Cerebellar responses to penicillin-induced cerebral cortical epileptiform discharge

123

Electroencephalography and Clinical Neurophysiology, 19"/4, 37: 123-132 Elsevier Scientific Publishing Company, Amsterdam Printed in The Netherlands

CEREBELLAR CORTICAL

RESPONSES

EPILEPTIFORM

TO PENICILLIN-INDUCED DISCHARGE

CEREBRAL

1

R. M. JULIEN AND K. D. LAXER Department o/" Medical Pharmacolo.qy and Therapeutics, California College of Medicine, University o1 Calilornia at lrcine. lreine, Cal(ll 92664 (U.S.A.) (Accepted for publication:January 21, 1974)

Electrical stimulation of the cerebellar cortex has been shown to inhibit or abolish epileptiform activity both in animals (Cooke and Snider 1955 ; Dondey and Snider 1955; Iwata and Snider 1959; Dow et al. 1962; Mutani et al. 1969; Hutton et al. 1972) and in man (Cooper et al. 1973, 1974). Indeed, the cerebellum has been proposed as possessing an inhibitory influence over cortical excitability (Dow et al. 1962). Julien and Halpern (1972) demonstrated that cerebellar Purkinje cells (P-cells) ceased discharging during development of prolonged synchronous epileptiform episodes and that diphenylhydantoin appeared to exert at least part of its seizure-depressant effect concomitant with augmentation of P-cell discharge rate. However, studies attempting to clarify the physiological responses of cells in the cerebellar cortex and deep nuclei to epileptiform discharges originating in cerebral cortex have not been reported. That the cerebellum should respond to cerebral cortical epileptiform discharge is not surprising since there is increasing appreciation for anatomic and physiologic cerebrocerebellar interactions (Evarts and Thach 1969). The cerebellar cortex receives information from cerebral cortex via mossy and climbing fiber inputs. In turn, cerebellar cortical activ!ty via the P-cells inhibits the discharge of cells located in cerebellar nuclei thus reducing their tonic facilitatory 1 Supported by U.S. Public Health Service Grant No. NS-09835, National Institute of Neurological Diseases and Stroke, and by a grant from the Rebecca Payne Livingston Foundation.

ascending influence to cerebral cortex (Eccles et al. 1967; Thach 1972).

Thus, studies were undertaken in order to describe the cerebellar responses which occurred during the various stages of abnormal electrographic discharges which develop from an epileptogenic focus located in cerebral cortex. METHODS

Fifity cats (2.5-4.6 kg) of both sexes were used. Under halothane anesthesia the trachea and femoral artery and vein were cannulated. Body temperature was measured by means of a thermistor probe placed in abdominal muscle and the animal was maintained at 37.5°C by moderate heating, Bone overlying the left anterior sigmoid gyrus and over cerebellar cortex (anterior or posterior vermis or left or right lateral hemisphere) was removed and dura reflected. To minimize pulsations during microelectrode recordings, cisternal drainage was performed and a small (4 mm diameter) well of dental acrylic filled with silicone lubricant (DowComing) was located over exposed cerebellar cortex. EEG recording screws were located bilaterally over frontal and occipital cortex. Bone over frontal sinus was used as an indifferent electrode. Long-lasting local anesthetic (20"/,I benzocaine, free base, in talcum powder) was liberally applied to wound margins and to the e a t b a r s . Animals were paralyzed with a constant infusion of D-tubocurarine (0.45 mg/kg/h). Halothane was discontinued and the locally anesthetized animals were mechanically venti-

