Long latency responses evoked in the anterior brain stem under pentobarbital anesthesia

LONG

LATENCY

RESPONSES EVOKED

BRAIN STEM UNDER

IN THE

PENTOBARBITAL

ANTERIOR

ANESTHESIA ~

SHAUL FELDMAN, M . D . ~ and ROBERT W . PORTER, P h . D . Departments of Medicine (Neurology) and Anatomy, UCLA School of Medicine, and the Neurosurgery Section, Veterans Administration Hospital, Long Beach, California

(Received for publication: January 19, 1959) I n 1936 Derbyshire, Rempel, Forbes and L a m b e r t d e m o n s t r a t e d t h a t a stimulus applied to the sciatic nerve u n d e r deep pentobarbital anesthesia evoked a long latency response a p p e a r i n g all over the cortex. I f the recording electrode was n e a r the sensory area this long latency response was preceded by a short latency response r e p r e s e n t i n g the arrival of the a f f e r e n t impulse in the cerebral cortex. L a t e r experiments b y Forbes and his associates (1939 ; 1949) and others ( D e m p s e y et al. 1941 ; Morison et al. 1941a, 1941b) explored the distribution a n d characterietics of this cortical response which was designated as the "seconda r y r e s p o n s e " in contrast to the " p r i m a r y res p o n s e " recorded only at the sensory area or its vicinity. D u r i n g our investigations of the effect of pentobarbital on evoked potentials in the h y p o t h a l a m u s and m i d b r a i n reticular formation it was observed t h a t u n d e r anesthesia a long latency response a p p e a r e d which was not seen in the waking state. I t is the purpose of this r e p o r t to describe some of the characteristics of this response and to suggest t h a t this is the "secondary r e s p o n s e " of Forbes recorded at b r a i n stem levels. 3/IETHODS T w e n t y - f o u r eats were used in these experiments. A f t e r the necessary surgical proeedures were p e r f o r m e d u n d e r light ether anesthesia all p a i n f u l points were infiltrated with procaine. Animals were immobilized with gallamine triethiodide (Flexadil, A m e r i c a n C y a n a m i d ) and m a i n t a i n e d on artificial re-

spiration thereafter. The ipsilateral or cont r a l a t e r a l sciatic nerve was stimulated with single shocks of 0.1 to 2.5 V. for .01 to 0.1 msee. duration (threshold) through silver electrodes by means of a Grass stimulator (S4-A) with its isolation unit. Responses were amplified with Tektronix t y p e 122 low level preamplifiers, observed on a D u B I o n t 322 double-beam cathode r a y oscilloscope and recorded with a Fairchild camera. The evoked potentials were recorded f r o m concentric stainless steel electrodes introduced stereotaxically into different regions of the hypothalamus, i n t r a l a m i n a r nuclei of the thalamus and m i d b r a i n reticular formation. The cortical recordings were obtained from the s u p r a s y l v i a n g y r u s with the aid of chlorided silver ball electrodes. Monopolar recordings f r o m the brain stem and cortex were carried out with respect to the indifferent reference electrode which was applied to the wound margin. A f t e r the responses in the nnanesthetized animals were established, various doses of sodium pentobarbital (Nembutal, Abbott) were injected into the femoral vein, and their effect upon the evoked potentials d,~termined. The effect of high frequency stimulation (17.5 V. ; 0.01 msee. d u r a t i o n ; 100/see.) (,f the midbrain reticular formation u p o n the evoked potentials in the h y p o t h a l a m u s was examined as well. At the end of the experim~.nts brains were fixed in formalin, serially sectioned and stained with thionine to facilitate identification of electrode placements. RESULTS Stimulation of the sciatic nerve evoked hypothalamic potentials the distribution and characteristics of which are described in detail elsewhere (Feldman, V a n der Heide and Por-

1 Supported by grants from the National Institute of :Mental Health (B-611 and 21Vf-6415). 2 On leave of absence from the Department of Nervous Diseases, Hadassah University Hospital, Jerusalem, Israel [ 11~ ]

