for instance, the posture accompanying "triumph" is suggested and "locked" in hypnosis, a depressive mood cannot be brought about unless the postural setting is changed (770).f These experiments and considerations suggest that a mood depends to an important degree on posture or, physiologically speaking, on the quantity of proprioceptive impulses which by their action on the posterior hypothalamus influence the hypothalamic balance. Apparently not only abnormal degrees of muscle tension seen in the neurotic but also physiological variations in the degree of proprioceptive discharges have an im*The inner attitude may be induced through the external posture, and vice versa. See also Bull (130), who emphasizes on psychological grounds that "no mental attitude is possible without a motor attitude." f Bull's book (130), which I read after this section and the greater part of this book had been written, contains psychological formulations in which the "attitude" is considered the basis of feeling of emotion and action. The balance of the hypothalamus, which determines mood and posture through upward and downward discharges, seems to be closely related to the motor attitude described by Bull.

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portant influence on the state of "hypothalamic tuning" and thereby on emotional responsiveness. Needless to say, many other factors such as age and experience not yet amenable to further analysis are responsible for producing the numerous shades of mood known to us and expressed by appropriate verbal symbols (84). The fact that the happy as well as the tense mood is associated with increased proprioceptive discharges and that, conversely, a loss in muscle tone occurs in such widely different moods as sadness and postprandial happiness shows that mood and the tendency to experience certain emotions is not solely determined by afferent impulses. As Schachter expresses it, "an emotional state may be considered a function of a state of physiological arousal and a cognition appropriate to this state of arousal. The cognition, in a sense, exerts a steering function. Cognitions arising from the immediate situation as interpreted by past experience provide the framework within which one understands and labels one's feelings." Depending on the immediate situation, an emotional arousal induced by adrenaline may result in euphoria or anger (868). These situations and past experiences may produce different states of ergotropic-trophotropic tuning, however, and thereby predispose to certain emotions. As experiments by Lissak et al. (639) (see Chapter III) have shown, the same stimulus applied to the centrum medianum elicits an escape reaction (suggesting fear) in one situation but sleep in another. Although the hypothalamic balance influences the general type of hypothalamic-cortical discharge which will appear in response to stimulation, it seems highly probable that specific emotions require, in addition, a great variety of stimuli. They may consist of numerous and complex events, but relatively simple stimulus situations may also play a significant role. 2. Facial Movements and Emotions Since Darwin (192) and Duchenne (229) published their work, the role of the movements expressing emotions has been studied intensively. The theory of James and Lange that the emotions are based on visceral effects was rejected by Cannon (146) partly on the grounds that these actions, due to their slowness and lack of differentiation, could not account for the great variety of human emotions (see also 370). This argument would hardly hold for the expressive movements of the face. In a recent review Tomkins (954) emphasizes the following facts: (a) the great density in the newborn of receptor-effector units in the face; (b) the dominance of the face in tactual experiments on children when face and another cutaneous area are stimulated simultaneously; (c) the greater persistence of movements to repeated startle reactions as compared with movements in other parts of the body; (d) the absence of fascia in facial muscles, which makes it possible to contract small bundles of these mus-

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cles through the extensive branches of the facial nerves and thereby to increase the variety of contraction patterns. From the neurophysiological point of view it seems probable that in the development of an emotion in the social setting the following phenomena play an important role: 1. The hypothalamic discharge, which, initiated by the sight of a smile or the sound of laughter, the threat of an intravenous injection or the sight of blood, etc., leads to alterations in autonomic balance, muscle tone, and cortical excitation; 2. The specific facial movements which are similar to those resulting from stimulation of the hypothalamus (887) or limbic brain (655, 900) and fundamentally different from cortically initiated movements.* The former are preserved when, on account of capsular lesions, willed movements of the lower face are abolished (681), and are present also in the newborn in which, due to fetal disturbances, the cerebral hemispheres are lacking (241,544); 3. The proprioceptive and cutaneous impulses elicited by tonic and phasic changes in the facial and skeletal muscles. Sensations as well as stimuli of a higher order involving symbols and memory processes arouse emotions. Murphy & Gellhorn's work (743, 744), showing that strychninization of a cortical site located in the sensory projections or association areas leads to the appearance of strychnine spikes in the hypothalamus, illustrates, at least in principle, the underlying neurophysiological mechanisms.f Excitation of the hypothalamus causes upward and downward discharges, and proprioceptive discharges resulting from the contraction of any skeletal muscles are enhanced via the gamma system when the brain stem is aroused in emotion. Although the activation of the hypothalamic-cortical system through proprioceptive impulses is well established (71), no specific experiments have been performed on the relation of the facial muscles to the hypothalamus 4 In view of their involvement in emotion and their contraction in typical emotional patterns on hypothalamic stimulation, it is to be expected that afferent impulses arising from the face during emotional expression contribute to hypothalamic excitation and hypothalamic-cortical discharges. The great density of the cutaneous receptors in the face and the considerable variety of the patterns of contraction of the facial muscles suggest that the resulting patterns of neocortical excitation and hypo*See Hinsey (471) for the persistence of hypothalamically induced movements after degeneration of corticobulbar and corticospinal fibers. tSee also 337. | It would be of great interest to determine whether stimulation of various facial muscles, singly and in combinations characteristic for emotional expression, would lead to distinct patterns of hypothalamic excitation through afferent discharges originating in the skin of the face, muscles, joints, etc.

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thalamic-cortical discharges will match in diversity the variety of emotional expressions.* The interaction at the cortical level between impulses originating during emotional expressions in tactile cutaneous end organs of the face and transmitted through specific afferent systems to the sensori-motor cortex and the hypothalamic-cortical discharges originating in proprioceptive discharges from the facial and skeletal muscles has not yet been investigated. It is not unlikely, however, that work on the interaction between hypothalamic and sensory impulses involving optic and acoustic stimuli has furnished results which are applicable to our problem. These studies (336, 367, 368) have shown that direct stimulation of the hypothalamus or activation of this structure via nociceptive reflexes leads to a marked enhancement of the effect of either optic or acoustic stimuli on the cortex. Thus, direct or reflexly induced hypothalamic excitation, which does not seem to alter the electrocorticogram, increases the frequency and/or amplitude of the optically induced potentials. Often multiple responses appear in response to the sensory stimuli during hypothalamic excitation while single potentials prevail in the control test (without hypothalamic involvement). Moreover, the duration of the enhanced response is greatly increased (prolonged after discharges) and even cortical areas which do not respond to the sensory stimulus by itself show marked reactions under the influence of hypothalamic facilitation. The magnitude of these effects is quantitatively related to the intensity or frequency of hypothalamic stimulation and is particularly well demonstrated when a small area of the sensory cortex is strychninized.f This interaction is thought to underlie perception, behavioral observations supporting this interpretation (338). Thus a cat which does not react to a certain optical or acoustic stimulus will follow this stimulus during a mild stimulation of the posterior hypothalamus which by itself results only in pupillary dilation and contraction of the nictitating membranes But the application of these findings goes further. Experiments involving *Brodal (107) suggests that proprioceptive impulses from mimetic muscles are transmitted through the facial and not through the trigeminal nerve. f Further investigations should determine whether cutaneous stimulation of the face tends to excite the underlying muscles as Hagbarth (421) established for skeletal muscles. If this were the case, the pattern of the proprioceptive facial discharges would probably undergo quantitative and qualitative changes depending on the intensity and spatial distribution of the excitation of the cutaneous area and its relation to the facial muscles. The diversity of the proprioceptive facial patterns impinging on the hypothalamic system in different emotions would thus be greatly increased. Although the fast-conducting muscle afferents (group I) do not project to the cortex (741), there is little doubt that movements or muscle tension, resulting in excitation of Pacinian corpuscles (697) and joint receptors, excite the motor cortex (327, 672) and modify its reactivity (365). Moreover, increased discharges from the muscle spindles induce diffuse cortical desynchronization (740). JSee also Thompson (944), concerning the loss of visual discriminative behavior in rats with posterior hypothalamic lesions.

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stimulation of the limbic brain have shown that there is a gradual transition from arousal, during which the animal reacts to environmental stimuli, to an emotional state disclosed by signs of fear and anger (161, 441, 502). It seems not improbable, therefore, that the sensory-hypothalamic interaction in the neocortex accounts also for the qualitative changes in sensations and perceptions during emotional excitation. The fact that this facilitative action of hypothalamic-cortical discharges is not confined to the sensory projection areas and to the motor cortex (744) but extends to the association areas as well (336) suggests that it may play a role in recalling past events. It should also be remembered that memory processes as well as perceptions are facilitated in the emotional states (696, 811). In the light of this discussion facial proprioceptive and cutaneous impulses seem to play an important role in facilitating the complex interactions between brain stem and limbic and neocortex which occur during emotion, and to contribute to the variety of cortical patterns of excitation which underlie specific emotions. It should be added that the facial expressions accompanying the emotions which were emphasized in this discussion, as well as the associated vocal behavior, can be elicited from the dorsomedial parts of the amygdala, the anterior and intermediate hypothalamus, and the central midbrain. In this sequence, lesions in these areas interfere to an increasing degree with these characteristic expressions of behavior (288, 289).* A complete destruction of the hypothalamus at the level of the mammillary bodies in the cat does not interfere with the emotional expression to nociceptive stimulation but delays it in response to a barking dog (563). Studies on patients have likewise shown that smiling, laughter, and an urge to excited speech similar to that seen on mechanical stimulation of the hypothalamus can be elicited from the pallidum and parts of the ventral thalamic nuclei. It is worthy of mention that corresponding emotions are evoked at the same time (436). 3. The Significance of Loss of Facial Expression The hypothesis which links proprioceptive discharges in general and proprioceptive and cutaneous impulses from the facial area in particular to perception and emotion receives support from unexpected quarters. Clinical psychiatric observations have shown that in paranoid schizophrenia rigidity of facial expression and changes in muscle tone are associated with the complaint of the patient that the persons in his environment behave like marionettes and have masks — as if the loss in emotional expressiveness were associated with a disturbance in perception (214). This suggestion is corroborated by the finding that in these conditions — *Skultety (905) observed that vocalization often returns many months after lesions in the rostral part of the periaqueductal gray matter.

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in contrast to states of depression — those phenothiazine derivatives are therapeutically effective in which the autonomic (tranquilizing) action is small but the extrapyramidal diencephalic stimulation considerable. The latter leads to symptoms of Parkinsonism in man and to catatonia in the experimental animal (933). As von Ditfurth (214) points out, these drugs seem to modify the relation existing between environment and emotional expression and determine thereby whether a "normal" or a "paranoid" world is seen. Since the emotions from their very beginning — the smile of the infant induced by the mother's smile in the favorable setting of postprandial muscular relaxation — evolve in a certain social milieu, it is perhaps not surprising that the physiological mechanisms underlying the emotions are also of social significance. It remains to be seen whether the fundamental role which von Ditfurth attributes to the expression of the emotions for the maintenance of normal interpersonal relations is justified in man, in whom communication is chiefly attained through symbolic speech. Nevertheless, it is of interest to call attention to the fact that caudate stimulation may change social behavior in monkeys although "the motor effect may seem negligible to the observer" (200). Since the extrapyramidal system regulates expressive movements (544, 681), a change in the latter may result from caudate stimulation and may account for the alterations in social behavior. The experimental exploration of this area may bear fruit for physiology, psychology, and psychiatry, and may even contribute to an understanding of social relations.** It has been shown elsewhere (370) that the hypothalamic balance plays a central role in the neurophysiological mechanisms underlying the emotional process. Peripheral stimuli as well as excitation of the hypothalamus or of the limbic brain, to mention only a few factors, alter this balance and lead to repercussions in somatically and autonomically innervated peripheral structures as well as in the cerebral cortex. Obviously, the emotions are determined by many factors and only in special conditions may one factor become of critical significance. Although emotions are facilitated through appropriate posture and facial expression, a trained actor knows that he may evoke emotions in the audience without experiencing them. In stressing the modulating rather than the causative role of proprioceptive and cutaneous impulses for the emotions, one hardly lessens their practical significance. The educational and therapeutic value of the control of the expressive movements (including that of the tone of the skeletal muscles) lies in the fact that these movements may be used to trigger or to inhibit the emotions by the employment of relatively simple physiological procedures. *For another important contribution to these problems, see 616.

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4. On Empathy The facial' expressions were said to contribute to the development and differentiation of the emotions. In addition, they play an important role in the communication of the emotions,* although in general this role is in man secondary to that exerted by verbal behavior. In view of the great importance of empathy for the emotional life, some ingenious experiments (713, 714, 715) on the transmission of emotions in monkeys are briefly described. In this work two monkeys acquired two instrumental c.r. in which one type of light symbolized food and another shock; the food was delivered when the monkey pressed one bar and the shock was avoided when it operated another. After these responses had been established, a paired conditioning experiment was performed in which monkey A in a cage without bars was exposed to the lights serving as c.s., whereas monkey B did not see the lights (c.s.) but instead a television picture of monkey A. Monkey B's cage was provided with bars which controlled delivery of food and shock for both monkeys. The experiments showed that monkey B operated the two bars in response to the facial expression of monkey A correctly at a level of 85 to 95 per cent (instead of the 100 per cent correct response found in the nonpaired condition). This experiment proves that emotional reactions can be transmitted from one animal to another and that they are specifically related to the type of emotion which has been evoked experimentally. These investigations are of interest for at least two reasons. First, they illustrate in animals "sympathetic induction" (empathy), which plays a dominant role in such specifically human actions as artistic creation and psychological understanding (including psychotherapy). Second, they disclose, to a certain extent, the physiological factors involved in this interpersonal communication. As early as 1924, Allport (18) recognized that empathy is not an innate but an acquired (conditioned) emotional response in which kinesthetic impulses are involved. As Mirsky et al. (715) express it, "kinesthetic cues were originally associated with subjective experiences and later, when the cues recur in an imitative response, they reinstate the original experience." The experiments described above give an opportunity to test this hypothesis by determining whether paralysis of the facial muscles in the "test monkey" abolishes its empathic reaction to the sight or pictorial representation of an excited "stimulus monkey."f Moreover, the work of Mirsky, Miller, and Murphy gives an opportunity to 'See 130, especially p. 9. fit is, of course, not improbable that after these empathic reactions have been established through cutaneous and proprioceptive cues, they may persist in response to a visual stimulus (monkey in distress), although these cues are absent.

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study the question of which neurological structures are necessary to carry out an act of imitation.* It should be stressed, however, that the solution of such problems leaves the main question — what underlies the act of imitation? — unanswered. Although this act is important in learning, it seems fundamentally different from those processes involved in Pavlovian and instrumental conditioning. Under the latter circumstances the stimulus (c.s.) evokes a highly adaptive response (for example, avoidance of pain), whereas in the experiment on the communication of emotion the stimulus represents a message which in animals may presage the approach of an enemy and in man add a new dimension to his emotional life, provided that it is properly decoded.! This decoding takes place when, during the copying of the facial expression of another organism, cutaneous and proprioceptive impulse patterns elicit characteristic emotions. | IV. EMOTION AND PERCEPTION

Studies of the interaction of hypothalamic excitation (particularly its ergotropic division) and sensory stimulation were shown earlier to result in an intensification of sensory-evoked potentials in the cortex. Even subthreshold stimulation of the hypothalamus exerts this effect. Moreover, the evoked potentials remain increased for some time after the cessation of hypothalamic stimulation. These changes were thought to underlie perception, since minimal hypothalamic stimulation facilitated the responsiveness of the unanesthetized animal to sensory stimuli. In the preceding pages in which the state of the hypothalamus and the role of cutaneous and proprioceptive patterns of activity for the development and the modulation of emotions were evaluated, the integration of hypothalamic-cortical discharges and sensory impulses was again emphasized. Although quantitative and qualitative differences must exist in the physiological events underlying perception and emotion, the elementary processes seem to be similar in both phenomena. This is indicated also by the fact that perceptual arousal may be converted into emotional excitement by merely increasing the intensity of limbic or hypothalamic stimulation. These data suggest that a further exploration of the interrelation between perception and emotion may be useful. Pertinent observations concern the development of perception in the "It is of interest to point out that even in severely disturbed neurotic cats the act of copying another cat's behavior is not interfered with and has been utilized for therapeutic purposes (690). f We neglect a discussion of the simultaneously occurring vocal response which is probably evaluated in a similar manner. As Mirsky et al. (715) have shown, its absence does not abolish the "message." |For an ingenious psychological interpretation of these and related phenomena see 590.

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newborn baby and the influence of emotions on the threshold of sensory perception. The newborn reacts to the nipple when it touches the mouth, but about a week later the whole situation in which the nipple is presented elicits reactions preparatory to or accompanying the act of feeding: sucking movements appear and the infant becomes quiet when a bib is placed under its chin. Apparently a conditioning process takes place in which various stimuli associated with the feeding situation act as c.s., provided that these stimuli are applied at the proper time, i.e., when the infant is hungry (301). Some weeks later the sight of the person who feeds the infant or of the bottle elicits similar reactions in the hungry state, indicating that distance receptors may now act as c.s. Finally, a stage of development is reached in which sensory stimuli of various modalities evoke responses even when the infant is not hungry. At this stage of development sensory stimuli elicit the orienting reflex. Bearing in mind that conditioning does not require the integrity of the cortical projection area of the c.s., we can easily understand that a conditional reflex develops before the sensory cortex, functions adequately. In such circumstances discharges originating in the lateral hypothalamic feeding center contribute to a shift in the ergotropic-trophotropic balance to the ergotropic side and facilitate thereby the conditioning process (see Chapter III). Thus, a c.r. occurs provided that the feeding center is in a hyperactive state due to hunger. On the other hand, the orienting reflex requires cortico-reticular interaction. Novel stimuli acting on the cortical sensory projection areas are said to call forth the orienting reflex by corticofugal impulses which impinge on the reticular formation (977). In the fully developed brain perception depends upon a complex active cortical process which selectively modifies the sensory input, but even under these conditions the interaction between the multisynaptic reticulo-hypothalamic ascending system and specific afferent impulses is required for perception: barbiturates which block the former without affecting the latter eliminate perception. Further experiments have shown that minimal and even subthreshold emotional stimuli influence perception. The perception threshold of optically or acoustically presented words is known to be different for neutral and for emotionally charged stimuli. The threshold for the latter may be lower or higher than that for neutral words, the assumption being that psychological processes of perceptual vigilance or defense account for these results (794). A more physiological interpretation seems to be warranted, since low degrees of emotional excitation raise the perception threshold whereas high degrees lower it, this effect taking place regardless of whether the total emotional excitation is varied through intensification of the stimulus or through the selection of subjects of high emotional reactivity.

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Dixon and his collaborators (215, 216, 217, 218) have extended this area of investigation by showing that even subthreshold presentations of emotionally charged words alter perception. Thus, emotive words presented below threshold to one eye raise or lower the threshold of the other eye for a specific color or the appearance of grey (resulting from a mixture of red and green). Obviously, conscious processes involving voluntary suppression of embarrassing words cannot account for these results. A physiological explanation of this fundamental phenomenon should take into account: 1. That in a small group of cases of depression and paranoid schizophrenia opposite changes in threshold occur as this test is applied: the threshold rises in the depressive and falls in the paranoid group; 2. That EEC recordings taken while the intensity of the stimulus word is raised from subthreshold levels to the threshold of awareness and, finally, to that of recognition show a relation to the emotional reactivity of the subject. If the emotional stimulus produces a rise in the threshold of perception, it tends to be associated with a greater abundance of alpha potentials whereas the alpha potentials become less marked if the threshold of perception is lowered (Fig. 5-4). These data suggest that the type of reactivity to emotional stimulus words is related to the ergotropic-trophotropic balance. It is assumed that the low-threshold group shows a greater reactivity of the ergotropic system than the high-threshold group. This is borne out by the greater emotionality of the low-threshold group and its tendency to show increased desynchronization of cortical potentials as the intensity of the emotional words rises to the threshold of perception and recognition. There is also some evidence from psychopharmacology and from Mecholyl tests that the ergotropic system is more dominant in paranoid than in depressive patients (370). If this interpretation is correct, one would expect that drugs (for example, Chlorpromazine and amphetamine) which alter the ergotropic-trophotropic balance would change the type of reactivity to emotional stimulus words.* V. SUMMARY

Some aspects of sensori-motor integration, a major characteristic of the activity of the central nervous system, were dealt with in the preceding pages. Movements are enhanced in the subconvulsive state through sensory and hypothalamo-reticular stimuli which act on the pyramidal and extrapyramidal systems at cortical and spinal levels. In the normal organism these facilitatory processes make fight and escape more effective, but they also account for the spread of convulsive discharges if an ab*It is not unlikely that low- and high-threshold groups could be further differentiated by the alpha frequency in the EEC and by certain vascular indicators which distinguish between sympathotonic and vagotonic persons (370).

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Fig. 5-4. Percentage difference in alpha rhythm (alpha E-alpha N), as between presentations of "emotive" and "neutral" words, for the high-threshold group A and the low-threshold group B. AE: awareness threshold for "emotive" words; AN: awareness threshold for "neutral" words. (From Dixon & Lear. Electroencephalograph correlates of threshold regulation. Nature 198:870, 1963.)

normal focus is present. Although nociceptive stimuli induce diffuse hypothalamic-cortical discharges and enhance the reactivity of the motor cortex, neither willed movements nor reflexes originating in subcortical areas (shivering) invade the muscles of an injured limb. The defensive (flexor) reflex is prepotent and prevents other impulses from reaching the final common path while the extensor neurons are blocked by reciprocal inhibition. Thus the resting of the injured limb is ensured even though the dog carries out vigorous movements with the three intact legs throughout the period of recovery. Reorganization of the central locomotor pattern is unnecessary.

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The interrelations between the sensory (somatic) and the ergotropic and trophotropic systems were illustrated in three groups of observations: I. It was shown that exteroceptive, interoceptive, and proprioceptive impulses contribute to the central tone of the ergotropic system whereas visceral and cutaneous impulses play a similar role in that of the trophotropic system. Moreover, feedback processes account for the maintenance and the enhancement of the activity of hypothalamus and reticular formation. Excitation of these structures is reinforced through increased proprioceptive impulses and probably also through activation of cutaneous sense organs following sympathetic excitation. II. Experimental data were presented supporting the hypothesis that proprioceptive discharges elicited in the facial muscles and the associated excitation of cutaneous sense organs in the skin of the face play an important role in the development of the emotions and a subsidiary role in their reinforcement after they have been established. A closely related problem, the role of facial expression in the production of empathy, was also discussed. III. Suprathreshold as well as subthreshold emotional stimulus words modify the sensory perception threshold. The psychological explanation given previously to account for the changes in perception resulting from emotional arousal is not applicable when similar effects are produced by emotional stimulus words presented at subthreshold intensities. An attempt was made, therefore, to explain this fundamental phenomenon in terms of alterations in ergotropic-trophotropic balance and reactivity.

VI

Physiological Collisions and Psychological Conflicts

IT WAS stressed in Chapters II and IV that simultaneous upward discharges of the trophotropic and ergotropic systems are associated with disturbances in consciousness and behavioral changes, provided that a state of high central excitation of the ergotropic system prevails (104). If this is correct the question arises: what rules govern the interaction of the ergotropic and trophotropic downward discharges? One would expect that, for example, parasympathetic and sympathetic reflexes occur all the time in different organs without interference. More interesting is the problem of determining the interaction of antagonistically acting stimuli on the same organ or system. Such studies reveal that under certain conditions simple algebraic summation processes do not account for the actually observed effects but that some actions take precedence over others and that the outcome of these "collisions"* reflects the importance of the individual actions for the functioning of the organism as a whole. It is for this reason that the study of collisions of excitatory processes at various levels of the central nervous system may serve as an introduction to, and as a guide for, the physiological interpretation of the "psychological" conflicts arising as the result of interactions at the hypothalamic and cortical levels. I. PHYSIOLOGICAL COLLISIONS INVOLVING THE NUTRITIVE REFLEX A series of investigations was performed by Rein (820, 821) on the effect of various stimuli on the blood flow of the active as compared with the resting muscle. The active muscle, regardless of whether its activity is induced by peripheral nerve stimulation, reflexly, or as the result of stimuli applied to the motor cortex, shows an increased rate of blood flow which is the result of the peripheral action of metabolites, axon reflexes originating in the nerve endings in the blood vessels of the muscle (290), and sympathetic vasodilator action of diencephalic and cortical genesis *We adopt this terminology from Meyer (704) and use "collisions" when physiological interactions and "conflicts" when psychological disturbances (in man) are involved.

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(4, 249, 250). The multiplicity of mechanisms contributing to this nutritive reflex (461) indicates the importance for the organism of maintaining an increased blood supply during increased activity. This fact is further illustrated by Rein's experiments involving the application of stimuli which in the resting muscle tend to reduce the circulation through the muscle and which were therefore expected to interfere with the nutritive reflex. The first example of such physiological collisions concerns the action of sino-aortic baroreceptor reflexes on the blood flow through the active muscle. Lowering the pressure in the carotid sinus by clamping the carotid arteries below the bifurcation causes a central release of sympathetic discharges manifested in a general vasoconstriction. By using his thermostromuhr Rein found that this procedure reduces the blood flow in the resting muscle. If, however, the muscle is in a state of activity due to rhythmic stimuli applied to the peripheral nerve, the lowering of the pressure in the carotid sinus fails to exercise any influence on the blood flow in the muscle. From these experiments it may be inferred that when the nutritive reflex is called into action, the blood vessels of the muscle cease to participate in general circulatory adjustment reactions which interfere with the nutritive reflex. A marked dilatation of the muscle vessels, accompanied by an increase in the blood flow, occurs also on stimulation of the motor cortex, hypothalamus, and other parts of the brain stem (631). This reaction is obviously of great importance for the sustained muscular action required in fight and flight. It is part of a general defense mechanism characterized by diffuse sympathetic discharges and arousal (4). Under these conditions the baroreceptor reflexes are inhibited: a rise in the carotid sinus pressure, which elicits a fall in blood pressure and heart rate in the control test, induces no vascular effects during the hypothalamically induced muscular dilatation (467). Thus the increase in blood pressure, heart rate, and the force of the heart is maintained while the perfusion rate of the muscles is augmented. Dilatation of vessels in the muscle is evoked in these circumstances through cholinergic sympathetic vasodilator-nerves (249). A similar vasodilator effect can be induced in the resting muscle by baroreceptor reflexes through inhibition of sympathetic constrictor fibers (307), but the increased blood flow cannot be sustained for prolonged periods because the blood pressure falls at the same time. The suppression of the baroreceptor reflexes during the centrally evoked defense reaction is therefore of great adaptive value. The central ergotropic discharges remain unopposed; their adrenergic components cause optimal general circulatory conditions, whereas their cholinergic components account for prolonged increase in the flow of blood through the active muscles. Similarly, it is found that adrenaline in doses which cause a reduction

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in the blood flow of the resting muscle fails to have this effect in the active muscle (702). Moreover, CC>2 inhaled in very small concentrations shows the same differential effect (824). The experiments seem to indicate that whereas the blood vessels of resting muscle form a part of the circulatory system which can be called upon readily by means of general circulatory reflexes, thereby serving the circulatory system as a whole and consequently improving the blood flow in brain and heart, the blood vessels in the active muscle behave differently. Apparently the local requirements of the active muscle take precedence over baroreceptor functions serving the general circulation. The differential action of vasoconstrictor impulses and neurohumors on active and inactive tissues contributes greatly to the nutritive reflex whereby an increased blood flow is maintained in the active organs through collateral vasoconstriction in the inactive organs. But there are definite limits to these and similar adjustment reactions: a reduction in the blood flow through the resting muscle by mechanical means makes these blood vessels nonreactive to vasoconstrictor action induced by CO2 or the stimulation of the sympathetic trunk (823). The teleological significance of these findings is obvious, but the underlying physiological mechanism needs to be determined. That the kidney is, at least during the waking hours, a continually active organ may explain the fact that it behaves in several respects like the striated muscle in the state of activity: in both instances general circulatory reflexes have little or no effect on these active organs. Thus a decrease in intrasinusal pressure does not alter the blood flow through the kidney although it reduces the blood flow through the femoral artery (433) and through the resting muscles and the intestine (647). Moreover, adrenaline does not influence the kidney circulation in doses which reduce the flow through the resting muscles although higher doses are effective. Similarly, brief periods of asphyxia were found to restrict the blood supply to the intestine and the resting muscle while the perfusion rate through the kidney is unaltered. Here again the threshold for the action on the kidney is high: only a prolonged asphyxia causes a reduction in blood flow. Yet conditions are known in which renal flow is altered in the interest of general circulatory adjustment reactions. Stimulation of those hypothalamic sites which evoke a defense reaction (including increased blood flow through the active muscles) causes a distinct vasoconstriction in the kidney. In view of the large renal flow such a reaction is bound to benefit the general circulation. As Feigl et al. (280) express it, "if sudden intense muscular activity is to be supported by the cardiovascular system a shortlasting restriction of kidney blood flow is consistent with the over-all economy of the organism in an emergency situation."