124 lated to 3.0 3.2"~,~iend-tidal CO2 in the mixed tracheal gas. Experiments were started 1.0-1.5 h following discontinuation of halothane. EEG, arterial blood pressure and tracheal CO 2 were continuously monitored on a polygraph (Grass model 78). An epileptogenic focus was induced in sensorimotor cortex by intracortical injection of 5,000 units potassium penicillin (in 0.05 ml distilled water) approximately 1 mm deep into the left anterior sigmoid gyrus. In 36 cats, two glass coated plantinum iridium microelectrodes (F. Haer and Co.) were used to record Purkinje cell activity in the cerebellar cortex and both cellular discharge and epileptiform activity in the anterior sigmoids gyrus at points within 1 2 mm of the site of penicillin injection. Purkinje cells were identified by the amplitude of their extracellular spikes (0.4 mV or larger), depth.below cortical surface (300~00 It), and their characteristic climbing fiber responses. In all animals, the spontaneous discharge activity of several P-cells in the anterior and posterior cerebellar vermis and in the right or left paravermal hemisphere was sampled and photographed prior to intracortical injection of penicillin. Additional P-cells were sampled over a period of at least 7 h following penicillin, during development of progressively longer and more intense epileptiform bursts and ictal interictal episodes. Similarly, the discharge of several cells in sensorimotor cortex was sampled prior to penicillin injection, after which time additional cells were studied over the next 1 2 h period until high voltage epileptiform bursts made it technically difficult to record cellular discharge. In 14 additional animals, dye-filled glass microelectrodes (2.7 M KC1, 1.5-2.5 Mf~) were located stereotaxically in the left or right dentate nucleus and an additional electrode was located in sensorimotor cortex near the site of the penicillin focus. Sampling patterns similar to those used to study P-cells were used to study cells in the dentate nucleus. Dentate cells were identified by stereotaxic location, spontaneous discharge rate of approximately 35~10 c/sec (Thach 1972), and by post-recording injection of dye at the recording site for later histologic verification. At the completion of each experiment, the animal was anesthetized with pentobarbital, perfused

R. M. J U L I E N A N D K. D. LAXER

with formalin, and electrode placement verified. Data were ~inalyzed only from cells near dye marks located within the dentate nucleus. RESULTS

A. Purkinie cell responses Prior to intracortical injection of penicillin into sensorimotor cortex, simultaneous recording of cells in the cerebellar cortex and in the anterior sigmoid gyrus indicates that cellular activity in the midline cerebellar vermis or in the right paravermal hemisphere is asynchronous with respect to activity of cells located in the left sensorimotor cortex. No cerebellar Purkinje cells have been found which discharge in patterns which correlate with the spontaneous activity of single cells in cerebral cortex. This asynchrony between cerebral and cerebellar activity persists for up to 20 rain after intracortical injection of penicillin into sensorimotor cortex, even though focal discharges accompanied by bursts of cellular discharge are readily recordable from the area of penicillin injection (Fig. 1, A). In this example, Purkinje cell discharge (from posterior vermis) is low in frequency (15-20 c/sec) and apparently random and uninfluenced by either cellular or gross activity occurring in the developing focus. Shortly thereafter, l~owever, the cerebellar cortex begins to respond to activity in the cerebrum and bursts of Purkinje cell discharge are evoked at latencies of approximately 20 msec (Fig. I,B and C).As the penicillin focus develops (30~,0 rain after application), higher frequency bursts of Purkiilje cell discharge are evoked over wide areas of the anterior and posterior vermis (Fig. I,D) and in the contralateral paravermal hemisphere (Fig. 2). During this early stage of seizure development, P-cells in the ipsilateral paravermal area seldom are evoked by focal discharge. Similarly, on the EEG, penicillin-induced epileptiform discharges are only poorly conducted to contralateral cortex. By approximately 45 rain after penicillin application, short (2-10 sec) bursts of penicillininduced epileptiform activity appear. Purkinje cells, throughout the cerebellar cortex, discharge at high frequencies (150 200 c/sec) for the duration of these bursts and cease discharging follow-

125

CEREBELLAR RESPONSES 1N EPILEPSY

A

B

IO.5

mV

D

IlOmv iO0 ms=:

Fig. I. Cellular discharge recorded in posterior cerebellar vermis (upper trace) and anterior sigmoid gyrus (lower trace) 15 min (A), 20 min (B), 25 min (C) and 45 rain (D) following injection of 5,000 units penicillin at a point approx. 2.0 mm medial to the recording microelectrode in sensorimotor cortex. In this and in Fig. 2-4 upper traces are from the cerebellar cortex while the lower trace is recorded from cerebral cortex (left anterior sigmoid gyrus). Note the increasing responsiveness of the Purkinje cell as focal discharge intensifies.

ing cessation of the episode. These short episodes are conducted to the right cerebral hemisphere and Purkinje cells in theleft paravermis discharge in a manner identical to that of cells contralateral

to the focus. It is not clear whether Purkinje cells in cerebellar cortex ipsilateral to the focal area respond directly to high voltage focal discharge or indirectly as a result of involvement of cortex

126

R. M. JULIEN AND K. D. LAXER

0,5 mV

episodes. In addition, in the study of 95 cells located in the dentate nucleus (see below) such loss of cellular discharge did not accompany intensification of epileptiform activity.

