Effect of metrazol on cortical and subcortical evoked potentials

E F F E C T OF M E T R A Z O L O N C O R T I C A L A N D EVOKED POTENTIALS

SUBCORTICAL

TERUO O K U M A , M . D . ~

Department of Anatomy, University of California at Los Angeles School of Medicine and Veterans Administration Hospital, Long Beach, Calif. (Received for publication: October 1, 1959

Since the advent of Metrazol t h e r a p y of the nmjor psychoses there have been m a n y reports on the effects of pentamethylenetetrazol (SIetrazol) on the central nervous system. The recent development of Metrazol and photo-3Ietrazol activation of E E G a b n o r m a l i t y as well as the habitual seizure ill epileptics and other neurological patients has f u r t h e r stimulated s t u d y in this field (Cure et at. 1948; Gastaut 1950; Ajmone Marsan and Ralston 1957). Subsequent studies on the electrical activits" of the brain in experimental seizm'es induced by Metrazol alone or subconvulsive doses of Metrazol combined with repetitive sensory stimulation have been reported by several authors and interest has been focussed upon the site of action of 5Ietrazol as well as upon the mechanism of irradiation of seizure discharge f r o m specific loci to other p a r t s of the brain ( G a s t a u t and H u n t e r 1950; Dell el al. 1951; Starzl el al. 1953; H u n t e r and l n g v a r 1955). More recently White, Eidelberg and F r e n c h (1960) found t h a t direct cortical response of monkeys was tremendously increased in amplitude by Metrazol suggesting the participation of the cortical dendrites in the development of a generalized seizure. In the present s t u d y the author has explored the action of slow intravenous injection of Metrazol u p o n cortical and snbcortical responses evoked b y sciatic stimulation as well as u p o n the b a c k g r o u n d electric activity of the brain of eats, to get f u r t h e r information on the neural mechanisms u n d e r l y i n g epileptic seizures. 1 Department of Neuropsyehiatry, University of Tokyo, Japan. Present Address: Department of l°sychiatry, Massachusetts General Hospital, Boston, Mass., U.S.A.

M A T E R I A L S AND METHODS

The experiments were p e r f o r m e d on 25 adult cats of 3 to 4.5 kg. body weight. A tracheal cannula was placed and each animal was fixed in a stcreotaxic f r a m e while u n d e r ether anesthesia, pressure points and exposure margins being anesthetized by procainization. A eraniectomy was made to expose appropriate cortical areas for placing the cortical and subeortical electrodes. Following this initial s u r g e r y the animal was inunobilized with Flaxedil (R) and maintained on arlificial respiration. The sciatic nerw, on one side was dissected and divided and stimuli were applied to it by means of a pair of silver wire electrodes separated by 2 ram. R e c t a n g u l a r pulses (0.01 to 0.05 msec., 4 to 10 V.) were delivered once every 5 sec. from a Grass stimulator with an isolation unit. The electrical activity of the cortex was recorded f r o m silver ball electrodes. Concentric needle electrodes were used for recording f r o m subcortical structures. The b a c k g I o n n d electric activity obtained through all these leads was recorded on a Grass I I I - D 8-channel electroencephalograph. Evoked potentials obtained f r o m the cortical and subcortieal electrodes were recorded f r o m the screen of a DuMont 333 oscilloscope by a Grass camera a f t e r suitable amplification b y Grass P5 R-C coupled preamplifiers. I n all cases records were " m o n o p o l a r " against a common reference electrode on the cut edge of the scalp. Surface electrodes were placed on somatosensory (posterior sigmoid), auditory, visual and anterior s u p r a s y l v i a n cortex. Deep electrodes were oriented stereotaxieally in N. ventralis posterolateralis and N. centrum m e d i a n u m of the thalanms, lateral geniculate body, hippoeampus, meseneephalic reticular fornmtion and medial lemniscus. All deep

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TERUO OKUMA

placements were verified in serial histological sections stained with thionine. Amplitude of evoked responses was always measured from baseline to peak and the latency from the onset of the stimulus to the peak of each response. To make the results comparable from experiment to experiment, ahnost all graphs were plotted expressing the relative amplitude of each component in per cent of the pre-test control values. One per cent solution of Metrazol was injected intravenously at the rate of 1 ce. (10

neither 10 to 12/see. sl)indle bursts nor 4 to 7/see. theta activity being apparent (fig. 1, left). The initial change of background activity induced by Metrazol was signaled by the onset of more pronommed desynehronization of the eleetroeortieogram and the appearance of 4 to 7,/see. theta waves characterizing hippoeampal arousal (Green and Arduini 1954), chiefly in the subeortical eleetrogram (fig. 1, middle). The theta activity was usually induced by the initial l0 rag. of Metrazol.