112

SHAUL FELDMAN and ROBERT W. PORTER

ter 1958). Briefly, short latency (7-10 msec.) biphasic responses were f o u n d in the posterior and lateral regions of the h y p o t h a l a m u s which p r o b a b l y signalled the arrival of the evoked potentials f r o m collaterals of the lemniscus, and longer latency negative potentials (17 to 45 msec.) were recorded in t h e medial and anterior p a r t of the hypothalamus. The voltage of these short and long latency potentials ranged between 50 and 150 ~V. The potentials A. @

a p p e a r e d long latency high voltage responses in the f o r m of monophasic negative waves at the same anatomical points where the responses in the unanesthetized animal were recorded (fig. ] A ; 2). The lateneies of these responses were between 50 and 90 msec., their duration 80-100 msec. and their amplitude 200-300 /~V. They could be evoked both by stimulation of the ipsi- and the contralateral sciatic nerves. The points from where these

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Fig. 1 A. Effect of pentobarbital given in divided doses upon evoked potentials in the anteromedial (upper beam) and posteromcdial (lower beam) hypothalamus from stimulation of sciatic nerve. Initial small dose caused slight diminution in amplitude of potentials (2) and additional pentobarbital resulted in their disappearance (3). Deepening the anesthesia further facilitated the appearance of longer latency potentials (4), which disappeared when the anesthetic was allowed to wear off (5), but reappeared after an additional dose of pentobarbital (6). B. Comparison of long latency potentials evoked in the hypothalamus and suprasyh-ian cortex under deep pentobarbital anesthesia. This and subsequent figures were made using the nnipolar recording technique. evoked in the i n t r a l a m i n a r nuclei of the thalamus and the m i d b r a i n reticular formation also a p p e a r e d as negative waves but usually these were of shorter latency than were responses observed in the hypothalamus. Following the administration of pentobarbital in small doses (5 m g / k g . ) there was a slight decrease in the amplitude of the longer latency evoked potentials; with doses of 10 to 20 rag. per kilogram body weight, these potentials were m a r k e d l y depressed and later abolished completely. A few minutes following the administration of an additional 15 or 20 rag. per kilogram of pentobarbital there

potentials were recorded in the brain stem are shown in figure 3. At this stage of anesthesia in some of the experiments the p r i m a r y brain stem response disappeared completely but in others the positive short latency wave (fig. 4) and occasionally even the reduced longer latency negative wave of the p r i m a r y response persisted, ill spite of progressively deepenino" b a r b i t u r a t e anesthesia. Administration of f u r t h e r amounts of pentobarbital to a total of 60 or 70 rag. per kilogram depressed or abolished the long latency responses in the brain stem, At this depth of anesthesia, still long'er latency re-

EVOKED RESPONSES DURING ANESTHESIA 5 mq/Kg Pentoborbito]

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Fig. 2 Effect of pentobarbital upon evoked potentials in thalamus (centralis lateralis, upper bean: ~ and lateral midbraiu reticular formation (including short latency lemniscal response, low~.r beam) from sciatic nerve stimulation. The intravenous injection of a total of 30 mg/kg, has diminished (2) then abolished (3) the thalamic and reticular responses and passed throuFh the stage during which the long latency, secondary responses can be elicited (4). After ]5 min. the long latency responses are fully developed (5). An additional 25 rag. pentobarbit it abolishes these responses (6), but after 30 rain. they reappear (7). Their gradual deerea.e in amplitude with deepening anesthesia is shown in the last three figures (8, 9, 10). No'e that the ]emniscal response remains throughout.