A

IDmV 200 m'sec

•

Iri,, ~ II,.,i ~ , ,i

B

I

!

50 w-,=e¢ Fig. 2. Response of Purkinje cell in contralateral paravermis (upper trace) to epileptiform activity originating in sensorimotor cortex (lower trace). Note the difference in time bases in A and B. High frequency (100 c/see) Purkinje cell discharge begins approx. 20 msec after the initial negative deflection of the gross epileptiform potential.

contralateral to the focus, as would be predicted by known anatomic pathways (Evarts and Thach 1969). As the penicillin focus develops and activity in sensorimotor cortex intensifies, an unusual phenomenon is observed in the cerebellum. As discussed above, short ictal episodes are accompanied by evoked bursts of Purkinje cells. However, commencing approximately 75 90 min after penicillin, Purkinje cell discharge abruptly ceases during periods of sustained focal discharge and epileptiform activity intensifies and becomes maximal, rhythmic, synchronous, and prolonged (Fig. 3) spreading from the focus to involve both cerebral hemispheres. Purkinje cells remain quiescent during the remainder of the episode and seldom resume discharging for up to 30 sec after cessation of the seizure. The possibility exists that this observed loss of P-cell discharge could be an artifact caused by movement resulting in loss of spike resolution. This possibility is lessened, however, by the study of over 250 P-cells from 31 animals. In each animal, loss of P-cell discharge accompanied development of the maximal, bilateral, epileptiform

B. Responses of dentate cells Spontaneous discharge recorded from cells located in the dentate nucleus is characteristically higher than that recorded from P-cells, averaging approximately 30-40 c/see (Fig. 4,A). By 15 min following injection of penicillin into sensorimotor cortex, slight increases in dentate cell firing are observed (30-80 c/see in Fig. 4,B) concomitant with penicillin-induced cortical epileptiform spikes. By 30 rain after penicillin, cerebral cortical activity evokes a more complex dentate response (Fig. 4,C and D), i.e., during the high voltage epileptiform spike, dentate cells are quiescent while at the termination of the spike, high frequency (up to 250 c/sec) bursts of dentate activity occur. These bursts are usually of short duration (150 msec or less) and are followed by a short period of quiescence with rapid return to control discharge frequency. By 45 rain after penicillin, short bursts of epileptiform activity develop and dentate cells continue to exhibit this pattern of complex high frequency bursts which follow the epileptiform spike. At the cessation of the episode, dentate cells cease discharging and within 0.2-0.5 sec resume spontaneous discharge rates. During prolonged epileptiform episodes (Fig. 5), dentate cells discharge at high frequencies throughout the episodes and do not cease discharging as did the P-cells during similar episodes. During these episodes, no differences in the activity of cells located in either ipsilateral or contralateral dentate nucleus have been observed. DISCUSSION

In the use of locally anesthetized, paralyzed animals in experimental epilepsy, several methodologic considerations are of importance (Purpura et al. 1972); first, there should be no anesthetic in the blood or brain as these agents tend to suppress seizure activity. This includes the local anesthetic used to obtund pain in paralyzed preparations. Benzocaine powder was chosen as an agent of choice since Demetrescu

127

CEREBELLAR RESPONSES IN EPILEPSY

.

.

.

.

.

.

.

.

.

.

IiilJlll 11[l fflllih I r " r V e v ~ T tlv[- PY'I[V[Y'V¢| r

I

"

,

I

_

a __

II

I

,,,-losmv

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

L

I

....

l

A

_

--IL0~ 02see Fig. 3. Activity of a Purkinje cell in the anterior cerebellar vermis before, during, and after a penicillin-induced epileptiform burst recorded in sensorimotor cortex. Note the spontaneous and evoked cellular discharge (top trace), cessation of cellular discharge during transition to high voltage seizure activity (left side of 2nd set of traces), and the return of spontaneous and evoked cellular discharge approx. 10 sec following termination of the seizure. Vertical deflections above the cerebellar recording during the last half of the seizure are high voltage spikes from the focus overshooting the cerebellar record. and Julien (in press) have demonstrated that only lipid-soluble, water-insoluble agents (such as benzocaine) are free of central effects, since they remain at the site of topical application. Second, the paralyzing agent should not alter cortical excitability. Thus, animals were paralyzed with D-tubocurarine rather than with gallamine (Halpern and Black 1968). Third, a slight hyperventilation of the animal (from a normal end-tidal C O 2 of 3 . 5 - 3 . 8 ~ to 3.0-3.2,Vo) appears necessary in order to induce prolonged ictal interictal episodes rather than merely interictal spiking. With these parameters controlled, reliable patterns of epileptiform discharge can be induced following application of penicillin to cerebral cortex.

