On the role of subthalamic areas in the maintenance of brain-stem reticular excitability

EXPERIMENTAI.

NEUROLOGY

1,

407-426 (1959)

On the Role of Subthalamic Areas in the Maintenance of Brain-Stem Reticular Excitability W. Ross ADEY AND DAVID F. LINDSLEY~ Departments

CaZiforniu,

of Anatomy and Veterans

ati Physiology, Administration

University Hospitals,

of California,

Long

Beach

Los Angeles, and Sawtelle,

California Received

June

16, 1959

The responsiveness of midbrain tegmental zones constituting the reticular formation to various sensory inputs has long been recognized. The influence of cortical and subcortical influxes on the excitability of these reticular zones is less clear. The influence of various diencephalic areas, and particularly of the subthalamic region, on midbrain responses to peripheral volleys has been tested here in cat and monkey. In animals with chronic subthalamic lesions, spontaneous unit firing and unit responsiveness to peripheral stimuli in dorsal tegmental zones of the rostra1 midbrain were much reduced. In acute experiments, bilateral subthalamic coagulation was followed by marked reduction in the amplitude of the midbrain reticular responses to sciatic stimulation. Brief tetanization of the midbrain recording site restored the responses to their original amplitude, but they then decayed in a fashion resembling declining post-tetanic potentiation. Behavior changes in cat and monkey following these lesions included altered feeding habits, “catatonic” postures, reduced spontaneous movement, and a failure to make avoidance responses in previously trained animals. It is concluded that the subthalamic areas may exercise a tonic excitatory influence on midbrain reticular neurons, which may not be inherently available to peripheral influxes in the absence of this tonic excitation. Evidence is also presented for a phasic inhibitory subthalamic influence occurring briefly after a peripheral influx, and which is lost following subthalamic lesions. The possible relationship of these findings to mechanisms of sleep and wakefulness is discussed. Introduction

The concept of an ascending reticular system, extending through the medulla and midbrain to intralaminar nuclei of the thalamus, by collaterals of more laterally situated lemniscal pathways,

and activated has been ad-

1 This work was assisted by Grants B-1183, B-610, and B-611 from the National Institutes of Health, United States Public Health Service, and by a grant from the Parkinson Disease Foundation. 401

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vanced by Moruzzi and Magoun (32), and suggested to provide the basis for mechanisms of sleep, wakefulness, and arousal. These studies, and those stemming from them, have been the subject of a number of recent reviews and symposia (7, 27, 37, 40). Attention has been directed to both ascending and descending fluxes through this central core, with evidence that widespread corticifugal influences are exerted at thalamic and mesencephalic levels (21, 23)) and that these descending influences may considerably modify ascending reticular conduction (6). More recently we have directed attention to effects exerted on neural units in the dorsal tegmentum and periaqueductal gray matter of the rostra1 midbrain, by descending volleys from rhinencephalic cortex, including the amygdala and entorhinal area, and from the basal ganglia. These studies have indicated that certain inhibitory effects can be induced in firing patterns of these reticular units by descending pallidal and amygdaloid volleys, including the induction of rhythmic firing patterns during repetitive trains of paired amygdaloid-sciatic and pallidal-sciatic volleys (1, 2, 3). Many of these descending rhinencephalic and basal ganglionic influences appear to run in ventral thalamic and dorsal hypothalamic areas towards the midbrain (4, 5). For this reason, it has been the purpose of the present study to test the effects of acute and chronic lesions in the subthalamic. area on reticular excitability at the rostra1 midbrain level. Certain behavior changes following these lesions will be briefly described, and presented in detail elsewhere. Material

and

Methods

Eighteen cats and 11 monkeys have been used. In acute experiments, all surgical maneuvers have been conducted under ether anesthesia and the animals subsequently immobilized with Flaxedil. No recordings were taken for at least 2 hours after the conclusion of ether anesthesia. The arrangement of recording amplifiers for use with both coaxial electrodes and stainless steel microelectrodes has been described elsewhere (3). Electrolytic lesions in the subthalamic area were prepared by anodal polarization of a monopolar eIectrode, bared approximately 1.0 mm at the tip, with a current of 2.0 to 3.0 ma passed for 1 to 2 minutes. A remote cathodal connection was provided on the scalp or muscles of the neck. Altered feeding habits in chronic animals with these lesions necessitated considerable postoperative care, but all were in good condition at the time