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The interaction between circulatory reflexes and regulation of the body temperature is illustrated by the influence of bleeding on cooled and warmed animals (825). The fall in blood pressure is counteracted in both cases by vasoconstriction in some areas, but whereas in the cool animal the peripheral constriction is most marked, in the heated animals the greatest reduction in blood flow is found in the abdomen and the least in the cutaneous vessels. The reactions take place in such a way as to interfere least with the temperature-regulating processes. This observation furnishes an interesting illustration of the means by which the organism tries to reconcile general circulatory demands with the maintenance of the regulation of the body temperature. Under somewhat different conditions the predominance of the temperature-regulating mechanism over that serving general circulatory adjustments may have severe consequences for the organism. Rein (822) showed that when during continuous bleeding heat is applied, leading to a marked peripheral vasodilatation, an early circulatory collapse may ensue because of the disproportion between circulating blood volume and the capacity of the circulatory system. Similar observations were made on man when circulatory reflexes (produced by change from the reclining to the standing position) had to compete with the effect of a hot environment. Under these conditions the dilated cutaneous vessels were unable to constrict adequately and circulatory collapse followed (560). Another example of a physiological collision is presented to show that the constancy of some properties of the blood is apparently of greater importance to the organism than that of others. Thus, in the normal dog the intra-arterial infusion of water causes an increase in diuresis which is due to the increase in free water clearance, the excretion of electrolytes remaining unchanged. This phenomenon is suppressed if at the same time the animal is bled to a moderate degree, which by itself does not alter blood pressure or heart rate. Reinjection of the blood restores the diuretic effect of intra-arterial water infusion (35). The experiment shows clearly that in conditions involving competition of the mechanisms of control of volume and osmotic pressure of the blood the former take precedence over the latter. A final example concerns the action of severe anoxia and asphyxia (328, 366). The observation that these changes in internal environment are tolerated at room temperature but are fatal at 37 °C might suggest that the collision between the ergotropic constrictor impulses produced by anoxia and the temperature-induced dilator action on the skin vessels that antagonizes the former accounts for this effect. If this were the case, the action of anoxia or asphyxia at different temperatures would illustrate the same principle as the experiments of Rein and those of Keeton et al. (560).

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It is probable that such an interpretation is justified for moderate and gradual forms of anoxia. If, however, a severe anoxia is induced suddenly, a different mechanism is involved. The problem of meeting the demands of the tissues for oxygen is then solved not by a circulatory adjustment but by a lowering of the body temperature. Depending on the species the temperature may drop as much as 4°C in 15 minutes at room temperature and the animals survive, whereas in a warm environment which prevents this reaction the animals die. By contrast with the experiments of Rein (822), reported earlier, in which reactions serving the regulation of the body temperature took precedence over circulatory adjustments and thereby weakened the latter and increased fatality, the maintenance of the normal body temperature is sacrificed in severe anoxia and the fall in temperature saves life. Since no experiments have been performed to elucidate the underlying mechanism, the following interpretation, capable of experimental verification, is suggested. It was mentioned earlier that mild anoxia or asphyxia causes primarily an excitation of the ergotropic system, whereas severe forms of these states induce a dominance of trophotropic effects. Such a shift in balance is likely to activate the heat-releasing center in the unanesthetized animal and to cause a fall in body temperature, particularly in small animals (having a relatively large surface), in favorable environmental conditions. The fact that no shivering was noted in these animals in spite of a considerable and rapid drop in body temperature supports this interpretation, since shivering is inhibited on activation of the heatreleasing center in the anterior hypothalamus (443). In spite of large gaps in our knowledge several important facts have been established which disclose the presence of complex organismic reactions when an organ or system is subjected to two stimuli acting on the ergotropic and trophotropic systems at the same time. Although the analysis of these phenomena has hardly begun, it is already obvious that the effect is not simply the result of peripheral summation processes acting on the same structures (vasodilators, for instance), but that alteration in central states of excitability or shifts in balance play a major role. But regardless of the nature of the underlying mechanisms, actions seem to prevail which are of great adaptive value. The ineffectiveness of the baroreceptor reflex on the perfusion rate of the active muscle and of the kidney is a striking example of this phenomenon. On the other hand, if bleeding is carried out while heat elicits cutaneous vasodilatation, antagonistic reactions are evoked at the same time: trophotropic reactions serve the control of the body temperature while ergotropic effects attempt to counteract circulatory collapse. The results are of course unfavorable. However, under less severe conditions both types of reactions may contribute to homeostasis: bleeding causes in the cool animal greater vaso-

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constriction in the skin and in the warm animal greater vasoconstriction in the abdominal blood vessels. III. COLLISION OF PHYSIOLOGICAL PROCESSES UNDERLYING INSTINCTS

The study of collisions at the instinctual level is our next topic. Unfortunately no systematic studies of this problem have been carried out on higher animals, and the hazard of applying research of this kind to man need not be stressed. Nevertheless, a brief discussion of the principles which govern interaction of instincts may be a guide to the understanding of the more complex conflicts in man. With certain precautions taken, the stimulation of different sites (A and B) of the brain stem through aseptically implanted electrodes gives reproducible effects of characteristic instinctive acts or parts thereof, as von Hoist (484) has shown for the chicken and Meyer (704) for the cat on the basis of experiments published earlier by Hess (463). In von Hoist's and Meyer's work sites A and B were first stimulated separately and the behavior thus obtained was compared with that seen on simultaneous stimulation (A -j- B). The results show that three different types of reactions occur. In the first (combination) the two acts are virtually unchanged under A -f- B whereas in the second (suppression) only one act (A or B) appears when A -|- B are stimulated. Finally, in the third group a new instinctive movement appears on combined stimulation which is different from that seen when A and B are stimulated separately. Combination seems to be seen more frequently in the chicken than in the cat, but more data are needed before this finding can be related to the phylogenetic state of the brain. As examples from the experiments on chickens the following combinations may be cited: (1) pecking ( A ) and turning of the head (B) in which the individual components appear unchanged under A-f-B; (2) turning the head to the left (A) and to the right (B) so that no movements appear on simultaneous application of both stimuli (A-f-B); (3) movements indicating increased attention (A) and postural changes (B) which are part of the instinctive repertoire of the chicken. Under these and similar conditions both components appear under A-j-B, but in some instances slight quantitative differences appear on combined stimulation, as the following experiment shows. If A induces sleep and B grooming in the cat, the latter may be combined with some drowsiness under A-f-B, but grooming is absent when sleep occurs. It seems to be characteristic for both species that combinations with complete or nearly complete preservation of the individual components occur only if the emotional arousal is slight or results from the application

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of only one of the two stimuli, as in the pecking experiment listed under (1). Of great interest is the phenomenon of suppression of one component under stimulation of A -f- B. If A elicits brooding behavior and B a flight reaction in the chicken, the latter is suppressed under stimulation of A-j-B. A catatonic-like reaction (similar to that seen in so-called animal hypnosis) elicited on brain stem stimulation is commonly found dominant so that other reactions produced in combination with it are suppressed. Like a rebound of an inhibited spinal reflex the suppressed reaction may appear after the cessation of A-j-B stimuli. In the cat the grooming reaction evoked by stimulus A persists for many minutes following the cessation of stimulation. If during this period the B stimulus is applied, which elicits a threatening reaction, grooming disappears, but it reappears again after the cessation of B. Similarly, if sniffing results from stimulus B and this stimulus is applied while grooming persists following stimulus A, the grooming reaction is likewise suppressed temporarily. Even more effective is the use of an aggressive reaction as a B stimulus. Under these conditions the grooming behavior disappears during B and the "rebound" is absent. There is a certain resemblance between these instinctive reactions and the reflex collisions discussed in the preceding section. The suppression of grooming behavior through a diencephalically elicited threatening or aggressive act is based on the physiological antagonism which exists between these two types of behavior. Grooming, although resulting from stimulation of a relatively wide area, is best obtained from the septum (464) and adjacent parts of the limbic brain (gyrus cinguli) and represents a trophotropic reaction which is frequently associated with increased salivation and symptoms of "enhanced pleasure" (659), but aggressive actions are of an ergotropic nature. The observations suggest that ergotropic instinctive acts suppress those involving primarily the trophotropic system. Aggressive behavioral reactions tend likewise to suppress syndromes of pleasure as well as of sleep which for anatomical and physiological reasons belong to the trophotropic system. These phenomena seem to be analogous to the suppression of the trophotropic action of the baroreceptor reflexes when an ergotropic defense syndrome is elicited from the hypothalamus.* It was shown earlier that trophotropic and ergotropic reflexes may occur without mutual interference provided that the reflexes are of moderate intensities. Similarly, it was found in cats and, more frequently, in chick*On the other hand, repeated hippocampal after-discharges elicited by stimulation of the septum and rostral parts of the hypothalamus are associated with a change in mood: an aggressive monkey becomes placid and remains so for several hours (659).

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ens* that combinations of instinctive reactions may occur when the individual acts are of low intensities or when only one stimulus evokes a strong instinctive act such as pecking while the other elicits a motor effect like turning of the head. This movement modifies but does not interfere with the pecking act. Perhaps the most interesting result of instinctive collisions produced through two simultaneous stimulations of the brain stem is the appearance of a new syndrome. Thus if flight and attack instincts are elicited in the chicken by the A and B stimuli respectively when applied separately, combination of the stimuli may produce increased activity, vocalization, and bristling of feathers as seen in a hen on the nest when it is facing danger. Since the instinctive acts which are evoked by stimulation of the brain stem are altered with the increasing intensity of the stimulus, it is conceivable that the new syndrome occurring when A and B are stimulated simultaneously is due to simple summation processes. There are, however, good reasons to adopt a different interpretation. Thus, a hungry chicken in which A causes a flight and B a sleep syndrome will not eat on application of A or B, but simultaneous stimulation (A-(-B) causes the animal to eat before it falls asleep. It seems that flight inhibits eating and that sleep inhibits flight, so that before sleep supervenes the tendency to eat is released (484). This interpretation is applicable to the quantitative studies of lersel & Bol (507) on terns which are summarized by Barnett (57) as follows: "The readiness to perform a fixed act, such as brooding, tends to inhibit others, such as preening or nest-building. The 'drive' for each act can be given a numerical value in terms either of a threshold value or of number of movements in a given period. When the values for two mutually inhibitory acts have a certain ratio, neither is performed, but a third act is. This is supposed to be a consequence of a reduction in the inhibitory effects of the first two. If, for instance, the drives for brooding and flight are at equivalent levels, neither occurs; but preening, released from the inhibitory effects of brooding, does occur." IV. SUBSTITUTIVE BEHAVIOR

In discussing the work of lersel and Bol, Barnett suggests that their findings may explain substitutive or displacement behavior which has been observed in a great variety of animals either spontaneously or when certain willed acts have been interfered with. It consists of the appearance of a behavior pattern which is completely unrelated to the biological situation. Thus, if mating is interrupted by the flight of the partner, nest-building, preening, eating, or other stereotyped activities are carried out. The following observations seem relevant for a physiological interpre*See also Tinbergen, cited by Meyer (704).

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tation of these phenomena. It was pointed out in Chapter IV that when an air blast is applied during eating (evoked by a conditional stimulus), neurotic behavior results which consists not only in refusal to eat but in the appearance of marked trophotropic symptoms such as diarrhea, salivation, and vomiting. Moreover, licking, sharpening the claws, and rubbing head and neck against the wall of the cage, which are apparently forms of substitutive behavior, also appear. When the air blast is omitted normal behavior (eating through rapid operation of the switch which gives access to the food) is gradually restored as the trophotropic symptoms and signs of substitutive behavior disappear (518). The parallelism between trophotropic symptoms, neurotic behavior, and displacement activities suggests that neurotic and displacement behavior occur as the trophotropic-ergotropic balance is altered. The dominance of the ergotropic system which characterizes the normal organism, particularly under the stress of conditioning, is lost in the neurotic state in which both systems discharge at the same time. We assume (see Chapter IV) that the neurotic state is characterized by a maximal discharge of the two systems, and it is probable that nearly the same conditions prevail in the reversible preneurotic state investigated by Jacobsen and Skaarup. Since the trophotropic and ergotropic systems are physiological antagonists,* it is conceivable that components of the downward discharges inhibit each other and thereby release patterns of displacement activities while the simultaneous corticopetal discharges of the two systems account for the "mental" disturbances (for example, fear of the food box) of the preneurotic state. If this state continues, it passes over into the neurotic condition in which the outward behavior becomes rather chaotic and the well-coordinated but inappropriate displacement behavior no longer occurs. V. PSYCHOLOGICAL CONFLICTS

The considerable resemblance between experimental and clinical neuroses was pointed out earlier. In both, trophotropic and ergotropic symptoms prevail. Whereas fear and anger appear to result mainly from the activation of the trophotropic and ergotropic systems respectively, anxiety (as seen in neurotic and psychotic states) is a state of fear (trophotropic discharge) arising on the basis of intensive ergotropic activity. Anxiety, characterized by intensive ergotropic and trophotropic discharges, may occur also in an acute condition when a person reacts with rage in a situation in which fighting is inappropriate. Under these conditions he is likely to inhibit the tone and activity of the skeletal muscles by willed action while a strong central ergotropic discharge continues. **It should, however, be borne in mind that the antagonism between various instinctive actions is complex and cannot be solely explained by their relation to the ergotropic and trophotropic systems.

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The decrease in muscle tone lessens the proprioceptive feedback to the posterior hypothalamus and thereby shifts the trophotropic-ergotropic balance somewhat to the trophotropic side. This facilitates the overflow of ergotropic impulses into the trophotropic system. Depending on the intensity and duration of the rage reaction and the corresponding activation of the ergotropic system, this spilling over may result in a brief but strong trophotropic discharge accompanied by intense fear or, if rage and ergotropic discharges persist, in a state of anxiety associated with trophotropic and ergotropic discharges.* VI. SUMMARY

Moderate degrees of simultaneous excitation of the ergotropic and trophotropic systems are compatible with the principle of reciprocity. The adaptive character of the resulting reactions is maintained either by intraorganismic adjustments (see the effect of bleeding in cold and warm environments described on p. 176) or by inhibition of the reactivity of one of the two systems. The latter is illustrated by the ineffectiveness of the baroreceptor reflex during a strong ergotropic defense action resulting from stimulation of the hypothalamus and including vasodilatation in the muscles. If, however, both systems are intensely excited at the same time or if the ergotropic system is activated by noxious stimuli which induce an overflow of this excitation into the trophotropic system, the principle of reciprocal innervation breaks down. In these conditions physiological functions are altered and pathological symptoms appear which are related to the level of central nervous activity that is primarily involved. At the lowest level, ergotropic reflexes are weakened and may cause failure of homeostatic emergency reactions. At an intermediate level physiological interaction underlying the arousal of antagonistic instincts leads to the appearance of displacement behavior. And at the highest (symbolic) level, studied in the animal through conditioning and experimental neurosis, organized behavior collapses. Under analogous conditions induced in man through psychological conflicts, anxiety appears which seems to be based on corticopetal discharges resulting from the simultaneous excitation of the trophotropic and ergotropic systems. *For a further analysis of the neurophysiological basis of anxiety see 352.

VII

Patterns of Ergotropic Discharges

THE pattern of ergotropic and trophotropic discharges described in the Introduction and illustrated in Chapters I-IV represents the basic design, but does not do justice to the variety of combinations seen in different states of excitability and under different conditions of stimulation. To survey ergotropic patterns systematically is the task of this chapter. Some notes on the trophotropic system will be added. By studying autonomic changes in defense reactions (rage, fight, flight), in severe hemorrhage, or exposure to cold, in insulin hypoglycemia, and during exercise, and by utilizing denervated structures as indicators of adrenomedullary secretion, Cannon (147) concluded that the sympathetico-adrenal system acts as a whole and serves as a homeostatic mechanism in conditions of emergency. Excitatory effects on the smooth muscles of the eye, the heart and vascular system, and the piloerectors in the skin, combined with an inhibitory action on the gastrointestinal tract, clearly indicate widespread activity of the sympathetic system. The responsiveness of denervated structures, the rise in blood sugar, and the shortening of the coagulation time of the blood show that adrenomedullary secretion is also increased. These autonomic reactions, together with the increased tone of the striated muscles, contribute to the restoration of the circulation after bleeding, maintain the body temperature in the cold, and create favorable conditions for fight and flight. The concept of homeostasis developed on the basis of these and related experimental findings (see also 55) has been fruitful for biology and medicine. It is not surprising that data indicating that the total sympathetico-adrenal discharge is not the only form of activity in which the sympathetic system is engaged has found scant recognition. As Cannon realized, the sympathetico-adrenal discharge consists of two components: first, a widespread sympathetic discharge which continues to raise heart rate and blood pressure, to dilate the pupil, and to inhibit the gut after the adrenomedullary secretion has been eliminated through 183

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ligation of the adrenal veins or denervation of the adrenals, and second, the activation of the adrenal medulla via the splanchnic nerves. (For the sake of brevity the first component will be referred to as the neurogenic and the second as the hormonal factor.) Theoretically the sympatheticoadrenal system may operate in three different forms in which: 1. The neurogenic and the hormonal factors are combined as in Cannon's emergency reactions. 2. The ergotropic pattern consists of sympathetic (and somatic) activity while the adrenomedullary secretion remains unchanged. 3. The hormonal factor is activated while no distinct change in the neurogenic discharge is recorded. These different types of ergotropic discharges have been observed, and it will be our task to define the conditions for their occurrence and to evaluate their physiological significance. We begin this discussion with the description of some recent work in which a sympathetico-adrenal discharge was observed as in Cannon's classical work. Three aspects of this activity will be considered: the excretion rates of noradrenaline and adrenaline and their utilization as an indicator of a sympathetico-adrenal discharge; the question whether the hormonal factor plays a dominant role in the reinforcement of sympathetic excitation as Cannon thought; and, finally, the physiological mechanism underlying the vasodilatation in the skeletal muscles which is of vital importance for fight and flight. I. SYMPATHETICO-ADRENAL DISCHARGE

The rate of excretion of noradrenaline and adrenaline has been used in recent years as an indicator of the activity of the sympathetico-adrenal system in the intact organism. Noradrenaline liberated from the adrenergic sympathetic nerve endings reflects the state of the neurogenic sympathetic system whereas adrenaline mirrors that of adrenomedullary activity. From experiments in the cat (see 432 for the literature) it was inferred that adrenomedullary secretion as indicated by the denervated pupil and nictitating membrane (n.m.) is increased in exercise. In recent work on man (554) physical work (woodcutting competition) was shown to be accompanied by marked increases in noradrenaline and adrenaline excretion which are quickly reversible (Table 4). Similar results are obtained from marathon runners and long-distance skiers. The rise in the excretion of noradrenaline is accounted for by the general sympathetic discharge (especially vasoconstriction), whereas the enhanced excretion of adrenaline may be due in part to fall in blood sugar and oxygenation of the blood which are known to affect specifically the adrenaline level, and in part to emotional excitement. The effect of noxious stimuli is illustrated by the effects of thermal burns in man (395). If one eliminates from consideration of the physio-

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Patterns of Ergotropic Discharges Table 4. Mean Urinary Excretion of Noradrenaline and Adrenaline (in Mg) by 4 Participants in a Woodcutting Competition for Periods before, during, and after the Competition Mean Excretion Period Night before (11 P.M.—7 A.M.) . . . Work period (7 A.M.—2 P.M.) Evening (2 P.M.—11 P.M.) Night following (11 P.M.—7 A.M.)

Noradrenaline 8.1 100.2 13.2 7.0

Adrenaline 2.5 12.9 3.7 2.7

Source: Karki (554).

logical action of noxious stimuli those patients who died from the burns with some indication of insufficiency of the adrenal medulla, one finds an approximate parallelism between severity of burns and elevation of the catecholamine excretion. Noradrenaline rose from 32.3 ju,g/24-hour to 78570 /xg, whereas the control value for adrenaline was 15.7 and the experimental value 25-260 jug! Finally, a few illustrations of the effect of strong emotional excitement are presented. Parachuting (81) raises the excretion of noradrenaline and adrenaline. Moreover, the observations suggest that severe excitement is not subject to habituation since the effect on the catecholamines remained unchanged on repetition and was' no different in the more experienced officers than in the trainees. Inhalation of CO2 (7-14 per cent), which is known to cause a profound excitation of the hypothalamic system with increased hypothalamic responsiveness and hypothalamic-cortical discharges (333) and enhanced ergotropic activity (increase in heart rate, blood pressure, respiration, and muscle tone), is likewise accompanied by an increase in the noradrenaline and adrenaline excretion in man (883). At the same time the subjects are emotionally aroused. The experience is described as "horrible," "suffocating," etc. These experiments illustrate conditions in which the sympatheticoadrenal system is aroused. They can hardly all qualify as emergency situations but all involve strong excitation of the hypothalamic-reticular system. Similar results are obtained by the injection of drugs such as cocaine whose affinity to central ergotropic structures and to catecholamines has long been established. Fig. 7-1 shows the magnitude of the increased excretion of noradrenaline and adrenaline and its reversibility after the daily injections of the drug have ceased (414). II. THE PHYSIOLOGICAL SIGNIFICANCE OF ADRENOMEDULLARY SECRETION

Increased adrenomedullary secretion in situations of emergency was demonstrated by Cannon and others through the reactivity of denervated

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Fig. 7-1. Effect of cocaine on excretion of adrenaline (black columns) and noradrenaline (white columns) in three groups of rats. Black horizontal bar below indicates daily administration of 100 mg/kg cocaine. (From Gunne & Jonsson. Effects of cocaine administration on brain, adrenal and urinary adrenaline and noradrenaline in rats. Psychopharmacol. 6:125, Springer-Verlag, New York, 1964.)

structures such as the pupil, the n.m., and the heart. Thus, exposure to cold produces a dilatation of the denervated pupil, but the effect is absent after demedullation of the adrenals or sectioning of the splanchnics. The greater resistance to cold of the normal as compared with the adrenodemedullated animal was attributed by Cannon to the reinforcement of the adrenergic constrictor effect and also to the thermogenetic action of adrenaline. The latter action is undisputed, as is the homeostatic importance of the adrenomedullary secretion to combat the insulin-induced fall in blood sugar through the glucogenetic effect of adrenaline, but no good evidence has been found for the intensification of sympathetic impulses on peripheral structures such as the blood vessels through the secretion of adrenaline. Celander (157) compared neurogenic and hormonal action in skin, muscle, and kidney by stimulating sympathetic vasoconstrictors and splanchnic nerves (liberating adrenomedullary neurohumors) at the physiological range of frequency (1-10/sec). In these experiments and also in tests on pupil and n.m.'s the neurohumors contributed to sympathetic action to only a small degree. This holds true even for the effect of prolonged asphyxia, known to increase adrenomedullary secretion greatly. It follows from this research that the physiological significance of the adrenomedullary secretion in conditions of intensive arousal of the ergotropic system lies not in a synergistic action of sympathetic impulses and secreted adrenaline on smooth muscles but rather in the metabolic action of adrenaline. It must, however, be added that injected or secreted adrenaline tends to contribute to the central excitation of the ergotropic system.

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Even in small doses it produces a diffuse excitation of the cortex via the reticulo-hypothalamic system. On nociceptive stimulation the excitation consists of two phases, an early (neurogenic) and a late (hormonal) phase, the latter being absent after elimination of adrenomedullary secretion. Prebulbar section of the brain stem eliminates the neurogenic but not the hormonal phase (87).* On the other hand, an increase in intrasinusal pressure by mechanical means or by injection of noradrenaline or adrenaline reduces the intensity of the hypothalamic-cortical discharge and increases cortical synchronization. Since this effect is abolished by sino-aortic denervation (747; see Fig. 1-4), the experiments suggest that adrenomedullary secretion may inhibit the hypothalamus via baroreceptor reflexes. Thus, as Fig. 7-2A shows, blood pressure and adrenomedullary secretion, indicated by the

Fig. 7-2. The effect of hypothalamic stimulation in the postasphyxial state. Cat, prepared under Pentothal (25 mg/kg i.v.) and local anesthesia with procaine, later intocostrin. A: 75 sec. of asphyxia (horizontal bar) followed by hypothalamic stimulation (2.5v., 99/sec, 1.6 m.s. for 5 sec.) indicated on the last line; B: same hypothalamic stimulus under control conditions. The experiment shows that adrenomedullary secretion diminishes sympathetic (ergotropic) reactivity. (From Gellhorn & Redgate. The physiological significance of the adrenomedullary secretion. Arch, internat. physiol. &biochem. 66:145, 1958.) *See Baust et al. (62) for the role of the rise in blood pressure in the action of adrenaline.

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contraction of the denervated n.m., rise rapidly in the postasphyxial period. During this phase the ergotropic reactivity is minimal: the response of blood pressure and innervated n.m. to a hypothalamic stimulus is only a fraction of that seen under control conditions (Fig. 7-2B). Ligation of the adrenal veins abolishes this reduction in response (376). Although the conditions under which secreted adrenaline may intensify or inhibit central ergotropic action have not been adequately defined (358), it appears at present that an important role of adrenomedullary secretion consists of the modulation of the corticopetal and peripheral discharges of the ergotropic system which originate in the reticulo-hypothalamic care. It is likely that not only the intensity of the adrenomedullary secretion but also the state of excitability of reticular formation and hypothalamus determines the type of action which is going to prevail.* III. SYMPATHETIC VASODILATATION AS PART OF THE SYMPATHETICO-ADRENAL DISCHARGE

Recent studies have shown that an important reaction associated with a generalized sympathetico-adrenal discharge concerns the dilatation of the blood vessels in the skeletal muscles. It occurs when the muscles are activated through peripheral nerves, via reflexes, or by stimulation of brain stem (in the mesencephalon or the hypothalamus) or motor cortex. There are two fundamentally different mechanisms by which this effect can be accomplished: either by inhibition of the sympathetic tone or by excitation of sympathetic dilator nerves, f By stimulation of different sites of the medulla oblongata, the separateness of the two mechanisms can be demonstrated (632, 633). Stimulation of lateral sites elicits a vasodilatation which is blocked by atropine and accompanied by minimal or no change in blood pressure and no slowing of the heart rate. On the other hand, stimulation of the medial area, which is the medullary vasodilator center, causes marked slowing of the heart rate and fall in blood pressure. After sinoaortic denervation stimulation of this area evokes a depression of blood pressure accompanied by an increased blood flow through the muscles, but these effects are not altered by atropine. Apparently, stimulation of the depressor area induces a dilatation of muscle vessels which is due to inhibition of adrenergic vasoconstrictors and is therefore not sensitive to atropine. Stimulation of the lateral area, however, activates cholinergic sympathetic vasodilators which continue to function even after destruction of the depressor area (967), but this vasodilator effect is abolished by atropinization. *See Chapter III, p. 91, and Chapter VIII for further data on the relation between the ergotropic system and glands of internal secretion. f There is no evidence that the dorsal root vasodilator fibers have an effect on muscle vessels.

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It is of great importance that this cholinergic dilatation of the muscle vessels which guarantees adequate blood supply to the skeletal muscles during activity is part of the general defense reaction described by Hess. Thus, stimulation of the hypothalamus, particularly of the perifornical area (which elicits widespread ergotropic effects such as spitting, baring teeth, movement of limbs and tail associated with vasoconstriction, contraction of spleen and n.m., and pupillary dilatation), also increases the flow of blood through the muscles by means of a cholinergic mechanism (249). Apparently, adrenergic constrictor and cholinergic dilator effects occur at the same time in different organs and systems. Thus, a hypothalamically induced muscle dilatation has been found to be associated with an intensive vasoconstriction in the kidney (911) while the contractile force of the heart (841) and adrenomedullary secretion (404) are augmented. Further studies (4) showed that the characteristic ergotropic syndrome of increased attention passing over into fight or flight is aroused from a large section of the hypothalamus, the central grey and the tegmentum in the mesencephalon from which also the cholinergic effect on the vessels in the muscles had been elicited (Fig. 7-3). Moreover, earlier observations on the effect of nociceptive and other sensory impulses on the hypothalamus (71) were confirmed and extended by Abrahams et al. (3), who reported that sensory stimuli evoke multisynaptic long-latency responses in hypothalamus and mesencephalic reticular formation. These phenomena thus appear to be involved in the production of emotional excitement underlying the defensive reaction. Since they can also be elicited from the motor cortex (250) and certain parts of the amygdala (469), and since the blood flow through the muscles is likewise increased under these conditions, it seems that cortical, diencephalic, and reflex excitation create favorable conditions for the performance of muscular work regardless of whether it is carried out in exercise, fight, or flight. Vasodilatation in muscles can be produced not only through cholinergic sympathetic nerves and through inhibition of sympathetic constrictors via baroreceptor reflexes but also through metabolites. The latter lead to increased adrenomedullary secretion (145), which may account for the fact that little or no difference was found in muscular performance and blood flow in man between the normal and the sympathectomized extremity (54).* Nevertheless, the bulk of the data compels us to assume that the central setting of the ergotropic discharges via motor cortex and brain stem is essential for the execution of maximal action. Moreover, inhibition *Hudlicka & Bass (497) claim that in the unanesthetized animal the dilatation of the muscle vessels is due to adrenaline and not to a cholinergic agent, but Hilton & Zbrozyna (469.) find that a cholinergic action as well as a defense syndrome is elicited by stimulation of certain parts of the amygdala in the unanesthetized cat. See also 876 for a survey of the recent literature.