Development of penicillin-induced epileptiform activity passes through several stages over a 1.5-2 h period. Within a few minutes after injection of penicillin into cerebral cortex there is an increase in cellular activity near the site of injection accompanied by gross deflection of the baseline (Fig. 1,A). Cellular discharge is superimposed over both positive- and negative-going components of the potential. By 20-30 min after injection, the amplitude of the gross potential increases and both the Purkinje cells (Fig. I,B and C) and the cells in the dentate nucleus (Fig. 4,B) discharge in response to epileptiform activity. At this early stage of seizure development, the inhibitory p a u s e seen before the high frequency dentate burst is not observed (compare

128

R. M. JULIEN AND K. 1). LAXER

I

Illll

="

II

I.III

.

I

II

.

-

IIII

C

D

I 2.0mY

.I QSmV I

L

2OO ~ Vig. 4. A: spontaneous unit activity in dentate nucleus prior to penicillin injection. B I5 min after penicillin injection. Upper trace, recording from focus in anterior sigmoid gyrus. Lower trace, recording from dentate nucleus. C and D: recording from focus (upper trace) and from dentate (lower trace) 30 min after penicillin.

Fig. 4, B with 4, C). Presumably, this inhibitory pause has not developed since at this stage of seizure development, P-cell bursts are only weakly evoked by epileptiform activity (compare Fig. I,A with 2,A). This inhibitory pause in the dentate seems to appear only after development of P-cell responses similar to those illustrated in Fig. 2. As the focus continues to develop, P-cells respond to each focal discharge by exhibiting a high frequency burst of spikes with a latency of approximately 20 msec and a burst duration usually lasting 75 100 msec (Fig. 2). During the time period of this P-cell bursts, cells in the dentate nucleus exhibit the characteristically inhibitory pause and after a latency of approximately 100 msec burst at frequencies greater than 250 c/sec (Fig. 4, C and D). As the penicillin focus develops further, epileptiform activity becomes progressively more intense, eventually developing into episodes

which become maximal, synchronous and prolonged in both cerebral hemispheres. As presented in Fig. 3 and 5, P-cells cease discharging during the development of such episodes while dentate cells discharge at high frequencies throughout the episode. This loss of P-cell discharge during the development of maximal epileptiform episodes has also been observed by Snider (personal communication). To date, however, no cause and effect relationship can be ascribed between loss of P-cell discharge and intensification of epileptiform activity. Post-ictally, dentate cells cease their high frequency burst pattern and usually within 1 sec return to random rates (Fig. 5). The P-cells, however, which ceased discharging as the episode developed, do not resume discharging spontaneously until many seconds later (Fig. 3). This implies that the cerebellar cortex is not involved in the active termination ofepileptiform episodes.

129

CEREBELLAR RESPONSES IN EPILEPSY

:--7---'----:-

-

- -

~ , , ~. ., . .

:

:

L

.L, . . . . . .

[

Iil[

I

•

L

,

,

-,

,-,,-

-

T

.

20m',/

osmv

2 O 0 m s~c

Fig. 5. Thirty second epileptiform burst recorded approx. 1.5 h after penicillin. Upper trace, recording from focus. Lower trace, discharge of cell located in dentate nucleus. Note continuous high frequency discharge of dentate cell during entire epileptiform episode.