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of terminal explorations of the rostra1 midbrain tegmentum 6 to 8 weeks after operation. In all experiments, the extent of the lesions and the disposition of electrode tracks have been determined histologically, in frozen sections stained by the Nissl method. Results

The disposition of the coagulating electrodes and the magnitude of the coagulating current was approximately the samein all experiments in the cat, but the size of the lesion varied in each case. In all cases,the lesion involved the subthalamic nucleus, but extended beyond it to involve the dorsal hypothalamus and the zona incerta. In some instances, the adjoining parts of the centralis medialis thalami and of the nucleusreuniens were also involved (Fig. 1). Histologic studies have confirmed that a distance of approximately 5 mm separated the margin of the lesion from the midbrain recording site. MICROELECTRODE

STUDIES

Our initial observations on the effects of lesionsin the subthalamic area were made in cats with chronic lesions (Fig. 1) , using stainlesssteel microelectrodes inserted in vertical paramedian tracks at the rostra1 midbrain level. Certain basic differences were immediately noted in the pattern of unit activity recorded in dorsal tegmental areas, as compared with the findings in normal animals (3). In progressivepenetration of the rostra1 midbrain (Horsley-Clarke plane A4) in normal animals, at distancesof 1 to 2 mm from the mid-line, entry into the optic tectum was signalled by a great deal of unitary activity, with many units firing at high speed and essentially uninfluenced by sciatic nerve stimulation. Many of these tectal units gave typical “on” and ‘Luff” effects when a light was shone in the eyes. As the recording microtip passedfrom tectum to periaqueductal gray and adjacent dorsal tegmentum, optic responseswere lost, but many spontaneously active units were observed here which responded to repetitive sciatic stimulation at 1 to 10 per secondwith a sharp increase in firing rate. Indeed, such units appeared more numerous here than in more ventral zones of the tegmentum, including the red nucleus. Increased firing rates induced by repetitive sciatic stimulation were tonically maintained and did not reflect the rhythmic nature of the stimulus. By contrast, progressive penetration of the midbrain of the operated animals failed to show normal numbers of spontaneously active units in

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FZ G. 1. Examples of typical chronic subthalamic be st:en that in each case the lesion also involves thala rmic areas.

lesions in 3 different ventral thalamic and

cats. dorsal

It will h) rpo-

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the periaqueductal gray and dorsal tegmentum. All these animals exhibited the norlpal tectal activity, both in spontaneous activity and in units responding to light. However, this activity diminished sharply as the microtip passed into the periaqueductal gray and dorsal tegmentum. In the dorsal tegmentum, a relatively small number of units were evoked into activity by sciatic stim&ation, but typically these units responded in a phasic fashion to each stimulus of a repetitive train at rates up to 5 per second (Fig. 2). NORMAL

t CHRONIC

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FIG. 2. A comparison of typical midbrain tegmental unit behavior in normal cats and those with chronic bilateral subthalamic lesions. Intact animals show many spontaneously firing units which show a tonic rise in firing rate cn peripheral stimulation (upper traces, A and B). After lesions, the number of spontaneously firing units is reduced, and on peripheral stimulation, units are either evoked briefly into phasic activity (lower trace, A) or are unresponsive (lower trace, B). A, 3 per second, and B, 5 per second sciatic stimulation (7 volts, 1 msec duration) ; vertical calibration, 100 WV; horizontal calibration, 100 msec.

Since obviously a statistical survey of unit behavior at various depths in the rostra1 midbrain is virtually impossible, these observations were repeated using coaxial recording electrodes, in the hope that wave responsesso recorded might afford supporting evidence for the behavior of individual units seenafter subthalamic lesions.