? )

S Fig. 3 Distribution of long latency potentials in the midbrain ( A ) , posterior (B) and anterior ((~) hypothalamus from sciatic nerve stimulation under deep pentobarbital anesthesia. BCI - Brachium of inferior eolliculus; CG - - Central grey substance; CS - - Superior eollicutus; En - - N. entopeduneularis; :Fil - - :N. fill formis; F x - - Fornix ; H L - - Hypothalamus lateralis ; Hp - - Hypothalamus posterior; Item - - Hypothalamus ventro-medialis; I P - - N. nit~*rpeduncularis; LM - - L e m n i s c u s medialis; MD - - N. medialis dorsalis; M F B - - Median forebrain bundle; Mm - - Corpus mamillare; NCM - - N. centralis medialis; N P L - - N. paralemniscalis; P e d Peduneulus cerebralis; P V H - - N. periventricularis hypothalaui; RE - - N. reuniens; SO - - N. supraopticus; Sth - - N. subthalamicus; TO - - Tractus opticus; V A - - N. ventrulis anterior. sponses (130-150 msec.) appeared but these were usually of lower amplitude ( f i g . 5, 6 ) . Increasing the level of anesthesia further, abolished completely all the evoked potentials. In order to obtain the long latency potentials after the disappearance of the primary

responses in the brain stem, graded amounts o f 10 rag. p e r k i l o g r a m p e n t o b a r b i t a l h a d t o be administered in successive doses. It was observed that if a high total dose was administered in one injection, the primary response disappeared and in most cases the long latency

114

S H A U L :PELDMAN and ROBERT W. P O R T E R

brain was diminishing, these responses would become unstable and later disappear. However, the injection of an additional 10 rag. per kilogram would restore and stabilize these evoked potentials (fig. 1). Contrastingly IO m g / K 9 Pentolgorbital slight overdosage of pentobarbital would eliD D minate the response temporarily (fig. 2). The stimulus threshold for activation of the long latency response was found to be that required to exicte all the A fiber activity; hence was comparable to that required to ~J evoke the p r i m a r y response in the hypothalamus (fig. 7). A similar threshold has been found by others for the cortical " s e c o n d a r y " response (Dempsey et al. 1941; Forbes el al. 1949). In a number of experiments the evoked 20 rng / Kg potentials were recorded simultaneously from g O the hypothalamus and the suprasylvian gyrus (fig. I B ) . The latency of the cortical response was usually longer by 10-20 msee. than was that in the hypothalamus. One of the characteristics of the long latency response was its fatigability to repeated stimuli ; sometimes it was necessary for several seconds to elapse before another response could :Pig. 4 be obtained. High frequency stimulation of E f f e c t of pentobarbital on a short latency, biphasic the reticular formation caused diminution in response in the posterior hypothalamus from sciatic nerve stimulation. The initial dose abolishes the neg- amplitude of the long latency response both ative phase (2). Additional anesthesia allows the in the hypothalamus and thalamus (fig. 8).

response was not elicited. The response was not seen with every stimulus and varied in appearance, but additional amounts of pentobarbital increased the consistency of the re-

S'f~

I

1:o

appearance of a long latency negative response (3, 4), with the initial positive wave still remaining.

COMMENT

sponse and augmented its amplitude. Some 20-30 rain. after administration of a dose of pentobarbital which had established long latency potentials, probably at a time when the concentration of the anesthetic agent in the

Since the studies of French, Verzeano and Magoun (1953) on the effect of anesthetics upon the brain stem reticular formation it has been established that relatively small amounts of barbiturates and other anesthetics will de-

40 mg/Kg Pentobarbitel

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20 mg/Kg

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A 50 msec

Fig. 5 E f f e c t of additional pentobarbital upon long late]lay responses evoked in the hypothalamus (upper beam) and midbrain reticular formation (lower beam) from sciatic nerve stimulation under deep anesthesia. Note diminishing amplitude and increasing latency a f t e r subsequent injections.

EVOKED RESPONSES DURING ANESTHESIA 45 mg/Kq

Pentoborbit(]l

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Fig. 6

Long latency evoked potentials in the medial (upper beam) and lateral (lower beam) anterior hypothalamus from stimulation of sciatic nerve under deep pentobarbital anesthesia. Additional doses reduce amplitude of long latency response but allow the appearance of a second, still longer latency potential. 50 m g / K g