Schematic representation of this sequence of events involving P-cell and dentate responses to focal spikes and prolonged epileptiform episodes is illustrated in Fig. 6, A and B respectively. The above P-cell sequence agrees to a large extent with the earlier data of FernandezGuardiola et al. (1962). They reported that low voltage, single or repetitive stimulation of cerebral cortex was incapable of modifying the discharge of cells in the cerebellar cortex, agreeing with our observation of the failure of the early stages of penicillin seizures to elicit Purkinje cell discharge (Fig. 1,A). They found, however, that high intensity shocks to cerebral cortex could elicit high frequency bursts of cerebellar cortical cells (agreeing with our observa-

tions that well-developed penicillin discharges were followed at short latency by high frequency bursts of Purkinje cells) (Fig. 2). In their study Of Metrazol and Megimide, they demonstrated that cerebellar cortical cells initially discharged at high frequency but ceased discharging during the clonic phase of the convulsive activity (similar to Fig. 3, above). However, they noted that cerebellar cortical cells resumed discharging before the termination of the seizure and they interpreted this to mean that the increased cerebellar activity may have acted to actively terminate the seizure. The data presented here, however, indicate that P-cells do not resume discharging until after termination of the seizure.

130

R. M. JULIEN AND K. D. LAXER A

C

Finally, demonstration that Purkinje cells do not resume discharge until after termination of iIII prolonged epileptiform episodes indicates that once Purkinje cells have ceased discharging and the episode generalizes, termination of the epilOOms sode is likely by a mechanism outside the cereB bellum. If an active inhibitory process exists in the cerebellum, it may act primarily to prevent d 2OOHz short, focally restricted seizures from spreading d z and becoming generalized. 300Hz~ -1 Q: 150Hz The well-established anatomy of the PurkinjeOHz [ dentate-cortical loop can be displayed in the conI0 20 30 40 50 60 70 80 90 I00 I10 trol block diagram presented in Fig. 6, C. Activity TIME (SEC) in sensorimotor cortex projects to brain stem Fig. 6. Schematic representation of Purkinje (P) cell and nuclei which in turn project to both P-cells and dentate (D) cell responses to: A = focal cortical spike; and dentate cells (Evarts and Thach 1969). P-cells in B = prolonged epileptiform bursts. C is a block diagram for turn are inhibitory in their projection to the cerebral cortical~zerebellar interactions. S-M Ctx = sensorimotor cortex; P N = p o n t i n e nuclei; IO=inferior olive; dentate (Eccles et al. 1967; Ito 1970). Finally, P C = P u r k i n j e cell; D N = d e n t a t e nucleus; T H A L = n o n cells in the dentate project largely to nucleus specific thalamus. For simplicity, the intermediate steps ventralis lateralis of the thalamus and ultimately between the pontine cells and the P-cells have been omitted. to cerebral cortex (Evarts and Yhach 1969: See text for discussion. Massion and Rispal-Padel 1972). It is readily From the above data, therefore, the cere- apparent that a major site of inhibitory control bellum appears to have a rather high threshold in the circuit of Fig. 6, C is the P-cell projection of response to activity originating in cerebral to the dentate nucleus. Loss of P-cell discharge cortex. The cerebellar cortex, therefore, does not during the developing seizure might tend thereappear to provide a sensitive feedback circuit fore to perpetuate the episode. comparable to the cortico-thalamo-caudate cirSimilarly based on this diagram: (1) either cuits (Jung 1949; Kreindler 1964; Demetrescu interruption of the cortico-dendate-thalamic et al. 1965a, b: Demetrescu 1967; LaGrutta pathway or increased cerebellar cortical activity et al. 1971). However, when cerebellar responses should decrease seizure activity while (2) stimuare evoked by focal activity, high frequency lation of this pathway or inhibition of the cerebursts of Purkinje cells are induced (Fig. 2). bellar cortex should increase seizure activity. Such discharges are known to be inhibitory in There is some evidence for such effects. their projections to cerebellar nuclei (Eccles Electrical stimulation of the cerebellar cortex et al. 1967; Evarts and Thach 1969) as indicated inhibits or abolishes epileptiform activity both by the 100 msec inhibitory pause observed in the in experimental animals and in man (see Introdentate nucleus following a cortical spike (Fig. duction) and decreases unit discharge in the 4, C and D). thalamus and cerebral cortex (Snider eta/. 1970). The observation that P-cell discharge is lost Pharmacological augmentation of P-cell activity during development of maximal seizure activity. (Julien 1972; Julien and Halpern 1972) and an while dentate cell activity is not lost is indeed intact cerebellar cortex are necessary for the full curious. While such an observation might con- antiepileptic action of diphenylhydantoin (Gaceivably be artifact subsequent to toss of Spike breels 1970). Ablation of the cerebellar cortex resolution or to movement, this observation was may intensify seizure discharge (Dowet al. 1962: also reported by Fern/mdez-Guardiola et al. Gabreels 1970). In the dentate nucleus, electrical (1962) and by Snider (personal communication). stimulation may intensify seizure activity (Babb Neither the mechanism nor the significance of et al. 1974). In the thalamus, electrical or this loss of P-cell discharge during seizure devel- chemical stimulation induces, intensifies or opment are known. generalizes seizures (Mahnke et al. 1971) while F-c{,us