412

ADEY AND LINDSLEY RECORDS OBTAINED

WITH COAXIAL ELECTRODES

Effects of Subtha2;amicLesions on Midbrain Responsesin A&e Experime%ts. In control records prior to coagulation (Fig. 3), midbrain tegSCIATIC STIMULATION

TIME

REPEAT AFTER TETANIZATION: C

c

ME

c ME3

c

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MB

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FIG. 3. Control from sensorimotor Stimuli delivered

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6.0 records prior to subthalamic coagulation. Top trace in each record cortex (C) and lower from dorsal midbrain tegmentum (MB). every 30 set to contralateral sciatic nerve (5.0 volts, 1.0 msec) .

Right hand series of traces shows effects of brief tetanization at midbrain recording site (40 per second, 0.25 msec, 6.0 volts for 3 set), with evidence of potentiation of late polyphasic components of midbrain responses. Time is in minutes.

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mental and sensory cortical responses were simultaneously recorded to stimulation of the contralateral sciatic nerve every 30 seconds. The bi- or triphasic midbrain response was recorded at the same site as used in microelectrode experiments, viz., in the dorsal tegmentum 1 to 2 mm from the mid-line ventrolateral to the periaqueductal gray matter. Its latency was 20 to 25 msec. Tetanization of the midbrain recording site for a short period (40 per second, 0.25 msec, 6.0 volts for 3 set) did not significantly modify the cortical response to the sciatic stimulus, but was followed by augmentation of the late polyphasic components of the midbrain response (Fig. 3). Coagulation of the subthalamic area on the same side as the midbrain recording electrode produced no major change in the size of the midbrain response, although there was a temporary flattening of the cortical record, and reduction in amplitude of the evoked cortical response (Fig. 4). Following bilateral coagulation in the subthalamic area, however, the midbrain response was reduced to a small fraction of its original size. The large primary deflection was virtually eliminated, and was replaced by a series of small, rapid, polyphasic deflections (Fig. 4). Efects of Midbrain T.etanization Following Bilateral Subthalamic Coagulation. It was found possible to restore the primary deflection of the midbrain response to essentially its original size and configuration by a brief tetanic stimulation at the recording site (Fig. 5). Stimulation with square wave pulses (duration 0.5 msec, amplitude 9.0 volts) at 40 per second for 3 set produced a long lasting restoration of the primary response, which gradually decayed over a period of 10 to 15 minutes to the level seen after bilateral coagulation (Fig. 4). This phenomenon of potentiation and decay was repeatable, and the time course of the decay closely resembled that of a waning posttetanic potentiation (22). It was also noted that, despite the major changes induced in the midbrain response to sciatic stimulation by the subthalamic lesions, the sensorimotor cortical record showed normal waxing and waning of rhythmic activity, without evidence of high voltage spindle activity, such as is seen following midbrain tegmental lesions or in c,erveau iso2k preparations ( 15). Moreover, brief tetanic stimulation of the dorsal midbrain tegmentum after a bilateral subthalamic coagulation was followed by the normal “arousal” response in the sensorimotor cortical record, with low voltage activity replacing the rhythmic resting record (Fig. 6). Midbrain T#egmental Responses to Paired Sciatic Shocks Following Uni-

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STIMULATION

C

C I I.0

MB

MB

C

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Frc. 4. Same experiment as in Fig. 3. Responses in midbrain after unilateral subthalamic coagulation (left hand column) were relatively little altered. Bilateral coagulation (right hand column) produced a major decrease in the midbrain response. Time in minutes; C, cortex, MB, midbrain.

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heral and Bilateral Subthaabmic Coagubth. These results are summarized in Fig. 7. Paired sciatic stimuli (4.0 volts, 1.0 msec) were delivered once every 30 set at decreasing shock spacings from 300 to 50 msec. At each shock spacing approximately ten responses were recorded, and the mean amplitude of the first and second responses in the dorsal tegmentum of the rostra1 midbrain determined. It will be seen that unilateral subthalamic coagulation had relatively little effect on the amplitude of the first response of each pair, whereas bilateral coagulation reduced the amplitude of the first response to about 50 per cent of its initial size. SCIATIC STIMULATION CORTEX

MIDBRAIN

MB

.C

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MB C 8.5 MB

C IO.0 MB

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IIOOYV

FIG. 5. Same experiment as in FGd 4. Effects of brief tetanic burst (0.5 msec square waves, 9.0 volts amplitude, 40 per second for 3 set) on midbrain responses, which were potentiated to almost control amplitude and then decayed gradually over lo-15 minutes, Stimuli delivered once every 30 sec. Time in minutes.