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Fig. 7 Comparison of potentials evoked in the medial (upper beam) and lateral (lower be.ml) anterior hypothalamus by sciatic nerve stimulation during working state (A) and under deep pentobarbital anesthesia (B) to show that thresholds for primary and secondary responses are similar. crease the amplitude of potentials evoked in this structure, while higher doses will cause their abolition (Arduini and Arduini 1954; Collins and O ' L e a r y 1954; H a u g e n and Melzack 1957 ; Longo and Silvestrini 1958 ; R a n d t ef al. 1958). This sensitivity has been attributed to the highly multisyuaptic structure of the reticular formation. Similar observations have been made in our study on the hypotbalamus which was found to be even more sensitive to barbiturates than was the midbrain reticular formation (Feldman, Van der Heide and P o r t e r 1958). The present investigation demonstrates additionally, however, that when barbiturate anesthesia is continued progressively to deeper levels, a state of responsiveness can be reached in the retie-

Fig. 8 Effect of high frequency stimulation of midbrain reticular formation on long latency potenlials evoked under deep pentobarbital anesthesia in the anterior hypothalamus (Hyp.) and nucleus centralis lateralis of thalamus (C.L.) from sciatic nerve ~timulation.

During reticular formation stimulation potentials are considerably reduced.

the

evoked

ular formation, hypothalamus and the intralaminar nuclei of the thalamus which is characterized by the appearance of a long latency high voltage response, the properties of which suggest a relationship to the " s e c o n d a r y response" of Forbes as seen in tile cortex. The mechanisms and the pathways responsible for the appearance of this barbiturate induced secondary response throughout the cerebral cortex are not entirely clear. The initial suggestion that it is related to the arrival of the direct or p r i m a r y response in the sensory area from where it is distributed widely (Forbes and Morison 1939) does not seem to be supported by later experimental evidence submitted by Dempsey et al. (1941) and Morison et al. (1941a). These investigators studied the course of the secondary response by placing selective lesions in the brain stem

116

SHAUL FELDMAN and ROBERT W. PORTER

and by recording cortical potentials evoked from stimulation of the brain stem. Their experiments suggested that unlike the primary response the secondary response traversed the medial part of the midbrain and the dorsal and median part of the subthalamus to the level of anterior pole of the amygdala from where it became widely distributed to the cortex. This pathway has been identified with the extra-thalamic component of the ascending activating system described by Starzl, Taylor and Magoun (1951) and has been seen to migrate laterally from the sub- and hypothalamus into the internal capsule. Confirming this proposal is the observation of Purpura (1955) that all of the features of the secondary cortical response previously seen from peripheral stimulation could be reproduced by stimulating different points in the medial brain stem reticular formation of cats deeply anesthetized with pentobarbital. The simultaneous recording of the secondary response in the cortex and brain stem under a deep level of pentobarbital anesthesia and the differences in latency found in comparing these two potentials would suggest that they arc the same response recorded at different levels. Though our studies do not settle the question of the pathways of this response in the brain stem, it is evident that there are both intrathalamic and extrathalamie pathways involving the midbrain reticular formation, intralaminar nuclei of the thalamus and hypothalamus. •"V[orison, Dempsey and Morison (1941a), in their studies of generalized cortical responses from stimulation of the brain stem distinguished between one of medium latency (up to 80 reset.) and another of long" latency these two being otherwise identical in appearanee. These two kinds of responses correspond in latency to those recorded in our study in the brain stem. However, in our experiments, the longer latency response was usually associated with a greater depth of anesthesia, a phenomenon observed in the cortex also by Forbes and his associates (1939, 1949) and by Schneider et al. (1952). A critical level of pentobarbital anesthesia was necessary in order to obtain the long latency response and lowering" or elevating this concentration blocked the evoked poten-