L__

131

C E R E B E L L A R RESPONSES IN E P I L E P S Y

ablation reduces seizure frequency and duration (Kusske et el. 1972). Finally, Hobson and McCarley (1972) demonstrated that the discharge rate of Purkinje cells decreases during the transition from waking to synchronized (slow-wave) sleep. Since low frequency dentate stimulation synchronizes activity in non-specific thalamic nuclei (Hayrapetian and Vaghanian 1970) and thalamic stimulation synchronizes activity in sensorimotor cortex, loss of P-cell control over dentate activity might lead to cortical and subcortical hypersynchrony. These data are intriguing since there is clinical information that seizures frequently occur during the transition from wakefulness to synchronized sleep and synchronized sleep may facilitate the appearance of generalized bilateral hypersynchrony (Pompeiano 1969). All of the above data are in agreement with the circuit diagram of Fig. 6, C and with the proposed role of the cerebellar cortex in the modulation of epileptiform activity. Recently, Thach (1972) in investigations of the role of the cerebellum in the regulation of movement and posture came to the conclusion that the role of the P-cell is to modify through restraint the already initiated output of the cerebellar nuclei. The present results would suggest a similar role of the P-cell in the modulation of epileptiform activity. SUMMARY

In locally anesthetized, paralyzed cats with penicillin-induced loci in sensorimotor cortex, simultaneous microelectrode recordings were made in the cerebellum and in the anterior sigmoid gyrus near the site of penicillin injection. Cerebellar recordings were made from Purkinje cells (P-cells) and from cells located in the dentate nucleus. Data reveal distinct patterns of cerebellar responsiveness to the developing epileptogenic focus. Within 15 min after penicillin injection, high frequency (100-140 c/sec) P-cell discharges were evoked throughout the cerebellar cortex by focal "spike" activity of the cerebral cortex. These P-cell discharges outlasted short (2 10 sec) epileptiform bursts; however, if P-cell discharges ceased during periods of sustained focal discharge, prolonged

(up to 60 sec) convulsive episodes developed and became synchronous and maximal in both cerebral hemispheres. P-cell discharge did not reappear until after termination of the seizure. In the dentate nucleus, epileptiform activity evoked complex patterns of cellular activity. In contrast to the P-cells, cells in the dentate nucleus discharged at high frequencies during prolonged epileptiform episodes. The proposed role of the cerebellum in the control of cortical excitability is discussed. RESUME R E P O N S E S CEREBELLEUSES A DES D E C H A R G E S EPILEPTIEORMES C E R E B R O - C O R T I C A L E S 1NDUITES P A R PENICILLINE

Chez des chats paralyses sous anesthesie locale, porteurs de foyers induits par penicilline dans le cortex sensori-moteur, des enregistrements par micro-electrodes ont ate realises simultanement dens le cervelet et dens le gyrus sigmoide anterieur au voisinage du siege de l'injection de penicilline. Des enregistrements cerebelleux ont ete effectues au niveau de cellules de Purkinje (cellules P) et de cellules localisees dans le noyau dentele. Les donnees revelent des patterns distincts de reactivite cerebelleuse au fur et "a mesure du developpement du foyer epileptogene. Dans les 15 rain consecutives "a l'injection de penicilline, des decharges "a haute frequence des cellules (I00/l 140 c/sec) sont evoquees sur tout le cortex cerebelleux par une activit6 locale de pointes du cortex cerebral. Ces decharges de cellules P durent Nus longtemps que des bouff6es epileptiformes breves (2/t 10 sec); cependant si les dacharges des cellules P cessent au cours de periodes de dacharges focales intenses et prolongees (au-del'a de 60 sec), des episodes convulsifs se developpent et deviennent synchrones avec un maximum dans les deux hemispheres carebraux. La decharge des cellules P ne reapparait pas jusqu'apres la fin de la crise. Dans le noyau dentele, l'activite epileptiforme 6voque des patterns complexes d'activit6 cellulaire. Contrairement aux cellules P, les cellules du noyau dentel6 dechargent fi haute frequence au cours des episodes epileptiformes prolonges. Le r61e suggere du cervelet dans le contr61e de l'excitabilite corticale est discute.