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It may be remarked here that in this case the recording electrode was the dorsal tegmentum about 2.5 mm from the mid-line, more latera placed than in the experiment of Figs. 3 to 5, and that in this case residual response following bilateral coagulation was larger than at m medially placed recording sites. The maximum influence of bilateral s

STIM.

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FIG. 6. Sensorimotor cortex: after stimulus in the midbrain tegmentum cortical records.

bilateral subthalamic coagulation, a brief teta still produced a typical “arousal” response

thalamic lesions appeared to be exerted on paramedian zones of the do tegmentum and in the adjacent periaqueductal gray matter. Graphic representation (Fig. 8) of the effects in acute experiments the subthalamic coagulation on recovery cycles of the tegmental respon indicated that, whereas relatively little change was induced by unilate coagulation, major alterations appeared after the lesion was made bilate The graph in Fig. 8 clearly shows that the difference in amplitude betwe first and second responses to the paired stimuli was less following bilateral lesion than in control records. The second response had recove to the full amplitude of the first response at spacings around 150 m after bilateral coagulation, whereas in control records, and after unilate coagulation, there was a discernible difference between first and sec response amplitudes at spacings as long as 300 msec. It will also be obvious from inspection of the oscilloscopic records Fig. 7 that after bilateral coagulation the amplitude of the first midbra response was reduced to approximately half that in control records. Th would thus appear to be two separate aspects to influences exerted fluxes through the subthalamic area on reticular excitability in the ros midbrain. The reduction in amplitude of the first response to the pai stimuli after a bilateral subthalamic lesion appeared to indicate the

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of a tonic facilitatory influence. However, the more rapid recovery of the second response of the pair to the size of the first after bilateral subthalamic coagulation suggested the removal of an additional phasic inhibitory influence (or at least the removal of a brief phase of depressed excitability) in the first 1.50 to 300 msec following the first response. Related evidence from other workers will be discussed below. BEFORE

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FIG. 7. Dorsal tegmental response: Paired sciatic stimuli delivered at decreasing spacings from 300 to 50 msec in control records (left column), after unilateral subthalamic coagulation (middle column), and after bilateral coagulation (right column). Vertical calibration, SO pv; arrows indicate stimuli.

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Effects of DiencCephulic Lesions Outside the Subthalamus on Midbrain Responses in Acut.e Experiments. A series of acute experiments in which bilateral diencephalic lesions were made outside the subthalamus was not accompanied by the marked changes in midbrain responses to sciatic

g

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MSEC DELAY BETWEEN PAIRED SHOCKS FIG. 8. The difference in absolute amplitude between first and second responses in Fig. 7 is graphed. The response recovery cycle, and the absolute magnitude were little affected by unilateral coagulation. After bilateral coagulation, the response recovery cycle was shortened, as well as showing a marked decrease in absolute response amplitude.

stimulation seen after lesions in the subthalamus (Fig. 9). Lesions in the preoptic and supraoptic areas and in the basal septum were without effect. Hypothalamic lesions at the level of the median eminence likewise produced no change. Large thalamic lesions involving medial and dorsal nuclei were less effective in modifying midbrain responses than lesions in the subthalamus. Thalamic lesions confined to dorsal areas were usually without effect, but where the lesion extended ventrally toward junctional zones between thalamus and hypothalamus, reduction in midbrain responses occurred. It was found that where bilateral thalamic lesions reduced the amplitude

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FIG. 9. Results of a representative series of control experiments, with diencephalic lesions placed outside the subthalamus (see text). Control responses are shown on the left, and those following bilateral coagulation on the right. Little effect followed lesions in the preoptic, A (A 15.5) ; basal septal, B (A 15.0) ; or dorsal thalamic regions, D (A 9.0). Lesions in ventral medial thalamus and dorsal hypothalamus but anterior to the subthalamic areas, C (A 12.0)) produced effects resembling subthalamic lesions. Vertical calibrations, 50 WV; horizontal calibrations, 50 msec; arrows indicate stimulus; abbreviations: c, cortex; cr, contralateral reticular formation; ir, ipsilateral reticular formation; s, subthalamus; r, reticular formation.