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Fig. 7-3. Right: diagrammatic coronal section showing site in preoptic region of cat's brain of implanted electrode. Left: records of venous outflow from skinned hindlimb and of arterial blood pressure of same cat under chloralose anesthesia. At signals, stimulation through implanted electrode before (left) and after (right) intravenous injection of atropine (0.5 mg/kg). CA: anterior commissure; Ch: optic chiasma; RPO: preoptic area. Time marker, 30 sec. The experiment shows vasodilatation before and vasoconstriction after atropine. The same site evoked a defense reaction before anesthesia was applied. (From Abrahams, Hilton, & Zbrozyna. Active muscle vasodilatation produced by stimulation of the brain stem: its significance in the defence reaction. J. Physiol. 154:491, Cambridge U. Press, New York, 1960.)

of the adrenergic constrictors would tend to create unfavorable general circulatory conditions and seems therefore unsuitable for supporting the diencephalically integrated defensive reaction, whereas cholinergic sympathetic discharges initiate and, together with the action of local metabolites, maintain the increased blood flow through the muscles which is necessary for immediate and sustained action. The cholinergic vasodilators are capable of increasing the blood flow five to ten times and induce maximal effects at a stimulation rate of 10/sec. They appear therefore about equal in range and effectiveness to the adrenergic vasoconstrictors (294). For man it has been calculated that the complete inhibition of the adrenergic tone would increase the blood flow through the muscle by 1.51/min, whereas the blood flow is increased by about 20 1/min in exercise, i.e., under the combined influence of the nutritive reflex and cholinergic vasodilatation.

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IV. THE TRANSITION OF SYMPATHETIC TO SYMPATHETICO-ADRENAL ACTIVITY

It is a common laboratory experience that the degree of excitation of the centers of the ergotropic system induced directly or via reflex action determines whether the effect is confined to the sympathetic system proper or includes also the adrenal medulla. In studies of these phenomena the reaction of chronically denervated ocular structures again serves as an indicator of the secretion of adrenaline. For brevity's sake the neurogenic reaction indicated by pupillary dilatation and contraction of the n.m. of the normal eye is referred to as A and the hormonal response causing similar but delayed effects on the denervated eye as B. Sensory stimuli, such as increasing the intensity from a light touch to a strong pinch of the skin, transmute the A into an A + B response (374) in the unanesthetized animal. If either the ergotropic division of the hypothalamus or the medulla oblongata is stimulated electrically, a similar transition from A to A-f-B is effected. Fig. 7-4 shows that the weaker mm.

Time (sec.) Fig. 7-4. Effect of stimulation of the hypothalamus with increasing frequencies'on pupils and nictitating membranes of the awake cat. Removal of the left superior cervical ganglion 10 days before the experiment. Hess' electrodes in the posterior hypothalamus. Photographic recordings 5 hr. after ether anesthesia. Bipolar stimulation of the posterior hypothalamus (square wave discharges 2v., 51/sec, 0.8 m.s.) for 3 sec. in this figure; same stimulation except for 67/sec in the figure on p. 192. Normal pupil, solid line; denervated pupil, broken line; normal n.m., plus signs; denervated n.m., dots. (From Gellhorn & Redgate. The physiological significance of the adrenomedullary secretion. Arch, internat. physiol. & biochem. 66:145, 1958.)

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U

0

2

4

6

8

10

12

14

16

18

^26^245

Time (sec.)

stimulus acts on the innervated ocular structures only, whereas the stronger stimulus acts, in addition, on the denervated structures after the former reaction has subsided. This result is accomplished regardless of whether the state of increased excitation is induced by increasing the voltage or frequency of stimulation, the duration of the pulse of the square wave, or the total duration of stimulation (345, 376). Fig. 7-5 illustrates the effect of increasing duration of hypothalamic excitation on blood pressure and n.m.'s in the anesthetized animal. A brief stimulus (Fig. 7-5A), acts on the normal n.m. only and is without effect on the blood pressure and the denervated n.m., whereas a more prolonged stimulus acts on all indicators (Fig. 7-5B). The transition from the A to the A -f B response occurs also as a rebound phenomenon. Moderate trophotropic excitation of the anterior hypothalamus (through heating), during which ergotropic discharges are inhibited, is followed by an increase in noradrenaline excretion, whereas a more intensive excitation leads to an increase in noradrenaline and adrenaline excretion during the rebound phase (25). The release of the ergotropic system from the restraining action of the baroreceptors may likewise be utilized to demonstrate the transition from A to A-j-B. Fig. 7-6 shows these two stages of the Mecholyl-induced hypotension which result from the application of increasing doses of this drug. The smaller dose of Mecholyl evokes the A response (on the normal n.m.),

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Fig. 7-5. The appearance of sympathetico-adrenal discharges with increasing duration of hypothalamic stimulation. Cat, prepared with Pentothal, local anesthesia and Intocostrin. Stimulation of the posterior hypothalamus with lv., 158/sec, 0.8 m.s. for 0.5 sec. in A and for 8 sec. in B. NNM: normal nictitating membrane; DNM: denervated nictitating membrane; BP: blood pressure. Signal line indicates stimulation. (From Gellhorn. Further experiments on sympathetic and sympathetico-adrenal discharges. Acta neuroveg. 20:195, Springer-Verlag, New York, 1959.)

but the larger dose calls forth the B response also (on the denervated n.m.). Finally, if the reactivity of the ergotropic system is increased (sympathetic "tuning"), a stimulus which produces an A reaction in the control tests evokes an A-j-B effect when the sympathetic excitability has been raised by asphyxia or other procedures which by themselves do not elicit an effect on the denervated ocular structures (338, 341, 346, 347). It is obvious that when the degree of central ergotropic excitation exceeds a critical value, adrenomedullary secretion occurs. This critical

Fig. 7-6. The influence of Mecholyl on sympathetic and sympathetico-adrenal discharges. Cat, prepared as in Fig. 7-5. Mecholyl i.v. (at arrow), 0.0016 mg/kg in A and 0.0008 mg/kg in B. Horizontal bar in A = 12 sec. The experiment shows that with increasing concentration of Mecholyl the reflexly induced sympathetic discharge is converted into a sympathetico-adrenal discharge, the adrenomedullary secretion resulting in a contraction of the denervated nictitating membrane. (From Gellhorn. Further experiments on sympathetic and sympathetico-adrenal discharges. Acta neuroveg. 20:195, Springer-Verlag, New York, 1959.)

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value is modifiable by the "tuning" of the ergotropic system. That the threshold for the adrenomedullary secretion is higher than that for the neurogenic ergotropic response holds true also for the upward discharges from hypothalamus and reticular formation resulting from direct stimulation of these structures, or their activation through nociceptive stimuli to which we referred earlier. These investigations raise two questions: first, whether stimuli which evoke an A response only can show graded ergotropic effects or, to express it differently, whether in the absence of an adrenomedullary effect the sympathetic discharge may at low intensity of stimulation be restricted to some organs or even to some functions of one organ without affecting others, whereas at higher intensities widespread sympathetic effects prevail; second, whether it is possible to create conditions in which the adrenomedullary secretion is increased without significant alteration of the neurogenic sympathetic (A) activity. The subsequent pages will show that the answer to both questions is in the affirmative. V. PARTIAL ERGOTROPIC DISCHARGES IN MAN AND ANIMALS Partial ergotropic discharges can be elicited from various parts of the central nervous system. Thus, stimulation of the spinal cord at T4 produces a maximal rise in blood pressure without altering pupil and n.m. in the normal or sympathectomized eye. A different partial ergotropic response is seen on stimulation at a slightly higher level (Ti): ocular sympathetic effects are recorded while the blood pressure remains unchanged. Similar dissociations in sympathetic effects are obtained from the medulla oblongata and various parts of the hypothalamus (361). Contraction of the n.m. may occur without pupillary dilatation and vice versa. In experiments in which the blood pressure and the heart rate were recorded during stimulation of the brain stem, sites were found which greatly increase the contractile force of the heart muscle without influencing the heart rate (678), and others which alter the heart rate without changing the blood pressure (159). Similar differential effects are obtained on stimulation of the cerebral cortex. Although the stimulation of various parts of the central nervous system provides good evidence for partial ergotropic discharges we must admit that at least in some experiments the use of coaxial electrodes (microelectrodes) might restrict the excited area more than when it is activated through reflexes, emotional excitation, etc. It is therefore necessary to study ergotropic activity evoked through the latter procedures in order to ascertain the physiological validity of partial ergotropic discharges. Graded sympathetic reflexes are demonstrable in decapitate cats on stimulation of dorsal roots or afferent nerves in the limbs. The intensity of

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the reflex discharge recorded from preganglionic neurons can be graded by varying the intensity of the afferent stimulation (63). Since emotional excitement arousing the defense reaction in the experimental animal has been found to be very suitable for activating the ergotropic system, and since various degrees of such excitation are easily produced in the human subject, the physiological changes accompanying the performance of mental arithmetic under strain (for example, criticism, distraction) and other forms of emotional stress were studied. Fig. 7-7 shows a marked and quickly reversible increase in blood flow through the muscles (which is similar in magnitude to that seen in severe exercise), a minimal rise in blood pressure, an acceleration in heart rate, and no change in blood flow through the skin (78). The increased flow through the

Fig. 7-7. Effect of severe emotional stress on arterial pressure; triangles=heart rate, solid dots = forearm blood flow, and open circles = hand blood flow. During the time represented by the rectangle it was suggested to the subject that he was suffering from severe blood loss. (From Blair, Glover, Greenfield, & Roddie. Excitation of cholinergic vasodilator nerves to human skeletal muscles during emotional stress. J. Physiol. 148:633, Cambridge U. Press, New York, 1959.)

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muscles and the absence of change in the skin are further indicated by the increase in the oxygen saturation of the blood in the deep forearm veins, whereas the oxygen saturation of the superficial veins was unchanged. The absence of the increased blood flow through the muscles in the sympathectomized forearm after blocking of the radial nerve with novocaine (390), and in some experiments after atropinization, suggests that a partial ergotropic discharge characterized by a (cholinergic) sympathetic dilatation of the muscular bed and an increase in heart rate may occur, although no vasoconstriction in the skin is detectable. The quick reversibility indicates that no adrenomedullary secretion is involved. Further studies indicate that depending on the emotional reactivity of the experimental subject these ergotropic changes may be associated with similar but delayed increases in the dilatation of muscle vessels and that under the influence of habituation the latter effects disappear. These experiments demonstrate in the human partial ergotropic discharges and transition from sympathetico-adrenal to sympathetic discharges with decreasing emotional reactivity. It should be added that the increased blood flow through the muscles seen under these conditions is unrelated to muscular activity: it persists after curarization (390). It is interesting to point out that the ergotropic discharges elicited in the animal in situations of fight or flight and in man during emotional excitement involving irritation and/or frustration are similar,* although the dilatation of muscle vessels in the latter case is of no adaptive value. With the phylogenetic development of the brain the emotional and associated cortical processes apparently become greatly diversified, but this is not true of the autonomic downward discharges. Further illustrations of partial ergotropic discharges are shown in studies of sweating. The sweat glands are excited through cholinergic sympathetic nerves on the palmar and plantar surfaces during emotional stress whereas sweating in trunk and limbs is induced by increased temperature. In spite of its restricted character, emotional sweating is associated with cutaneous vasoconstriction and other signs of ergotropic discharge, whereas the more diffuse sweating caused by heat is accompanied by vasodilatation. Visceral lesions may elicit reflex sweating confined to the hyperalgesic area.f Wang (978) points out that the galvanic reflex denoting sweat secretion is inhibited on exposure to cold although vasoconstriction is present. On the contrary, heat elicits the galvanic reflex but inhibits cutaneous vasoconstrictors. These observations show graded responses of the ergotropic system under physiological and pathological conditions. Not only the *See also Dudley et al. (231) who show that similar respiratory and metabolic changes occur in exercise and emotional excitement in man. fThe extension of the low-resistance area in the skin of hand, foot, and face on awakening (832) and in ischemic pain (943) thought to be due to increased sweat secretion seems to exemplify graded responses of sympathetic activity.

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degree of stimulation but also the nature of the excitatory stimulus determines the character of the response. Partial ergotropic, trophotropic, and somatic discharges (movements) are combined in different patterns on exposure to heat and cold and thereby form adaptive reflexes. Furthermore, studies of the limbic system showed that inhibition of ergotropic discharges (measured by the fall in blood pressure and the decline in the galvanic reflex) is general from the hippocampus but partial from the amygdala (1008). VI. INSULIN HYPOGLYCEMIA AND RELATED CONDITIONS

The action of insulin-induced hypoglycemia deserves a close analysis. Cannon (147) demonstrated the importance of increased adrenomedullary secretion with falling blood sugar. Adrenodemedullated animals showed an increased sensitivity to insulin — convulsions occur earlier and more frequently and the slope of the hypoglycemic curve is steeper than in control animals. Since frequently the adrenal medulla is stimulated when the central sympathetic discharge has passed a critical level (or duration), it seemed logical to look upon hypoglycemia as a typical condition for the elicitation of a diffuse sympathetico-adrenal discharge. But the following observations require a reconsideration of this interpretation. They are based on the fact that although noradrenaline is the neurohumor of the sympathetic system, increased excretion of adrenaline (indicating enhanced liberation of this hormone from the adrenal medulla) occurs not only when excretion of noradrenaline is likewise augmented but also when the excretion of noradrenaline is unchanged. Fever (888), alcohol intoxication (394), severe hemorrhage and increased intracranial pressure (677) are typical of this phenomenon. To this category belongs also insulin hypoglycemia in which the excretion of adrenaline is increased while that of noradrenaline is either unchanged or diminished (268, 388, 785). This type of response is present in normal and decerebrate dogs and also in animals with spinal transection. Only removal of the lower part of the thoracic segments of the spinal cord from which the splanchnic nerves originate abolishes this action (149). The experiments prove clearly that adrenomedullary secretion may be increased through the spinal cord in conditions in which ergotropic discharges from supraspinal centers are eliminated. Carbon dioxide in high concentrations in which it acts as an anesthetic has a similar effect.* Severe anoxia and asphyxia produce hyperglycemia through increased adrenomedullary secretion (373), but here again there is evidence for a diminished activity of the ergotropic system. Animals subjected to low oxygen pressure show a marked fall in body temperature "See p. 142.

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(366), suggesting increased trophotropic activity, which is known to reciprocally inhibit the ergotropic system. On the other hand, it is known that anoxia and hypoglycemia in their initial stages evoke a characteristic ergotropic discharge with pupillary dilatation, sweat secretion, and rise in blood pressure and heart rate; but as the anoxic or hypoglycemic condition continues, this phase is replaced by one in which the trophotropic system dominates (470). This change, reflected in the increased secretion of adrenaline which is not accompanied by an increase in the excretion of noradrenaline, represents a partial discharge of the ergotropic system which is fundamentally different from the type of ergotropic patterns we have discussed thus far. Recent work indicates that even the activity of the adrenal medulla can be gradated in various experimental conditions. Histological studies of this organ show that following prolonged running on a treadmill the secretion of noradrenaline and adrenaline originating in different cells is increased, whereas hypoglycemia causes a depletion of adrenaline but not of noradrenaline. In hypoglycemia the chromaffin and other reactions were retained in the cells which liberate noradrenaline (261). This is a further proof of the existence of partial discharges in the ergotropic system and their adaptive value. The reader will remember that the glucogenetic effect of adrenaline is much greater than that of noradrenaline, and it is this action which aids in homeostasis. Moreover, the enhanced adrenomedullary secretion in hypoglycemia is associated with an increased release of adrenocortical hormones, since adrenalectomy lowers the resistance to insulin hypoglycemia more than adrenodemedullation (37). VII. THE ERGOTROPIC DISCHARGE IN THE PARADOXICAL PHASE OF SLEEP

Perhaps the most impressive example of a partial ergotropic discharge, which occurs under strictly physiological conditions since it develops spontaneously, is that seen during the paradoxical phase of sleep.* It is characterized by asynchrony of cortical potentials which in contrast to the asynchrony seen in the state of wakefulness is associated with a complete loss of the tone of the cervical muscles. At the same time the pupils are fissurated (68) and the blood pressure falls markedly, whereas it is rather constant in the preceding synchronous sleep phase (144). The ergotropic discharge is, under these conditions, confined to the reticulocortical activation while fall in blood pressure, bradycardia, and loss in muscle tone indicate a shift of the ergotropic-trophotropic balance to the trophotropic side. However, ergotropic discharges confined to the face appear periodically, consisting of movements of the vibrissae, eyes, and facial muscles. They are associated with moderate degrees of pupillary *See Chapter II.

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dilatation involving inhibition of the Edinger-Westphal nucleus and, to a slighter extent, excitation of the cervical sympathetic. These phenomena are linked to brief periodic fluctuations in the blood pressure (144, 324), but there is no arousal nor any change in the tone of the cervical muscles. VIII. INTERMEDIATE SUMMARY AND INTERPRETATION

Ergotropic patterns may be divided into three groups chiefly based on the type of sympathetic discharge involved. The first group comprises the classical diffuse sympathetico-adrenal syndrome as described by Cannon and consists of the sympathetic excitation acting on vasoconstrictors and other adrenergic nerves, on cholinergic vasodilators which are responsible for the increased blood flow through the muscles, and on adrenomedullary secretion. This sympathetic excitation is associated with increased somatic activity affecting muscle tone and movements; enhanced reticulo-hypothalamic-cortical discharges accounting for increased awareness; emotional excitement; and, particularly when the excitation is intensive and prolonged, liberation of ACTH and TSH through hypothalamically released neurohumors which act on the anterior hypophysis. The second and third groups represent partial sympathetic discharges inasmuch as sympathetic activity without involvement of the adrenal medulla (group II) or adrenomedullary secretion without generalized sympathetic activity (group III) occurs. For brevity's sake groups II and III are also referred to as neurogenic and hormonal respectively. The relation between groups I and II needs little comment. It is generally recognized and has been illustrated by several examples that there is a transition from group II to group I with increasing intensity and duration of excitation. This holds for both man and experimental animal. In the former, increasing intensity of stress may increase excretion of adrenaline in addition to that of nor adrenaline; in the latter mild stimuli may cause contraction of the innervated n.m. only (due to noradrenaline), whereas with stronger stimulation the denervated membranes (due to adrenaline) respond as well. In addition, a gradation in the neurogenic response is seen in group II with increasing intensity of stimulation. That conditions exist in which the sympathetic response is confined to the hormonal phase is an important and rather paradoxical finding. If the excretion of noradrenaline and of adrenaline are chosen as indicators of the neurogenic and hormonal activity respectively, the experiments suggest that adrenomedullary secretion may be increased while the neurogenic component is unchanged or lessened. The latter finding suggests that a release may account for the occurrence of adrenomedullary secretion. This interpretation is supported by the study of ocular reflexes with and without anesthesia (374). In the unanesthetized cat mild stimuli

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(touch, sound, or slight nociception) produce a brief, immediate dilatation of pupil and contraction of the normal n.m., whereas on the sympathetically denervated side only the pupil reacts and this effect (due to the inhibition of the Edinger-Westphal nucleus) is less than on the normal side. In anesthesia, however, the denervated side reacts to stimuli which are ineffective on the normal side; these reactions are prolonged and appear with a greater latent period than in corresponding tests performed on the unanesthetized animal. Even in the unstimulated cat such a paradoxical state (pupillary dilatation and contraction of the n.m. confined to the sympathectomized side) develops as the result of anesthesia (see also 21). Further work showed that generalized anesthesia is not necessary to induce increased adrenomedullary secretion per se (group III). It seems sufficient to inhibit the neurogenic sympathetic reactivity. In an experiment by Andersson & Persson (27) on temperature regulation in the goat it was observed that during and after stimulation of the trophotropic heat loss center in the anterior hypothalamus for three hours the following symptoms developed (Fig. 7-8): 1. A progressive fall in body temperature amounting to about 10°C; 2. A dilatation of the ear vessels; 3. An increase in respiration and panting; 4. Vigorous shivering immediately following the period of stimulation; 5. Marked hyperglycemia (blood sugar in the control 0.07 g/100 ml; after the 3-hour stimulation 0.2 g/100 ml). The enormous fall in body temperature indicates that the neurogenic sympathetic response is inhibited during stimulation. This is to be expected in view of the reciprocal relations existing between the anterior and posterior hypothalamus in general and the heat-releasing and the heat-conserving centers — the latter in the posterior hypothalamus — in particular. The failure of shivering and vasoconstriction to appear under these conditions is thus accounted for. The only means by which the fall in body temperature could be lessened would be to increase the production of heat. Since shivering is reciprocally inhibited, only the chemical regulation of heat is available to the organism. The rise in blood sugar through increased secretion of adrenaline strong enough to produce glycosuria shows that the adrenal medulla is activated (while the ergotropic division of the hypothalamus is reciprocally inhibited) and contributes to homeostasis through an increase in heat production.* Investigations of the action of carbon dioxide on the ergotropic system, *The prolonged stimulation of the heat-releasing center also produces cortical synchronization (263) and thereby drowsiness. It is unlikely that this moderate decrease in cortical activity contributes to the release of the medullary center which regulates the adrenomedullary secretion. In other words, Andersson's experiment should give similar results when performed on a decorticate goat.

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Fig. 7-8. Changes in respiration rate and rectal and ipsilateral ear surface temperature caused by 3 hr. of unilateral electrical stimulation of the preoptic "heat loss center" in an unanesthetized goat kept in an environmental temperature of —6°C. rect. control: the rectal temperature of an intact animal kept for the same period of time in this environment; shiv.: the onset of violent shivering at the end of stimulation. Double lining of respiration curve indicates duration of panting. The experiment shows that shivering is suppressed during the marked fall in body temperature induced by stimulation of the anterior hypothalamus. (From Andersson & Persson. Pronounced hypothermia elicited by prolonged stimulation of the "heat loss centre" in unanesthetized goats. Acta physiol. scand. 41:277, Karolinska Institute, Stockholm, 1957.)

performed with different concentrations for various periods of time and in different species, are very instructive in illustrating the principles which control the diverse forms of ergotropic activity. Administered to the experimental animal in low concentrations, carbon dioxide fails to raise the blood sugar (373), suggesting that adrenomedullary secretion is not increased although the ergotropic system is strongly activated. The latter

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action is indicated by the increased sympathetic responsiveness of the hypothalamus to electrical stimulation, the greater pressor effect on clamping the carotid arteries (baroreceptor reflex), the enhanced vasoconstriction (329), the intensification of the state of arousal and increased cortical desynchronization in response to various sensory stimuli (333; Fig. 7-9). The muscle tone is increased at the same time (445).

Fig. 7-9. The effect of nociception on hypothalamic and cortical potentials in control (A) and 2/2 min. after administration of 10 per cent CO2 ( B ) . Solid horizontal line = nociceptive stimulus: immersion of left hindleg into water at 60°C for 20 sec. 1: right hypothalamus; 2: left motor cortex; 3: gyrus suprasylvius; 4: left occipital cortex (strychninized). lOO/tv. Note that in CO2 the intensity and duration of the desynchronization of hypothalamic and cortical potentials and the frequency of the strychnine spikes are greatly increased. (From Gellhorn. On the physiological action of carbon dioxide on cortex and hypothalamus. EEC clin. Neurophysiol. 5:401, Elsevier, Amsterdam, 1953.)

If carbon dioxide (in a concentration of 10 per cent or less) is applied to experimental subjects for about twenty minutes, a marked excitation (and discomfort) results while the excretion of noradrenaline and adrenaline is increased (883). On the contrary, very high concentrations of carbon dioxide (25 to 35 per cent) have an anesthetic effect in man (699) and reduce cortical and hypothalamic activity. Cortical desynchronization characteristic of the action of low concentrations of CO2, is replaced by synchronized potentials, the amplitude of hypothalamic potentials is reduced, and hypothalamic-cortical discharges in response to nociceptive stimuli are abolished (333; Fig. 7-10). The excretion of adrenaline, but not that of noradrenaline, is increased in man (775), * and adrenomedullary secretion is greatly increased in the cat (938). It seems to follow from these and related observations discussed earlier in this chapter that several conditions in which cortical activity and ergotropic responsiveness of the hypothalamus are increased lead progressive**More data on these findings are needed.

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ly from sympathetic to sympathetico-adrenal activation, indicated by greater excretion of adrenaline as well as noradrenaline and also by the appearance of contractions of denervated smooth muscles (for instance, in the eye) in addition to the sympathetic effects seen on the normally innervated structures. It should be stressed that under these conditions, particularly in the unanesthetized animal, the neurogenic phase is more prominent than the hormonal phase. With marked changes in the internal environment and also in other conditions in which cortical and hypothalamic excitability is reduced, however, the reaction is reversed. The noradrenaline excretion remains unchanged or is diminished while that of adrenaline is increased.

Fig. 7-10. Effect of nociceptive stimulation (immersion of right hindleg in water at 70°C for 10 sec.) on potentials of right hypothalamus (1), left motor cortex (2), and left gyms suprasylvius (3). 100/AV., 1 sec. Pentothal cat. A: control; B: 70 sec. after administration of 30 per cent CO2. The experiment shows that 30 per cent CO2 abolishes the effect of nociceptive stimulation on hypothalamic and cortical potentials. (From Gellhorn. On the physiological action of carbon dioxide on cortex and hypothalamus. EEC clin. Neurophysiol. 5:401, Elsevier, Amsterdam, 1953.)

Apparently adrenomedullary secretion occurs under two very dissimilar conditions, one when the degree and duration of the sympathetic excitation surpass a certain level, the other when this excitation falls below a critical value. Since alterations in central sympathetic activity influence the trophotropic-ergotropic balance, it may be said that in the normal organism shifts in the balance to the ergotropic side tend to produce sympathetico-adrenal discharges, whereas shifts to the trophotropic side, associated with a loss in excitability of the cortex and of the ergotropic division of the hypothalamus, tend to produce increased adrenomedullary secretion without an increase in the activity of the neurogenic component.* The production of this syndrome in Andersson's experiment involving prolonged * These shifts seem to be responsible also for the changes in the excretion ratio of noradrenaline and adrenaline in different emotional states (see Chapter IV).

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stimulation of the trophotropic division of the hypothalamus strongly supports this interpretation. Moreover, reduction in the excitability of the posterior hypothalamus favored the hormonal and reduced the neurogenic ergotropic response to hypothalamic stimulation, whereas an increase in its excitability reversed the effect (815). The diffuseness of the sympathetico-adrenal response under severe stress (Cannon's emergency reaction) has its anatomical basis in the fact that the postganglionic sympathetic fibers are about thirty times as numerous as the preganglionic fibers (809). It is more difficult to explain how sympathetic reactions may appear in a restricted form so that, for instance, vasoconstriction may be confined to a fraction of the vascular bed or so that partial sympathetic effects lead to graded contraction of the n.m. and of the pupillary dilator muscles. Folkow (294), discussing the relevant literature, comes to the conclusion that "the postganglionic sympathetic neuron makes direct contact by axon ramifications with a group of smooth muscle cells, thus forming a 'motor unit' analogous to the innervation principle of the skeletal muscle." If this is the case, one would expect that with increasing intensity of excitation the number of activated "units" and the rate of discharge of the individual units would increase. There is ample evidence for increasing degrees of contraction of various smooth muscles with increasing frequency of stimulation and also for variations in threshold of vasomotor fibers innervating a certain vascular area (294). While these principles may account for the gradation of the smooth muscle action (vasoconstriction), marked differences in the density of the constrictor fibers in different areas also play an important role. This seems to be the reason why, at a given frequency of stimulation, cutaneous vasoconstriction is much greater than that of the vessels in the striated muscles (158) .* How complex these partial sympathetic discharges are is indicated by the following observations: 1. Lowering of the intrasinusal pressure causes vasoconstriction of increasing degree in kidney and in cutaneous, intestinal, and muscle vessels, but sciatic or hypothalamic stimulation elicits a particularly strong renal constriction in the same animal (280, 647). Moreover, as was mentioned in Chapter VI, the active muscle does not respond to the carotid sinus reflex, whereas the blood vessels of the resting muscle are particularly sensitive to it. 2. Hypothalamic lesions may abolish the increase in heart rate associated with eating while not interfering with the acceleration of the pulse rate during exercise (909). 3. Changes in the internal environment through CO2 (296) may abolish *Vasodilatation also differs in degree in various vascular areas following stimulation of afferent muscle nerves (528) or excitation of the cingulate gyrus (646). This effect involving inhibition of sympathetic discharges is determined quantitatively by the degree of sympathetic vascular tone prevailing at the time of stimulation.

