Further Studies on the Physiology and Pathophysiology of the Tuning of the Central Nervous System

Further Studies on the Physiology and Pathophysiology of the Tuning of the Central Nervous System E.

GELUIORl'O,

• It was shown in previous studies"":!o that the chan~es induced by stimulation (directly or via reflexes) of the parasympathetic and sympathetic divisions of the hypothalamus are not confined to these struetures but alter somatic functions at cortical and spinal levels as well. Applying Hess' terminology it may be said that sympathetic excitation leads to activation of the ergotropic system characterized by cortical desynchronization, heightened svmpathetic responsiveness and increased tone of the striated muscles whNeas activation of tIlt:' parasympathetic system leads to activation of the trophotropic system involving cortical svnchronization, increased parasympathetic responsiveness, and muscular relaxation. These states arc n'fNred to as states of ergotropic and trophotropic tuning respectively and represent an imbalance in which dominance of either tIll' ergotropic or the trophotropic svstem is accompanied by reciprocal relations be'tween the two systems. Since such states represent marked deviations from homeostasis the question is raised as to what processes tend to counteract and which forms of excitation tend to facilitate tIl<' tuning of the nervous svstcm. Further prohlems discussed in this paller concern the behavioral and clinical significance of reversal phenomena (in which stimuli acting on the ergotropic svstem under control conditions elicit trophotropic effects and vicc versa) and of the loss of reciprocity hetween the ergotropic and trophotropic svstems seen at markl'd de~re('s of tunin~. 'The importance' for

Dr. Cellhorn is Professor emeritus (NeurophysiolUnivt'rsity of Minnesota, ~linneapolis, ~linn. This work was supported hy Grant NIH-06552-07 from the National Institlltps of Health.

o~y)

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M.D., PH.D.

neurologieal and psychiatric disorders of the failure to maintain reciprocal relations between the ergotropic and trophotropic systems and the mechanism underlying this faih{re will he pointed out. Finally, physiological procedures of potential therapeutic value in the treatment of disease states characterized hv ' altered states of tuning are presented. TUri:I:>;C

A~D

HO:\IEOSTASIS

It is well known from the study of spinal reflexes that marked changes in tIll' state of excitation are followed hy compensatory phenomena. Thus the reflex contraction of the extensor muscles is enhanced subsequent to the inhibition of this reflex by a flexor reflex in the same leg. This phenomenon (Sherrington's succt'ssive induction) illustratt's the fact that inhibition is followed by "a rebound to superactivity" before the normal excitability is restored. The flexor and extensor reflexes arc reciprocally related and the "extensor-reflex predisposes to and may actuallv induce a flexion-reflex, and conversely the fl~xion-reflex predisposes to and may actually induce an extension reflex.""" The obst'rwltion that after vagal inhibition of the heart its contractions arc larger than before stimulation suggests a similar interpretation. Similar phenomenon occur at higher levels of the central nervous svstem and involve both the trophotropic and ergotropic systems. They may counteract tuning and related changes in central excitability. The following "rehound" phenomena are examples of this: 1. Excitation of the ergotropie system. Brief sllprathreshold stimulation of the ergotropic division of the hypothalamus which increases hlood pressure and heart rate during stimulation is followed by a sudden de<:rease in hlood Volume X

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pressure and heart rate immediately after stimulation. This trophotropic rebound is directly related to the intensity of the preceding sympathetic excitation regardless of whether increasing degrt>es of excitation had been produced by changes in voltage, frequency, duration of stimulation, or similar factors.~' 2. Excitation of the trophotropic system. Stimulation of the intralaminar thalamic nuclei with currents at a low frequency (3 to 5/sec.) which produces recruitment (waxing and waning of potentials in thalamus, caudate nucleus. and cortex) is followed after stimulation by a typical arousal pattern in the cortex consisting of potentials of low amplitude and high frequency."" It mav therefore be said that ergotropic patterns elicited by diencephalic stimuli are followed on cpssation of stimulation by trophotropic patterns and vice versa. These rebound phenomena tend to maintain ergotropic-trophotropic balance. From studies on asphyxia in animalszz,~" the following observations are pertinent: the fall in blood pressure and heart rate occurring in the late phasc of asphyxia is followed immediately on readmission of air by a strong sympathetico-adrenal discharge indicated by an abrupt rise in blood pressure and heart rate accompanied by a contraction of the innervated and denervated nictitating membranes. This phase in turn is succeeded by a period in which the blood pr('ssure remains elevated but the h('art rate decreases (late post-asphyxial phase). The testing of crgotropic and trophotropic systems during these phases discloses that during the late phase of asphyxia, ergotropic and trophotropic excitability is increased and that the trophotropic system is dominant. The readmission of air shifts the <'rgotropic-trophotropic balance forcefully to the ergotropie side by a strong sympathetieoadrenal discharge. During this phase the ergotropic responsiveness is greatly enhanced. This period is followed by one of trophotropic dominance: in the late post-asphyxial phase the trophotropic reactivity increases and that of the ergotropic system is diminished. Apparently gross disturbances in autonomic balance induce marked oscillations of the trophotropic and ergotropic systems before homeostasis is reestablished. The occurrence of brief periods of vasodila\Iarch-April, 1969