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of the midbrain responses, subsequent brief tetanization of the subthalamus produced a prolonged restoration of the midbrain reticular response toward its original level (Fig. IO). A

El

CONTROL

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AFTER SUBTHALAMIC TETANIZATION

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FIG. 10. In an animal with a thalamic and hypothalamic lesion anterior to subthalamic areas (lesion C of Fig. 9), subthalamic tetanization (30 per second, 60 volts, 0.5 msec, 4 set) restored the midbrain reticular response towards the level of the control response. Upper trace, subthalamus ; middle trace, reticular formation ; lower trace, cortex. Vertical calibration, SO pv; horizontal calibration, 50 msec; arrows indicate stimulus. BEHAVIOR

CHANGES

FOLLOWING

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LESIONS

These will be described in detail elsewhere,but since they seemto bear importantly on the general problem of reticular functions, will be outlined briefly here. Immediately following operation, both cats and monkeys displayed an inability to feed spontaneously, although they would eat food placed in their mouths, often with considerable vigor. This condition persisted in some cats throughout the survival period, but in the monkeys tended to regressafter 2 to 3 weeks. Spontaneous movements were reduced, and although there was no physical incapacity, the cage door could be left open without the operated monkeys attempting to escape. Escape behavior tended to return after 6 to 8 weeks,but was slower than in normal animals. With the diminished spontaneous movements, both cats and monkeys displayed bizarre postures and would rest as though they had stopped in a half-completed movement. Monkeys trained in a simple avoidance procedure to a visual stimulus showed greatly impaired performance postoperatively, and in many tests failed to make even an escape response. Improvement occurred over a period of 10 weeks postoperatively, but an abnormally high proportion of escaperather than avoidance responsespersisted in their test performance.

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Discussion

Classical concepts of activation of the central reticular areas of the brain stem by collaterals of the main lemniscal pathways have been extensively reviewed elsewhere(7, 16, 27, 37, 40). It has becomeapparent that the initial concepts of convergence of all sensory inputs on single neurons of the reticular system may require reappraisal (39), and that ascending conduction within the reticular areas is mediated not only by slow, multisynaptic connections but also through direct, more rapidly conducting neurons. The latter may arise from cell stations in the caudal reticular areasand run with little interruption to the intralaminar nuclear groupings of the thalamus (6, 12, 38). Additionally, evidence has grown concerning afferent activity ultimately influencing cortical excitability, with the production of the typical pattern of “cortical arousal” in the EEG record, by pathways which run, at least in part, an extrathalamic course (33, 34). Morison (29) has drawn attention to the possibility that ascendingimpulsesin the brain stem subserving arousal may follow the sameextrathalamic course as those producing long latency secondary sensory responses. In their experiments, subthalamic stimulation of animals under very deep Nembutal anesthesiaproduced a very prolonged arousal, with an almost convulsive type of electrical record. Behaviorally, these animals passed from unconsciousnesswith deep respiratory depressionto a state of extreme motor activity (20). Our results presentedhere suggestfurther that this subthalamic stimulation may have directly influenced the excitability of more caudally situated reticular neurons. The size of lesionsin the subthalamic area appearsto critically influence the resulting changesin habitus and behavioral patterns. With lesionsappreciably smaller than those in the present study, Carpenter, Whittier, and Mettler (18) induced tremor at rest in monkeys with lesions caudal to the subthalamus, involving the brachium conjunctivum, medial lemniscus, and rubrothalamic radiations. More recently, Carpenter and Brittin ( 17) have reported hyperkinesia in monkeys following subthalamic lesions, but mentioned that maintenance of this hyperkinesia appeared related to the degree of preservation of structures surrounding the subthalamic nucleus, including the ansa lenticularis and globus pallidus. The striking reduction in spontaneousmovement seen in both cat and monkey in our experiments with larger lesionsthan those employed by Carpenter and his associates,but still located maximally in subthalamic structures, would