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the baroreceptor reflex on the kidney while intensifying it on the muscle vessels. Graded sympathetic action may involve varying degrees of parasympathetic inhibition exerted on the same structure, but the application of this concept to certain areas of vascular physiology encounters considerable difficulty. We stressed sympathetic cholinergic vasodilator action in the muscle, but there seems to be no good evidence for the presence of parasympathetic vasodilators in this tissue or in the skin of common laboratory animals in which partial vasoconstriction was frequently recorded. On the other hand, the effectiveness of weak sympathetic stimuli is lessened on the pupil when the parasympathetic tone of the constrictor of the iris is considerable, and Berlucchi et al. (68) show in their experiments on cooling of the medulla oblongata that the diameter of the pupil is the result of the balance in the action of the ascending excitatory ergotropic and inhibitory trophotropic systems. A further factor involved in diminishing the effectiveness of sympathetic discharges is the metabolites which induce vasodilatation. They play an important role not only in the muscle but also through the formation of bradykinin (300) in the skin. Partial ergotropic discharges and differential reactivity of the ergotropic system seem to be the cause of certain phenomena which have puzzled psychologists and clinicians. When experimental subjects are tested in different stresses and various sympathetic indicators are used, marked differences in the responsiveness of several autonomic functions are noted which are the expression of partial activation of the ergotropic system. Moreover, the subjects "tend to respond with an idiosyncratic pattern of autonomic activation in which maximal activation is shown by the same physiological function, whatever the stress" (609). This response stereotypy is not confined to the autonomic but appears likewise in the somatic system, as indicated by differential states of activity of several striated muscles. It therefore seems justified to speak of an ergotropic response stereotypy. Studies of normal persons and psychiatric patients lead to the interesting conclusion that "each individual seems to be characterized by a different mode of response, some responding primarily by means of the autonomic nervous system, some by muscle tension, and others with overt muscle activity (movement)" (389). However, the psychophysiological significance of these intraergotropic differences (see next section) is not known (see also 587). These phenomena seem to be related to the "symptom stereotypy" shown by psychiatric patients. Such patients with neuromuscular disturbances are more likely to react with increased muscle tension than with acceleration of the heart rate to physiological or psychological stress (675); similarly, the autonomic discharge in stress is often confined to a specific organ, so that Wolff (998) speaks of "stomach reactors," "pulse reactors,"

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"nose reactors," etc. The mechanisms underlying these various types of stereotypy are not known, but obviously partial ergotropic discharges are involved which appear prominently in either somatic or autonomic restricted activities. Gradation from partial to total ergotropic discharges is also demonstrable in convulsive disorders. Thus, whereas generalized convulsions are accompanied by intensive ergotropic activity including adrenomedullary secretion, paroxysmal EEG discharges of lesser intensity may or may not be associated with autonomic symptoms. Most frequently, changes in heart rate and skin resistance occur (535). Diffuseness, intensity, and duration of these ergotropic discharges parallel the intensity of the clinical disturbance. IX. INTRAERGOTROPIC ADJUSTMENT REACTIONS The ergotropic patterns described in the preceding pages were distinguished from each other through the relative activity of the neurogenic and hormonal phases of the sympathetic system, but little attention was paid to the behavior of the somatic component under these conditions. In this section autonomic-somatic relations will be considered under the influence of cold adaptation in order to show important intraergotropic adjustment reactions. Numerous examples were given in previous chapters of the fact that in general, on excitation of the ergotropic system, sympathetic and somatic discharges vary in a parallel manner, in contradistinction to the behavior of the trophotropic system, in which increased activity is associated with diminished tone and responsiveness of the motor (and sensory) system. Confining our remarks to the ergotropic system, we may say that the parallelism between the intensity of sympathetic and somatic discharges tends to reinforce their action. Thus, increased muscle tone and sympathetic action exert a synergistic effect on the cardiovascular system and also on the diencephalon, since activation of the muscle spindles from the hypothalamus via gamma neurons enhances the central tone of the sympathetic system.* Such synergistic action suggests that the individual share which sympathetic and somatic components play in the total ergotropic action may undergo significant changes in different conditions. If this is true it would reveal a new facet of ergotropic organization heretofore not considered. Cannon (147) observed as early as 1932 that with increasing degrees of cooling, adrenomedullary secretion is increased and shivering occurs. If the cold stimulus is rather mild, it may lead to secretion of adrenaline without shivering, but the same stimulus evokes intensive shivering if the adrenal medullae are denervated. The cooling of the organism evokes two *See also Chapter V.

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types of calorigenic responses which affect the chemical and physical temperature regulation by increasing the secretion of adrenaline and the activity of the muscles respectively. These adjustment reactions seen under acute conditions of exposure to cold undergo fundamental changes in chronic conditions. Acclimation of rats to cold (6-10°C) for about five weeks greatly increases their resistance to cold. The O2 consumption at a given temperature is greater in the cold- than in the warm-acclimated animals and is maintained at low environmental temperatures at a greatly increased level for hours in the cold-adapted (430), although shivering as indicated by the electromyogram is greatly diminished. These findings disclose a fundamental change in the temperature regulation as the result of acclimation. In the unacclimated animal the augmented heat production on exposure to cold is mainly due to muscle activity,* since there is little increase in O;> consumption in curarized animals at low temperatures. On the contrary, cold-acclimated rats show an enormous increase in O2 consumption in the cold in spite of curarization (176), indicating that chemical processes not present in the unacclimated animal must account for the thermogenesis. An increased adrenomedullary secretion is not involved in the effects of cold acclimation, since adrenodemedullated cold-acclimated animals behave essentially as acclimated normal rats, although the O2 consumption is somewhat less. That the neurogenic component of the ergotropic system is altered is evident from the following facts: 1. The effect of acclimation (increase in Oa consumption! and maintenance of this level at low temperature in curarized animals) is abolished by drugs which block the action of adrenergic nerves (495). 2. The rise in body temperature and O2 consumption on injection of noradrenaline is marked in cold-adapted but negligible in warm-adapted animals (494; Fig. 7-11). Since there is no hyperglycemia, adrenaline is not involved. It is inferred from these experiments that cold acclimation results in a "substitution of nonshivering thermogenesis under the control of noradrenaline for heat production by shivering" (430)4 Apparently, the tissues °In the dog the O2 consumption varies directly with the intensity of the shivering (777). t According to Smith (910) the growth and the metabolic activity of the brown adipose tissue play a role in the thermogenesis in rodents. In cold-adapted animals it hypertrophies and its O2 consumption increases. Denervation or blocking of sympathetic impulses with hexamethonium interferes with these adjustment reactions. | It is interesting to point out that the temperature regulation in the newbo guinea pig is similar to that seen in adult cold-adapted animals. In both cases shivering is absent and chemical temperature regulation is solely responsible for maintaining the body temperature. Chemical blocking of adrenoreceptors leads to shivering in the newborn on exposure to cold, indicating that this mechanism is developed but has a higher threshold than that involving chemical temperature regulation (116).

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Fig. 7-11. Effects of L-noradrenaline, 0.2 mg/kg, on the oxygen consumption and rectal temperature of cold-adapted rats (solid dots) and warm-adapted rats (open circles). Experiments were conducted at 30°± 1°C. L-noradrenaline was injected intramuscularly at the point indicated by the arrow. Vertical bars indicate the standard deviation. Each point represents the mean of 4 experiments. (From Hsieh & Carlson. Role of adrenaline and noradrenaline in chemical regulation of heat production. Am. J. Physiol. 190:243, 1957.)

become progressively sensitized to noradrenaline with increasing duration of the acclimation period. The study of the behavior of noradrenaline and adrenaline in rats on the first and last days of a month of exposure to 3°C shows that the excretion of both neurohumors is increased at the beginning of the acclimation period. At the end, however, the excretion of adrenaline has returned to the control level, whereas that of noradrenaline is still greatly augmented (614). The maintenance of an increased tone of the neurogenic component of the ergotropic system is evident also from the persistence of an increased heart rate throughout the period of acclimation (431). From a comparison of the ergotropic actions before and during various phases of cold acclimation, it is inferred that adrenomedullary secretion and shivering protect the organism in the unacclimated state. Both factors play a very small role after acclimation, which is characterized by the maintenance of an increased tonic discharge of the neurogenic but not of the hormonal and somatic component of the ergotropic system. The augmented sensitivity of the tissues to the thermogenetic effect of 'noradrenaline makes shivering and adrenomedullary secretion unnecessary. The elimination of shivering, freeing the muscles for locomotion, is important for survival. Within the conceptual frame of this book it is emphasized

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that as the cold-acclimation studies show, the ergotropic pattern may undergo wide variations from the norm, since the somatic discharge may be lessened while the neurogenic component shows a greatly increased activity. According to Keller (562), some hypothalamic lesions abolish shivering while the chemical temperature regulation is retained to a certain extent, and since the dependence of shivering on the hypothalamus is well established, it seems that the adjustment reactions seen in the acclimation to cold involve not only a change in the sensitivity of peripheral organs to noradrenaline but also a reorganization of the hypothalamicall)' controlled ergotropic pattern. X. VARIATIONS IN THE CORTICAL ACTIVATION PATTERN ORIGINATING IN HYPOTHALAMUS AND RETICULAR FORMATION

It was shown in Chapter I that the activation of the ergotropic system leads to a diffuse excitation of the cerebral cortex which manifests itself in cortical desynchronization and behavioral arousal. The degree of desynchronization, however, is not the same in different cortical areas. In response to nociceptive and proprioceptive stimuli the magnitude and duration of this effect are greater in the sensori-motor than in the acoustic and optical projection areas (Fig. 5-2; 71).* Similarly, electrical stimulation of the auditory pathways shows that the desynchronization of the auditory cortex results from weaker stimuli than are required for generalized desynchronization and behavioral arousal. This differential response, which appears under various physiological and pharmacological conditions (567), may be of considerable significance, since it is thought that uniform activity of the whole cortex as in petit mal is associated with the loss of consciousness. The intensity, spread, and duration of the cortical desynchronization are related not only to the nature of the reflex stimulus but also to its intensity and to the reactivity of the hypothalamo-reticular core (modifiable through injection of strychnine or nembutal into the posterior hypothalamus, for instance). Furthermore, a gradation of this response is easily demonstrated by nociceptive stimuli involving increasing areas of the skin (spatial summation, 356). The investigation of the habituation of the arousal reaction, leading by repeated application of the same stimulus (sound) to a reduction and finally to the disappearance of the cortical desynchronization, illustrates further this gradation and furnishes evidence that several mechanisms are activated when a diffuse cortical excitation is initiated. A "phasic" arousal reaction of short latency and brief duration was found to be more resistant to habituation than a "tonic" reaction whose latent period and "Such differences in cortical reactivity were found also on stimulation of the reticular formation at low frequencies (139).

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duration were relatively long. Experiments involving lesions in the brain stem suggest that the tonic reaction is controlled chiefly by the reticular formation, whereas the phasic response depends on the diffuse thalamic system (890). However, physiological conditions which would specifically induce habituation via the tonic (and not through the phasic) reaction have not yet been determined. Studies of behavior and EEC in animals with lesions in the posterior hypothalamus indicate that the various parts of diencephalon and mesencephalon known to contribute to the diffuse activation of the cortex are of unequal importance for the maintenance of consciousness. Thus coagulation of the posterior hypothalamus, which causes somnolence (472, 807), does not prevent desynchronization from occurring in response to peripheral and reticular (mesencephalic) stimulation, but these stimuli fail to produce behavior arousal (251). On the contrary, animals with lesions in the midbrain reticular formation, "sparing most of the peduncles and periventricular grey" (286), react to visual and auditory stimuli behaviorally and also with appropriate shifts from synchronization to desynchronization in the EEG. These experiments* and the work on habituation discussed before suggest that the thalamic, hypothalamic, and reticular parts of the diffuse ascending system contribute different components to the behavioral and EEG components of arousal. This work was extended by Tokizane et al. (952) who showed that with near-threshold stimuli the reticular formation has a greater arousal effect on the neocortex than on the hippocampus, whereas this relation is reversed on stimulation of the posterior hypothalamus. Similarly, intracarotid injection of noradrenaline or adrenaline in cats with transection at the anterior mesencephalon and, consequently, synchronization of the neocortical potentials, fails to produce neocortical arousal but is still effective on the hippocampus as long as the posterior hypothalamus is intact (558). These experiments allow one to differentiate between the hypothalamichippocampal and the reticulo-neocortical arousal. The following data further illustrate the functional differences between the cortical discharges originating in the hypothalamus and those originating in the reticular formation: 1. The cortical activation which appears during the paradoxical sleep phase is suppressed by lesions in the hypothalamus but not by reticular lesions (541). 2. Secondary cortical potentials induced by sciatic stimulation are abolished by lesions in the posterior hypothalamus but not by lesions in the reticular formation (30). See also A58, especially p. 295. "See also Monnier et al. (721) concerning differences in the action of thalamus and reticular formation on behavioral and electroencephalographic aspects of sleep and arousal.

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3. The observation that unconditioned rats in a Y-shaped runway show as the trials are repeated an increase in exploratory activity but a decrease in defecation (924) may be a behavioral indication that increased reticular discharges are combined with lessened hypothalamic activity. The finding that lesions in the medial forebrain bundle suppress bar-pressing for food or water although the animals are "behaviorally alert" (727a) must be interpreted similarly. Pharmacological experiments show likewise that fundamental differences exist between the diencephalic and mesencephalic parts of Magoun's ascending excitatory system. Thus, morphine depresses cortical desynchronization induced by nociceptive but not by other sensory (cutaneous, acoustic) stimuli. At the same time the threshold for producing this action by electrical stimulation is raised at the thalamic level, whereas it is unchanged in the reticular mesencephalon (904). Similarly, scopolamine blocks the desynchronizing effect of a single sciatic shock, although the response of the reticular formation to this stimulus remains the same (650). Both experiments suggest that at least under the influence of certain drugs the diencephalic structures are more easily altered than the mesencephalic reticular formation, a fact that may play a part in differential forms of activation of the reticular system in various physiological conditions. Anokhin and associates (30, 31), utilizing the well-known physiological antagonism between alimentary and defensive reflexes (772), have furnished further evidence for this thesis through studies on rabbits. They note that in urethane anesthesia nociceptive stimuli produce desynchronization but no arousal, whereas Chlorpromazine eliminates the action of nociception on the EEG though the animal eats and searches for food. Orienting and alimentary conditional reflexes are retained. Particularly striking is the observation that a rabbit starved for forty-eight hours shows desynchronization in the frontal but synchronization in the remainder of the cortex during urethane anesthesia, whereas this anesthetic produces generalized cortical synchronization in nonstarved animals. Apparently impulses from the hypothalamic feeding center counteract the urethaneinduced synchronization, but this effect is chiefly restricted to the frontal lobe. This interpretation is supported by the fact that injection of glucose and feeding of milk in starved urethane-treated rabbits restore grouped potentials in the frontal cortex. It would appear that the balance between the hypothalamic feeding and satiety centers, which depends on the blood sugar and the state of gastric activity (hunger contractions), determines the degree of desynchronization in the frontal cortex of rabbits in urethane narcosis. Anodic polarization of the hypothalamus, which seems to reduce the activity of the feeding center, likewise restores frontal cortical synchronization in the starved rabbits.

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The conclusion drawn from the physiological and pharmacological studies reported above, that the hypothalamic-reticular ascending system shows some differentiation in its excitatory action on various parts of the cortex, holds for the trophotropic division, since the recruiting response following the stimulation of "unspecific" thalamic nuclei is more difficult to elicit in the visual and auditory projection areas than in the cortical association areas. This differential action is at least partly due to the "competitive interaction between the specific and unspecific projection systems for the control of cortical electrical activity in sensory areas" (524), since after destruction of the specific thalamic nuclei the recruiting response is increased. XI. CONCLUDING REMARKS

The study of the ergotropic system under numerous conditions has shown that contrary to Cannon's concepts the qualitative pattern of its discharge as well as the degree of its activity undergoes wide variation. The neurogenic (noradrenaline) response occurring without the adrenomedullary (adrenaline) phase may vary in degree in different organs and is modified by central and peripheral factors. Thus, changes in internal environment, as on inhalation of small amounts of CO2, intensify the central ergotropic responsiveness, whereas the state of activity in peripheral organs, particularly in muscles and kidney, modifies their reaction to ergotropic discharges. The hormonal (adrenomedullary) component may appear at relatively high degrees of ergotropic excitation in conjunction with strong neurogenic activity, as in Cannon's emergency states, but the importance of the hormonal phase is thought to lie primarily in its metabolic effect, whereas the reinforcement of the neurogenic action through adrenomedullary secretion is insignificant. In sharp contrast to this pattern of ergotropic activity is another one in which the hormonal phase is greatly increased, but the neurogenic activity is unchanged or lessened^ Thus, in the late phase of hypoglycemia excretion of adrenaline is increased, but that of noradrenaline — indicating the intensity of the neurogenic (sympathetic) discharge —is slightly diminished. Loss in cerebral and especially in hypothalamic sympathetic reactivity seems to be responsible for the release of adrenomedullary secretion. Since this syndrome also appears under conditions of prolonged stimulation of the anterior hypothalamus which is associated with an inhibition of its posterior (ergotropic) division, it is suggested that the diffuse sympatheticoadrenal discharge is the result of a shift in the hypothalamic trophotropicergotropic balance to the ergotropic side, whereas the opposite shift produces adrenomedullary secretion without increased excretion of noradrenaline. The functional significance of these two types of adrenomedullary se-

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cretion remains to be discussed. The emergency type of neurogenic plus hormonal activity attempts to maintain homeostasis in spite of increased metabolic requirements regardless of whether the latter are due to exposure to cold or increased muscular action. Sympathetic action on heart and vascular system, on the spleen, and on the vasodilators in the muscle, combined with the increased tone on the muscle, creates optimal conditions for the maintenance of circulation of heart and brain while the 62 consumption of the organism is increased. This adjustment is supported by the effects of adrenomedullary secretion on the blood sugar and by increased vago-insulin secretion (329) whereby the utilization of glucose is enhanced. If these mechanisms are unable to meet the demands of the tissues, as in severe anoxia or asphyxia, there is a shift in the ergotropic-trophotropic balance to the trophotropic side so that the metabolic requirements are greatly decreased. The lowering of the body temperature and the decrease in heart rate and muscle tone contribute to this effect. At the same time the adrenomedullary secretion is increased, inducing hyperglycemia which counteracts the deleterious effects of anoxia on the brain (329). The lessened receptivity to outside stimuli is also conducive to a state of rest and thereby furthers restitution.* In addition, it has been shown that not only the autonomic (sympathetic and parasympathetic) but also the somatic discharges (to the muscles) and the diffuse upward discharges (from hypothalamus and reticular formation to the cerebral cortex) are gradated depending on the nature of the stimulus, its intensity, and the state of excitability of the centers of the ergotropic and trophotropic systems. But the relations between brain stem and cortex are still more complex. Experiments involving lesions in the brain stem, and pharmacological studies, suggest that the diencephalic and mesencephalic parts of the reticular system, although contributing to cortical desynchronization, play differential roles in the maintenance of consciousness. That hunger and pain, which elicit similar ergotropic downward discharges and also cortical desynchronization, must, in addition, evoke fundamentally different central processes is obvious. Anokhin (29-31) has demonstrated such a difference in rabbits under urethane anesthesia but not yet in the normal organism. Nevertheless, there is good reason to assume that with the development of the cerebral cortex in the primates innumerable patterns of activity are elicited under the influence of various emotions and drives which show little differentiation in their downward discharges. Thus the emotional strain of mental work produces an increased blood flow through the muscles as in fight or flight although it is of no adaptive value in mental work; yet there is little doubt that the * Von Uexkiill (962) considers the occurrence of nausea in experimental and clinical conditions from a similar point of view.

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cortical processes in the two cases which reflect the accompanying psychic events are quite different. It would be erroneous to conclude, however, that the ergotropic downward discharges are not subject to adaptive changes. That fundamentally different types of ergotropic discharges occur is evident from the increased excretion of noradrenaline (without that of adrenaline) and vice versa. Moreover, adjustments take place even within the autonomic-somatic components of the ergotropic downward discharge, as illustrated by the fundamental differences in the rates of excretion of noradrenaline and adrenaline in acute and chronic states of exposure to cold and in the absence of shivering in the cold-adapted organism.

VIII

Internal Secretions and the Ergotropic and Trophotropic Sys

THAT increased ergotropic activity enhances the secretion of adrenomedullary hormones as reviewed in the preceding chapter is but one example of ergotropic-hormonal relations. The reader will remember that conditioning and other forms of stress associated with augmented ergotropic discharges were shown to cause an increased secretion of adrenocortical steroids (Chapter III). These and numerous related investigations constitute an important part of neuroendocrinology, the discussion of which is obviously beyond the scope of this book. But in order to illustrate further the dependence of internal secretions on the ergotropic and trophotropic systems and vice versa, a brief survey of the influence of hypothalamus on the activity of several endocrine glands is presented in this chapter. I. THE THYROID GLAND*

Clinical observations on Graves' disease and early physiological studies on prolonged stimulation of the cervical sympathetic nerves suggested but did not prove an influence of the ergotropic system on the activity of the thyroid gland. However, recent work involving the study of hypothalamic stimulations and lesions has firmly established this relation. The basic facts may be summarized as follows. In animals previously injected with radioactive I131 the difference in radioactivity between the venous and the arterial blood of the thyroid gland increases on stimulation of the anterior hypothalamus, the median eminence, or the tuber cinereum anterior to the median eminence, whereas stimulation of other hypothalamic sites is without effect (143). These results can be matched by the injection of thyrotropin (TSH). Furthermore, unanesthetized rabbits provided with a wire coil ending in a hypothalamic electrode in which a current is induced through a large primary coil (located outside the cage) likewise show an increase in thyroid activity on stimulation: radioactive 1131 is released in increased amounts from the thyroid gland while the plasma protein-bound I131 (FBI131) rises (429). In the rat, multiple 'For the literature see 114, 186, 642, 818, and 932.

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periods of stimulation of the anterior hypothalamus and of the median eminence but not of adjacent areas yield an increase in the circulating TSH (114) whereas lesions in the anterior hypothalamus or median eminence eliminate these effects. It is concluded that the stimulation of the anterior hypothalamus — this area partly overlaps the heat-releasing center (817) — leads to the liberation of a neurohumor which, conveyed through the portal system in the hypophyseal stalk to the anterior pituitary, causes an increase in the circulating TSH and, thereby, in the activity of the thyroid gland. Since destruction of the anterior hypothalamus and particularly of the median eminence, which seems to represent the "final common path" of the hypothalamic TSH-regulating apparatus, causes a lowering of the level of thyroid activity, it is suggested that tonic impulses from the anterior hypothalamus and also a continuous secretion of TSH of hypophyseal origin account for the activity of the thyroid in the resting organism (A34). The secretion of TSH, and thereby the activity of the thyroid gland, depends not only on the impulses impinging on the TSH-regulating areas in the hypothalamus but also on the concentration of the thyroid hormone in the blood. An increase in the circulating thyroxin inhibits the secretion of TSH and this action persists after transection of the stalk or following electrocoagulation of the median eminence. These data indicate that the hypothalamus is not needed for this negative feedback effect.* On the other hand, lowering of the thyroxin concentration in the blood, induced by goitrogenic drugs such as thiouracil derivatives, leads to increased activity of the thyroid gland and marked hypertrophy, which is interpreted as being due to increased secretion of TSH, since it is absent after hypophysectomy (411). Following lesions in the anterior hypothalamus this effect is absent or greatly reduced, although it is retained when hypothalamus, median eminence, and hypophyseal stalk are completely isolated from the adjacent parts of the brain (412). However, the response to a lowering of the thyroxin concentration in the blood is present in animals in which pituitary-thyroid units are grafted onto the anterior chamber of the eye: propylthiouracil causes the formation of an intraocular goiter (840) under these conditions. Further data suggest that at least some nervous and hormonal regulations of the thyroid secretion are interdependent. The tonic effect from the anterior hypothalamus, which tends to maintain the secretion of TSH at a relatively high level, is modified by the concentration of the thyroid hormone in the blood. Rats with hypothalamic damage leading to a marked lowering of TSH secretion still react to a further lowering of the *Microinjection of thyroxin into the anterior hypothalamus produces either no effect or a greatly delayed decrease in thyroid function, whereas the intrahypophyseal administration is highly effective (A35).

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thyroxin level in the blood with an increased secretion of TSH. Apparently "the pituitary itself acts as a thyrostat, the setting of which is governed by a hypothalamic mechanism" (568). For our purpose it is important to determine the kind of stimuli which alter thyroid activity via the anterior hypothalamus and also their relation to the trophotropic and ergotropic systems. Since the thyroid hormone is a powerful metabolic stimulant and the ergotropic system exerts catabolic effects (in contradistinction to the anabolic action of the trophotropic system ), one would expect that increased thyroid activity would be associated with enhanced ergotropic discharges and that lessened thyroid function would be accompanied by inhibition of ergotropic and/or augmentation of trophotropic discharges.* The study of the influence of changes in environmental and hypothalamic temperature on the activity of the thyroid gland has furnished valuable data for these problems. Upon exposure to cold the thyroid activity measured by the release of 1131 from the thyroid gland is greatly increased, but this action is abolished by lesions in the median eminence. Moreover, while maintaining normal thyroid function at room temperature, hypophysectomized animals with a functioning hypophyseal transplant fail to respond to cold with an enhanced release of thyroid hormone (585). Apparently the increased secretion of TSH on exposure to cold requires the integrity of the hypothalamic-hypophyseal system (186). Inasmuch as cold evokes a generalized sympathetico-adrenal discharge and intensifies muscular activity, it may be said that cold evokes an activation of the ergotropic system which is associated with an increased secretion of thyroid and adrenal hormones. Other pertinent experiments involve the heating and cooling of the anterior hypothalamus. As Andersson and collaborators (23, 24, 25) have shown cooling of the preoptic-anterior hypothalamic area (but not of thalamus, mesencephalon, or forebrain) causes an increase in the excretion of noradrenaline and adrenaline and a rise in the body temperature and thyroid activity which is indicated by a rapid drop of the thyroid radioactivity and a corresponding increase in the protein-bound I m in the blood (Fig. 8-1 ).f However, these effects are absent after lesions in the median eminence. Cooling of the body (through ice water administered by stomach tube) raises FBI131 while the temperature of the body and of the brain| falls. Apparently the cooling of the body leads to a lowering of the temperature of the hypothalamus and, thereby, to an activation of ergotropic system and thyroid gland. .

*The fact that the area controlling thyroid activity is located in the anterior hypothalamus is not in contradiction to this suggestion since, as was pointed out in Chapter I, trophotropic as well as ergotropic effects are commonly elicited from the same site through the use of different parameters of stimulation. tSee also 819. |Personal communication from B. Andersson.

Fig. 8-1. Stimulation of thyroid activity by preoptic cooling. Effects of local cooling of the preoptic area on thyroid radioactivity, plasma FBI131 content, and rectal temperature. Thyroid activity is measured as a percentage of the total 40/ctc dose given to the animal. The experiment shows that cooling of the preoptic area or of the anterior hypothalamus accelerates the release of thyroid hormone from the thyroid gland presumably via the hypothalamo-hypophyseal axis. (From Andersson, Ekman, Gale, & Sundsten. Activation of the thyroid gland by cooling of the pre-optic area in the goat. Acta physiol. scand. 54:191, Karolinska Institute, Stockholm, 1962.)

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On the contrary, warming the anterior hypothalamus intensifies trophotropic activity, lowers the excretion of noradrenaline and adrenaline, prevents shivering in spite of a 10°C fall in body temperature, and inhibits thyroid activity. This procedure also blocks the effects of cooling of the body: the thyroid activity decreases as if the body had not been cooled. The experiments show conclusively that through warming and cooling of the anterior hypothalamus the activity of the ergotropic system may be inhibited and intensified respectively, and that the thyroid activity parallels that of the ergotropic system under these circumstances (see also 426). It was stated earlier that the thyrotropic-regulating hypothalamic center reacts not only to electrical stimulation and environmental cold but also to a decline in the circulating concentration of thyroxin. Under these conditions the secretion of thyrotropin is enhanced. If this is the case, one would expect that the combination of such effective stimuli would produce a summation of excitation and greatly increase the secretion of thyrotropin. This seems to be demonstrated in Dempsey & Astwood's (210) work if it is interpreted in the light of the more recent studies through which the hypothalamic control of the secretion of thyrotropin has been established. These authors studied thiouracil-treated rats at different temperatures and determined the amount of thyroxin necessary to prevent the hypertrophy of the thyroid gland which usually results from thiouracil treatment. They found that at 1°, 25°, and 35°C, 9.5, 5.2, and 1.7 /*g thyroxin respectively were required. It must be assumed that the thiouracil-induced lowering of the thyroxin in the blood causes a release of the thyrotropincontrolling substance from the anterior hypothalamus in proportion to the excitability and the degree of tonic activity of this center. If this excitability is increased, as in a cold environment, more thyroxin is necessary to compensate for the action of thiouracil than in a hot environment in which the ergotropic thyroid-controlling center is inhibited. Bearing in mind that a shift in the environmental temperature from cold to heat is accompanied by a progressive diminution in the ergotropic-trophotropic quotient at the hypothalamic level, we may say that an alteration in hypothalamic balance produces parallel changes in ergotropic and thyroid activities under these conditions. There is, however, a fundamental difference in the relation between the activity of the ergotropic system and that of the thyroid and of the adrenal glands. It is true, in general, that regardless of the nature of the stimulus which induces sympathetic discharges, a certain intensity (and duration) will result in increased adrenomedullary and adrenocortical secretions; but most of these "stressors," such as emotional excitement (A36), nociceptive stimuli, hemorrhage, and tissue damage, cause an inhibition of thyroid activity (114).