tation which interrupt the ergotropic vasoconstriction induced by the immersion of the hand in cold water illustrates in man the homeostatic effect of trophotropic vasodilatation following ergotropic vasoconstriction. 49 The examples given above illustrate rebound phenomena in the autonomic and somatic (cortical) branches of the ergotropic and trophotropic systems. Since these systems act as units one would expect that vascular changes for instance would result in forms of rebound involving the vascular system as well as the cerebral cortex. This is shown in the following experiment.' A rise in blood pressure induced by inflation of a balloon in the thoracic aorta elicits a slight depressor effect (via sino-aortic baroreceptors) without altering thc synchronous EEG pattern of the sleeping cat. After deflation, however, arousal occurs which is associated with a rise in hlood pressure and cortical desynchronization. Obviously, a trophotropic reaction induced reflexly by an increase in sino-aortic pressure is followed hy a post-stimulatory rebound which manifests itself at cortical and subcortical (autonomic) levels and also in behavior. In addition there are processes involving neocortex and diencephalon which although not classifiable as rebound phenomena contribute to cortical homeostasis. Hugelin and Bonvallct'w.,o working on cats with post-bulbar transection of the brain noted that during anesthesia the masseter reflex (just as the spinal Bexor reflex in the intact organism) is facilitated during reticular stimulation and that this effect persists virtually indefinitely for the duration of this stimulation. In the unanesthetized animal, however, the period of facilitation is very brief, but it is restored by the cooling of the cortex suggesting that cortical excitation leads to increased corticofugal inhibitory impulses which impinge upon the reticular formation. Through this action reticular excitability and reticulo-cortical discharges are reduced and excessive cortical excitation is avoided under physiological conditions. It has also been suggested that such processes contribute to the homeostasis of sensory excitation in the cerebral cortex.'" It should be added that repeated stimulation of the reticular formation leads to a progressive diminution of the excitatory effect on H.5

PSYCHOSOMATICS

the cortex and to a decrease in the galvanic reflex response, but these effects are absent when through local drug action or surgical procedures the activity of the bulbar synchronizing area is reduced or eliminated,'''' From these and similar shldies involving activation of the ergotropic system (and inhibition of the trophotropic system) through stimulation of reticular fonnation or afferent nerves it is concluded that the bulbar synchronizing area inhibits the ergotropic system and contributes thereby to cerebral homeostasis. FACI"ORS E:"HA:-':CI:-':C THE 'ru:-;ING PROCESS A:-;D THE PERSISTE;,\CE OF THESE STATES FOR LO;,\G PERIODS

:\umerous examples of ergotropic and trophotropic tuning~'·:lI\ suggest that the homeostatic processes are effective to a limited degrep only and raise the question as to thp mechanisms hv which these processes are overcome so that marked acute and chronic states of ergotropic- trophotropic imhalance result. Observations on quantitative changes of the trophotropic rebound following increasing degrees of ergotropic excitation clicited hy stimulation of the hypothalamus may serve as a guide. If the hvpothalamus is stimulated at one ergotropic site with a hrief suprathreshold stimulus. a rise in hlood pressure and heart rate will result, followed hy a trophotropic rehound. If at another ergotropic site in the hypothalamus a more prolonged but near threshold stimulus is applied, little or no ergotropic changes occur. However, if the stimuli are comhined so that the hrief suprathreshold stimulus is applied in the middle of the prolonged subthreshold stimulation period, the supra threshold stimulus fails to produce a trophotropic rebound. Apparently, the minimal ergotropic excitation through the subthreshold :stimulus counteracts the trophotropic discharge which follows the suprathreshold stimulus when applied singly. This ohservation shows that the trophotropic rebound does not occur in the presence of minimal overt ergotropic discharges and suggests that ergotropic after-discharges produced hy increasing intensity, frequency, or duration of hypothalamic stimulation counteract the homeostatically acting rebound phe96