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Fig. 1 Effect of intravenous Metrazol on the background EEG. Left: A control record showing fairly activated pattern. The arrow shows a contralateral sciatic stimulation onc,~ every 5 sec. Middle: After injection of 40 rag. of Metrazol. Note appeartmce of theta .tctivi@ in subcortical and also in cortical leads. Subeortical evoked potentials were suppressed. Right: After 80 mg. of Metrazol. Short bursts of seizure discharge -~ppeared in all leads. Abbreviations: PSG, posterior sigmoid gyrus; LAT G., lateral gyrus; VPL, nuc]eus ventralis posterolateralis; CM, nucleus centrum medimmm; RF, mesencephalie reticular formation; LM, medial lemniseus; GL, lateral geniculate body; ItIPPO, dorsal hippocanqms. Vpwttrd deflection is surface negative. rag.) per rain. until a generalized, sustained seizure diseharge was recorded on the E E G . Stimulation and recording were carried out before, d u r i n g and after a generalized seizure. Because of a sustained effect of Metrazol, only the data from the first injection were used for evaluation. RESULTS L

E f f e c t of Metrazol on the background electric activity.

I n all cases control records showed low voltage fast or moderately fast activity with

A later change seen after larger amount of the drug had been injected, usually 10 to 30 mg/kg., was the appearance of short bursts of high voltage irregular spike and wave activity lasting for a few seconds in the reeord (fig'. 1, right). This change appeared ahnost simultaneously in eorth, al and subcortieal eleetrograms and the incidence of these bursts increased gradually towards the onset of a generalized seizure. Background eleetrographie activity during the preietal period following Metrazol administration displayed two different patterns.

METRAZOL AND EVOKED POTENTIALS

687

Change in responses evoked in the primary somatoscnsory cortex. The oscilloscopic appearance of potentials evoked by sciatic stimulation in the posterior sigmoid gyrus consisted of a primary positive deflection (latency 10 to 13 mese.) followed by a first negative potential (latency 16 to 18 reset.). After Metrazol, a second positive deflection appeared (latency about 25 reset.) to be followed by second and third negative waves with latencies of 40 to 70 msec. and 200 msec. The p r h n a r y positive component of the evoked respou.~e, as shown in figure 2A, was

In one type, the background electrogram did not show much slowing except for occasional bursts of seizure discharge and generalized seizure occurred rather abruptly. In another type cousiderable slowing of background electrogram appeared for a few minutes preceding a generalized seizure and sciatic stimuli sometimes provoked after discharges of slow waves. The preictal enhancement of subeortical evoked responses which was observed in some cases and will be described later seemed to correlate with the slowing of the ba(,kground activity.

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Fig. 2A A. P r o g r e s s i v e c h a n g e of a m p l i t u d e of cortical evoked response t)y i n t r a v e n o u s M e t r a z o l (early positive a n d n e g a t i v e c o m p o n e n t s ) . T h e s i g n " B u r s t s of seizure d i s c h a r g e " shows the onset of a p p e a r a n c e of s h o r t b u r s t s of seizure d i s c h a r g e such as i l l u s t r a t e d in f i g u r e 1, r i g h t . N o t e r e m a r k a b l e e n h a n c e m e n t of the n e g a t i v e c o m p o n e n t (2, solid line) c o m p a r e d w i t h a relative s t a h i l i t y of the positive c o m p o n e n t ( d o t t e d line). I n the p o s t i c t a l period, delayed recovery of the n e g a t i v e c o m p o n e n t a n d following e n h a n c e m e n t of b o t h are noted.