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How are these differences to be explained? Species differences may play a role, since fever resulting from bacterial toxins causes an increase in thyroid function in guinea pig and monkey but a decrease in rat, mouse, and rabbit (382). The results are, at least in part, due to secondary inhibiting effects of the increased secretion of ACTH, which suppresses thyrotropin secretion (115), but obviously these factors are inadequate for a full explanation. From the organismic point of view these technical details are less important than the recognition of the fact that different responses of thyroid and adrenal glands in a given stress are necessary for homeostasis. The significance of increased adrenomedullary secretion in emotional excitement (fight) and cold was pointed out earlier, and the importance of adrenocortical hormones for the prevention of capillary damage under conditions of excessive sympathetic discharges is well established (806). This may account for the occurrence of increased adrenocortical activity in a wide variety of stresses in which the ergotropic activity is augmented. On the other hand, a fundamentally different response of the thyroid to emotional excitement (including fight) and to cold is necessary for homeostasis. The marked increase in metabolic rate due to the hypothalamic action on thyrotropin secretion in cold is obviously beneficial, but such action would greatly curtail muscular performance in fight (and exercise). II. HYPOTHALAMIC BALANCE AND ACTH It was shown in the preceding section that a positive correlation exists between the excretion of noradrenaline and adrenaline (and also the activity of the thyroid gland) and the quotient ergotropic hypothalamic discharges trophotropic hypothalamic discharges provided that this quotient is altered through changes in the temperature of the anterior hypothalamus. These data raise the question whether or not other hypothalamically regulated hormones follow this rule. The secretion of ACTH is considered in this respect because, like the secretion of the thyroid hormone, it is regulated by the hypothalamus and increases with increasing ergotropic discharges.* Furthermore, the neuroendocrine organization is similar in the two cases, since the lowering of the corticosteroid level in the blood raises the ACTH secretion through the activation of the hypothalamus (tubero-mammillary area), whereas raising this level inhibits ACTH chiefly by direct action on the anterior hypophysis.! For *For the literature see the surveys listed on p. 93 and p. 215. f There is, however, some evidence that the hypothalamus is influenced when the corticosteroid level in the blood is either raised or lowered. Szentagothai et al. (932) report that conditions leading to a hypertrophy of the adrenal cortex are accompanied by a decrease in the size of the cell nuclei of the ventromedial hypothalamic

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our problem an adequate procedure to determine the influence of the ergotropic-trophotropic balance on adrenocortical functions would be to study ACTH secretion while the temperature of the anterior hypothalamus is lowered or raised as in Andersson's experiments. Such data are not available. However, marked variations in ACTH secretion can be brought about by stimulation of hypothalamus and reticular formation. The corticosteroids in the adrenal vein are lessened on stimulation of the preoptic area, the antero-lateral part of the hypothalamus, and the lower part of the septum, whereas stimulation of the posterior hypothalamus and the mesencephalic portion of the reticular formation as well as of the tuberomammillary area (and the median eminence) raises the output of ACTH considerably (254). In the light of our earlier discussion it may be said that the trophotropic system (at the hypothalamic level) inhibits and the ergotropic system enhances the secretion of ACTH. This result has been duplicated by chemical stimulation of these areas with cholinef gic drugs (257). Studies involving stimulation of, and lesions in, certain parts of the limbic brain suggest that stimulation of the amygdala enhances and that of the hippocampus inhibits hypothalamic ergotropic activity. It is therefore of interest to mention that stimulation of the amygdala produces maximal ACTH secretion in the monkey (684), whereas bilateral destruction of this area delays the release of ACTH and results in atrophy of the adrenal cortex (584). On the other hand, stimulation of the hippocampus inhibits ACTH secretion. Consequently, only insignificant changes in circulating eosinophils and lymphocytes and in the ascorbic acid content of the adrenal cortex occur in response to pain, histamine, and other conditions of stress which activate the ergotropic system (255). The bearing of the antagonism between hippocampus and amygdala on the function of the ergotropic division of the hypothalamus is further illustrated by the fact that stimulation of the amygdala or of the hypothalamus fails to produce increased ACTH secretion if it is preceded by stimulation of the hippocampus (684). That the level of the corticoids is raised in the blood after hippocampal lesions (287, 584) suggests that the hippocampus exerts a tonic inhibitory action on the ergotropic part of the hypothalamus (A57). It should be borne in mind, however, that in spite of these suggestive facts ergotropic as well as trophotropic effects may result from stimulation of hippocampus* and amygdala (591).f That changes in ergotropic-trophnucleus, whereas atrophy of the adrenal cortex (regardless of its origin) is associated with the reverse effect. *See Endroczi & Lissak (252) who inhibited ACTH secretion by hippocampal stimulation at low frequencies but increased it with high frequencies. (The frequency effect on the ergotropic and trophotropic systems has been described in Chapter I.) tSee also Slusher & Hyde (907) who, like Koikegami (591) found evidence for the fact that the lateral part of the amygdala inhibits and the medial part enhances ACTH secretion.

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otropic balance and consequent alteration in ACTH secretion may originate in the limbic brain is an intriguing assumption but not yet an established fact. Further studies in this area as well as the suggested work on changes in ACTH secretion through temperature changes in the anterior hypothalamus are needed to broaden the experimental base for an understanding of the relation between ergotropic-trophotropic balance and hypothalamically controlled hormonal secretions. III. HYPOTHALAMUS AND SEXUAL FUNCTIONS This topic is briefly touched on for two reasons: 1. To show that complex autonomic-somatic discharges are integrated into specific behavioral acts as the result of stimulation of the hypothalamus with sex hormones; 2. To demonstrate that hormones alter not only the ergotropic but also the trophotropic system. The first phenomenon is illustrated by the implantation of stilbestrol esters into the hypothalamus between the anterior preoptic area and the mammillary bodies. This procedure results in almost 100 per cent estrous behavior and mating in ovariectomized cats. Such reactions are due to a direct action of these substances on the hypothalamus since the effects may occur although the genital tract remains atrophic (706). In this remarkable experiment central chemical stimulation results in estrous behavior in an anestrous animal, the state of the genital organs being used as the criterion of the anestrous condition. The second phenomenon refers to the fact that sexual intercourse induces a state resembling the paradoxical phase of sleep in the rabbit. The greatly intensified ergotropic discharges occurring during sexual intercourse are indicated by an increase in heart rate, respiration, and muscle tone. This phase is followed by a period of relaxation and, according to Pliny's statement, "Omne animal post coitum triste," by an alteration in mood. One would expect that these fundamental changes are the expression of a shift in ergotropic-trophotropic balance. The excessive ergotropic discharges accompanying orgasm seem to be replaced by a phase of trophotropic dominance in which the tendency to relaxation and sleep prevails. Although such a rebound phenomenon probably plays a role in the causation of the behavioral reactions appearing post coitum, hormonal factors are likewise involved, particularly in animals in which the sexual receptivity of the female depends on the presence of sex hormones. We confine our report to the investigations of Sawyer & Kawakami (866) who investigated in the female rabbit postcoital reactions and the nervous and hormonal factors involved in them (see also 277 and 278). In animals provided with chronically inserted electrodes in various parts

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of the brain in which EEC changes and behavior could be correlated, it was found that three phases follow vaginal stimulation. In the first, cortical spindles are associated with drowsiness, whereas in the second a hyperreactivity of the hippocampus prevails. The potentials are large, synchronized, of a frequency of 8/sec* or higher, and appear not only in the hippocampus but in almost all limbic areas and even in the neocortex. During this period the animal displays the classical symptoms of the paradoxical phase of sleep: the pupils are constricted, heart rate and respiration are slowed, the ears are retracted, the head sinks to the floor (loss oi tone of the neck muscles), and arousal is difficult. This phase is followed by one in which the normal EEG pattern and wakefulness reappear. Behaviorally it is initiated by "ravenous eating." This sequence of events is seen not only after mechanical stimulation of the genital organs but also after coitus. For an evaluation of the physiological mechanism which underlies this syndrome it is important to know that this sequence may be elicited by stimulation of various hypothalamic sites (ventromedial and mammillary nuclei, lateral hypothalamic area) provided that low frequency (5/sec) is used. As was shown earlier, this form of stimulation applied to the hypothalamus insures activation of the trophotropic system. It was implied that the intensive postcoital trophotropic activity culminating in a syndrome resembling the deep phase of sleep is due to a rebound activity of the trophotropic system, just as brief hypothalamically induced sympathetic discharges leading to an acceleration of the heart rate are accompanied by a post-stimulatory rebound phase consisting of a sudden slowing of the heart rate (339). The fact, however, that coitus and excitation of the hypothalamus induced reflexly or directly (at low frequency) elicit deep sleep (with hippocampal hyperreactivity) after a considerable delay — the mean latent period of the deep sleep phase varied in different experimental groups between 7.5 and 13 minutes — suggests that additional factors are involved. Since the hypothalamically induced release of the pituitary ovulating hormone takes place within a minute post coitum, this process is not involved, but other hormones seem to play a part: gonadotropins from the placenta, pitocin and pitressin from the neurohypophysis, and adrenaline are effective in producing the postcoital after-reaction. We are inclined to believe that the inhibitory action of these hormones is intensified because it occurs after a period of severe ergotropic excitation. Under such conditions phases of increased ergotropic and trophotropic reactivity tend to alternate (Gellhorn, 338). *In contrast to the 4-7/sec (theta) potentials seen during arousal.

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Different degrees of excitation of the ergotropic system, observed in various experimental conditions and resulting also from intraindividual differences in ergotropic reactivity, are reflected in corresponding degrees of secretion of the thyrotropic and adrenocorticotropic hormones. Since these hormones influence brain functions quantitatively and qualitatively, such a change in internal environment, associated with prolonged excitation of the ergotropic system, may give rise to pathological phenomena. Within physiological limits stimulation and lesion experiments give clear evidence that specific hypothalamic areas control the secretion of the thyroid and the adrenal cortex through TSH and ACTH respectively. The activity of these hypothalamic areas is, in turn, influenced by deviations of the hormone concentrations from the physiological level. Numerous factors which excite the ergotropic system raise the ACTH level, whereas an increase in TSH is chiefly caused by the action of cold. It is suggested that the greatly increased metabolism associated with enhanced thyroid secretion would add to the burden imposed upon the organism during fight and flight and thereby interfere with homeostasis under these conditions. As the result of adaptations achieved during evolution, the defense reaction and the closely related emotional responses elicit not an increase but a decrease in the secretion of the thyroid hormone. On the other hand, increased ergotropic discharges lead to increased secretion of TSH on exposure to cold when a heightened production of heat is of adaptive value. It is interesting to note that under special circumstances ergotropic discharges may lead to increased thyroid secretion in spite of its maladaptive effect. Emotional excitement produced by intensive auditory, visual, and nociceptive stimuli and carried out over many days leads to an increase in thyroid activity, and this effect is said to be lessened by Chlorpromazine (38). Mason (cited by Reichlin, 818) reports that avoidance conditioning causes an increase in the thyroid concentration in the blood of the monkey. If we bear in mind that fever increases the hypothalamically induced thyroid secretion at least in some species, it seems to follow that under the influence of strong and prolonged stimulation involving the ergotropic system the secretion of the thyroid is increased in spite of its maladaptive character. Although the relative importance of hypothalamus and hypophysis for the regulation of TSH and ACTH under conditions in which the level of the thyroid and adrenocortical hormones is below or above the physiological concentration is still under dispute,* it is obvious that positive (and probably also negative) feedback mechanisms alter the activity of the thyrotropic and adrenotropic centers in the hypothalamus. There is like*See Hodges & Jones (478).

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wise good evidence for feedback mechanisms which regulate gonadotropic hormones via the hypothalamus. Thus, implants of estradiol into the tuberal area of the hypothalamus posterior to the median eminence prevent postcoital ovulation in rabbits while intrahypothalamic implants of androgen produce genital atrophy in male dogs (196a and 196b) and grafts of ovarian tissue reduce the weight of the uterus (291). If we consider the centers regulating the secretion of the adrenomedullary hormones a part of the ergotropic system, we must apply this concept to the hypothalamic areas which regulate the secretion of the thyrotropic, adrenotropic, and gonadotropic hormones. It was mentioned earlier that the sympathetico-adrenal discharges can be reduced via the baroreceptors and also that adrenomedullary secretion may contribute to the intensification of the ergotropic discharge. Similarly, hypothalamic and hypophyseal feedback mechanisms may intensify and inhibit the secretion of TSH and ACTH. One would expect that these changes would alter the reactivity of the ergotropic system as a whole and thereby the ergotropic-trophotropic balance. This is largely a terra incognita, but a few data show that such fundamental changes may take place. Thus, the injection of hydrocortisone facilitates the synchronized potentials which are induced in the intralaminar nuclei in response to a sciatic shock (285), and small doses of ACTH increase spindles in the EEC while higher concentrations enhance desynchronization (458). It is of interest in this respect to call attention to the greater sensitivity of the polysynaptic reticular and hypothalamic systems to deficiency in adrenocortical hormones than is seen in oligosynaptic pathways involving the lateral lemniscus (283). Corresponding studies on the" influence of thyroid hormones are not available. Magoun (668) is inclined to interpret the hydrocortisone-induced increase in intralaminar thalamic potentials as an indication of increased internal inhibition, i.e., in our terminology, of increased trophotropic responsiveness. This is in agreement with behavioral data suggesting that exogenously administered ACTH intensifies trophotropic processes: it accelerates the extinction of conditional reflexes. On the contrary, endogenously produced ACTH is quantitatively related to the excitability of the ergotropic system and parallels the ease with which different animals can be conditioned.* A systematic study of the influence of various hormones which are released through hypothalamic impulses on the reactivity of the trophotropic and ergotropic systems is needed. For this purpose the determination of the spindle and arousal thresholds as described in Chapter I is recommended. Our brief discussion of some facts pertaining to gonadal influences on hypothalamically regulated ergotropic and trophotropic functions con"See Chapter III, p. 94.

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firms the general thesis that hormones profoundly alter hypothalamic functions and vice versa. This is illustrated by (1) the production of sexual receptivity and mating behavior in castrated animals through hormone implantation in certain areas of the hypothalamus; (2) the postcoital afterreaction, resembling the paradoxical phase of sleep, which seems to result from hormonal inhibition of ergotropic activity occurring during a period of trophotropic hyperreactivity; and (3) ovulation resulting from sexual intercourse and direct or reflexly induced excitation of the hypothalamus, and, furthermore, by the fact that this process is prevented through the section of the hypophyseal stalk (A37, A38).

IX

The Role of the Neurohumors in Sleep and Arousal

THE work of the last forty years has established the role of chemical transmitters in nervous action. Loewi's classical experiment* demonstrating the liberation of acetylcholine from the endings of the vagus nerve became the foundation of the theory of neurohumoral transmission. The functional differentiation between the action of parasympathetic and sympathetic nerves is reflected in the chemical specificity of the transmitters. Parasympathetic nerves liberate acetylcholine and sympathetic nerves, with few exceptions, noradrenaline. Bearing these exceptions in mind and using Dale's terms (185), we may say that adrenergic processes are prominent in the sympathetic and cholinergic processes in the parasympathetic system, but cholinergic processes underlie sympathetically induced vasodilatation in the muscle and the secretion of sweat through sympathetic nerves and are involved in the transmission of impulses through sympathetic ganglia and the neuromuscular junction. The theory of neurohumoral transmission of the central nervous system rests on a less secure foundation, since in most instances indirect methods have been used. Thus, it was shown that acetylcholine influences synaptic transmission of excitatory and inhibitory processes through the spinal cord. These data and the effect of acetylcholine and of inhibitors of cholinesterase on cortical activity suggest that acetylcholine may be important as a transmitter or modulator of central nervous activity in general and of central trophotropic and ergotropic functions in particular. Moreover, the marked concentration of noradrenaline in hypothalamus and reticular formation and its alteration by stimulants of a sympathetico-adrenal system (976a)f seem an indication that these neurohumors likewise play a role in arousal. I. ADRENALINE AND THE INITIATION OF AROUSAL In a series of investigations an attempt was made to show that arousal in its behavioral and electroencephalographic manifestations results from "Concerning the literature see 136, 265, 335, and 645. tSee also 415 on the decrease of the noradrenaline concentration in the brain stem following a rage reaction induced by stimulation of the amygdala.

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the liberation of adrenaline or noradrenaline in the recticular formation. Important steps in formulating this idea and creating the experimental basis for demonstrating its validity were the following observations: 1. Reticular or nociceptive stimulation causes an immediate (neurogenic) and a delayed (hormonal) cortical desynchronization, which were shown to be associated with ergotropic discharge and increased adrenomedullary secretion, respectively. 2. Similar effects on cortical activity and blood pressure are produced by the injection of adrenaline. 3. On sectioning of the brain stem from the bulbar part rostrally the adrenaline eifect disappears at the intracollicular level (87). This work implies that there is a well-circumscribed area in the reticular formation, comprising the posterior hypothalamus and the adjacent part of the mesencephalic tegmentum, the activation of which with adrenaline or by electrical stimulation leads to arousal. Rothballer (847), extending this work, showed that partial bilateral lesions in the mesencephalic tegmentum increase the arousal threshold of adrenaline, and that complete coagulation of this area abolishes the adrenaline effect whereas a unilateral lesion restricts the adrenaline arousal to the intact side. It is interesting that the release of the ergotropic system from the restraining action of the bulbar inhibitory area alters the state of arousal as well as the arousal action of adrenaline: after section of the brain stem in the pons (midpontine preparation, 59) the state of arousal is enhanced and the threshold of the adrenaline-induced arousal is lowered (203). The slowness of action of adrenaline and noradrenaline in producing arousal and the relatively long persistence of this action resemble the change in the state of awareness from sleep to awakening. Throughout this book it has been stressed that the ergotropic system acts as a unit. If adrenaline (or noradrenaline) is the physiological agent through which the reticular formation is activated, one would expect that it would induce not only cortical desynchronization but also increased peripheral somatic effects. Monosynaptic proprioceptive reflexes have indeed been facilitated under these conditions (205). II. SOME PHARMACOLOGICAL OBSERVATIONS

Of pharmacological experiments which support the physiological role of adrenaline in arousal only a few may be mentioned. Amphetamine, which mimics the action of adrenaline, seems to sensitize the brain stem to it. In the cerveau isole (intracollicular transection of the brain stem), in which adrenaline fails to produce arousal, it produces arousal after amphetamine has been administered in a subarousal dose (466). Also, pyrrogallol, which potentiates the action of adrenaline through inhibition

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of the enzymatic inactivator O-methyl transferase (42), enhances the adrenaline-induced arousal (203, A52). Recent work has shown that systemic application of amphetamine lowers pari passu the behavioral and EEC arousal threshold of the reticular formation (95). Furthermore, dopa and inhibitors of monoamine oxidase (MAO) likewise intensify arousal. This seems to be due in the first instance to the fact that dopa* is the precursor of noradrenaline, and in the second to the inhibition of the enzymatic oxidation of catecholamines. Apparently MAO inhibitors of very different chemical constitution cause an increase in the dopamine and noradrenaline concentration in the brain and in general activity. Brain amines may increase two to three times. If MAO inhibitors and dopa are administered to the same animal, the degree of alertness shown in EEG and behavior and the catechol amine levels in the brain increase beyond the control level and symptoms of aggressiveness and irritability appear (273, 274). The significance of the catecholes in the brain for alertness is further illustrated by experiments with reserpine. This drug reduces the noradrenaline level in the brain and abolishes the arousal reaction. However, with the restoration of the catechol amine level — by the injection of dopa, for instance — arousal (151) and general activity reappear (136). Cocaine,! which intensifies the physiological effect of adrenergic substances, may likewise be used to illustrate the fact that ergotropic action is determined by the amount of free noradrenaline present in the central nervous system. The concept of "free" noradrenaline is derived from experiments in which the influence of cocaine on the uptake of noradrenaline was studied in rats perfused with a constant amount of noradrenaline. It was found that with increasing concentration of cocaine the sympathetic action of noradrenaline is enhanced, whereas the uptake of noradrenaline by various tissues such as heart and spleen is lessened. A similar action seems to take place in peripheral sympathetic nerves and in skeletal muscles. It is therefore assumed that cocaine blocks the uptake of noradrenaline (or its precursors) by tissues in general and sympathetic nerves in particular. Noradrenaline is thereby released, and it is this "free" noradrenaline which accounts for the ergotropic effect. This mechanism is also operative when noradrenaline is not injected but is released from the endings of sympathetic nerves. This explains the fact that in the normal organism peripheral effects on nictitating membrane or heart resulting from stimulation of appropriate sympathetic nerves are increased on injection of cocaine. *From dopa is derived dopamine by decarboxylation. The latter, together with noradrenaline and adrenaline, "comprise the naturally occurring catecholamines in the mammalian organism" (914). tFor the literature see 136.

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Now it is known that cocaine is a powerful stimulant of the central nervous system. Symptoms such as excitement, a feeling of well-being, and increased motor activity suggest increased central ergotropic discharges. If the interpretation of the peripheral action of cocaine is applicable to its central effects, it should be possible to show that conditions leading to variations in the concentration of the free noradrenaline are accompanied by corresponding changes in the state of arousal. The following experiments seem to fulfill these requirements. The tranquilizing action of reserpine is thought to be due to the disappearance of noradrenaline from the brain and, particularly, the hypothalamus. Mice injected with this drug show arrest of the general activity which characterizes the behavior of normal mice. If, however, dopa, which passes the blood-brain barrier, is administered to these animals, activity is restored because noradrenaline is formed from this precursor. Cocaine increases the activity of mice beyond the normal level, but it fails to produce this effect in reserpine-treated animals. Apparently the excitatory action of cocaine presupposes the presence of noradrenaline. This is further illustrated by the fact that dopa in a dose inadequate to restore activity in the reserpinized animal sensitizes it to cocaine: it restores normal activity. Burn (136) suggests that blocking the uptake of noradrenaline by the tissues through cocaine is also responsible for its central action. "The central effects of excitement and of euphoria may be due to a rise in the concentration of free noradrenaline in the hypothalamus and in other parts of the brain, due to interference with uptake" (136). Finally, quite different procedures leading to an accumulation of noradrenaline within the brain produce similar results. For example, mice were treated with an MAO inhibitor* and thereafter with a drug (MMT) which blocks the storage of noradrenaline in the brain. Consequently, noradrenaline was released, protected from enzymatic destruction, and trapped by the blood-brain barrier. The accompanying symptoms were characteristic for intensive ergotropic activity: enormous hyperactivity, exophthalmos, hyperthermia, and supersensitivity to afferent stimuli (108).f These pharmacological experiments seem to show that the activity of the ergotropic system is related to the amount and the stability of the free noradrenaline (or its precursors) in the brain, but they give little information concerning the site of action of these neurohumors. Since Vogt's work as well as the experiments of Dell, Rothballer, and others points in particular to the border between mesencephalon and diencephalon as an area of crucial significance for adrenaline-induced arousal, it *See also the potentiating effect of MAO on cocaine convulsions (243). t Concerning the relation of the action of reserpine to the free serotonin in the brain and the importance of serotonin for the humoral transmission within the trophotropic system, see also 109, 383, and 899.

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seems necessary to discuss investigations in which the action of adrenaline is confined to the reticular formation. III. ADRENALINE, ACETYLCHOLINE, AND THE BRAIN STEM In this work (172, 173, 177) minute amounts of adrenaline (and also of acetylcholine) were injected into various parts of the brain stem of unanesthetized cats which had been provided with stereotactically implanted canulae. Adrenaline produced arousal whereas acetylcholine induced somnolence and sleep. The arousal effect was stronger, since it was easy to produce cortical desynchronization and to awaken a sleeping animal, whereas it was necessary for the cat to be in a state of trophotropic tuning induced by feeding and quiet environment to evoke cortical synchronization and sleep. Such effects were obtained from the mesencephalic to the bulbar part of the reticular formation, but the effect of adrenaline was the greatest in the rostral sections and the weakest in the caudal sections, whereas the action of acetylcholine was maximal in the bulbar part. These experiments as well as those involving electrical stimulation of the brain stem lead to the conclusion that the trophotropic and ergotropic systems are represented throughout the whole brain stem. That the sites of maximum sensitivity of one system coincide with those of minimum responsiveness of the other system is evident from experiments on excitation of the brain stem through direct stimulation with neurohumors or electrical currents and also reflexly via cutaneous nerve fibers. These findings illustrate the principle of reciprocal innervation. Certain phasic effects are altered in opposite manners through injection of acetylcholine and adrenaline: the cortical potential evoked in the visual cortex by stimulation of the optic chiasma is enhanced by intrareticular injection of adrenaline but diminished by injection of acetylcholine. These experiments suggest that the evoked potentials may be used as an indicator of the ergotropic-trophotropic balance. Indeed, procaine injected into the rostral part of the reticular formation decreases this potential, whereas the caudal injection has the opposite effect. Equally striking is the comparison of the action of procaine with that of acetylcholine on the same site. On the bulbar reticular formation procaine enhances and acetylcholine diminishes the evoked potential (172). Obviously, in this instance procaine shifts the ergotropic-trophotropic balance to the ergotropic and acetylcholine to the trophotropic side. The former is accomplished by the partial elimination of the inhibitory (trophotropic) bulbar area and consequent release of the ergotropic system; the latter results from the stimulation of the trophotropic bulbar section and consequent reciprocal inhibition of the ergotropic system.

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It was pointed out in the first chapter that sectioning of the brain stem in the middle of the pons (rostral to the Vth nerves) leads to an intensification of the cortical desynchronization (release from bulbar inhibition); on the contrary, Bremer's classical experiment on the cerveau isole (intracollicular transection) causes cortical synchronization through elimination of the mesencephalic reticular formation. The two diametrically opposed states can be combined in the same animal if the pretrigeminal section is followed by a hemisection of the brain stem at the intracollicular level. In such a preparation the cortex shows the typical synchronous sleep pattern at the side of the hemisection and a state of arousal on the other side. In view of the fact that the state of arousal as indicated by the EEC is fundamentally different in the two hemispheres while the circulatory conditions are the same, this preparation seems most appropriate for the study of the biochemistry of sleep and wakefulness. The assay of the cortex for acetylcholine showed that in the control animals (midpontine pretrigeminal cats) the average difference between the two sides varied between 6 and 13.5 per cent. In the experimental animals (pretrigeminal cats with midbrain hemisection) the cortex of the hemisectioned side showed an increase in acetylcholine of 74, 98, and 139 per cent respectively for the frontal, parietal, and occipital cortex (778). If, however, a drug was injected which produces arousal, so that both sides of the cortex showed desynchronization, the characteristic difference in the acetylcholine content was abolished. The experiment indicates that changes in the state of wakefulness are accompanied by reversible changes in the concentration of acetylcholine in the cerebral cortex. These experiments bring to mind earlier work in which an inverse relation between the acetylcholine content of the brain and the state of cerebral activity was found, the acetylcholine content being highest in deep anesthesia and lowest during convulsions (833). Important as these findings are, their usefulness in solving the problem of the biochemical basis of sleep is questionable. Rather they seem to be due to the fact that the release of acetylcholine from the brain increases with increasing activity (282,717,A39). In view of these and other difficulties, a new approach on a wider biochemical basis seems promising. It should take into consideration the role of glutamic acid in excitation (182) and that of gamma aminobutyric acid (GABA) in inhibition (835).* Such studies, recently begun by Jasper et al. (525), may bear fruit for the problem of the neurohumoral basis of *In spite of important relations between cerebral GABA concentration -and brain excitability and the influence of GABA on cortical potentials and interhemispheric conduction (see 835 for the literature), there is not sufficient evidence to assume that GABA is a neurohumoral transmitter. Moreover, the action of L-glutamic acid is different from that of physiological transmitters on membrane permeability (181).

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ergotropic and trophotropic functions. Their preliminary report indicates that in animals in the state of sleep or arousal resulting from sections of the brain stem at different levels, more GABA is released from the cerebral cortex in sleep and less glutamic acid. In arousal this relation is reversed. V. FURTHER STUDIES ON THE ACTION OF ACETYLCHOLINE ON SLEEP

Let us return to the discussion of the biochemical means by which sleep is produced. Cordeau's experiments (173) were confined to the brain stem from mesencephalon to the medulla oblongata. They are supplemented by investigations involving more rostral parts of the brain stem and the limbic system which contributes afferent impulses to hypothalamus and reticular formation. In this work a few crystals of acetylcholine and eserine were injected through stereotactically oriented canulae into the preoptic area and other parts of the limbic-midbrain circuit of Nauta (750). This form of application tends to localize the action of the drugs even more than when minute quantities of the dissolved substances are injected with microcanulae as in Cordeau's work. Velluti & Hernandez-Peon (968) showed that cholinergic substances such as acetylcholine and eserine may selectively activate sleep from: 1. The upper medial preoptic area and septum from which the medial forebrain bundle is formed; 2. The lateral and the posterior dorsal hypothalamus likewise intimately related to the medial forebrain bundle; and 3. The mesencephalic interpeduncular nuclei and the more caudally located nuclei of Bechterew and Gudden, into which numerous limbic pathways project (750). Sleep in its electroencephalographic and postural characteristics appeared under these circumstances with a latent period of up to four minutes. As in spontaneous sleep, the paradoxical sleep phase showing desynchronization of cortical potentials followed the synchronized phase. Sleep persisted for several hours unless the animal was aroused by stimulation of the reticular formation. Injection of atropine crystals prevented the hypnogenic action of cholinergic drugs. This applies not only to experiments in which the two antagonistic drugs were injected into the same site but also to tests in which atropine was applied (with respect to the limbic-mesencephalic circuit) caudally to the site where acetylcholine or eserine had been administered. Thus, sleep induced by acetylcholine through the preoptic area was abolished by atropinization of the interpeduncular, Bechterew, or Gudden nuclei. Similarly, a lesion in the caudal segments of the medial forebrain bundle prevented the hypnogenic action of acetylcholine from rostral sites of this structure (for instance, the preoptic area). On the contrary, stimulation of a caudal area of the medial

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forebrain bundle with acetylcholine remained effective after a lesion in a more rostrally located segment: it induced sleep. The experiments suggest that a cholinergic transmission of impulses from the limbic brain to the mesencephalon is involved in the production of sleep through acetylcholine and eserine applied to septum and preoptic area. The fact that the application of noradrenaline or adrenaline to limbic, mesocephalic and diencephalic sites failed to evoke sleep adds weight to this argument. Acetylcholine- and eserine-induced sleep is also elicited from several cortical areas (the basal parts of frontal and temporal lobes and the anterior section of the gyrus cinguli), from the medial thalamic nuclei close to the massa intermedia which Hess used in his classical sleep experiments, and from parts of the corpus striatum. To what extent these areas produce the hypnogenic action via the cholinergic circuit described earlier is under investigation, but Hernandez-Peon (450) has reported already that acetylcholine-induced effects originating in the frontal lobe are blocked when this circuit is interrupted. A diagram (Fig. 9-1) illustrates the sites from

Fig. 9-1. Diagram illustrating the anatomical substrata of the sleep system disclosed by localized cholinergic stimulation. The system is composed of two parts: a descending component with corticofugal projections from the pyriform cortex, the orbital surface of the frontal lobe and the anterior part of the gyrus cinguli which converge upon the limbic midbrain circuit extending down to the ponto-mesencephalic tegmentum. The three round or oval extensions in the diagram refer to the interpeduncular, Bechterew, and Gudden's nuclei. The descending component joins at the pontine level with an ascending component originating in the spinal cord. (From Hernandez-Peon. Central neuro-humoral transmission in sleep and wakefulness. Progress in Brain Research 18:96, Elsevier, Amsterdam, 1965.)