nomenon. The correctness of this conclusion is illustrated by the fact that with increasing duration of hypothalamic stimulation (in one example from two to 15 seconds) two phases are observed: as the duration increases from two to eight seconds the trophotropic rebound increases pari passu with the magnitude of the preceding ergotropic excitation; but with stimulation periods of ten and 15 seconds thp trophotropic rebound is progressively reduced while the ergotropic afterdischarge increases. 21 Such stimuli are particularly effective in bringing about a marked shift in ergotropictrophotropic balance when they are repeatedly applied in brief intervals to the ergotropic division of the hypothalamus. 2 " They result in increasing degrees of rise in blood pressure and heart rate during stimulation (ergotropic tuning). and a progressively increasing level of the blood pressure in the interval (ergotropic afterdischarge). At the same timp the post-stimulatory trophotroj)ic rebound indicated by the fall in pulse rate diminishes or disappears with a rising level of the hlood pressure. These ohservations seem to be nhvsiological models of the mechanisms which.~ at least in part, play a role in the genesis of chronic states of ergotropic-trophotropic imbalance such as chronic hypertension ( see also reference 30). Whereas stimuli of high frequencv (100/ sec.) produce a state of ergotropic hlning those of low frequency (less than lO/sec.) and intensity activate the trophotropic system. If applied repeatedly. or for nrolonged periods, the effects persist bpvond the period of stimulation. Tbus stimulation of thp basal forehrain area for one to two min. elicits synchronization, drowsiness and. finallY, behavioral sleep13 and low frequency stimuli applied to cutaneous nerves likewisp induce cortical synchronization and sleep. Apoarently ergotropic and trophotropic afterdischarges are involved in states of ergotropic and trophotropic tuning. In animals which are spontaneouslv aroused. low frequency stimuli may be only slightly effective. However, if through repeated presentation of the same (arousing) stimuli the responsiveness to this stimulus is lessened (habituation) ,61 the low frequency stimuli beoome increasingly effective and produce sleep."n It is thought that the lessened activity Volume X

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of the ergotropic reticular formation in habituation or following low frequency stimulation of peripheral or central structures:· l releases, through reciprocal innervation, the trophotropic system and contributes thereby to the establishment of a state of trophotropic tuning. Even signs of reversal occur under these circumstances: stimuli which before habituation evoked arousal and cortical desynchronization elicit synchronization and sleep after habituation:' It should be stressed that the persistence of reciprocal relations between the ergotropic and trophotropic systems under physiological conditions facilitates the state of tuning. This was illustrated for the trophotropic system by the role of sensory habituation involving inhibition of the ergotropic system in the production of sleep. It is further illustrated by the study of proprioception. Prolonged wakefulness depends on proprioceptive activity4:; and procedures which reduce this activity lead to a diminished responsiveness of the ergotropic division of the hypothalamus and also to cortical synchronization ' " and sleep.~" In the light of these findin~s it is suggested that the active trophotronic discharges underlying sleep are facilitated hy a reduction of sensory and particularly proprioceptive impulses which tend to increase ergotropic discharges at cortical, diencephOllic. and mesencephalic levels.

STATES OF TU:\"IXG

(The spindle threshold based on the synchronized response elicited by single shocks applied to the c;ludate nucleus is one of the indicators of the excitability of the trophotropic system.) High degrees of trophotropic and ergotropic tuning lead to reversal phenomena. As mentioned earlier,~' if a state of trophotropic tuning prevails, stimuli exerting trophotropic and ergotropic effects under control conditions evoke only trophotropic actions and an ana]ogous statement applies to the state of ergotropic tuning showing reversal. Since under physiological conditions some forms of sensory stimulation act chiefly on the ergotropic and others mainly on the trophotropic system, the loss of responsiveness of one svstem in the state of reversal must further enhance the state of tuning. The abnormal character of the reversal response suggests that it is closely related to the neurotic state in which the reciprocity of ergotropic-trophotropic relations is disrupted. Pschonik's experiments:" on conditioning in man show indeed that neurotic symptoms are accompanied by ergotropic and trophotropic vasomotor effects but frequently also hy reversal reactions. The assumption that the loss of reciprocity in the reaction of the ergotropic and trophotropic systems in these and similar conditions is the result of the "spilling over" of ergotropic excitation into thl:' trophotropic system is supported by the following facts:

To gain an understanding of the sih'llificance of ergotropic- trophotropic relations in physiological and pathological conditions, it is necessarv to studv these relations at different levels of tuning. 'At low levels of stimulation it is easy to show that the increased responsiveness of the stimulated svstem is accompanied hy a lessened responsiveness of the reciprocally related antagonistic system. Both factors contrihute to the shift in ergotropictrophotropic halance. This statement applies to the behavior of the autonomic"'~O and also the somatic components of the ergotropic and trophotropic systems. To exemplify the latter, increasing degrees of ergotropi~ excitation induced hy stimulating the posterior hypothalamus or the mesencephalic portion of the reticular formation are associated with progressively rising thresholds for cortical spindles.""