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increased slightly in a m p l i t u d e only preceding a generalized seizure. The following first negative component, however, began to become a u g m e n t e d at an early stage in the injection of Metrazol and was not suppressed d u r i n g the generalized desynchronization of background electrogram. The duration of the negative potential also increased as the amplitude increased. W h e n an evoked response coincided with a spontaneous spike and wave

positive and negative components increased considerably above normal for several minutes d u r i n g a time when the background electrog r a m showed i r r e g u l a r slow waves. Then the response r e t u r n e d g r a d u a l l y to the control level as the background eleetrogram recovered to the pre-Metrazol pattern. The second positive component showed a slight decrease in amplitude throughout the Metrazol injection except for enhancement GENERALIZED SEIZURE

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Fig. 2B B. Change of the third negative wave. Note the marked enhancemeRt preceding the appearance of bursts of seizure discharge and also in the postictal period. burst, both positive and negative components became increased as shown in figure 2A, but always enhancement of the negative defleetion f a r exceeded that of the positive component. I m m e d i a t e l y a f t e r a generalized seizure, the positive component showed similar amplitude to t h a t which occurred d u r i n g the control period, while the negative component disappeared and did not r e t u r n until 20 to 30 see. later. T h e r e a f t e r the amplitude of the

shown in some eases immediately preceding a seizure. The second negative deflection began to decrease in amplitude in the early stages of the injection and disappeared later altogether. The third negative wave (fig. 2B, ( 6 ) ) , which was of v e r y low amplitude in the control period, became a u g m e n t e d gradually as the amount of injected Metrazol increased and became exceedingly large preceding the appearance of short bursts of seizure discharge.

689

METRAZOL AND E V O K E D P O T E N T I A L S

beginning of Metrazol injection during early desynehronization of the backgrouud electrogram (fig. 3, ( 2 ) ) . This component, ihowever, became augmented slightly in some cases immediately preceding a generalized seizure. W h e n a stimulus fell during a burst of seizure discharge both positive and negative components became augmented (fig. 3). When the somatoseusory cortex showed sus-

This negative wave showed enhancement also in the postietal period. IlI. Changes in the cooked response in the sensory relay nucleus of the thalamus. The evoked response in the nucleus ventralis posterolateralis consisted of an initial positive component (latency 10 to 11 reset.)

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Fig. 3 Progressive change of evoked response in the specific sensory relay nucleus of the thalamus, showing the early positive component ( l , dotted line) and the early negative component (2, solid line). Note the suppression of the negative component compared with the minor change of the positive one. Enhancement of both occurred during a burst of seizure discharge (peaks below the arrow).

followed by an early negative component with latency of 20 to 35 msee.). These earlier events were followed by a slower negative wave (latency about 200 msee.). The positive component showed little change or slight decrease in amplitude following Metrazol injection. The early negative component was reduced in amplitude immediately after the

tained but localized seizure activity for a few minutes preceding a generalized seizure, the negative component showed considerable enhancement during the focal cortical seizure. This component was suppressed during the postictal period. The later negative wave was decreased in amplitude slightly during the injection and

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TERUO OKUMA

showed occasional augmentation during the postietal period. IV. Changes in evoked response i~* the other subcortical structures. A p p e a r a n c e of the evoked potential in nucleus centrmn medianum varied considerably but usually consisted of an initial

ure. The late negative wave showed postietal fluctuation and enhancement similar to that displayed by the relay nucleus of the thalamus (fig. 4, ( 2 ) ) . The potentials evoked in the mesencephalic reticular formation also showed a small initial positive deflection with a following negative COml)onent of 30 to 35 reset, latency. These GENERALIZED SEIZURE

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Fig. 4 Progressive change of evoked response; in the nucleus centrum medianum of the thalamus. Note the suppression of the earlier negative component (1, solid line) during injection and also in the postietal period. Later negative wave is suppressed slightly during injection but shows fluctuation with occasional enhancement postictally (broken line).

positive component followed by an early negative deflection with a latency of 30 to 35 msec. and a later slow negative wave with a latency of about 200 msec. Usually the early negative component became decreased in amplitude during injection and postictal period (fig. 4, ( l ) ) , although occasionally enhancement occurred immediately preceding a seiz-

were followed also by a late negative wave with latency of about 200 taste. A small amount of Metrazol reduced the amplitude of the early negative component and its recovery a f t e r a generalized seizure induced by larger amounts was delayed when compared with that of the cortical early positive and negatiw, responses. In some cases the early negative

METRAZOL AND EVOKED POTENTIALS response in the reticular formation showed enhancement immediately preceding a generalized seizure but discrepancy between cortical and subcortical responses was evident as a whole (fig. 5, (2)). The change of the late negative wave in the reticular formation was similar to that in centrum medianum.