tials. Forbes et al. (1949), have also commented upon the necessity for adjusting the nareosis to a desired intermediary range in order to obtain the secondary response. It has been suggested that secondary responses cannot be recorded over the surface of the unanesthetized brains because enhanced cortical activity of the aroused state masks or precludes these slowly conducted potentials. (Beecher et al. 1938; Morison 1954). Our studies would indicate, rather, that the actual propagation of the secondary response is related to the state of excitability of the brain stem hence that it is transmitted or blocked at the brain stem level. The participation of multisynaptic structures which are known to fatigue on repeated stimulation, especially under light barbiturate anesthesia, may account for refractoriness of the secondary response to repeated stimuli (King et al. 1957). The identity of the activation thresholds for responses in unanesthetized animals and the long latency response under deep pentobarbital anesthesia suggests that the differences in latency of the two potentials are not related to peripheral conduction in different group fibers. It has been shown by Mornzzi and Magoun (1949) that high frequency stimulation of the brain stem reticular formation reduced the amplitude of the secondary response in the cortex of cats under chloralosane anesthesia. A comparable effect was observed in our experiments in which the response was recorded in animals anesthetized with pentobarbital. The effect of brain stem stimulation in depressino' potentials evoked in the hypothalamus and thalamus would indicate that the reduction of the intrinsic spontaneous activity in the multisynaptic brain stem system induced by barbiturates permits the appearance of the secondary response while activation of the reticular formation could eansc its blockade. Brazier (1954:) employing responses cortically evoked by light flashes noted that increase of pentobarbital anesthesia depressed the primary but augmented the secondary ]ong latency response. This phenomenon was explained as a " r e l e a s e " effect, as though at that stage of barbiturate anesthesia some inhibitory system, possibly in the diffuse ascending system, had been put out of action

EVOKED RESPONSES DURING ANESTHESIA by the drug, thereby releasing from control the responses carried rostrally from this system. A similar observation has been made in the brain stem in our studies though a much greater range in anesthesia existed between the disappearance of the p r i m a r y and appearance of the secondary response. Since Magoun and Rhines (1946) showed that the brain stem reticular substance exerted caudally directed inhibitory influences upon segmental activity, evidence has accumulated indicating that sensory transmission is affected by such an inhibitory mechanism as well ( H a g b a r t h and K e r r 1954; Hernfindez-l'edn 1955). To envision this inhibitory system ~|ffecting conduction within the reticular t'orm~tion itself does not seem unfound¢,d ~t this time. Suppression of such tonic inhibito|'y influences during certain stages of ~,,,eslh(~sia would thus permit the manifestatim, o[ these reticular responses which are otherwise not detectable. (hn. observations on the inhibition of evoked potentials u n d e r certain levels of anesthesia, the appearance of longer latency responses when the level of anesthesia is increased and finally the abolition of all responses confirms the existence of facilitatory ,and inhibitory mechanisms in the brain stem which are differentially susceptible to deepening anesthesia. The relevance of these nenrophysiologically delineated stages of barbitnrate anesthesia to the well known clinical stages of anesthesia is the subject of f u r t h e r investigation. 8UIVIMAI~Y

Evoked potentials recorded in the hypothalamus, intralaminar nuclei of the thalamus and midbrain reticular formation from stimulation of the sciatic nerve were compared in animals without anesthesia and following the administration of pentobarbita]. Moderate doses of pentobarbital decreased and larger doses abolished the evoked potentials. Additional anesthesia caused the appearance of high voltage responses with latencies ranging between 60 and 160 msee. The threshold :for the activation of these responses was similar to that for activating the evoked potentials in unanesthetized animals. These long latency responses could be reduced by high frequency

117

stimulation of the midbrain reticular formation. The effect of barbiturates on the evoked potentials in the multisynaptie systems of the brain stem in terms of inhibition and activation of various mechanisms under different levels of anesthesia is discussed and the relation of the long latency response in the brain stem to the " s e c o n d a r y response" of Porbes emphasized. ~su~]~ On a fait la comparaison des p,~tentiels ~voqu~s, enregistr~s dens l'hypothalamus, dans les noyaux intralaminaires du thalamus, et dans la formation rSticulaire mSse~c~phalique, ~. p a r t i r de la stimulation du nerf seiatique, chez des animaux sans anesth~sie, et aprSs administration de pentobarbital. Des doses mod~r~es de pentobarbital faisaient diminuer, et des doses plus larges faisaient abolir, les potentiels ~voqu~s. L'anesth~sie additionnelle faisait apparaltre des r6p, mses de haut voltage avee des latences variant de 60 ,, 160 reset. Le seuil de ]'activation de ces r6ponses 6taft semblable h eehfi de l'a:~tivation des potentiels 6voqu6s chez des animaux non anesth6si6s. Ces longues p6riodes d,. latenee pouvaient 6tre r6duites par la stimulation h haute fr6quence de la formation r~:ticulaire m6senc6phalique. On diseute l'effet des barbituriques sur ]es potentiels 6voqu6s des syst~mes multisynaptiqnes du tronc e6r6bral en term~.s d'inhibition et d'activation des m6canismes divers h des niveaux diff6rents d'anesth6si,~, et on souligne le r a p p o r t de la r6ponse h ]ongue p6riode de latence du tronc c6r6bral, et ]a <>de Forbes. ZUSAMMENFASSUNG