1. Whereas conditioning in animals is associated with hdghtened ergotropic activity, experimental neurosis shows in addition to behavioral dishtrbances also strong trophotropic discharges. 2G • 43 Spontaneous cures of the neuroses are accompanied by the disappearance of the abnormal trophotropic symptoms. \Ioreover, henacty7ine which is a tranquilizer with strong anticholinergic effects"3 relieves experimental neurosis while at the same time, symptoms of strong trophotropic discharge ( nausea, vomiting) disappear. Since only those derivatives of benactyzine which exert central anticholinergic effects are able to restore neurotic animals 30a the data suggest that these drugs counteract the spilling over of ergotropic excitation into the trophotropic system and contribute thereby to behavioral restitution. 2. Certain amphetamine derivatives produce

PHYSIOLOCICAL \'ERSUS PATHOLOGICAL

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in man hallucinogenic effects while amphetamine causes only alerting. Quantitative EEG studies of these drugs in unanesthetized cats disclose that the hallucinogenic drugs cause, in addition to strong ergotropic effects, a synchronizing action on the cortex whereas amphetamine induces desynchronization. H It seems nqt unlikely that the differential effects on EEG and behavior are due to the fact that amphetamine activates the ergotropic system only, whereas the hallucinogenic derivatives activate the ergotropic and trophotropic systems with the latter dominant on the EEG. 3. In states of severe anxiety characterized by intensive ergotropic and trophotropic discharges,~"'~~ motor behavior' as well as the quality (and even modality) of the sensations are fundamentally altered. 29 ,"7 Clinical and experimental findings suggest that when strong excitation of the ergotropic system is followed by a sudden trophotropic rehound. the emotion subsides quickly and normal conditions arc restored in accordance with the principles discussed earlier. Prolonged intensive ergotropic excitation. however. tends to induce trophotropic excitation after the activation of the ergotropic system has surpassed a certain level. It is believed that the simultaneous bombardment of the cerebral cortex through discharges from the ergotropic and trophotropic systems accounts for the behavioral disturbances in states of anxiety .~r..z. 4. Symptoms of anxiety occur on application of electric shock at the place of feeding in rats which cannot control the electric shock. but not in those which hy jumping terminate thc shock. intensitv and duration of the latter being the same in 'hoth groups.~'·:':: The reason for these hehavioral differences is that through massive muscular action (jumping) proprioceptivc impulses which impinge upon the ergotropic system particularly at the hypothalamic level are greatly and suddenly increased.:' Thus conditions arc created which as in the hypothalamic stimulation experiments described earlier~1 favor a rebound discharge of the trophotropic system and thereby, through reciprocal innervation, an inhibition of ergotropic activity and emotional excitement. On the contrary. in the absence of such a rebound. the ergotropie excitation tends to increase even after the termination of the shock and may spill over into the er9R

gotropic system and produce anxiety. 5. Several authors""·:··.. lJo have observed that inescapable shock leads to experimental neurosis in which ergotropic arul trophotropic discharges occur~'; and massive parasympathetic discharges are prominent. Similar results were obtained on wild rats forced to swim in conditions in which neither a rest (through floating) nor an escape was possible. The animals died after relatively brief periods. The heart rate first accelerated but declined markedly later. At death there was a standstill of the heart in diastole. Cholinergic drugs aggravated, and atropine retarded these effects.'" These data and the finding of gross hypothalamic lesions at autopsy suggest that in this condition intensive trophotropic discharges are associated with states of strong ergotropic excitation and that the hypothalamic system is primarily involved. CLINICAL APPLICATIONS