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The change produced by Metrazol administration in the potential evoked by sciatic stimulation in the somatosensory cortex is essentially the same as that known to occur in rest)onses recorded in the visual cortex (Gastaut and t I u n t e r 1950; H u n t e r and Ingvat 1955) and auditory cortex (Dell c/ al. GENERALIZED SEIZURE

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Changes of evoke(1 potentials in the sensory cortex and in the nlesencephalic reticular formation. Another cat. In this case the early negative component of the reticular response ((2), dotted line) shows an augment~/tion in the period immediate]y preceding a generalized seizure. DISCUSSION It is well established that repetitive peripheral sensory stimulation with a frequency of around ]/see. or higher, combined with subconvulsive Metrazol injection, provokes a generalized seizure starting in the cortical area specific; to the sensory modality stinmlated (Gastaut and H u n t e r 1950; Starzl e l al, 1953; etc.). I n the present study single sciatic shocks were applied once every 5 see. in order to minimize the incidence of such a sensoryevoked seizure and permit a study of the effect of Metrazol alone.

1951; Starzl e l al. 1953) following appropriate excitation. Almost all studies agree that the dominant effect of Metrazol is the enhancement seen in the first and third negative components of cortical ew)ked response. The ()rig'in of the various components of responses evoked in p r i m a r y cortical areas has been studied by m a n y authors (Bishop and t ) ' L e a r y 1938; A d r i a n 1941; Marshall e t al. 1941; Chang and K a a d a 1950; Eccles 1!151; Amassiau e t al. 1955; Clare and Bishop 1955; Perl and Whitlock 1955; Li e t al. 1!)56; Bremer 1958; etc.). Concerning early corn-

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ponents evoked in the cortex B r e m e r (1958) has summarized recently a prevaling opinion as follows: " t h e initial positive potential is the electrical sign of the nearly synchronous local postsynaptic potential of the cortical interneurones and of the bodies and basal dendrites of pyramidal cells lying in proximity to the granular l a y e r ; the following negative component has been identified with the subsequent depolarization of the apical dendritic arborization which forms a dense network in the molecular l a y e r . " The present study presents no direct evidence to assign an anatomical basis for each component, but the similarity in appearance and behavior of the first negative response evoked by sciatic stimulation here, and that elicited by direct electrical stimulation of the monkey cortex (direct cortical response-DCR) (White, Eidelberg and F r e n c h 1960) suggest that the same cellular structures - - the apical dendrite has been implicated in the DCR - - are involved in both studies in the development of Metrazol seizure. The third negative wave, of v e r y low amplitude during the control period, became enhanced considerably in response to increasing doses of Metrazol. The fact that the enhancement of this wave parallels the aug'menration of the first negative component with increasing amounts of the drug suggests that a close relationship exists between these two components in the development of a seizure. Gastaut and H u n t e r (1950) demonstrated that, u n d e r Metrazol, repetitive 2 to 3/see. photie stinmlation resulted in enlargement of the third negative wave until it formed a complex with the preceding earlier negative component sinmlating the " s p i k e and w a v e " complex. The importance of this wave in the development of a seizure in response to repetitive sensory stimulation also has been emphasized (Gastant and H u n t e r 1950; Dell el al. 1951). The initial positive component of the evoked potential in the sensory relay nucleus of the thalamus showed little change following Metrazol administration. It has been suggested that this deflection denotes a response in the afferent fibers to the thalamus (Mar-