Die dutch Sciatieusreizung erzeng'ten Potentiale im ttypothalamns, in den intralaminaren K e r n e n des Thalamus und in der Formatio reticularis des Mittelhirns w~lrden bei Tieren ohne Narkose und nach Vera.}reiehmlg yon Pentobarbital verg]ichen. :\.I~iss ;a'e Dosen yon Pentobarbital verminderten di~ Rcizantworten, w~ihrenddem gr5ssere Dosen eine komplette AuslSschuno' dieser Potentiale herbeiffihrte. ~Venn noch hShere Dosen des An~stheticums verabreicht wurden, traten hoeh-

ll8

S H A U L F E L D M A N and ROBERT W. P O R T E R

gespannte Reizantworten auf, welche Latenzzeiten zwischen 60-160 msec. aufwiesen. Die Reizschwe]le fiir die Aktivierung dieser Reizantworten war derjenigen, fiir die Aktivierm~g d e r R e i z a n t w o r t e n b e i m u n n a r k o t i s i e r t e n Tier iihnlieh. Diese Reizantworten mit langer L a t e n z z e i t k o n n t e n d u r e h h o c h f r e q u e n t e R.eizung der Formatio retieularis des Mittelhirns vermindert werden. I)er Einfluss yon Barbitursiiureverbindunsen auf die reizerzeugten Antworten in multisynaptischen Systemen des Itirnstammes im Sim~e der IIemmung und Bahnung versehiedener Meehanismen be] v e r s e h i e d e n e n T i e f e n der Narkose wird besproehen und die Reizantworten mit langer Latenz, welehe im Hirnstature auftreten werden in Beziehung gesetzt mit der "secondary response" yon Forbes. The authors wish to express their gratitude to Ludwig Marrone for technical assistance, to Georgia Seherer and Cora Rucher for histological preparation of brains, to Dan Slotton and Tim Dodge for preparation of figures and to Mrs. Gertrude Rhoades for preparation of manuscript. REFERENCES ARDUINI, A. nnd ARDUINI, M. G. Effect of drugs and metabolic alterations on brain stem arousal mechanism. J. Pharm. Exper. Therap., 1954, 110: 76-85. BEECHER, H. K., McDoNOUGH, F. K. and FORBES, A. Effects of blood pressure changes on cortical potentials during anesthesia. J. Neurophysiol., 19I~B, 1: 324-331. BRAZIER, .-~[. The action of anesthetics on the nervous system, in Brain Mechanisms and Conscio~ts~ess, Springfield, Thomas, 1954, pp. 163-199. COLLINS, W. F. and O'LEAR¥, J. L. Study of somatic evoked response of midbrain reticular substance. EEG Clin. Neurophysiol., 1954, 6: 619-628. DEMPSEy, E. W., MORISOSr, R. S. and 3~ORISO~r, B. R. Some a f f e r e n t diencephalic pathways related to cortical potentials in the eat. Amer. J. Physiol., 1941, 131 : 718-731. DERBYSHIRE, A. J., RE),IPEL, ]~., FORBES, A. and T~AI~rBERT, E. F. The effects of anestlwtics on :~etion ootentials in the cerebral cortex of the cat. Amer. J. Physiol., 1936, 116: 577-596. PELDI~fAN, S., VAN DER HEIDE, C. S. and PORTER, R. W. A study of evoked potentials in the hypothalamus. Amer. J. Physiol., 1958, 196: 1163-1167.