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appear consistent with the view that the degree of involvement of adjacent structures may determine the final picture. Histologic examination in our animals has indicated a clear separation of 5 mm between the caudal limits of the lesion and the recording site in the midbrain. Equally important is the temporal factor of progressive change, usually towards recovery, occurring in the weeks following infliction of any subcortical lesion (14). For this reason, chronic preparations have been used as far as possible in the present study. Batsel and Gauch (11) have reported that whereas the acutely isolated cerebrum (prepontine section) exhibits slow waves and “sleep spindles” as did the original Bremer preparation, chronic preparations showeda fast, low-voltage electrocorticogram similar to the normal wakinggattern, thus differing from the findings of Bonvallet, Hugelin, and Dell (13) in that acute preparations were uniformly unresponsive to adrenaline, whereas chronic preparations were always activated. Altered feeding habits and absenceof appropriate behavioral responses in both cats and monkeys characterized our chronic preparations, even though the animals seemedalert. Lateral hypothalamic lesions have produced fasting to death in cats (8, 9)) and localized subthalamic lesionsat the level of the median eminence have produced aphagia and adipsia in rats (30, 31). Destruction of any subcortical region is an essentially crude procedure if the prime purpose of the lesion is to elucidate the intrinsic role of that particular area. Such lesions can do little to elucidate the relative significance of influences arising inherently in that region, and those which result from fluxes of activity carried by fibers which may terminate in the lesioned area, or by fibers which may be merely in passagethrough the area. In addition to the evidence already cited of ascending influences mediating arousal which may passthrough the subthalamus, there is evidence for a variety of corticifugal influences running caudally through the ventral thalamic areas, the mid-line nuclei of the reuniens system and the adjacent zonesof the dorsal hypothalamus. In particular, these diencephalic zones appear to have major links with rhinencephalic areas (4, 19, 36). It is also through these diencephalic areas that numerous interconnections arise with the basal ganglia. Hugelin and Bonvallet (24, 25, 26) have drawn attention to corticifugal influences inhibitory to a monosynaptic trigeminal motor reflex, which they have detected in edphale isalk prepa-

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rations, These inhibitory influences run through the lateral hypothalamus to enter the dorsal, posterior diencephalic tegmentum. They pass ventral to the thalamus and dorsal to a tegmental region yielding a cortical response and facilitation of motoneuron excitability when stimulated. From their account, these inhibitory and facilitatory zones overlap extensively. In our experiments, examination of unit behavior in the dorsal midbrain tegmentum in animals with chronic subthalamic lesions has shown only a reduced unit excitability to peripheral stimulation. Examination of wave responses in acute experiments has suggested, however, that the subthalamic influence may be more subtle, since subthalamic destruction appears to be associated with the loss of both a tonic facilitatory influence, and also with the disappearance of a much briefer phasic inhibitory process occurring in association with the second of closely spaced paired responses. It would appear from these experiments that aspects of both facilitation and depression of ascending reticular conduction are lost following interference in the subthalamic area. The results presented here suggest that reticular neurons in the rostra1 midbrain may not be inherently excitable by peripheral volleys entering the reticular formation in collaterals of axons of the primary sensory pathways, but rather, that certain tonic descending influences, arising in the caudal diencephalon, and particularly in the subthalamus, may determine their availability to respond to various ascending volleys. In this connection, the findings of Batini and his colleagues (IO) are of particular interest, since they suggest that the synchronized EEG following rostra1 pontine or mesencephalic section results from critical injury to a small area in the rostra1 pons. Previous work from the same laboratory had implicated the trigeminal influx as essential to the maintenance of the “aroused” desynchronized EEG (35). While the precise role of the trigeminal inflow may need re-examination, the present study and those of Batini and associates suggest that states of sleep and wakefulness may depend on the interplay at the midbrain level of tonic influences descending from more rostra1 diencephalic levels with ‘Ca synchronizing, or possibly sleep-inducing, influence exerted by some structure in the caudal brain stem.” References 1.

ADEY, W. R., The organization tion of the Brain.” Boston,

of the rhinencephalon. Little, Brown, 1958

In “The Reticular (ref. pp. 621-644).