shall 1941 ; Mountcastle and H e n n e m a n 1949), while contrasting opinion proposes that it represents a postsynaptie response in the nucleus itself ( H u n t and O ' L e a r y 1952; Cohen and Grundfest 1954). The lack of effect of Metrazol on this positive component is reminiscent of its relative resistance to anesthesia (Davis et al. 1957; Cohen and Grundfest 1954) and hypothermia (Stevenson et al. 1958). This relative resistance to eonvulsants and depressants may be explained possibly by its relatively simple synaptic configuration (Cohen and Grundfest 1954). ]n striking contrast to results of cortical recording, the early negative potential in the thalamie sensory relay nucleus was reduced in amplitude when sufficient Metrazol had been administered to induce activation of the background eleetrograin, though on occasion, preceding a generalized seizure it showed slight augmentation. Potentials evoked in the nucleus centrum medianum and meseneephalic reticular formation displayed a similar change in response to 3{etrazol as did those elicited in the specific relay nucleus. The early negative component was comparable in latency and wave form to similarly evoked responses recorded in the central brain stem by F r e n c h et al. (1.953 a, b). These latter potentials were found to be selectively blocked by anesthetics presumably by action of the drug upon the central brain stem, and it is possible that 5{etrazol acts directly upon these midline structures also. In other studies these negative waves were, found to be suppressed by concurrent cortical, subcortical, or peripheral repetitive stimulation (Hern~ndez-Pe6n and IIagbarth 1955) apparently through enhaneed inhibitory inputs to the reticular system. It is possible that Metrazol produees its action in reducing the amplitude of those evoked potentials by means of a comparable generalized stinmlation: under such circumstances the diminished wave form might be a reflection of an activated, desynchronized cortex. In smnmary, Metrazol administration was found to have small influence upon the initial positive eomponent of the response in specific sensory pathway. It enhanced the

METRAZOL

AND

EVOKED

first and third negative components recorded in the cortex and reduced in amplitude the early negative component evoked in subcortieal loci except for its occasional enhancement during the preictal period. The cortical changes occurred earlier in time and were greater in m a g n i t u d e than the subeortieal changes. This supports the opinion t h a t the ~,erebral cortex is the p r i m a r y site of action of Mq'trazol (Starzl c t a l . 1953; H u n t e r and I n g v a r 1954). Although the participation of subeortical structures in these effects has been stressed by other investigators (Freedman and Ferriss 1956; Gastaut and H u n t e r 1950), the present s t u d y suggests that while hoth surface and deep strm~tures are affected, the changes in cortex seem to be of p r i m a r y importance in the develol)ment of a Metrazol seizure. SUM~C[ARY

1. The effect of slow intravenous administration of Metrazol on the responses in the somatosensory cortex and various subcortical structures, evoked by single-shock sciatic stimulation, was investigated and analyzed simultaneously with the changes in the background electrograms. 2. The most remarkable changes induced by Metrazol were found to reside in cortex where marked enhancement of first and third negative components of the response were demonstrated. A decrease in amplitude of earlier negative component of subcortieal evoked potentials was also observed and apl)eared to have close t e m p o r a l relationship with the a p p e a r a n c e of a generalized activation p a t t e r n in the background electrogram. 3. The p r i m a r y positive component in the somatosensory cortex and specific thalamie relay mwleus showed little change except for ttw slight enhancement of the former in the period preceding a generalized seizure and in the l)ostietal period. R~::SUM~:: 1. L ' e f f e t de l ' a d m i n i s t r a t i o n iniraveineuse lente de M6trazol sur les %ponses darts le cortex soraatosensitif et diverses structures sous-eorticales ~1 la suite de stimulation