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which acetylcholine-induced sleep can be evoked (including cerebellum and spinal cord) and also the cholinergic limbic-midbrain circuit. VI. ACETYLCHOLINE, NORADRENALINE, AND AROUSAL The relation of the neurohumors to the arousal system is complex. Acetylcholine and eserine cause arousal from parts of the limbic cortex, the septum, the dorsolateral hypothalamus, and the mesencephalic reticular formation. Apparently the excitation is conducted from the septum caudally to the reticular formation along a path which lies dorsal to the cholinergic hypnogenic system. In addition, there are sites such as the preoptic area, the ventromedial hypothalamus, and the mesencephalic reticular formation from which noradrenaline elicits arousal (450). Arousal is, of course, a complex process and different areas and chemical excitants may elicit different components of arousal. Thus, such diverse states as "magnetic attention" (characterized by "following for many seconds any indifferent object moving within its visual field"), increased alertness combined with hyperactivity, an orienting reaction, and an escape response have been evoked. It is not unlikely that the manyfold arousal reactions elicited by acetylcholine and noradrenaline from different sites mimic the physiological activities which are initiated by sensory impulses. VII. SOME UNRESOLVED PROBLEMS

There are several groups of data which a theory of neurohumoral transmission of sleep and arousal should take into account. It was emphasized that in general acetylcholine evokes sleep and noradrenaline produces arousal and such effects may be produced even from the same site. Apparently these neurohumors excite certain neurons which due to their anatomical connections lead to an inhibition and an excitation of the reticular formation respectively. The experiments suggest a particular sensitivity of the sleep- or arousal-initiating neurons to acetylcholine and noradrenaline, respectively. This particular relation is confirmed in numerous experiments described in this chapter except for the observation that from certain cortical and subcortical sites acetylcholine may induce arousal. The question arises whether this observation is a real or an apparent exception to the rule according to which acetylcholine is associated with sleep and not with arousal. In view of the close proximity of acetylcholine- and noradrenaline-sensitive neurons in the reticular formation, it is conceivable that noradrenaline and acetylcholine are involved in the activation of the ergotropic system. There is rather extensive evidence for such an assumption in experiments in which the peripheral sympathetic system is stimulated under conditions which are unfavorable for the activity of the ergotropic component (norad-

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renaline). Thus when the noradrenaline content of the target organ is depleted by reserpine,* stimulation of the splenic nerves leads to dilatation of the spleen, which is due to acetylcholine since this effect is intensified by eserine and abolished by atropine, and because the substance liberated behaves similar to acetylcholine in certain biological assays. Similarly, sympathetic stimulation causes a contraction of the nictitating membrane which persists after reserpine but is abolished by atropine and therefore seems to be due to the liberation of an acetylcholine-like substance. Corresponding results were obtained on other organs. Burn (136) suggests on the basis of these and similar experiments that "the principal function of acetylcholine is not to act directly, but to liberate noradrenaline." The presence of noradrenaline in synaptic terminals of sympathetic ganglia (757) is of great interest in this respect. In the light of these findings it is appropriate to call attention to Marrazzi's work (679) showing that adrenaline and noradrenaline diminish the postganglionic responsiveness to a preganglionic stimulus in autonomic ganglia and also in intracortical processes. Moreover, Costa et al. (175) reported that the cholinergic transmission through the superior cervical ganglion is enhanced (as indicated by the height of the postganglionic potentials) by depletion of ganglionic noradrenaline with reserpine or by blocking of sympathetic impulses with ergotamine. Conversely, increasing the level of free noradrenaline in the ganglion reduces this transmission. The significance of these data for the biochemical interpretation of changes in the state of arousal induced by stimulation of the trophotropic and ergotropic systems remains to be seen. The second problem concerns the observation that a stimulus which produces arousal in the control animal may evoke sleep under certain experimental conditions. Thus, nociceptive stimulation during a state of sensory deprivation may induce sleep (see p. 49). Similarly, it has been shown that negative conditioned stimuli increase synchronization of cortical potentials in sleep but cause desynchronization (followed by increased synchrony) in wakefulness. Apparently the trophotropic-ergotropic balance has a decisive eifect on the responsiveness of the ergotropic and trophotropic systems to afferent stimuli. If Gellhorn's work on hypothalamic "tuning" is taken into consideration, it may be said that this effect of the trophotropic-ergotropic balance applies to central and peripheral discharges of the trophotropic and ergotropic systems.! The fact that acetylcholine-induced sleep in Cordeau's experiments provided the room was quiet and the animal had been well fed shows that the investigator took advantage of the postprandial state of trophotropic tuning! Such an interpretation would be supported if it could be shown that * Reserpine causes blockage of sites where noradrenaline and adrenaline are stored. fSee p. 47.

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the reticular formation consists of neuronal units of great flexibility. This is, indeed, the conclusion of Scheibel & Scheibel (871), which is based on the continued study of single units over many hours. These authors state "that the functional inputs to many reticular neurons are not rigidly ordered following the specific anatomical pattern of afferents. Rather, they appear flexible; capable of entering upon periods of activity and inactivity, thui repeatedly coupling and uncoupling the neuron from one system or another." The application of the concept of flexibility to experiments involving stimulation with neurohumors is justified by the fact that adrenoceptive and cholinoceptive units are present throughout the reticular formation and show a wide range of responsiveness (excitation as well as inhibition) to these neurohumors (96, 97). The third problem lies in the physiological evaluation of certain pharmacological experiments which demonstrate a fundamental difference between EEC and behavioral arousal. Acetylcholine (or eserine) evokes a prompt cortical desynchronization which is abolished by atropine (92, 834), but this effect is not accompanied by corresponding alterations in behavior: the atropinized animal is awake in spite of large "sleep-like" potentials and the acetylcholine- or eserine-induced desynchronization is not associated with arousal. For an analysis of these phenomena it is important to compare the effects of eserine and amphetamine under various conditions, since amphetamine causes desynchronization with arousal. The following differences were established: 1. Amphetamine induces behavioral and electrographic arousal in animals with transection of the brain stem below the medulla oblongata, in the pontine, and in the mesencephalic part of the reticular formation. If the section interferes with the hypothalamus (section in the front of the mammillary bodies), both effects disappear, but the action of eserine on the EEC is not abolished by the latter section.* 2. Amphetamine elicits a typical rage reaction in unanesthetized chronic decorticate cats, whereas eserine fails to evoke behavioral changes in this preparation (211). 3. Atropine blocks the desynchronizing effect of stimulation of the reticular formation but not the behavioral and electroencephalographic action of hypothalamic and nociceptive stimulation. These data suggest that there is a cortical cholinergic component in physiological and pharmacological arousal which is inadequate to produce behavioral arousal. That excitation of the brain stem and particularly of the hypothalamus is necessary for behavioral arousal is illustrated by the *Perhaps the finding of Desmedt & La Grutta (212) that cholinesterase inhibitors may produce desynchronization and some slight arousal (pupillary dilatation) is due to their special technique of intra-arterial injection whereby adequate concentrations of these inhibitors may be obtained in the brain stem.

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crucial importance of this structure for amphetamine-induced arousal, by the fact that this drug significantly reduces the noradrenaline content of the hypothalamus (863), by the failure of atropine to block hypothalamic excitation* (649), and by the differential effects of Chlorpromazine which blocks the action of amphetamine but is without influence on eserine- or atropine-induced EEC effects (94). An attempt will be made below to utilize these findings for a neurohumoral theory of arousal.f VIII. THE NEUROHUMORAL TRANSFER OF SLEEP AND AROUSAL As was pointed out at the beginning of this chapter, the proof of the neurohumoral nature of nervous processes lies in the demonstration that the perfusate obtained during the excitation of a nerve (as in Loewi's classical experiment) elicits changes in an unexcited organ which match those obtained on nervous stimulation. If sleep and arousal are due to the liberation of specific neurohumors from the different diencephalic and mesencephalic sites, it should be possible to show their specific action on an unstimulated brain by suitable perfusion experiments. Ingvar (511) used a large neuronically isolated slab of the parietal cortex as an indicator and found that it shows signs of excitation following arousal induced by stimulation of the reticular formation. Purpura (799) employed cross-circulation experiments and found that stimulation of the reticular formation of the donor leads, after a rather constant interval which corresponds to the circulation time, to an activation of the cortex in the recipient. Kornmiiller et al. (597), using a similar technique, evoked diffuse slow potentials of high amplitude in the donor upon stimulating various parts of the trophotropic system (caudate nucleus and several thalamic nuclei), and observed similar sleep patterns in the EEC of the recipient. The most extensive work of this kind was carried out by Monnier et al. (723) on rabbits. They employed stimulation of intralaminar thalamic nuclei for the induction of sleep and stimulation of the reticular formation for arousal. Repeated stimulations led to statistically significant differences in the EEC. The delta potentials decreased on stimulation of the reticular formation and were augmented on activation of the thalamic nuclei. As expected, the changes were less in the recipient than in the donor animals. Moreover, the dialysate of cerebral venous blood obtained *The failure of atropine to block the action of nociceptive stimuli on the cortex is also thought to be due to the fact that the hypothalamus is an important link in this chain of events (71). fit is of considerable interest that through suitable drugs reticular functions can be fractionated. Thus, scopolamine induces cortical synchronization and blocks arousal through sensory stimuli although the response of the reticular formation to a sciatic shock is unchanged (650).

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from a sleeping rabbit — the sleep was induced by thalamic stimulation — induced on intravenous injection in a normal rabbit the behavioral and electroencephalographic changes of sleep. The physiological effects of induced arousal were likewise transferable through the dialysate to another animal (720). The factors responsible for this humoral transfer have not yet been determined. Nevertheless, the principle that sleep and wakefulness are associated with the liberation of specific neurohumors seems established. IX. CONCLUDING REMARKS

The work reviewed in this chapter gives, on the basis of cross-circulation experiments, strong evidence for the role of neurohumors in the production of arousal and sleep and, through microinjection studies, for the specific relation of acetylcholine to the initiation of sleep and of noradrenaline and its precursors to the initiation of arousal. Yet some physiological data mentioned earlier and pharmacological findings such as the lack of correlation between the catecholamine level of the brain and certain druginduced states of arousal (383) are as yet unexplained. Also the role of serotonin, which Brodie & Shore (109) considered as the neurohumor of the trophotropic system (see also 302), remains to be clarified, particularly in its relation to the action of acetylcholine as a sleep-producing agent. In spite of considerable gaps in our factual knowledge and in the writer's understanding, an attempt is made at a theory of neurohumoral transmission in the brain on the basis of the data presented in this chapter. For this purpose it is of importance to distinguish between the role of chemical substances in interneuronal transmission and in neuronal excitation. Neurons excited by noradrenaline or acetylcholine, for instance, may or may not liberate the same substances in neurohumoral transmission. Thus, the ganglion cells of the parasympathetic and sympathetic systems are cholinoceptive (i.e., excitable by acetylcholine), but in general the sympathetic postganglionic neurons are adrenergic and the parasympathetic are cholinergic. Similarly, the work of Cordeau and collaborators (172, 173), Bonvallet et al. (87), and Rothballer (848) and others has given clear evidence for the existence of adrenoceptive neurons, particularly in the rostral part of the reticular formation — excitation of these neurons leads to awakening — and of cholinoceptive neurons, especially in the caudal part of this structure, which on stimulation produce sleep. Pharmacological experiments support this statement by showing that the arousal effect of drugs is related to the increase in free noradrenaline. The work of Hernandez-Peon presents ample proof for the initiation of sleep by acetylcholine and the inhibitors of cholinesterase from diencephalon and mesencephalon. This process seems to be involved in the activation of trophotropic symptoms

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(including sleep) by stimulation of thalamic, hypothalamic, and reticular sites and of cutaneous receptors with low-frequency currents (under 10/sec), since this form of stimulation applied to the cortex or afferent nerves leads to maximal liberation of acetylcholine (313).* Assuming, on the basis of these arguments, that the first step in arousal and sleep is the activation of specific adrenoceptive and cholinoceptive neurons respectively, the nature of the neurohumoral transmitter involved in these two processes remains to be discussed. First, it should be remembered that acetylcholine accounts for the transmission of excitation from preganglionic to postganglionic nerves in autonomic ganglia. Its role in the synaptic transmission of excitatory and inhibitory processes in the somatic nervous system is highly probable in view of the extensive experiments of Biilbring & Burn (129) and Eccles et al. (239) on the spinal cord. Although modification of synaptic transmission by noradrenaline or adrenaline has been observed frequently, no convincing proof of their role as transmitters has been established (180). It therefore seems appropriate to determine whether acetylcholine is involved in the neurohumoral transmission of arousal and sleep. The experiments of Hernandez-Peon (449, 450) and co-workers described earlier argue strongly for a cholinergic transmission from forebrain to mesencephalon as the basis of sleep and for the inhibitory action of the impulses thus transmitted on the ascending mesencephalic arousal system of Magoun. Just as cholinergic impulses originating in a motor neuron lead via a Renshaw cell to an inhibition of another motor neuron in the spinal cord, so it is thought that the cholinergically transmitted impulses from septum, hypothalamus, and mesencephalic nuclei (but probably also from the intralaminar thalamic nuclei and the bulbar part of the brain stem) impinge on the arousal system and reduce its ascending and descending rate of discharge. Consequently desynchronization is converted into synchronization, the tone of the sympathetic system and of the striated muscles is reduced, and, as the result of reciprocal innervation, parasympathetic discharges are enhanced. As to the arousal initiated by direct (through electrical stimuli or microinjection of noradrenaline or adrenaline) or reflex activation of Magoun's activation system, it is suggested that a cholinergic transmission is responsible for the EEC changes in arousal. Noradrenaline, adrenaline, and other drugs such as amphetamine acting on adrenoceptive neurons fail to elicit cortical desynchronization after atropine. This drug blocks also the cortical desynchronization resulting from stimulation of the reticular formation or from the release of this structure which accompanies the section of the brain stem between medulla oblongata and pons (989). Apparently diffuse * Stimulation at higher frequencies fails to increase the acetylcholine level in the brain (313).

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activation of the cortex via the ascending reticular formation involves cholinergic transmission. This is suggested also by the high concentrations of cholinesterase found in this system (901). In addition, recent work by Hernandez-Peon (450) has shown that from certain telencephalic, diencephalic, and mesencephalic areas arousal may be elicited by acetylcholine. Whether acetylcholine in turn mobilizes noradrenaline, as Burn suggests on the basis of numerous effects involving stimulation of the peripheral ergotropic system, remains to be seen. At any rate, this cholinoceptive arousal system is anatomically separated from the cholinoceptive sleep system described earlier, and its neurotransmitters are not known. Although in view of the available evidence cholinergic transmission seems to play an important role in sleep and arousal, it would be wrong to infer that adrenergic neurohumors play no role in the function of the ergotropic system. It was mentioned earlier that the EEC arousal elicited by stimulation of the hypothalamus and of nociceptive nerves (which activate the ergotropic division of the hypothalamus) is not blocked by atropine. These findings imply that this form of arousal is not mediated by a cholinergic transmitter. Recent experiments give a more direct indication of adrenergic transmission in arousal. Certain forms of ergotropic activity such as the strong affective reactions induced by stimulation of the amygdala in unanesthetized animals cause, as histochemical studies reveal, a depletion of the catecholamine stores at synaptic levels if the synthesis of these substances is prevented by specific inhibitors. It is of particular interest that this change is present in numerous nuclei from the preoptic area to the boundary between hypothalamus and mesencephalon but does not appear in the mesencephalon (312). Does this indicate that emotional excitement involves adrenergic transmission from the amygdala to the hypothalamus in contrast to the cholinergic arousal of mesencephalic origin (A54) ? It is to be expected that work on single neurons, their individual behavior over time, and their reactions to acetylcholine and noradrenaline will contribute importantly to the elucidation of the problems regarding chemoreceptivity and neurohumoral transmission. One result of such studies, the functional flexibility of the reticular neurons (871), may be in part responsible for certain effects of "tuning" of the sleep-arousal system so that the same stimulus evokes sleep in one state of the organism and arousal in another. Finally, a brief comment is necessary about the absence of behavioral changes following the injection of eserine and atropine which produce desynchronization and synchronization in the EEC respectively, as in arousal and sleep. Various experiments discussed earlier showed that behavioral arousal accompanied by EEC desynchronization is due to

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strong stimulation of the brain stem at the diencephalic and mesencephalic border or of the hypothalamus. This is confirmed by Feldman & Waller (286), who report that behavioral arousal is lost after lesions in the posterior hypothalamus, although stimulation of the reticular formation under such conditions causes desynchronization. Conversely, lesions in the reticular formation do not abolish behavioral arousal, but the correlation between arousal and desynchronization is poor. In contradistinction, eserine-induced desynchronization may occur in the isolated brain (211). These data suggest that specific patterns of cerebral (and also of downward) discharges organized at the boundary between hypothalamus and reticular formation are necessary for arousal. Apparently the changes in EEC and EGG produced with minute amounts of eserine in the cortex (710) or on intravenous injection show the characteristics of asynchronous excitation as if the reticular formation had been stimulated, but they seem to depend on the action of eserine on the cholinesterase in the brain and not on the state of the brain stem. X. SUMMARY

That the neurohumoral concept is valid for the sleep-arousal phenomenon is proven by cross-circulation experiments in which sleep and arousal initiated in the donor by appropriate stimulation of thalamus and reticular formation respectively are also evoked in the recipient. The substances responsible for this effect are not yet known, but their action is transferable through the dialysate of the blood of the donor. This work is supplemented by studies in which, through microinjection of acetylcholine and noradrenaline in certain parts of the reticular formation, sleep and arousal have been elicited respectively. These and other experiments suggest that there are cholinoceptive and adrenoceptive neurons in selected parts of the central nervous system which, on direct or reflexly induced stimulation, initiate sleep and arousal respectively. Pharmacological experiments show, in addition, that the state of arousal increases with increasing liberation of free noradrenaline in the brain. There is no evidence that the chemically activated neurons transmit the excitation through various synapses by means of noradrenaline or adrenaline. On the contrary, the failure of the catecholamines and related drugs such as amphetamine to produce electroencephalographic arousal after atropine supports the thesis that this form of arousal involves cholinergic transmission. This principle also underlies the neurohumoral transmission of sleep and holds true particularly for the limbic-mesencephalic circuit of Nauta, which is closely related to the medial forebrain bundle extending from the septum through lateral and posterior dorsal hypothalamus to the mesencephalon. Acetylcholine may evoke sleep from any site

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of this circuit, this effect being blocked by atropine when applied to the more caudally located parts of this cholinergic circuit. Its relation to the massa intermedia and the intralaminar thalamic nuclei which are commonly used to elicit sleep remains to be explored. It is believed that the cholinergically transmitted impulses of the trophotropic system impinge on the tonically innervated neurons of the ergotropic system and inhibit them, thereby converting the desynchronization of cortical arousal into various degrees of synchronization, depending on the state of activity of the ergotropic system and the intensity of the inhibition originating in the trophotropic system. Acetylcholine also elicits arousal from certain diencephalic sites which are different from those inducing sleep. The transmitters of this arousal system are not known. Emotional arousal induced by stimulation of the posterior hypothalamus and of nociceptive nerves is not blocked by atropine. Moreover, similar states of arousal resulting from stimulation of the amygdala lead to depletion of catecholamines at synaptive levels. The experiments lead to the tentative conclusion that emotional arousal involves adrenergic transmission (A40-A44). Experiments showing that eserine and acetylcholine induce cortical desynchronization (as in arousal) and that atropine elicits synchronization (as in sleep) without changing the state of awareness of the animal indicate that far-reaching synaptic changes in the cerebral cortex do not by themselves cause behavioral changes. The latter require the direct or indirect activation of special "centers" of organization in the brain stem which influence not only the EEC but also numerous somatic and autonomic processes in a specific manner. It is only in this case that an apparently purposive action such as rage, attention, or sleep results in which behavioral changes are in harmony with changes in EEC and peripheral ergotropic and trophotropic discharges.

X

Behavioral Implications

ALTHOUGH an effort has been made not to neglect the effects of the ergotropic and trophotropic systems on behavior, as evidenced by our emphasis on the relation between the trophotropic-ergotropic balance and the sleepwakefulness cycle and by our discussion of conditioning and experimental neurosis, the following data will be of value in amplifying the significance of ergotropic-trophotropic relations for behavior. I. THE ERGOTROPIC AND TROPHOTROPIC SYSTEMS AND BEHAVIOR The earlier findings of Hess (463) and others showing that stimulation of the ergotropic division of the posterior hypothalamus causes rage and that activation of the trophotropic system from the septal area, anterior hypothalamus, and centrum medianum is associated with grooming behavior, signs of a pleasant mood (purring), sexual behavior (705), and a tendency to fall asleep have been amply confirmed by more recent work (see 370). We are here not so much concerned with the sites (in the limbic cortex, for instance) from which these and related reactions have been evoked as with their ergotropic-trophotropic basis. From this point of view it is of interest to suggest the relatedness of the observation that weak stimuli evoke approach behavior and strong stimuli withdrawal behavior to the fact that low-frequency stimulation of cutaneous receptors tends to produce trophotropic effects such as cortical synchronization (via the inhibitory medullary area of the reticular formation), whereas stimuli of higher frequency or intensity elicit ergotropic effects such as cortical desynchronization (via the excitatory ascending system of Magoun). The decorticate cat, in which weak stimuli evoke sham rage, lends itself well to the investigation of the influence of the ergotropic and trophotropic systems on behavior at a level intermediate between relatively simple reflexes and complex actions involving the cerebral cortex. In such preparations lowering of the carotid sinus pressure elicits an outburst of sham rage. This effect is likewise present after elimination of the chemoreceptors in the carotid sinus but is abolished after the sectioning of the 244

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carotid sinus nerves. Conversely, raising the pressure in the carotid sinus inhibits spontaneously occurring fits of sham rage (413, A55). Inhalation of 5 per cent OL» induces bursts of sham rage in the decorticate cat, but this effect is absent after inactivation of the chemoreceptors or following sino-aortic denervation (413). Apparently stimulation of the sino-aortic chemoreceptors reflexly activates the posterior hypothalamus in the decorticate animal, whereas stimulation of the pressoreceptors inhibits it. These stimuli were also shown to activate the ergotropic and trophotropic systems respectively, producing in the deeply anesthetized animal shifts in the autonomic balance (indicated by changes in heart rate and blood pressure, for instance) and in addition, in the lightly anesthetized animal, desynchronization of the potentials of the posterior hypothalamus and cortex with ergotropic excitation and synchronization of these structures with trophotropic excitation. Finally, in the intact animal arousal and sleep, with corresponding changes in muscle tone, appear as the ergotropic-trophotropic balance is altered through changes in sino-aortic pressure or through stimulation of the chemoreceptors. There can be little doubt that the changes in wakefulness (in the intact organism), in emotional display (in the decorticate cat), and in autonomic balance (in the deeply anesthetized animal) are the result of changes in the ergotropic and trophotropic systems. The release of the hypothalamus through decortication magnifies the behavioral effects. Further examples show that characteristic motor, autonomic, and behavioral changes result from stimulation of the trophotropic and the ergotropic systems and that, conversely, changes in the state of behavior are associated with characteristic trophotropic-ergotropic changes. Thus, the drowsy animal in which the trophotropic system is dominant shows an increased sensitivity of the (trophotropic) heat-loss center in the hypothalamus (24). Gently stroking the back of the cat, which apparently elicits pleasure, arouses the trophotropic system: cortical synchronization, cutaneous vasodilatation, and inhibition of shivering occur while the body temperature falls (264). Stimulation of the lateral hypothalamus not only evokes eating in satiated rats but motivates "satiated and previously untrained rats to learn the location of food in a T-maze" (701). Caudate stimulation lessens postural tone and other signs of ergotropic activity but also lessens aggressiveness (201). Similarly, it was found that the aversive response resulting from stimulation of the reticular formation is diminished by stimulation of the septal area (767). Feeding may prevent symptoms of anxiety (57), and stimulation of the medial frontal lobe may cause vocalization to cease and a state of quietude accompanied by penile erection to develop (228). Of particular interest is the observation (926) that stimulation of the basal forebrain area (rostral to the optic chiasma from which cortical synchron-

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ization and sleep can be induced) interferes dramatically with strong emotional behavior and ergotropic activity: a cat which is about to kill a rat interrupts this attack immediately on stimulation of this area, retreats to a corner of the cage, and pays no further attention to the rat. This stage is followed by drowsiness and sleep. Whereas stimulation of the amygdala increases ergotropic discharges and induces behavioral changes signifying fear and anger, removal of the amygdaloid complex in cats leads to a hypersexed state and to an "increase in pleasure reactions to stroking and petting" (580). At the same time, ergotropic hypothalamic reactivity and aggressiveness are lessened. The observation (660) that cold and excitement reduce the effectiveness of diencephalic stimuli to evoke erection probably indicates that the peripheral and central effects — the latter resulting in feelings of pleasure — of trophotropic excitation are lessened in a state of ergotropic tuning. These are but a few examples of specific behavioral antagonisms involving the trophotropic and ergotropic systems. They show that the principle of reciprocal innervation is valid for behavioral acts controlled by the ergotropic and trophotropic systems. Rebound, known from somatic and autonomic reflexes, also occurs in the behavioral field. Thus ergotropic "aversive manifestations" (vocalization, biting, struggling, etc.) elicited by stimulation of the anterior thalamus are followed after cessation of stimulation by a trophotropic rebound consisting of prolonged hippocampal discharges and grooming behavior. The shift in balance to the trophotropic side is further indicated by the fact that after the hippocampal after-discharges a state of quiescence prevails: even somnolence associated with corresponding changes in the EEG may appear. During this period wild animals become tame (660). From these data it is concluded that complex behavioral effects are as characteristic of ergotropic and trophotropic excitation as are changes in simple autonomic and somatic functions. Moreover, reciprocal innervation and post-stimulatory rebound are demonstrable in both groups of phenomena. The qualitative changes in the reactivity of the ergotropic and trophotropic systems, which were described earlier as "tuning," manifest themselves behaviorally also. Delgado (201) reports that a stimulation of the amygdala which does not elicit any noticeable effects reverses the response to petting in the cat: instead of rubbing its head against the experimenter's hand, it exhibits aggressive behavior. The presence of another animal may produce a similar reaction. Apparently the subthreshold stimulation of the amygdala or the increase in alertness resulting from an environmental stimulus raises the excitability of the ergotropic system sufficiently to account for an ergotropic behavioral response to a stimulus which evokes a trophotropic reaction under control conditions. The im-

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portant work of Kopa et al. discussed earlier (p. Ill) supports this conclusion. Such qualitative changes in reactivity, which seem to be due to a shift in the trophotropic-ergotropic balance, are not uncommon in clinical conditions. Thus patients with nervous dyspepsia may, in response to an attempt to elicit a rage reaction, show nausea instead (72). Individual differences to the action of certain drugs seem to have a similar basis.* A relation between approach reflexes and the excitation of the trophotropic system on the one hand and withdrawal (defensive flexor) reflexes and the excitation of the ergotropic system on the other was suggested earlier. On a higher level this contrasting pair appears as pleasant and unpleasant reactions not only in response to stroking and painful stimuli respectively but also in more subtle situations. Thus empathy, associated with increased trophotropic discharges (lowered heart rate and blood pressure), may be evoked in response to an emotionally charged, taperecorded recitation, whereas increased ergotropic activity (rising heart rate and blood pressure) is produced by mental tasks. According to Lacey et al. (608) the physiological difference between the two types of attitude is due to the fact that one requires the experimental subject to pay attention to "environmental inputs" whereas the other (involved in mental tasks) calls for their rejection. A preferable physiological interpretation bears in mind that increased heart rate and blood pressure are commonly the result of ergotropic excitation and may be independent of complex psychological attitudes since they occur in the spinal animal on nociceptive stimulation. Mental tasks are likewise related to the ergotropic system, but indirectly, through emotional excitement (frustration). Under these conditions the ergotropic system is activated as in exercise or in the hypothalamically induced defense reaction. The muscle tone increases and this effect further enhances ergotropic activity through proprioceptive feedback.! On the other hand, the instruction to attend to environmental stimuli (a flash of light) or to "empathize" favors a passive attitude, resulting in the relaxation of the muscles and a shift in the ergotropic-trophotropic balance to the trophotropic side. This interpretation is supported by the study of respiratory and metabolic changes occurring in different states of activity and in persons showing different emotional reactions to adverse situations. Respiratory volume, alveolar ventilation, and oxygen uptake are increased in hypnosis at the suggestion of anger, whereas these changes are reversed at a suggestion of relaxation and depression (230). Subjects exposed to an adversive life situation react with increased metabolism and respiration if they respond with anger but with a decrease in these functions if they react with de*For these and related problems see 370. f See also Chaper V.