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ADEY, W. R., and W. A. BUCHWALD, Amygdaloid and pallidal influences on midbrain reticular units responding to sciatic nerve stimulation. Physiologist 1: pt. 4, l-2, 1958. ADEY, W. R., N. A. BUCHWALD, and D. F. LINDSLEY, Amygdaloid, pallidal and peripheral influences on mesencephalic unit firing patterns with reference to mechanisms of tremor. Electroencephulography, Montreal (in press). ADEY, W. R., C. W. DUNLOP, and S. SUNDERLAND, A survey of interrelations of the rhinencephalon with the brainstem. J. Camp. Neur. 110: 173-204, 1958. ADEY, W. R., A. F. RUDOLPH, I. HINE, and N. J. HAMITT, Glees staining of the monkey hypothalamus; a critical appraisal in normal and experimental material. J. Anat., Lond. 92: 219-235, 1958. ADEY, W. R., J. P. SEGUNDO, and R. B. LIVINGSTON, Corticifugal intluences on intrinsic brain stem conduction in cat and monkey. J. Neurophysiol. 20: I-16, 1957.

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ADRIAN, E. D., F. BREMER, and H. H. JASPER (ed.), “Brain Mechanisms and Consciousness.” Oxford, Blackwell, 556 pp., 1954. ANAND, B. K., and J. R. BROBECK, Localization of a “feeding center” in the hypothalamus of the rat. Proc. Sot. Exp. Biol., N. Y. 77: 323-324, 1951. ANAND, B. K., and J. R. BROBECX, Hypothalamic control of food intake in rats and cats. Yale J. Biol. 24: 123-140, 1951. BATINI, C., G. MORUZZI, M. PALESTINI, G. F. ROSSI, and A. ZANCHETTI, Persistent patterns cf wakefulness in the pretrigeminal midpontine se&m. Science 128:

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BATSEL, H. L., and R. R. GAUCH, Synchronization and desynchronization in the chronic cerveau isolC of the dog. Physiologist 1: pt. 4, 4, 19.58. BERRY, C. M., F. D. ANDERSON, and D. C. BROOKS, Ascending pathways of the trigeminal nerve in cat. J. Neurophysiol. 19: 144-153, 1956. BONVALLET, M., A. HUGELIN, and P. DELL, Sensibilitb cornparke du systkme reticult activiteur ascendant et du centre respiratoire aux gaz du sang et & l’adrenaline. J. physiol., Par. 47: 651-663, 1955. BRADY, J. V., and W. J. H. NAUTA, Subcortical mechanisms in emotional behavior: the duration of affective changes following septal and habenular lesions in the albino rat. J. Camp. Physiol. Psycho!. 48: 412-20, 1955. BREMER, F., Cerveau isole et physiologie du sommeil, C. YeEd. sot. biol., Paris 118: 1235-42, 1935. BRODAL, A., “The Reticular Formation of the Brain Stem.” Edinburgh, Oliver and Boyd, 87 pp., 1956. CARPENTER, M. B., and M. B. BRITTIN, Subthalamic hyperkinesia in rhesus monkey. Effects cf secondary lesions in red nucleus and brachium conjunctivum. J. Neurophysiol. 21: 400-413, 1958. CARPENTER, M. B., J. R. WHITTIER, and F. A. METTLER, Tremor in the rhesus monkey produced by diencephaiic lesions and studied by a graphic method. J. Comp. New. 93: l-12, 1950. CARRERAS, M., G. MACCHI, and F. ANGELERI, Ricer&e sulle connesioni talamocorticali. ~0 Sulle projezioni dei nuclei della linea mediana ed intralaminari, Arch. ital. anat. 60: 413-440, 1955.

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20. DEMPSEY, E. W., R. S. MORISON, and B. R. MORISON, Some afferent diencephalic pathways related to cortical potentials in the cat. Am. J. Physiol. 131: 71% 731, 1941. 21.

FRENCH,

J. D.,

R. HERNANDEZ-PEON,

cortex to cephalic brainstem

18: 74-95,1955. R., “Receptors and 1955 (ref. pp. 108-110). HANBERY, J., and H. JASPER,

and

(reticular

R.

B. LIVINGSTON,

formation)

Projections J.

in monkey.

from Neuro-

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