POTENTIALS

693

du sciatique p a r ehoc unique ont ~t~, investigu6es et analys6es en mgme t e m p s que les ehangements de l'aetivit6 61eetrique de fond. 2. II a 6t~ trouv~ que l ' e f f e t le phls frapp a n t prodnit p a r le M6trazol cst dans lc cortex of1 il y a une augmentation eonsid4rable de la prenli@e et de la trois(brae coml)osantes n6gatives de la r6ponse. Uue (tim(tuition dans l ' a m p l i t u d e de la composante n6gative plus pr6eoee des potcntiels 6voqu6s souseortieaux a 6% aussi observ6e et semblait avoir une relation temporelle 6troite avec l ' a p p a rition (l'ml p a t t e r n d'activation g~n6ralis~e de l'~leetrogramme (lc fond. 3. La eomposante positive l)rimaire dans le cortex somatosensitif et dans les noyaux de relais sp6cifiques du thalamus lie montrait que pcu de changement si ce n ' e s t mm 16gSrc a u g m e n t a t i o n au niveau du cortex d u r a u t la p@iode pr6c6dant une erise g6n6ralis(~e et durant la p6riode I)ost-ictale. ZUSAMMENFASSI;N(I 1. Die W i r k u n g yon l a n g s a m e r intraveniiser Infusion yon Metrazol ((/ar
auf Reizantworten im somatos,,nsorischen Kortex und versehiedenen subkortikalen S t r u k t u r c n , hcrvorgerufen d u t c h Stimulation des N. isehiadicus mit Einzelschoeks, wurde untersueht und analysiert zuglei(;h mit den Verhnderungen in der elektrisehen Itintergrundaktivit:,it. 2. Die bemerkenswertesten Veriimterungen durch Metrazol wurden in der l t i r n r i n d c gefunden wo eine deutliche VergrSsscrung der ersten mid der dr((ten negativcn K((ml)oncnten der Rcizantworten zu schen waren. Eine Verklcinerung der A m p l i t u d e der friiheren ncgativen Komponente der subkortikalen Reizantworten wurde auch beohachtet (rod schien eine enge zeitliche Beziehun~z zu dem Erscheinen generalisierter Akt (vat(on im I l int(~rg r u n d des E E G s zu haben. 3. Die prim~ire positive l(omponente in dec somatosensorisehen Rinde und den spezifisehen Sehaltkernen des T h a l a m u s zeigtcn weni~'e Verh.nderungeu ah~'esehen yon ether geringen VergrSsserung der erstercn km'z vor einem allgemeinen K r a m p f a n f a l l und in der Zeit kurz damteh.