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pressed behavior (231). There is apparently a close similarity between metabolic, autonomic, and somatic functions in states of marked activity (exercise) and anger (under hypnosis or without hypnosis), on the one hand, and in sleep, relaxation, and depression on the other. Dudley and collaborators (230, 231) refer to these phenomena as the result of actionoriented or non-action-oriented behavior. Since with increasing ergotropic activity sympathetic discharges, muscle tone, and respiration increase whereas these functions decline with increasing trophotropic activity, there is little doubt that the action-oriented behavior and the non-actionoriented behavior are due to ergotropic and trophotropic activity respectively. If one type of reaction appears predominantly or invariably, it may be considered to be the expression of an ergotropic-trophotropic imbalance.* II. SELF-STIMULATION AND THE TROPHOTROPICERGOTROPIC SYSTEMS

From the work of Olds (762, 763, 766), briefly referred to in Chapter III, it is known that large areas of the brain, particularly in the hypothalamus and the midbrain, are involved in two diametrically opposed forms of behavior. Electrodes inserted in an area extending from the rhinencephalon to the lateral edge of the hypothalamic-midbrain boundary induce positive reinforcement behavior: if the experimental animal is permitted to close the current and thereby to stimulate a site in the above-mentioned area, it learns quickly to reach and maintain very high rates of self-stimulation. The "rewarding" stimulus illustrates the phenomenon of positive reinforcement. On the contrary, the periventricular grey of the mesencephalon is an area of negative reinforcement, stimulation of which the animal seeks to avoid or terminate. These two areas, therefore, have also been called "start" and "stop" areas respectively (630). From the behavior of the animals, and corresponding observations in man on intracranial stimulation, it is inferred that the periventricular grey calls forth unpleasant sensations and emotions (fear, panic), whereas stimulation of the start area seems to evoke pleasant sensations. There is a close relation between the activity of the lateral hypothalamic feeding center and the rate of self-stimulation mediated by this structure: lesions in the ventromedial hypothalamic nucleus (satiety center) increase feeding as well as the rate of lateral hypothalamic self-stimulation. It was therefore suggested that the high rate of self-stimulation of the feeding center is due to pleasure "similar to the gratification obtained by eating" (478a, 479). On the basis of this information and additional work by Olds (767) and Stein (922) an attempt is made to relate self-stimulation to the trophotropic and ergotropic systems. For this purpose self-stimulation is compared with conditioning and the interaction of the two processes is "See 370 for the psychosomatic implications of these findings.

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analyzed. The reader will remember that the activation of the ergotropic system was shown (see Chapter III) to be indispensable for the establishment of the conditional reflex (c.r.). The following observations seem to support the assumption that the basic mechanisms of self-stimulation and of conditioning are similar in that both involve excitation of the ergotropic system at the hypothalamic level: 1. Stimulation of the "rewarding" points in the hypothalamus (but not of the nonrewarding periventricular area) accelerates the formation of c.r. (922). 2. C.r. and self-stimulation are enhanced by psychostimulants such as amphetamine that antagonize the action of reserpine, and their relative efficacy is the same for both phenomena; but stimulants such as picrotoxin, Metrazol, and strychnine fail to alter either self-stimulation or the instrumental conditioning rate (922). 3. Spreading depression (as reported in Chapter III) abolishes selfstimulation and conditioning. This reversible effect is associated with a temporary lessening of hypothalamic activity. 4. Hunger increases and satiety decreases alimentary c.r. and also selfstimulation (765). It follows from this work that as hypothalamic ergotropic activity is increased the rates of acquisition of c.r. and of self-stimulation are likewise increased. It may therefore be surmised that conditions leading to a loss of c.r. inhibit self-stimulation. This is illustrated not only by the effect of spreading depression and satiety but also by comparing the action of various forms of internal inhibition on both phenomena. Thus, just as the conditional stimulus (c.s.) not reinforced by food (reward) leads to gradual extinction of the c.r., so self-stimulation declines and disappears when the bar-pressing does not elicit any intracerebral stimulation. Conversely, a few properly timed rewarding stimuli delay the extinction of self-stimulation (922), in agreement with similar experiences of Pavlov showing a delay in the extinction of the c.r. under these conditions. There is a surprising parallelism between conditioning and self-stimulation experiments under conditions of nonreinf or cement. Apparently the laws of internal inhibition apply to both phenomena, and it appears logical to assume that similar physiological mechanisms underlie these behavioral changes. Therefore, and in view of the data presented in Chapter III showing that in c.r. internal inhibition in its various forms is associated with the appearance of trophotropic symptoms (cortical and peripheral), the decline in self-stimulation due to lack of reinforcement, and the delay in the extinction of self-stimulation due to the application of sporadic reinforced stimuli, are assumed to be the results of opposite changes in the trophotropic-ergotropic balance (A45).

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We agree with Stein (922) that the hypothalamic "go mechanism" — in our terminology the ergotropic system at the hypothalamic level —is responsible for self-stimulation, but we do not believe that the mesencephalic "stop mechanism" is responsible for the inhibition of self-stimulation. The "stop mechanism," associated with strong sympathetico-adrenal discharges, is involved in the freezing of animals in danger and is related to panic and flight (289), whereas internal inhibition is accompanied by trophotropic discharges and leads to the extinction of c.r. and eventually to sleep. The physiological analysis of self-stimulation may be carried still farther. Since the stimulus applied to the hypothalamic feeding center in satiated rats induces a search for food as well as self-stimulation, it is assumed that the motor activity is initiated by a pleasant sensory event, possibly related to feeding. That such sensations involve the trophotropic system is suggested by the finding that electrical stimulation of the tongue elicits, in addition to sensations of taste, muscular relaxation and feelings of pleasure and happiness (700).* Moreover, in rats self-stimulation by an electrode in the septal area is associated with a decrease in heart rate, whereas in the cat chewing and licking automatisms and numerous trophotropic symptoms are elicited from this area (463). However, pleasurable reactions involving the trophotropic system are by themselves inadequate to cause self-stimulation: stimulation of the anterior parts of the "lateral hypothalamic tube," which in the intact rat induces self-stimulation, becomes ineffective following a lesion in the posterior part of the "tube" (767). It is therefore assumed that self-stimulation involves at least two processes, a trophotropic excitation (and pleasure) and an ergotropic excitation leading to increased general activity during which the lever is bound to be moved, thus causing intracranial stimulation. That the latter process is repeated at an increasing speed is due to the tendency of ergotropic hypothalamic centersf to show marked temporal summation (344), which manifests itself in increasing degrees of excitation on repetition of the same stimulation at brief intervals. Since the rats in experiments in which the stimulus producing positive reinforcement is applied in a particular part of the test chamber return to this part on a greater-thanchance basis (763), it must be assumed that specific sensory cues likewise play a part. In conclusion it may be said that the ergotropic activity, particularly at the hypothalamic level, plays a crucial role in various forms of conditioning and in self-stimulation. The degree of activity of this system regulates the intensity of both forms of behavior. This statement is based on *It would be of great interest to repeat these tests on normal persons since the original work was done on psychiatric patients. f Stimulation of the posterior lateral hypothalamus not only produces sympathetic effects directly and reflexly but also increases motor activity.

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physiological experiments involving stimulation of the posterior hypothalamus, alteration in the state of excitability of the latter via the ventromedial hypothalamic nucleus, and pharmacological tests. The hypothalamic discharges evoked under these circumstances set off the motor activity patterned on the basis of previous experience, the trigger mechanism being closely related to motivation. Only passive avoidance reflexes are fundamentally different, since the trigger mechanism is inhibited in response to the conditional stimulus (see Chapter III). It has been emphasized throughout this book that central and peripheral (autonomic and somatic) discharges are altered in a parallel manner in a variety of circumstances. Thus, if the excitability of the ergotropic division of the hypothalamus is lowered, the EEG shifts from desynchronization to synchronization, and sympathetic discharges and muscle tone are lessened. Autonomic reactivity in response to Mecholyl, for instance, indicates the relative state of hypothalamic excitability and, indirectly, of cortical excitation. Somatic activity should serve the same purpose. The experiments described in this section have shown that self-stimulation is, in skilled hands, an accurate somatic indicator of the state of the ergotropic system at the hypothalamic level, and, therefore, presumably also of the intensity of the hypothalamic-cortical discharges. There are good reasons to assume that the ergotropic-trophotropic balance and the intensity of the hypothalamic-cortical discharges vary in different normal and abnormal emotional states (370). Psychopharmacological research concerned with the objective investigations of these problems has adopted self-stimulation as a valuable test after ingenious studies by Stein & Ray (923) of rats led to a method by which the threshold for self-stimulation could be recorded continually. Chlorpromazine was found to raise and amphetamine to lower the self-stimulation threshold, and the action of amphetamine was potentiated by imipramine (921).* The functional changes underlying the depressions cannot be discussed (see 370 and 921), but it should be mentioned that depressions are occasionally produced by Chlorpromazine and related drugs and offset by imipramine, suggesting that a shift in trophotropic-ergotropic balance is involved in the therapeutic effect of this drug, although details are lacking. Obviously the method of self-stimulation is of great value for testing and analyzing the action of potential therapeutic agents. Moreover, this method furnishes further insight into the state of the ergotropic-trophotropic systems in the intact organism. *A similar potentiation between the two drugs is also demonstrable in conditioned avoidance reflexes (921).

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REFERENCES

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References

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Autonomic-Somatic Integrations conditioned avoidance behavior in cats. Folia Psychiat. Neurol. Japon. 16:159167, 1962. (89) Yerkes, R. M., & J. D. Dodson: The relation of strength of stimulus to rapidity of habit-formation. J. comp. Neurol. Psychol. 18:459-482, 1908. (128) Yokota, T., A. Sato, & B. Fujimori: Inhibition of sympathetic activity by stimulation of limbic system. Japan. J. Physiol. 13:138-144, 1963. (197) Yokoyama, S., K. Inoue, & T. Ban: Urinary bladder responses to the electrical stimulation of the cerebellum in rabbits. Med. J. Osaka Univ. 13:271-284, 1963. (11) Yoshii, N., Y. Hasegawa, & H. Yamazaki: Electroencephalographic study of defensive conditioned reflex in dog. Folia Psychiat. Neurol. Japon. 13:320-367, 1959. (104) Yoshii, N., & W. J. Hockaday: Conditioning of frequency characteristic repetitive response with intermittent photic stimulation. EEC clin. Neurophysiol. 10:487-502, 1958. (75, 88, 110) Yoshii, N., P. Pruvot, & H. Castaut: Electrographic activity of the mesencephalic reticular formation during conditioning in the cat. EEG clin. Neurophysiol. 9:595-608, 1957. (78,132) Yoshii, N., & K. Tsukiyama: Electroencephalographic studies on conditioned behavior of white rat. Japan. J. Physiol. 2:186-193, 1952. (132) Yoshii, N., & Y. Yamaguchi: Studies on "memory tracer" with conditioning technique. I. Conditioning by electrical stimulation of the brain stem in the dog. Med. J. Osaka Univ. 13:1-19, 1962. (89, 114, 125) Youmans, W. B., Q. R. Murphy, J. K. Turner, L. D. Davis, D. I. Briggs, & A. S. Hove: Activity of abdominal muscles elicited from the circulatory system. Am. J. Phys. Med. 42:1-70, 1963. (5, 7, 8) Young, R. D.: Drug administration to neonatal rats: effects on later emotionality and learning. Science 143:1055-1057, 1964. (82) Zanchetti, A., S. C. Wang, & G. Moruzzi: The effect of vagal afferent stimulation on the EEG pattern of the cat. EEG clin. Neurophysiol. 4:357-361, 1952. (158) Zuckermann, E.: Effect of cortical and reticular stimulation on conditioned reflex activity. J. Neurophysiol. 22:633-643, 1959. (82, 84)

BIBLIOGRAPHICAL APPENDIX

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Bibliographical Appendix

Al.

W. Rautenberg, E. Simon, & R. Thauer. Die Bedeutung der Kerntemperatur fur die chemische Temperaturregulation beim Hund in leichter Narkose. I. Isolierte Senkung der Rumpfkerntemperatur. Arch, ges Physiol. 278:337-349, 196,3. (10) A2. E. Simon, W. Rautenberg, R. Thauer, & M. Iriki. Die Auslosung von Kaltezittern durch lokale Kiihlung im Wirbelkanal. Arch, ges Physiol. 281:309-331,1964. (10) A3. F. W. Klussmann. The influence of temperature on the activity of spinal a- and y-motoneurons. Experientia 20:450,1964. (10) The decisive role which the hypothalamus plays in the regulation of the body temperature has been the reason why the significance of lower parts of the central nervous system for this regulation was overlooked. But recent work shows clearly that if the temperature of the brain and of the skin is kept at normal or elevated levels the cooling of the deep tissues of the trunk elicits shivering and a marked increase in oxygen consumption ( A l ) . (High environmental temperature and perfusion of the carotids after ligation of the vertebrals made it possible to maintain brain and skin temperatures at the desired levels.) Furthermore, cooling of the vertebral canal induces (in warm environment) increased oxygen consumption, shivering, and vasoconstriction (in the paws), in spite of the constancy of the brain and skin temperatures (A2). Apparently, ergotropic discharges are induced at the spinal level by cooling the spinal cord, although the thermoreceptors in the diencephalon and in the skin are not activated. The conclusion that the ergotropic system involving sympathetic, adrenomedullary, and somatic discharges is organized in a similar manner in the diencephalon and in the spinal cord (although the latter is only subsidiary to the former) is supported by the more detailed investigation of the somatic discharges. By recording the activity of the alpha and gamma neurons in cats in which the spinal cord was cooled it was found that first the gamma and later the alpha neurons increase their rate of discharge (A3), a result similar to that seen under the influence of conditioning (see p. 103) which is thought to involve primarily diencephalic mechanisms (see Chapter III). A4.

N. Dafny, E. Rental, & S. Feldman. Effect of sensory stimuli on single unit activity in the posterior hypothalamus. EEC clin. Neurophysiol. 19:256-263,1965. (10) The differential responsiveness of individual hypothalamic neurons to sensory stimuli of different modalities is reported in this paper. AS.

H. Torii, M. Endo, Y. Shimazono, S. Ihara, H. Narukawa, & M. Matsuda. Neuronal responses in the cerebral cortex to electrical stimulation of the non-specific thalamic nuclei in cats. EEC clin. Neurophysiol. 19:549-559,

1965. (14)

am

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The authors describe the different degrees of synchronization induced by low-frequency stimulation of the intralaminar thalamic nuclei in various cortical areas (association area > motor area > somatosensory area) and their relations to the responsiveness of single neurons in these areas. A6.

J. Villablanca. The electrocorticogram in the chronic cerveau isole cat. EEGclin. Neurophysiol. 19:576-586,1965. (23) A7. N. Khazan & C. H. Sawyer. Mechanisms of paradoxical sleep as revealed by neurophysiologic and pharmacologic approaches in the rabbit. Psychopharmacol. 5:457-466, 1964. (57) Similarly, the frontal cortex responds in the paradoxical sleep phase to stimulation of the reticular formation with potentials of an amplitude and latent periods comparable to that seen in the alert state, whereas no response occurs during the spindle sleep. A8.

M. Guazzi & A. Zanchetti. Blood pressure and heart rate during natural sleep of the cat and their regulation by carotid sinus and aortic reflexes. Arch. ital. Biol. 103:789-817,1965. (57) The fall in blood pressure which occurs in the paradoxical sleep phase is greatly increased after sino-aortic denervation. It seems to me that this phenomenon is due to the elimination of the baroreceptors and, consequently, to the absence of the release of the sympathetic centers as the blood pressure falls. (The greater fall in blood pressure in response to hemorrhage of sino-aortic denervated as compared with animals not operated upon (329) is based on a similar mechanism.) A9.

G. Carli & A. Zanchetti. A study of ponrine lesions suppressing deep sleep in the cat. Arch. ital. Biol. 103:751-788,1965. (58) For further details concerning the neurology of the paradoxical sleep phase, see A9 and the literature cited in this paper. In these experiments loss of this phase occurred although the nucleus reticularis pontis caudalis was intact, but extensive lesions of the oral reticular nucleus of the pons were associated with prolonged loss of the paradoxical sleep phase. A10. M. Jeannerod. Organisation de 1'activite electrique phasique du sommeil paradoxal. Thesis, Lyon, 1965. (59) All. P. Vimont-Vicary. La suppression des differents etats de sommeil. Thesis, Lyon, 1965. (59) A12. W. D. Neff. Auditory discriminations affected by cortical ablations. Interriat. Symposium on Sensorineural Hearing Processes & Disorders, 1965.

(72)

This paper gives details concerning patterns of sound which can be learned after bilateral ablation of the auditory cortex and those which cannot be learned. A13. A. F. Guardiola, C. Mejia-Bejarano, E. Roldan, & D. Berman. EEC and reaction time changes during intermittent sensory stimulation in humans. Bol. Inst. Estud. Med. Biol., Mex. 23:101-144,1965. (72) A14. J. S. Buchwald, E. S. Halas, & S. Schramm. Comparison of multiple-unit and electroencephalogram activity recorded from the same brain sites during behavioural conditioning. Nature 205:1012-1014, 1965. (75) Simultaneous recordings of multiple-unit discharges, integrated-unit activity, and EEG show that the first two furnish a much better indicator of conditioning than the EEC. In experiments in which an acoustic stimulus was used as conditional stimulus and the unit potentials were recorded from the medial geniculate nucleus, habituation and extinction were accompanied by an inhibition of unit discharges when the EEG changes were indistinct or inconstant. Similarly, the unit discharges were increased when desynchronization of the EEG was not yet clearly developed.

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A15. N. Yoshii, K. Miyamoto, & M. Shimokochi. Electrophysiological studies on the conditioning of frequency specific waves. Med. J. Osaka U. 15:321344,1965. (75) From the extensive work of Yoshii et al. it may be mentioned that such labeled responses may be recorded in the cortex when low-frequency stimulation of the reticular formation serves as conditional stimulus and a nociceptive stimulus as unconditional stimulus. These responses can be inhibited by lack of reinforcement and are abolished by lesions in the medial thalamus.

A16. H. C. Nielson, A. H. Mclver, & R. S. Boswell. Effect of septal lesions on learning, emotionality, activity, and exploratory behavior in rats. Exp. Neurol. 11:147-157,1965. (82) That still other factors such as handling affect emotionality and the conditioning response is stressed by Nielson et al.

A17. G. H. Bower & N. E. Miller. Rewarding and punishing effects from stimulating the same place in the rat's brain. J. comp. physiol. psychol. 51:669674,1958. (83) A18. L. Koranyi, E. Endroczi, & K. Lissak. Disinhibition of extinguished conditioned reflex under spreading depression. Acta physiol. hung. 27:353357,1965. (87) For further information about the importance of diencephalic-cortical relations for conditioning see the experiments of Koranyi et al., who established and then extinguished conditional reflexes in rats, subjected them to spreading depression, and applied reinforced trials during this state. Although during the spreading depression the reinforced conditional stimuli are ineffective, these stimuli elicit conditional reflexes 24 hours later. The experiments suggest that information can be stored in the cerebral cortex during spreading depression, but its responsiveness to "subcortical triggering mechanisms" is lost during spreading depression, and it is these processes which underlie conditioning.

A19. F. Klingberg & L. Pickenhain. t)ber die Beteiligung des Hippokampus an der Ausarbeitung eines bedingten Fluchtreflexes bei der Ratte. Acta physiol. hung. 27:359-374,1965. (89) A20. E. Endroczi & L. Koranyi. The effects of electrical stimulation of the limbic system on conditioned somatomotor patterns in double-choice conditioned reflex situation in cats. Acta physiol. hung. 28:327-337, 1965. (90) A21. L. Koranyi & E. Endroczi. The effect of electrical stimulation and lesions of the limbic structures on the development of conditioned somatomotor patterns in the albino rat. Acta physiol. hung. 28:339-347,1965. (90) A22. C. Morpurgo. Drug-induced modifications of discriminated avoidance behavior in rats. Psychopharmacol. 8:91-99,1965. (91) It would be of considerable interest to determine whether active and passive avoidance responses are influenced differently by psychoactive drugs. It is well established that neuroleptic drugs such as Chlorpromazine inhibit active avoidance without altering passive avoidance (A22), but no drugs seem to be known which selectively inhibit the passive avoidance response.

A23. W. E. Grueninger, D. P. Kimble, J. Grueninger, & S. Levine. GSR and corticosteroid response in monkeys with frontal ablations. Neuropsychol. 3:205-216,1965. (93) It may be added that frontal lesions may abolish the psychogalvanic response to a conditional stimulus without interfering with its action on the cortex to elicit desynchronization and on the hypothalamus to produce increased excretion of corticosteroids.

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A24. L. S. Seiden & L. C. F. Hanson. Reversal of the reserpine-induced suppression of the conditioned avoidance response in the cat by L-DOPA. Psychopharmacol. 6:239-244,1964. (101) A25. L. C. F. Hanson. The disruption of conditioned avoidance response following selective depletion of brain catecholamines. Psychopharmacol. 8:100-110,1965. (101) The following findings give further evidence for the significant role which the catecholamines play in the maintenance and restitution of conditional reflexes: (1) the reserpine-induced suppression of conditional reflexes can be restored by L-dopa. This effect is associated with an increased concentration of dopamine in various parts of the brain (A24); (2) it is possible to deplete selectively the catecholamines in the brain without altering the serotonin concentration. This effect of alpha-methyl-tyrosine methylester-HCl is associated with a loss of conditional reflexes. Upon administration of L-dopa conditional reflexes and catecholamines are restored (A25). A26. E. Taub, R. C. Bacon, & A. J. Berman. Acquisition of a trace-conditioned avoidance response after deafferentation of the responding limb. J. comp. physiol. psychol. 59:275-279, 1965. (104) A27. E. Taub & A. J. Berman. Avoidance conditioning in the absence of relevant proprioceptive and exteroceptive feedback. J. comp. physiol. psychol. 56:1012-1016,1963. (104) A28. E. Taub, S. J. Ellman, & A. J. Berman. Deafferentation in monkeys: effect on conditioned grasp response. Science 151:593-594,1966. However, recent work has shown that monkeys are able to establish avoidance conditional reflexes in completely deafferented legs. These findings do not contradict the assumption that gamma discharges play an important role in the acquisition of conditional reflexes, but show that at least in some species central discharges (in our theory reinforced by hypothalamic activity) are sufficient for this process. A29. S. I. Cohen, B. M. Shmavonian, P. Hein, & L. Graham. Cardiovascular responsivity in classical and instrumental conditioning. XVIIIth Internat. Congress Psychol., Moscow, 1966. (104) Experiments on the effect of positive and negative conditional stimulus on the heart rate in man are likewise compatible with the assumption that vagal discharges become prominent on application of nonreinforced conditional stimulus. A30. G. T. Sakhiulina & G. K. Merzhanova. The recruiting response mechanism used as a conditional stimulus for the elaboration of the defensive conditioned reflex. EEGclin. Neurophysiol. 17:497-505,1964. (112) A31. J. Pecci-Saavedra, R. W. Doty, & H. B. Hunt. Conditioned reflexes elicited in squirrel monkeys by stimuli producing recruiting responses. EEG clin. Neurophysiol. 19:492-500,1965. (112) Several authors (A30, A31) used low-frequency stimulation of midline thalamic nuclei as a conditional stimulus and were able to establish a conditional reflex based on a nociceptive unconditional reflex. Apparently, trophotropic changes in the cortex resulting from stimulation of the limbic brain or from low-frequency stimulation of the diencephalon may be used as a conditional stimulus and conditional reflexes may be formed under these conditions. A32. J. Antal. Preparatory reaction of the cardiorespiratory system to muscular activity. In: Central and Peripheral Mechanisms of Motor Functions, E. Gutman, ed. Prague, Cz. Acad. Sci., 1963, pp. 247-253. (113) Closely related to these phenomena is the following observation. Dogs trained on the treadmill were exposed to the acoustic and vibratory stimuli associated with this

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experiment, although no running took place. The sham running led to an increase in blood pressure, heart rate, and respiration similar to that seen in the actual running test. A33. J. Gaddum. The neurological basis of learning. Persp. Biol. & Med. 8:436474,1965. (113) Gaddum denies that there is a temporal paradox in Pavlovian conditioning. The time sequence is the same as in experiments on facilitation in which the first stimulus increases the effect of the second. Similarly, "the effect of the first stimulus (conditional stimulus) in a conditioned reflex is to reduce the threshold for the second stimulus [unconditional stimulus] to zero." A34. S. Kovacs, A. Sandor, Z. Vertes, & M. Vertes. The effect of lesions and stimulation of the amygdala on pituitary-thyroid function. Acta physiol. hung. 27:221-227,1965. (216) In view of the importance of the amygdala for the activity of the ergotropic system it is interesting that electrical stimulation of the amygdala alters the activity of the thyroid gland. This effect depends on the parameters of stimulation, since low frequency increases and high frequency decreases the uptake of I1S1 by the thyroid gland. The latter effect is apparently secondary to the increased secretion of ACTH, because the I131 uptake is unchanged after adrenalectomy. A35. B. Bohus, K. Lissak, & B. Mezei. The effect of thyroxine implantation in the hypothalamus and the anterior pituitary on pituitary-adrenal function in rats. Neuroendocrinol. 1:15-22,1966. (216) However, recent experiments of Bohus et al. showed that implantation of thyroxin dissolved in agar-agar into the median eminence elicits increased cortico-steroid secretion combined with inhibition of thyroid function. This effect is not obtained from other parts of the hypothalamus or thalamus. A36. C. S. Evans & S. A. Barnett. Physiological effects of "social stress" in wild rats: 3. thyroid. Neuroendocrinol. 1:113-120,1966. (219) Wild male rats attacked by a member of their own species show a marked decline in thyroid activity for many hours, whereas the excretion of the adrenal corticosteroids is increased. A37. M. Kawakami, E. Terasawa, & J. Kawachi. Studies on the oxytocin sensitive component in the reticular activating system. Japan. J. Physiol. 14:104-121,1964. (226) A38. S. Kovacs, M. Vertes, & S. Imhof. A further study of the effect of oxytocin on pituitary-thyroid function in vivo. Acta physiol. hung. 25:39-45, 1964. (226) Kawakami et al. showed that injection of oxytocin induced "hyperarousal" potentials in the hippocampus which are abolished by lesions in the reticular formation in the midbrain as well as by lesions in the lateral hypothalamus. There is some evidence that the areas from which hyperarousal waves can be elicited in the hippocampus are determined by the nature of the hormone. Thus in spite of the absence of a hippocampal response to oxytocin after a reticular lesion, adrenaline (or stimulation of the posterior hypothalamus) may induce a typical hyperarousal response in the hippocampus. For illustration of the oxytocin-thyroid relations and the significance of the anterior hypothalamus for these relations see A38. A39. T. Kanai & J. C. Szerb. Mesencephalic reticular activating system and cortical acetylcholine output. Nature 205:80-82,1965. (232) This is further illustrated by the fact that acetylcholine is released in increased amounts from the surface of the brain on stimulation of the reticular formation.