Reversal phenomena. and the loss of fl'ciprocity in the activity of the ergotropic and trophotropic systems can he illustrated in neuropsychiatric disorders. In addition to the few examples given in the preceding paper.'" the following observations seem pertinent. 1. Reversal phenomena.-Phohic states may he accompanied by reversal reactions. This is indicated by the fact that positive 011(1 negative conditional stimuli produce a strong psychogalvanic reflex, 1 whereas this effect is restricted to positive conditional stimuli under control conditions. (It has been shown that positive and negative conditional stimuli activate the ergotropic and trophotropic systems respectively.~tl) These r('suIts illustrate reversal phenomena in states of ergotropic tuning. In clinical depressions, however, reversal reactions characteristic for a state of trophotropic tuning occur. The responsiveness of the ergotropic system (as measured by the psychogalvanic reflex to positive conditional stimuli) may be very weak or absent in these patients, yet such stimuli evoke an increase in the alpha potentials of the EEG, i.e., a trophotropic response ( synchronization) instead of the normal desynchronization. If a state of trophotropic tuning is characteristic for the depressions one would expect that therapeutic procedures would change the ergotropic-trophotropic balance to the ergoVolume X

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tropic side. Such shifts in balance are suggested by the influence of electroshock on vascular reactions and the psychological state. The hypotensive effect of Mecholyl is greatly reduced in patients benefiting from electroshock treatment. t'; Since similar changes in the vascular response to Mecholyl occur following procedures which enhance the excitability of the crgotropic division of the hypothalamus,t" and since repeated clectroshocks greatly increase sympathetic reflexes in animals,"" it seems probable that electroshock causes improvement in depressives by shifting the ergotropic-trophotropic balance to the ergotropic side. Changes in mood accompanying successful electroshock treatment"" suggest a similar shift in the state of tuning. As extensive work on the sedative and excitatory action of drugs'-· 9 shows the biochemical basis of these changes in crgotropic-trophotropic balance to the ergotropic side, there is an increasing level of noradrenaline in the brain.

2. Loss of reciprocal relations between ergotropic OIu1 trophotropic systems in neurotic and psychotic conditions.-Observations on neurotic patients present evidence that in states of anxiety, as in experimentally induced animal neurosis, strong trophotropic discharges ( retching, nausea, vomiting, dizziness) are combined with greatly increased tone and n>activity of the ergotropic system indicated by increased frequency of the potentials in the EEG, enhancement of muscle tone and somatic responsiveness to unspecific stimuli, and augmented excretion of 17-ketosteroids, frequently paralleling sympathetic effects on blood pressure, heart rate and sweat secretion. It is assumed that in these conditions, and also in certain psychotic states, an intensive ergotropic discharge induces the excitaHon to flow into the trophotropic system. 2 r..21 The following facts support this interpretation: a. Procedures reducing tone and responsiveness of the ergotropic system tend to eliminate abnormal trophotropic symptoms and cure anxiety. b. Carbon dioxide and amphetamine exert paradoxical effects (discussed in the preceding paper"O on the consciousness of catatonic patients). These effects are explainable by the presence of strong ergotropic and trophotropic activity indicated in this state by the Mareh-April, 1969

combination of stupor with muscular rigidity. c. The subjective and objective findings of Pschonik" 7 consist first of the establishment of a conditional vasoconstrictor reflex to a bell (reinforced by a 63°C pain stimulus) and a conditional vasodilator reflex to a tone reinforced by a 43° C warmth stimulus (these two reactions are referred to as A and B respectiveIy); then application of the two conditional stimuli in quick succession reinforced with the 63° or the 43° C stimulus. This and similar procedures induced mild neurotic symptoms, and the plethysmograms of the left and right arms showed asymmetric wave forms suggesting simultaneous vasoconstrictor aru1 vasodilator reactions. At the same time the subject reported that he perceived the stimulus as hot and not as pain or warmth and this perception (as well as the asymmetrical vasomotor reactions) appeared for sometime also in response to the standard stimuli A or B. Since the sensation of heat is due to the combined stimulation of cold (ergotropic) and warmth (trophotropic) receptors in the skin,lo it may be said that in certain forms of near neurotic states in man developed on the basis of conditional vascular reflexes, simultaneous trophotropic and ergotropic effects are demonstrable through vascular reactions and associated sensations. d. EEG studies on spontaneolls and experimentally induced delirium offer a striking evidence for the simultaneitv of ergotropic and trophotropic discharges. Ditran produces an increase in the slow (theta and delta) as well in the fast (beta) pott'ntials. The former is primarily associated with clouding of consciousness, the latter with increased psychomotor activity.41 The participation of both systems in the production of delirium is supported by the Bndings that improvement of the delirium is associated with a decline of slow and fast potentials in the EEG and "a progressive increase in the amount of alpha activity." The degree of activity of the two systems and the clinical symptomatology vary widely in different patients. Some patients show predominantly fast (beta) activity and are improved by drugs which reduce ergotropic tuning and shift the balance to the trophotropic side. In others the EEG shows chiefly slow potentials who are improved by drugs which activate the ergotroj>ic system. 99