694

TERUO OKUMA

Arch. Neurol. Psychiat., Chic'Jgo, 1953a, (;9: 505-518. FRENCH, J. D., VERZEANO, M. and MAGOUN, It. W. A neural basis of the anesthetic state. Arch. Neurol. Psychiat., Chicago, 1953b, 69: 519-529. GASTAUT, H. Combined photic and Metrazol qctivaREFERENCES tion of the brain. E E G Clin. Ne~rophysiol., 19~0a, 2: 249-261. ADRIAN, E. D. A f f e r e n t discharges to the cerebrtd GASTAUT, ~{. and ~-~UNTER, 5. An experimental study cortex from peripheral sense organs. J. Ph.qsiol., of the mechanism of photic activation in idio1941, 100: 159-191. pathic epilepsy. EEG Clin. Neurophysiol., 1950b, AJMONE )¢~ARSAN, C. and RALSTON~ B. 1~. The Epi2: 263-287. leptic Seizure. A Clinical.Electrographie Analysis GREEN, J. D. and ARDUINI, A. Ao Hippocamp'd eleco f Metrazol-Indueed Attacks. Charles C. Thomas, trical activity in arousal. J. Neurophysiol., 1954, Publisher, Springfield, Illinois, U.S.A., 1957. 17 : 533-557. AMASSIAN, V. E.~ ]°ATTON~ ,]-. W.~ WOODBURY, A. T. t{ERN~NDEZ-PESN, R. and HAGBARTFI, K. E. I n t e r and SOHLAO, J. E. An interpretation of the action between afferent and cortically induced surface-response in somatosensory cortex to perireticular responses. J. Neurophysiol., 1955, 18: pheral and interareal afferent stimulations. EEG 44-55. Clin. Neurophysiol., 1955, 7: 480-482. HUNT, ~r. E. and O'LEARY, J. L. Form of thalamic BISHOP, G. ]~. and O~LEARY, J. })otential records response evoked by peripheral nerve stimulation. from the optic cortex of the eat. J. NeurophyJ. Comp. Neurol., 1952, 97: 491-514. siol., 1938, 1: 391-404. HUNTER, J. and IN~VAR, D. H. Pathways mediating BaEM~R, F. Cerebral and cerebellar potentials. PhyMetrazol induced irradiation of visual impulses. siol. Rev., 1958, 38: 357-388. EEG Clin. Neurophysiol., 1955, 7: 39-60. CHAN(b H. T. and KAADA, B. An analysis of primary LI. (~. L., CULLEN, C. and JASPER, H. II. Laminar response of visual cortex to optic nerve stinlulamicroelectrode studies of specific somatosensory tion in cats. J. Neurophysiol., 1950, / 3 : 305-318. cortical potentials. J. Yeurophysiol., 1956, 19: CLARE, M. ~I. and BISHOP, G. H. Dendritic circuits: 113-]30. the properties of cortical paths involving denMARSHALL, W. H. Observations on subcortic,ql somatic drites. Amer. J. Psychiat., 1955, Y11: 818-825. sensory mechanisms of cats under Nembutal CO~EN, S. M. and GRUNDFEST, I{. Thalamic loci of anesthesia. J..Neurophysiol., 1941, ~i: 25-43. electrical activity initiated by afferent impulses MARSHALl,, W. ~-~., WOOLSEY, C. N. ail(] BARD, ]~. in eat. J. Neuvophysiol., 1954, i7: 193-207. Observations on cortical somatic sensory mechCURE, C.~ RASMUSSEN, T. and JASPER, ]{. Activation nnisms of cat and monkey. J. Neurophysiol.. of seizures and electroencephalographic disturb1941, 4: 1-24. antes in epileptic and in control subjects with MOUNTCASTLE, V. B. and ]~ENNEMAN, E. Pattern of Metrazol. Arch. Neurol. Psychiat., Chicago, 1948, t:,ctile representation in thalqmus of cat. J. 59: 691-717. Neurophysiol., 11949, 12: 85-100. DAVIS, H. S., COLLINS, W. F., RANDT, C. T. and DILPE~L, E. R. and WHITLOCK, D. G. Potentials evoked LON, W. tI. E f f e c t of anesthetic agents on in cerebral somatosensory region. J. Ne~rophyevoked central nervous system responses: gaseous siol., 1955, 18: 486-501. agents. Anesthesiology, 1957, 18: 634-642. STARZL, T. E., N1EMER, W. T., DELL, M. ,qnd FORBELL, M. B., BONVALLET, ~'[. et DELL, P. Evolution Gm~VE, P. R, Cortical and subcortical electrical corticale des crises 6pileptiques provoqu6es chez activity in experimental seiz,lres induced by Metle chat. Bey. Neurol., 1951, 84: 595-602. razol. J. Neuropath. Exper. Neurol., 1953, I2: ECCLES, J. C. Interpretation of action potentials 262-276. evoked in the cerebrql cortex. EEG Cli't~. NeuroSTEVENSON', G. C., COLLINS, W. F., RAND'r, C. T. and physiol., 1!951, 3: 449-464. SAURWEIN, T. I). E f f e c t s of induced hypothermia FORBES, A. add MORISON, B. R. Cortical response to on subeortical evoked potentials in the c a t . . 4 tltel'. sensory stimulation under deep barbiturate llarJ. Physiol., 1958, 194: 423-426. cosis. J. Neurophysiol., 1939, 2: 112-138. WHITE, J. C., EIDELBERG, E. and FRENCh, . I . D . ExFREEDMAN, D. A. and FERRISS, G. S. E f f e c t of mesperimental assessment of epileptogenesis in the encephalic lesions on Metrazol-induced cortical monkey cerebral cortex. I. E f f e c t of sleep, arousal activity. Neurology, 1956, 6:173-178. and drugs. Arch. .Ye~rol. Psillehiat. (!hicago, ]~'RENCII, Z. D., VERZEANO, M. and MAGOUN. []~. ~%r. 1960, 2: 376-383. An extralemnisc'd sensory system in the bruin.

The author would like to express appreciation to Dr. J. D. Frenel b Dr. H. W. Magoun -rod Dr. E. Eidelberg for their continuous help and valuable criticisms.

R(,ferenee: OKU~IA, T. E f f e c t of Metrazol ell cortical and subcortic,ql evoked potentials. rophysiol., 1900, l:?: 685-694.

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