FORBES, A. and MORISON, B. R. Cortical response to sensory stimulation under deep barbiturate narcosis. J. Neurophysiol., 1969, 2: 112-128. FORBES, -~., BATTISTA, A. F.~ CttATFIELD, P. O. and GARCIA, J. P. Refractory phase in cerebral mechanisms. EEG Clin. Neurophysiol., 1949, 1: 141175. ~RENCtI, J. D.~ VERZEAN0, M. and ]~/[AGOUN, II. W. A neural basis of the anesthetic st,qte. Arch. Neurol. Psych]at., Chicago, 1953, 69: 519-529. HAGBARTH, K. E. and KERR, D. I. B. Central influences on spinal afferent conduction. J. N~trophysiol., 1954, 17: 295-307. HAUGEN, F. P. and MELZAK, R. The effeets of nitrous oxide on responses evoked in the brain steal by tooth stimulation. Ancsthesiolog?l, 1957, 18: 18.% 195. HEIIN]~NDEZ-I°ESN, t~. Central mechanisms controlling conduction along central sensory pathw'~ys. Aeta Neurol. Latinoamer., 1955, 1: 256-264. KING, E. E., NAQUET, R. and MAGOUN, t]. W. Alterations in somatic a f f e r e n t transmission through the t!mlamus bv central mechanisms and barbiturates. ,l. Phar,~. Exper. Therap., 1957, 1 ~ 9 : 4 8 - 6 3 LONGO, 3~T.G. et SILVESTRINI, B. Contribution 5, ] '~tude des rapports entre le potent]el r6tieulaire 6voqug, l ' 6 t a t d'anesth6sie et l'aetivit5 61ectrique cdr6brale. EEG Clin. Neurophysiol., 1958, ll): l l l : ' 120. MA(~OITN, t{. W. and RHINES, R. An inhibitory mechanism in the bulbar reticnlar formation. J. Ne~ropl~ysiol., 1946, 9: 165-171. MORISON, R. S., DEMPSEY, E. W. and MORISON, B. R. Cortical responses from electrical stimulation of t)r'Sn stem. Amer. J. Physiol., 19413, 13l: 732743. MOalSO~', R. S., DEIVIPSEY, E. W. and 5IORISON, B. R. On l)rop,qgation of certain cortical potentials. Amer. J. Physiol., 1941b, 131 : 744-751. MORISO-'L B. R. in Discussion of BRAZIER, M. The action of anesthetics on the nervous system, in Brain Mechanisms and Co~scious~ess, 1954, Springfield, Thomas, pp. 193-194. ~ffORUZZI, G. and MAGOUN, }[. W. Brain stem reticular formation and activation of the EEG. EEG CISL Neurophysiol., 1949, 1 : 455-473. PURPURA, D. P. F u r t h e r analysis of evoked ~secondarv d l s c h a r g e " ; a study in retleuloeortical relations. J. Neurophysiol., 1955, I3: 246-260. I~AXDT. C. T.. COLLINS, W. F., DAVIS, H. S. and DILLON, W. H. DifferentiM susceptibility of afferent pathways to anesthetic agents in the eat. A~n(~r. J. Physiol., 195@, 192: 305-310. SCIINEIDER. J . WORINGER, E., TTm~[ALSKE, G. et BROGLY, G. Bases 61ectrophysiologiclues des m6can]sines d ',action du Pentotha] chez le chat. Rev. .Veurol., 1952, 87 : 433-451. STAPZI,. T. E., TAYLOR, C W. and MAC.OU~. H. W. Ascending conduction in reticular activating system with special reference tu the dienceplmlon. ,I..Ve~rophysiol., 1951, 7i: 461-477.

RQft~r('nce: FELDMAN, S. and PORTER, R. W. Long latency responses evoked in the anterior ])rain stem under pentobarbital anesthesia. EEG Cli~..Veurophysiol., 1960 12: 111-118.