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e. A final remark on depressions and their relation to the ergotropic-trophotropic systems may be in order. Evidence was presented that depressive states show an increased reactivity of the trophotropic system (trophotropic tuning including reversal phenomena), that at the same time, as disclosed by the Mecholyl test, the ergotropic reactivity is (reciprocally) lessened, and that procedures such as electroshock which enhance the responsiveness of the ergotropic system and thereby tend to restore the ergotropic-trophotropic balance are of therapeutic value. The observation that in some forms of depression treatment with MAO inhibitors followed by electroshock are necessarv for a successful treatment does not invol~e any theoretical difficulties and suggests that in these instances stronger mpans are necessary to counteract the state of trophotropic hming. However, there are cases of depression in which the Mecholyl test shows an increased ergotrop:c responsiveness. Such patients are not benefited by electroshock. to Since anxiety and tension~'·GG are commonly seen in depressions and anxiety involves increased reaetivity of the ergotropic Q.1ul trophotropic systems, one would expect that under these conditions a shift of the ergotropic-trophotropic balance to the ergotropic side would ag~ravate rather than alleviate the condition if the theoretical frame work presented in this paper is correct. A survey of the literahIre seems to support our thesis."" Therapeutically beneficial effects in anxiety should be accomplished by: (1) a reduction of the ergotropic tone which by itself and through the elimination of the spilling over of the excitation into the trophotropic system would abolish anxiety; and (2) a limited ergo tropic action sufficient to counteract depression without evoking symptoms of ergotropic excitation and anxiety. It is of great interest that imipramine and related compounds which have been very successful in agitated forms of depression showing anxiety and tension,"" exert these two apparently opposing effects. Imipramine reduces ergotropic activity as seen in behavioral (avoidance) and arousal reactions in a manner similar to, but of a lesser degree than chlorpromazine~s and it enhances central ergotropic actions of amphetamine disclosed in selfstimulation experiments.r.4 100

PHYSIOLOGIC METHODS TO PRODUCE A SHIFT IN TROPHOTROPIC-ERGOTROPIC BALANCE AND THEIR CLINICAL SIGNIFICANCE

From the data presented in this and the preceding paper (see also references 27, 32) it is obvious that psychotropic drugs, electroshock, insulin coma and related procedures may be used to alter the ergotropic-trophotropic balance. The specificity of these effects, however, leaves much to be desired. Thus, electroshock greatly enhances the state of ergotropic tuning but the action of the induced convulsions is not restricted to the ergotropic system. The fall in blood sugar after electroshock seen in the adrenomedullated but not in the adrenomedullated-vagotomized animal shows that the vago-insulin system is likewise activated although the effect on the ergotropic system is dominant, as indicated by the hyperglycemic effect of electroshock in the normal organism." Insulin hypoglycemia is likewise known to stimulate the vagus 37 and the syrnpathetico-adrenal system. ' " Barbihlrates which enhance trophotropic tuning" also increase adrenomedullary secretion. " The question arises, therefore, of whether more specific effects could be obtained by the use of physiological methods. The intimate interrelations existing between autonomic and somatic components of the ergotropic and trophotropic systems"6 make it certain that changes in autonomic functions produce corresponding alterations in somatic activities and vice versa. Since the somatic but not the autonomic system is subject to voluntary control, the method of choice for the quantitative alteration of the tone of the ergotropic and trophotropic systems is via the somatic component. Proprioceptive discharges are very suitable to alter the state of tuning. If they are increased, ergotropic effects are enhanced as seen in desynchronization of potentials in hypothalamus and cortex." Moreover, the reactivity of the reticular formation is enhanced as indicated by autonomic (sympathetic) indicators.' Contrariwise, reduction or elimination of these impulses by curare-like drugs reduces the sympathetic responsiveness of .the ergotropic division of the hypothalamus and produces cortical synchronization. I9 In the unanesthetized animal this cortical synchronVolume X