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A40. A. Dahlstrom & K. Fuxe. Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta physiol. scand. 62:1-55,1964. (243) A41. A. Dahlstrom & K. Fuxe. Evidence for the existence of monoamine neurons in the central nervous system. II. Experimentally induced changes in the intraneuronal amine levels of bulbospinal neuron systems. Acta physiol. scand., Suppl. 247, 1965. A42. K. Fuxe. IV. Distribution of monoamine nerve terminals in the central nervous system. Acta physiol. scand. 64:1-85,1965. (243) A43. K. Fuxe. Evidence for the existence of monoamine neurons in the central nervous system. Thesis, Stockholm, 1965. (243) A44. N.-E. Anden, A. Dahlstrom, K. Fuxe, L. Olson, & U. Ungerstedt. Ascending noradrenaline neurons from the pons and the medulla oblongata. Experientia 22:1-4,1966. (243) The studies initiated by Hillarp and continued by Anden, Carlsson, Fuxe, and their collaborators have shown that through histochemical fluorescence methods adrenaline, noradrenaline, dopamine, and serotonin can be demonstrated in cell bodies and, particularly, in synaptic terminals of the central nervous system where the concentration of the neurohumors is relatively high. The appearance of these terminals is altered through sections of the axons and through the action of drugs (reserpine and monoamine oxidase inhibitors). Moreover, electrical stimulation of peripheral as well as central neurons leads to the release of neurohumors from the varicosities of the terminal structures. For the problems discussed in this chapter it is of great interest that noradrenaline has been found in the terminals of the limbic system, the hypothalamus, and the reticular formation, and that lesions in the lateral reticular formation lead to a marked decrease in the number of noradrenaline terminals in neocortex, limbic brain, and hypothalamus. Correspondingly, it was found that in these areas the noradrenaline but not the dopamine level was decreased. The finding that the morphological and functional changes which occur under different experimental conditions are similar in certain central and in peripheral adrenergic neurons supports the assumption that noradrenaline plays a role as a central transmitter, but the specific functional states which are characterized by an increased release of noradrenafine remain to be determined, as well as their relation to the changes in the function and release of acetylcholine which were described in this chapter. A45. R. H. Wurtz. Steady potential correlates of intracranial reinforcement. EEC clin. Neurophysiol. 20:59-67,1966. (249) This work gives some evidence for a relation between high self-stimulation rates and surface-negative shifts of steady cortical potentials which were shown in Chapter III to be associated with the formation of conditional reflexes and interpreted as signs of a shift of the ergotropic-trophotropic balance to the ergotropic side. A46. V. Bloch. Le controle central de 1'activite electrodermale. Etude neurophysiologique et psychophysiologique d'un indice sympathique de 1'activation r&iculaire. J. Physiol. (Paris) 57, Suppl. 13:1-132,1965. (32) This work is closely related to several topics discussed in Chapter I. By recording simultaneously the electrodermal response (ER) based on the sympathetically induced sweat secretion of the foot pads of the cat, the masseter reflex, and the EEC, Bloch shows a parallelism in the intensity of the three reactions with increasing intensity of stimulation of central (reticular) or peripheral (afferent nerves) structures. Exploring the reticular formation from the medulla oblongata to the hypothalamus, he finds that the three reactions are obtained with low intensities of stimulation from the same area. Sectioning of the brain stem at the level of the anterior commissure does

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not alter these reactions, but elimination of the reticular formation by prebulbar transection raises the threshold to nociceptive stimuli greatly and, to a similar degree, for the cortical, somatic, and sympathetic reactions which constitute the ergotropic system as defined in this book. These investigations confirm our conclusion that the ergotropic system acts as a unit. It was emphasized in Chapter I that the diencephalic-mesencephalic activating reticular system and the inhibitory area located in the medulla oblongata are reciprocally related. Combining Bloch's experiments on the electrodermal response elicited from the inhibitory bulbar area with the results described earlier it may be said that under the influence of anesthetics the threshold of the reticular formation for excitation of the ergotropic system is raised, whereas the threshold for the inhibition of this system (from the bulbar area) is lowered. Finally, Chapter I discussed the fact that proprioceptive impulses have a great influence on the tone and the responsiveness of the ergotropic division of the hypothalamus, since drugs with a curare-like action decrease the effect of hypothalamic stimulation on the nictitating membrane and on cortical arousal (340). Similarly, Bloch found that the ER induced by a nociceptive stimulus is diminished in the intact but not in the spinal animal under the influence of Flaxedil. It is inferred that this drug does not interfere with the ER at peripheral or spinal levels. The diminution of sympathetic responsiveness and cortical arousal following the blockage of the neuromuscular junction in the intact animal appears to be due to the loss of proprioceptive action on hypothalamus and reticular formation and consequent lessening of the upward and downward ergotropic discharges arising from these structures. A47. H. Scherrer. Inhibition of sympathetic discharge by stimulation of the medulla oblongata in the rat. Acta neuroveg. 29:56-74,1966. (16) This paper brings further evidence for the anatomical and functional separability of the bulbar inhibitory areas. A48. F. Baldissera, G. Broggi, & M. Mancia. Monosynaptic and polysynaptic spinal reflexes during physiological sleep and wakefulness. Arch. ital. Biol. 104:112-133,1966. (57) During this stage monosynaptic and polysynaptic spinal reflexes are reduced or abolished and the spontaneous activity of the sciatic nerve disappears. These phenomena seem to be due to inhibitory processes originating in the brain stem. A49. E. C. Beck, R. E. Dustman, & E. G. Beier. Hypnotic suggestions and visually evoked potentials. EEC clin. Neurophysiol. 20:397-400, 1966. (64) A50. K. L. Chow, W. Randall, & F. Morrell. Effect of brain lesions on conditioned cortical electropotentials. EEC clin. Neurophysiol. 20:357-369, 1966. (78,80} There is a disagreement between Doty's work described in Chapter III and the experiments of Chow et al. In addition, Chow et al. provide further evidence for the fact that transection of the reticular formation in the midbrain is compatible with the development of the conditioned local response in the visual cortex. A51. S. H. Snyder & M. Reivich. Regional localization of lysergic acid diethylamide in monkey brain. Nature 209:1093-1095, 1966. (63) A52. I. Izquierdo. Some observations on acute learning in rats and mice. In: Pharmacology of Conditioning, Learning and Retention, M. Ya. Mikhel'son, ed. New York, Macmillan, 1965, pp. 127-130. (229) But Izquierdo reports that this drug increases the rate of extinction of instrumental defensive c.r. in rats. A53. W. Dement, A. Rechtschaffen, & G. Gulevich. The nature of the narcoleptic sleep attack. Neurol. 16:18-33,1966. (50)

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A54. W. E. Bunney & J. M. Davis. Norepinephrine in depressive reactions. Arch. Gen. Psychiat. 13:483-494,1965. (241) Concerning the pathology of the emotions see the fascinating review of these authors who show that procedures (reserpine) leading to a depletion of noradrenaline are accompanied by depression. Conversely, monoamine oxidase inhibitors which increase the noradrenaline content of the brain prevent the reserpine-induced depression.

A55. G. Baccelli, M. Guazzi, A. Libretti, & A. Zanchetti. Pressoceptive and chemoceptive aortic reflexes in decorticate and in decerebrate cats. Am. J. Physiol. 208:708-714,1965. (245) A56. E. Grastyan, G. Karmos, L. Vereczkey, & L. Kellenyi. The hippocampal electrical correlates of the homeostatic regulation of motivation. EEC clin. Neurophysiol. 21:34-53,1966. (47) This important paper illustrates further the close relation between the loss of reciprocity of ergotropic and trophotropic reactions of high intensity and the occurrence of pathological behavior. It was found that weak stimulation of the posterior hypothalamus evokes general orientation movements and, on this basis, movements of approach accompanied by large hippocampal theta potentials (3-5 c/sec). With more intensive stimuli avoidance movements associated with desynchronization of the hippocampal potentials appear while the orientation reactions are inhibited. Finally, very strong stimuli elicit an "arrest reaction" the resemblance of which to petit mal discharges is well known. Bearing in mind that weak hypothalamic stimuli tend to activate the trophotropic system, by contrast with somewhat stronger stimuli which induce ergotropic reactions, the appearance of periods of frequent potentials of low amplitude superimposed on theta potentials in the hippocampogram seems to indicate that very strong stimuli lead to simultaneous ergotropic and trophotropic discharges and thereby to abnormal behavior characterized by the sudden cessation of movements and the failure to respond to various sensory stimuli. This interpretation seems to be applicable to the arrest reaction produced by strong stimulation of the intralaminar thalamic potentials. (J. Hunter, & H. H. Jasper. Effects of thalamic stimulation in unanesthetized animals. EEC clin. Neurophysiol. 1:305-324,1949.) A57. R. T. Rubin, A. J. Mandell, & P. H. Crandall. Corticosteroid responses to limbic stimulation in man: localization of stimulus sites. Science 153:767768,1966. (22i; The authors stimulated amygdala and hippocampus in five patients and found that the amygdala increases and the hippocampus decreases the concentration of the 17hydroxycorticosteroids in the plasma.

A58. M. Bonvallet & L. D'Anna. Reponses reticulaires immediates, reponses reticulaires tardives et oscillations spontanees du tonus reticulaire. Arch, ital. Biol. 104:280-306,1966. (87,210) This discrepancy is perhaps related to the fact that stimulation of the reticular formation elicits two distinct effects: 1. an immediate stable excitatory response consisting of a brief period of cortical desynchronization which is associated with a motor discharge to the neck muscles and an increased sympathetic activity combined with increased parasympathetic inhibition (recorded in the short ciliary nerves); 2. a similar but delayed unstable response consisting of prolonged oscillations of excitation which extend beyond the period of stimulation. Both responses are of an ergotropic character. Brief stimuli evoke only the immediate response, whereas prolonged stimuli elicit in addition the delayed reaction. Latent period and duration of the immediate response are expressed in ms (or fractions thereof) but in seconds for the delayed response. Similar time relations characterize the inhibition of an evoked sensory cortical potential through a brief shock applied to the reticular formation and the facilitation of such a response when the hypothalamus is stimulated for several seconds. Moreover, hypothalamic lesions abolish the delayed

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but not the immediate response to reticular stimulation. On this basis it seems possible that direct hypothalamic excitation or indirect (via the reticular formation) induces sensory facilitation whereas brief reticular stimulation (not involving the hypothalamus) induces sensory inhibition. A59. A. Rosina & M. Mancia. Electrophysiological and behavioural changes following selective and reversible inactivation of lower brain-stem structures in chronic cats. EEC clin. Neurophysiol. 21:157-167,1966. 305(2 In this work the effect of intravertebral injections of barbiturate was studied in chronic cats in which the basilar artery had been ligated at various pontine levels. The experiments provide further evidence for the existence of inhibitory areas in the lower brain stem and their role in various phases of sleep (see section on paradoxical sleep in Chapter II).

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INDEX

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Index

ACTH: hypothalamic stimulation, 221; injection of, and inhibition of ergotropic system, 95; and limbic cortex, 221; secretion of in conditioning, 93f. ACTH secretion: placebo effects, 62 Acclimation to cold, 207 Acetylcholine: and arousal, 235; effect in liberating adrenaline, 236; and evoked potentials, 231; and sleep, 232f. Adrenal cortex: in anxiety, 138; and conditioning, 93f., 96 Adrenal medulla: and conditioning, 97; effect of ergotropic system on, 137, 143 Adrenaline: and arousal, 227; ergotropic effect of, 228, 231; and excretion, 184; and sympathetic transmission, 241 Adrenomedullary secretion: 185f., 200f., 203, 207, 213; and anesthesia, 200; and asphyxia, 186; effect of cocaine on, 186; and homeostasis, 186; physiological significance of, 185f.; stimulation of anterior hypothalamus, 200; without increased noradrenaline excretion, 197f. Aggressiveness, 34 Alpha potentials: attention and, 63; in deprivation of sleep, 45; in narcolepsy, 50; in startle, 46; in yoga trance, 54 Amphetamine: and arousal, 237; and narcolepsy, 51; and reticular formation, 30; and self-stimulation, 251; toxicity in grouped animals, 99 Amygdala: 221; and conditioning, 89; and hypoglycemia, 60 Anesthesia: adrenomedullary secretion in, 200 Anger; see Fear Anoxia: body temperature in, 176f.; release of ergotropic system in, 60 Anxiety: 138f.; conditioning in, 143f.; and muscle tone, 181 Arousal: adrenaline and, 227f.; caudate

nucleus in, 28; and cortical desynchronization, 11; and d.c. potentials, 21n; and frequency of stimulation, 12, 18, 19n; and hypothalamus, 10, llf.; inhibition of, 16; neurohumoral transmission of, 238; psychophysiology of, 13f.; relation to thalamus and reticular formation, 37; and reticular formation, 10, 11; and sensory stimulation, 10, 11; and thalamic reticular nuclei, 33n; and vagus, 16n Aschner reflex, 41 Asphyxia: and release of ergotropic system, 60; and sympathetic and parasympathetic discharges, 43 Atropine: effect on behavior and EEC, 241 Attention: physiological basis, 65 Autonomic nervous system: general characteristics, 3 Autonomic-somatic correlations: at hypothalamic level, 25, 150f.; at reticular level, 150f. Baroreceptors: convulsions and, 8; denervation of, and effects on cortex, 17; denervation of, in narcolepsy, 51; effect of lowering intrasinusal pressure, 204; effect on blood flow of active muscle, 174; and gamma neurons, 8; and inhibition of adrenomedullary secretion, 187; and reciprocity principle, 24, 32; and sham rage, 32; and trophotropic effects, 7, 16, 32 Bleeding: and diuresis, 176 Blood flow: in active muscle, 174; effect of adrenaline on, 174; effect of cortex and brain stem on, 174; in kidney, 175; in resting muscle, 53 Bradykinin, 205 Brain stem: lesions of and paradoxical

313

314

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sleep, 58; transection and cortical desynchronization, 23 Bulbar inhibitory area: cortical desynchronization and, 23, 24; homeostasis and, 68; and hypothalamus, 16n; movements and, 15; and reticular formation, 12,30 Carbon dioxide; see CO2 Carotid sinus; see Baroreceptors, Chemoreceptors Cataplexy: 50; in experimental neurosis, 119 Caudate nucleus: arousal and, 11, 28; and cortical synchronization, 14f.; and hypercapnia, 29; and spindle threshold, 28; and trophotropic effects, 28 Cerebellum: ergotropic and trophotropic systems of, 11 Cerebral anemia, 41 Cerebral cortex: and d.c. potentials, 76; and homeostasis, 69 Cerveau isole, 23 Chemoreceptors: and asphyxia, 8; effect on medulla oblongata, 8; and hypercapnia, 8, 12 Chlorpromazine: and conditioning, 98f., 113; effect on caudate threshold, 28; effect on different parts of brain stem, 36; effect on hypothalamus, 27; and emotionality, 82; and habituation, 73; and self-stimulation, 251 Cholinergic transmission, 239f. Cholinoceptive neurons, 239 Cingulum; see Gyrus cinguli CO2: and adrenomedullary secretion, 202; effect on caudate threshold, 29; effect on noradrenaline and adrenaline excretion, 185, 202; and therapy, 142 Cocaine: 30; and ergotropic system, 230 Coitus; see Postcoital reactions Cold: effect on muscle activity, 6; and thyroid secretion, 217 Collisions, physiological, 173 Coma, hypoglycemic, 60 Conditional reflexes: difference between defensive and alimentary, 211 Conditioning: and adrenal cortex, 93f.; and adrenal medulla, 97; and alpha potentials, 74, 75; and amygdala, 89f.; and closure of conditional reflex, 78; and convulsions, 82; cortico-cortical, 76, 105f.; and d.c. potentials, 76; drugs and, 98f.; and EEC, 72; emotion and, 80, 112; and ergotropic-trophotropic balance, 11 Of.; extinction of, 83, 90; and gamma neurons, 102f.; gyrus cinguli in,

91; and habituation, 78; and hippocampus, 89f.; and hormonal secretion, 91f.; and hypothalamic lesions, 79f., 81; and hypothalamic stimulation, 83f.; and hypothalamic-cortical discharges, 87; and internal inhibition, 104f.; and lesions in reticular formation, 79; and limbic brain, 89f., 114; and neurohumors, lOOf.; and orientation reaction, 78; and reinforcement of conditional stimulus, lOlf.; and response to flicker, 75; and role of subcortical discharges, 76f., 78f.; and self-stimulation, 84f.; and septum, 81; and single-unit discharges, 75; and spreading depression, 84f.; and subcallosal gyrus, 90; temporal paradox and, 113; and thalamo-cortical discharges, 87f; and thyroid secretion, 224; and ventromedial hypothalamic nucleus, 81 Conflicts, psychological, 181f. Convulsions: conditioning and, 82; facilitation through hypothalamus and reticular formation, 155f.; reciprocity principle in, 44 Cortex: role in conditioning, 72; and subcallosal conditioning, 90 Cortical activation patterns, 209f. Cortical desynchronization; see Arousal Cortical synchronization; see Sleep Crying: inhibition of, 25 d.c. potentials, 21n, 76, 105 Depression: conditioning in, 144 Diuresis and bleeding, 176 Dominance: 52n; parasympathetic, 43f.; sympathetic, 43f.; and trophotropic system, 177 Dreaming, 56 Edinger-Westphal nucleus, 32 EEC: and alpha blocking in conditioning, 74; and conditioning, 72; effect of eserine on, 237; experimental neurosis and, 125, 132; in hypnosis, 61 Emergency reactions, 212 Emotion: and afferent impulses, 160f.; and conditioning, 80f., 82n; effect on noradrenaline and adrenaline excretion, 185; and ergotropic system, 244f.; and experimental neurosis, 123f.; and facial movements, 162f.; and limbic brain, 165; and narcolepsy, 50; and perception, 168; reciprocity principle in, 43; and response to Mecholyl, 135f.; and thyroid secretion, 220; and trophotropic system, 245; see also Aggressiveness, Anxiety, Fear

Index Empathy, 167f., 247 Erection: 41; in experimental neurosis, 121 Ergotropic discharges: in cold and heat, 196; in emotion, 195f.; partial, 194f., 205; patterns of, 183f. Ergotropic syndrome: 5, 33; and arousal, llf. Ergotropic system: and adrenaline, 188; adrenomedullary secretion and, 185f.; and amygdala, 18n; arousal and, llf.; and arousal in man, 13f.; and behavior, 244f.; and cerebellum, lln; definition of, 4; and different states of vigilance, 12; effect of sensory stimuli on, 10; effect of temperature on, 6; and gamma discharges, 27, 34; hypothalamus and, 10f., 41; inhibition of and adrenomedullary secretion, 200f.; inhibition of through ACTH, 95; and nociception, 26, 49; and orienting reflex, 62; patterns of discharge and, 67; and placebo effect, 62; reciprocal relation to trophotropic system, 24f., 27; and recruiting response, 28; and reinforcement of conditional stimuli, lOlf.; release of, 59f.; and self-stimulation, 248; in sleep deprivation, 45; and tonic innervation, 34; as unit, 32 Ergotropic-trophotropic balance: and acetylcholine, 231; and ACTH, 220f.; and afferent impulses, 27, 32; and anoxia, 41; and asphyxia, 41; and baroreceptors, 48f., 52; and brain stem, 22, 30; and caudate nucleus, 28; and conditioning, 100, llOf.; and convulsions, 44; and consciousness, 40f.; and emotionality, 134f.; and hypoglycemia, 42; and Metrazol, 28; and narcolepsy, 49f.; and pain, 44; in paradoxical sleep, 57; and postcoital reactions, 222; and psychological attitudes, 247; and psychosomatic medicine, 48; and sensory deprivation, 49; tuning, 47f. Ergotropic-trophotropic relations: and reciprocity, 24 Eserine: and EEC, 237; effect of on behavior, 241 Fear: acute and subacute, 133f. Feedback mechanism, 159 Fever, 43 Forebrain, basal: cortical synchronization, 30 Galvanic reflex: and mental activity, 54

315

Gamma neurons: 34f., 50, 159; and conditioning, 102f. Glutamic acid, 232 Grooming, 178f. Gyrus cinguli: and conditioning, 91; and inhibition of movements, 16; and narcolepsy, 51; and pleasure, 179 Habituation: 209; and Chlorpromazine, 73; and evoked potentials, 64; and orientation reaction, 72, 78; and septum, 33 Hallucinations: in sleep deprivation, 47 Hippocampus: 221; and after-discharges, 16; and conditioning, 89; and theta potentials, 11 Homeostasis: 68f.; and adrenomedullary secretion, 186; and hormonal action on hypothalamus, 94; role of cortex in, 69 Hormones: and conditioning, 91 Hunger: and hypothalamus, 85, 107, 128, 130; and satiation, 107, 128 Hypercapnia: and caudate nucleus, 28; and muscle tone, 8 Hypnosis: 61f.; and attention, 63; and EEC, 61; palmar sweating in, 61; and perception, 62; relation to hypothalamus and reticular formation, 67 Hypoglycemia: 42; and adrenomedullary secretion, 197; and amygdala, 60, 100; and narcolepsy, 51; and release of ergotropic system, 60 Hypothalamic balance and ACTH, 220 Hypothalamic-cortical discharges distinguished from reticulo-cortical discharges, 21 Of. Hypothalamic system, 123 Hypothalamus: activation through afferent impulses, 156f.; activity of and motor system, 88; anatomy of, 9; balance of and emotionality, 134f., 161, 166; bladder and, 44; Chlorpromazine and, 99; and cortex, 10, 11, 163; cortical activation patterns of, 209f.; deviations from the reciprocity principle, 41f.; and discharges to the cortex, 44, 46, 87; and ergotropic syndrome, 10, 12; in experimental neurosis, 122; and facilitation of conditioning, 84; and facilitation of convulsions, 155f.; and feedback mechanisms, 93; and frequency and intensity of stimulation, 19, 41; and heating, 25, 43; and hunger, 85, 249; lesions of, 24, 34, 43, 79f., 81, 210; and limbic brain, 210f.; and paradoxical sleep, 58; and perception, 164f.; and pyramidal discharges, 151; reciprocity

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principle and, 24f.; relation to movements, 151f.; relation to spinal cord, 152; and self-stimulation, 250; septa! lesions and release of, 99; and sexual functions, 222f.; and sleeplessness, 34; and spreading depression, 85; stimulation of, 26; stimulation of and conditioning, 82; and temperature regulation, 10; and thyroid secretion, 215f.; and trophotropic syndrome, 10; and tuning, 47f., 162; and ventromedial nucleus, 81 Immobilization: effect on sensory stimulation, 27 Inhibitory systems: effect on cortical desynchronization, 34 Instincts: interaction of, 178f. Intracranial pressure: increase in, 42 Intraergotropic adjustment, 206 Insulin; see Hypoglycemia Lemnisci, medial: role in conditioning, 80 Limbic brain: and ACTH, 221; and conditioning, 89f., 114; and emotionality, 246 Limbic system; see Gyrus cinguli Lysergic acid, 30 MAO, 229f. Mecholyl: in different states of emotion, 134f.; and gravitation, 137 Medulla oblongata: and cortical desynchronization, 23; effect of cooling on, 205; lesion of and trophotropic and ergotropic effects, 33; see also Bulbar inhibitory area Medullary vascular centers, 188 Mental activity: and muscle, 53; psychogalvanic reflex, 54 Monoamine oxidase inhibitors, 229f. Mood: and posture, 160f. Motor cortex: threshold in paradoxical sleep, 57 Movements: and pain, 152f.; relation to hypothalamus and reticular formation, 151f, 163n Muscle: blood flow in, 53; and mental activity, 53; and yoga trance, 54 Muscle spindles; see Proprioception Muscle tension in sleep deprivation, 46 Muscle tone: and baroreceptors, 7; and gamma neurons, 8; and hypercapnia, 8; and hypothalamus, 10; and paradoxical sleep, 56f.; and relaxation therapy, 35; and sleep, 7, 55; and temperature, 6

Narcolepsy, 49f. Neurohumors: 2271; and conditioning, 100; in sleep, 232 Neuronal units: and paradoxical sleep, 57 Neurons: alpha, 5, 6, 8n; gamma, 5, 8, 12, 15, 27; single cortical and thalamic, relation to reticular system, 20; and sleep-wakefulness cycle, 22 Neurosis: 140f.; and conditioning, 143f.; drug action in, 145f.; and therapeutic principles, 141f. Neurosis, experimental: 116f.; and autonomic reactions, 122; and catapjexy, 119; conditional responses during, 119f.; and drowsiness, 130; drug action in, 146; and EEC, 132; and emotionality, 123; excitatory and inhibitory forms, 131f.; hypnotic stages, 120, 129f.; hypothalamic system in, 122; and intensity of hypothalamic excitation, 128; methods of producing, 117f.; paradoxical phases of, 129; and personality types, 119f.; physiological mechanism of, 124f.; physiology of therapeutic principles of, 139f.; and reciprocity principle, 125f.; and simultaneity of ergotropic and trophotropic discharges, 125f.; symptomatology of, 121f. Nociception: and ergotropic system, 26, see also Pain Noradrenaline: and cold acclimation, 207f.; and excretion, 184; free, and ergotropic action, 229; and reserpine, 230 Orbeli effect, 152 Orgasm and narcolepsy, 50 Orienting reflex: 11, 72, 78, 80; and reticular formation, 62; and spreading depression, 85 Pain: different types, 7; and ergotropic system, 26; and movements, 152f.; principle of final common path of, 154; and reciprocity principle, 44; visceral, 7 Paradoxical sleep; see Sleep, paradoxical Parasympathetic inhibition: gradation of, 205 Perception: and arousal, 13; and emotion, 168f.; and hypnosis, 62; and hypothalamus, 164f.; and loss of facial expression, 165f. Personality types and conditioning, 119f. Placebo: effect on ergotropic arid trophotropic systems. 62 Pleasure reactions, 246; see also Instincts Pons: influence of transection on cortical

Index desynchronization, 23; and paradoxical sleep, 58 Postcoital reactions: effect on cortex and limbic brain, 223; ergotropic-trophotropic balance in, 223 Posture and mood, 160 Potentials, evoked: and attention, 64; in conditioning, 75; in paradoxical sleep, 57 Potentials, d.c.: 76, 105; and arousal, 21 Proprioception: and arousal, 10; and conditioning, 104; and cortical potentials, 25; curare and, 26; and emotions, 162, 164, 166; feedback and, 159, 182, 247; inhibition and, 26; and mood, 160; and willed movements, 159f.; see also Gamma neurons Psychogalvanic reflex, 54 Pupil: in arousal, 22n; constriction of, 6; dilatation of, 5, 32, 33, 57; and discharges in long ciliary nerves, 12; and discharges in short ciliary nerves, 32 Pyramidal discharges: and hypothalamus, 151; relation to afferent impulses, 151, 156 Reaction time: in arousal, 13 Reciprocity principle: deviations from, 40f.; and experimental neurosis, 125f.; at extrahypothalamic levels, 27f., 31f.; and gamma system, 34; in neurosis, 144; at spinal, medullary, and hypothalamic levels, 24f., 34f. Reciprocal innervation; see Reciprocity principle Recruiting responses: 14, 19, 28; and arousal, 30; in paradoxical sleep, 56 Reflexes: deviations from the reciprocity principle, 40f.; nutritive, 173f.; vestibular, 6; visceral, 5, 7 Relaxation: 55; postprandial, 166; therapy, 142 Response stereotypy, 205 Reticular formation: activation of through afferent impulses, 156; and adrenaline, 228; and amphetamine, 30; in arousal, 11; and blocking of afferent impulses, 64; and bulbar inhibitory area, 12, 30; and cocaine, 30; and cortical activation patterns, 209; differences between rostral and caudal parts, 36; and facilitation of convulsions, 155; and habituation, 33; lesions of, 79f., 210; and lysergic acid, 30; pontine division, 23, 58; relation to hypothalamus, 19; relation to movements, 151f.; relation to

317 pons, 20; relation to thalamus, 19; single-unit activity, 158

Satiety: and conditioning, 107 Self-stimulation: 248; and conditioning, 84f., 249; effect of hunger and satiation on, 249; and spreading depression, 84f. Sensory deprivation and autonomic balance, 49 Septum: and aggressiveness, 179n; and habituation, 33; lesion of and conditioning, 81 Sex function and hypothalamus, 222f. Sham rage, 12, 32, 63, 99, 245 Shivering: 206f.; and anoxia, 177; temperature regulation, 10, 201 Sino-aortic denervation: effects of, 7, 8 Sino-aortic reflexes; see Baroreceptors, Chemoreceptors Sleep: and acetylcholine, 232; and basal forebrain, 30; cortical synchronization in, 14f., 52; and cutaneous receptors, 52; and delta potentials, 56; deprivation of, 45f.; and frequency of stimulation, 14; and hypothalamus, 34; and limbic brain, 17; and muscle tone, 7, 55; and neurohumoral transmission, 238f.; and somnolence, 10, 80, 130; and transection of brain stem, 11; and transition from wakefulness, 22 Sleep, paradoxical: 55f., 233; and blood pressure, 57; and brain stem lesions, 58; and cortical potentials, 56; ergotropic discharges in, 198; and evoked potentials, 58; eye movements in, 58; and muscle tone, 57; and pupil, 57; recruiting response in, 56 Somnolence; see Sleep Spreading depression: 249; and conditioning, 84f.; effect on hypothalamus, 63 Stress: adrenomedullary secretion in, 204 Substitutive behavior, 180f. Suggestibility, 62 Sympathetic action: gradation of, 205 Sympathetic activity and transition to sympathetico-adrenal discharges, 191f. Sympathetic discharges; see Ergotropic system Sympathetic vasodilatation, 188f. Sympathetico-adrenal discharges, 184f. Symptom stereotypy, 205 Temperature: and anoxia, 176; and baroreceptors, 6; and caudate threshold, 29n; and circulatory reflexes, 176; shivering, 10

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Temperature regulation: 10, 207; and anterior hypothalamus, 201 Thalamic-limbic relations in paradoxical sleep, 59 Thalamic reticular system: and single cortical neurons, 20 Thalamus, intralaminar nuclei: and arousal, 37; effect of coagulation on, 34; and recruiting response, 30 Thiouracil: effect of at different temperatures, 219 Thyroid: effect of cold on, 217; and emotion, 220; and ergotropic system, 219; and heating of hypothalamus, 217f.; secretion, 215f. Tilting: effect of on baroreceptor reflexes, 7 Trophotropic syndrome: 6, 33; and amygdala, 18n; and afferent stimulation, 16, 32, 52; and approach reflexes, 247; and baroreceptor action, 7, 8, 16; behavior and, 244; and cerebellum, lln; definition, 4; effect of on temperature, 6; effect on frequency of stimulation,

18; and hypothalamus, 14f., 41; and inhibition, 25; internal inhibition, 104f.; and limbic brain, 17; and nociception, 49; and paradoxical sleep, 56; patterns of discharge, 67; and placebo effect, 62; and pressure on larynx, 17; reciprocal relation to ergotropic system, 24f., 27f.; and self-stimulation, 248; and sleep deprivation, 45; and tonic innervation, 34; and vagus, 159 Tuning: and arousal, 236; and conditioning, llOf.; effect on cortex, 53; and emotional behavior, 246; and excitatory and inhibitory form of experimental neurosis, 131f.; and hypothalamus, 47; in narcolepsy, 50 Vagus: and cortical synchronization, 159; and secretion of insulin, 43, 45 Vasodilatation: through cholinergic discharges, 189; through inhibition of constrictors, 190; in muscle, 188f. Yoga trance, 54f.