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ization is shown to be associated with behavioral sleep.3G Furthermore, it has been shown in man that learned muscular relaxation diminishes emotional reactivity and its autonomic-somatic expression. 3 ' On the basis of these experimental findings one would expect that states with increased muscle tone would result in states of ergotropic tuning, whereas a lessening of this tone should diminish ergotropic activity and/or lead to, or be accompanied by, a state of trophotropic tuning. The importance of muscular relaxation is gent'rally recognized for the induction of sleep and for the therapy of neurotic behavior'2characterized above as the result of excessive ergotropic tone and consequent spilling over of this excitation into the trophotropic system. In the case of neuroses it is belived that the lessening of the proprioceptive bombardment of the diencephalon through relaxation restores the physiological level of ergotropic activity and through this reciprocal relations between ergotropic and trophotropic systems. It is not improbable that the contribution of different striated muscles to the tone of the ergotropic system varies widely. There is a complete loss of tone of the neck muscles during the paradoxical phase of sleep which is associated with the greatest degrce of trophotropic tuning seen during the sleep cycle. I I This observation suggests that the selective relaxation of these muscles (through heat, etc.) may be of a special physiological and. possibly therapeutic significance. On these grounds it is expected that a state of trophotropic tuning could be alleviated by enhancing muscle tone and proprioceptive discharges. The maintenance of wakefulness in sleep deprivation through upright postme (already mentioned) exemplifies the physiological significance of this phenomenon. The influence of posture on mood illustrates its psychological importance (see reference 24 for further discussion) as expressed by Kretschmer's" statement: "Die innere Haltung ist von der AussenhaItung induzierbar und umgekehrt." (The inner attitude may be induced through the external posture, and vice versa.) To produce therapeutic effects in pathological states of trophotropic tuning one needs methods by which the crgotropic tone can be enhanced for a long period. Since exercise March-April, 1969

SYSTE~I-GELLHOR:--;

greatly increases muscular activity one might think that it would have such an effect, but even outstanding athletes do not show during rest significant differences in the excretion of noradrenaline from that found in subjects who are not athletic." There is, however, some evidence that a shift in trophotropicergotropic balance to the ergotropic side may be achieved through respiratory training. Born'" reports that by practicing deep breathing for ten to 30 minutes over several months, the respiratory frequency may decline to as Iowa value as 1.3/min. and that the vital capacity increases by 30 percent. I suggest that the increased proprioceptive discharges from the respira-tory muscles enhance ergotropic vascular activity and shift the ergotropic-trophotropic balance to the ergotropic side. Born's observation that a~thma and orthostatic hypotension are favorably influenced by this procedurc supports this interpretation, although further physiological and clinical investigations on the reactivity of the ergotropic and trophotropic systems under these circumstances are obviously needed. SUlIIMARY

Brief stimuli applied to afferent nerves or central diencephalic structures which involve a rapid rise of the excitatorv process are followed by rebound phenomena from the autonomic and somatic components of the ergotropic and trophotropic systems. In addition, special cortica-reticular mechanisms exist which prevent cxcessive or prolonged excitation of the cerebral cortex. In contrast to these processes serving homeostasis, tuning of the central nervous system occurs when the excitation leads to afterdischarges which counteract or prevent the rehound effects. Repeated stimuli leading to slowly rising forms of excitation are particularly effective. \foreover, the balance of the ergotropic-trophotropic systems has a decisive influence on the degree and also on the form (ergotropic vs trophotropic) of tuning. In states of reversal the tuning of the nervous system is enhanced. Further evidence is presented for assuming that numerous pathological processes are associated with simultaneous activation of the ergotropic and trophotropic systems whereas under physiological conditions reo ciprocal relations prevail. Thus inescapable 101

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shock which leads to experimental neurosis is accompanied by massive parasympathetic discharges (in addition to a strong activation of the ergotropic system) and the lethal effects of prolonged forced swimming may be accelerated by cholinergic drugs. The fact that the therapeutic action of benactyzine and derivatives in curing experimental neurosis is restricted to those drugs which exert a central anticholinergic action is likewise compatihle with the hypothesis that strong ergotropic discharges invadl~ thc trophotropic system and that this loss of reciprocity is relatcd to the ahnormal hchavior secn undcr these conditions. The disappearance of ahnonnal parasympathetic symptoms is secn in cxperimt'ntal and also in clinical neurosis if procedures reducing tone and responsiveness of the ergotropic systcm are applied is in accord with this interpretation. The sensory responses to lmconditiOlnl tcmperature stimuli which elicit pain or warmth under control conditions are fundamentallv altered when in ncar-neurotic conditions tIle principle of reciprocity breaks down. This physiological experiment suggests a mechanism which may play a rok in the causation of pathological sensations. An attempt is made to interpret the action of imipramine in depression and the mechanism underlying delirium on the basis of the theoretical concepts presented in this paper. Electroshock, insulin coma, and certain drugs used in clinical practice tend to act on the ergotropic mul trophotropic systems although the action on the former dominates. Physiological procedures seem more specific. The therapeutic action of the relaxation therapy of Jacobson and others seems to be due to a lesscning of excessing ergotropic activity at the hypothalamic level as the result of a diminution of proprioceptive discharges. On the other hand, an increase in ergotropic tone counteracting a state of trophotropic tuning, or restoring ergotropic activity to the nonn from low levels seems to result from training in progressively increased slow breathing ( Born). The therapeutic effect of this procedure in trophotropic states such as asthma, and in conditions of subnormal ergotropic tone (as in orthostatic hypotension), supports this int(>rpretation, but more clinical and 102

physiological work is necessary to substantiate it. REFERE:-:CES

1. Alexander, L.: Effects of psychotropic drugs on conditional responses in man, (in) Rothlin, E., ed., NeIlTO-Psycho/llwmUlco[Dgy. Elsevier, Amsterdam, 2:93-123, 1961. 2. Aston, R., and Hibheln, 1'.: Induced hypersensitivity to barbital in the female rat. Science, 147: 1463-1464, 1967. 3. Barnett, S. A.: A Stu
Tlf:-.lI;\C OF THE CE:\TRAL NERVOUS SYSTE\I-GELLHOR:\ 21. (;dlhorn, E.: On successive autonomic induction of the parasympathetic system. Arch. Internal. Physiol. flterol., 7:607-614, 1946. 37a. Holten, C. H., and Sonne, E.: Action of a series of henactyzine-derivatives and other compounds on stress-induced behaviour in the rat. Acta Plwrmacol., 11: 148-155, 1955. 38. Holtz, P., and Westermann, E.: "Psychic energizers and antidepressant drugs," (in) Root, \Y. S., and Hofmann, F. G., eds., Physiological Plwmwcology. New York: Academic Press, 2: 201-236, 1965. 39. Hugelin, A., and Bonvallet, :\1.: Tonus cortical et controle de la facilitation motrice d'origine :\Iarch-April, 1969

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55. 56.

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chlorpromazine, reserpine and amphetamine on seU-stimulation: possible neurophysiological basis of depression. Recent Advances in Biol. Psychiat., 4:288-308, 1962. 65. Tokizane, T., Kawakami, ~I., and Gellhorn, E.: On the relation between the activating and the recruiting systems. Arch. Interned. Physiol. BiDchern., 65:415-432, 1957. 66. Whatmore, G. B., and Kohli, D. R.: Dysponesis: a neurophysiologic factor in functional disorders. Behavioral Science, 13: 102-124, 1968. 2 Fellowship Circle Santa Barbara, California 93105

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Announcement :\. new medical society has been formed for the purpose of interesting more physiciaus in the prohlems of alcoholism and other addictive disorders. It is known as 'The American Medical Society on Alcoholism, Ine.," and is an outgrowth of the :'IIew York :l.1l'dical Society on alcoholism, which has heen in existencc for about 15 years. The purpose of the Society is to serve as a meeting ground for physicians interested in the problems of alcoholism and other addictive disorders, to extend knowledge in these fields, to promote dissemination of that knowledge, and to enlighten and direct public opinion in regard to these prohlems. The membership is limited to physicians. The organization is divided into geographical areas, using the nine zones of the country used by the Department of Health, Education, and Welfare. Each zone will have its own leaders, hut there will he an annual meding of all members of the organization with the national officers and executive board. The head of each zone will direct the activities of that zone, and will be invitl'd to alleud thc medin!-:s of th., executive board of the sodety. The eommilll'CS of this organization include: hospitals, public relations, regional affairs, membership, industry, inter-agency cooperation, research, program, education, health plans, medical legal a(fairs, publications, and clergy liaison. Other committees will be appointed as ne"lkd. :"o:ational officl'fs include: President, Ruth Fox, ~I.D.; Vice President, :l.larvin A. Block, :\I.D.; Trl'asurer, Percy E. Rybl'rg, \I.D.; and Seeretary, Frank A. Seixas, :\I.D. Applications for memhership should he addressed to the American \Iedical SOdety on Alcoholism, Inc.: Ruth Fox, \I.D., President, 150 East 52nd Street, New York, N. Y. 10022; or \Iarvin A. Block, \I.D., 371 Linwood Avenue, Buffalo, N. Y. 14209. A regional ml'ding will 1)(' held in Forth Worth, Texas, on \Ionday, April 14, W69. Details of this meding will he sent to meml)('rs shortly. All physicians interested in alcoholism, drug dqlt'ndence, alltl other addictive disonl.'rs, are urged to hl'come members of the American \Icdical Society on Alcoholism, Inc.

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Volume X