132 REFERENCES BAB~, T. L., MITCHELL, A. G. and CRANDALL, P. H. Fastigiobulbar and dentato-thalamic influences on hippocampal cobalt epilepsy in the cat. Electroenceph. clin. Neurophysiol., 1974, 36:141 154. COOKE, P. M. and SNIDER, R. S. Some cerebellar influences on electrically-induced cerebral seizures. Epilepsia (Amst.), 1955, 4 : 1 9 28. COOPER, I. S., CRIGnEL, E. and AMIN, 1. Clinical and physiological effects of stimulation of the paleocerebellum in humans. J. Amer. Geriat. Soe., 1973, 21: 40~,3. COOPER, I. S., AMIN, I., GILMAN, S. and WALTZ, J. M. The effect of chronic s'timulation of cerebellar cortex on epilepsy in man, In The cerebellum, epilepsy and behavior. Plenum Press, New York, 1974. DEMETRESCU, M. Ascending inhibitory and facilitatory influences controlling primary thalamo-cortical responsiveness. Brain Res., 1967, 7: 3 6 ~ 7 . DEMETRESCU,M., DEMETRESCU,M. and IOSIF,G. The tonic control of cortical responsiveness by inhibitory and facilitatory diffuse influences, Electroenceph. clin. Neurophysiol., 1965a, 18:1 24. DEMETRESCU, M., DEMETRESCU, M. and IOSIF, G. The subcortical inhibitory structures and cortical seizure activity in cats. Proc. 8th int. Congr. Neurol. (Vienna), 1965b, 4: 265 258. DEMETRESCU, M. and JULIEN, R. M. Local anesthetics and experimental epilepsy. Epilepsia (Amst.), in press. DONDEV, M. and SNIDER,R. S. Slow potential shifts following cerebellar stimulation. Electroenceph. clin. Neurophysiol., 1955, 7:265 272. Dow, R. S. Extrinsic regulatory mechanisms of seizure activity. Epilepsia (Amst.), 1965, 6 : 1 2 2 140. Dow, R. S., FERNANDEZ-GUARDIOLA,A. and MANNI, E. The influence of the cerebellum on experimental epilepsy. Electroenceph. clhl. Neurophysiol., 1962, 14:383 398. ECCLES, J. C., ITo, M. and SZENTAGOT~AI,J. The cerebellum as a neuronal machine. Springer, New York, 1967. EVARTS, E. V. and THACH, W. T. Motor mechanisms of the CNS : Cerebrocerebellar interactions. Ann. Rev. Physiol., 1969, 31 : 451-498. FERNANDEZ-GUARDIOLA, A., MANNI, E., WILSON, J. H. and Dow, R. S. Microelectrode recordings ofcerebellar and cerebral unit activity during convulsive discharge. Exp. Neurol., 1962, 6 : 48-69. GABREELS, F. J. M. De invloed van phenytoine op de Purkin/ecell van de rat. Doctoral dissertation. Catholic University of The Netherlands, Nijmegen, 1970. (Summarized in Epilepsy Abstracts, 1972, 5: 110.) HALPERN, L. M. and BLACK, R. G. Gallamine triethiodide facilitation of local cortical excitability compared with other neuromuscular blocking agents. J. Pharmacol. exp. Ther., 1968, 162: 166-173. HAVRAPET1AN,A. A. and VAGHANIAN,L. G. Some peculiarities of neuronal activity on the thalamo-cortical regulatory system. Sechenov Physiol. J. (U.S.S.R./, 1970, 56: 527 534.

R. M. JULIEN AND K. D. LAXER HOBSON, J. A. and MCCARLEY, R. W. Spontaneous discharge rates of cat cerebellar Purkinje cells in sleep and waking. Electroenceph. elin. Neurophysiol., 1972, 33:457 469. HVTTON, J. T., FROST, J. D. and FOSTER, J. The influence or the cerebellum in cat penicillin epilepsy. Epilepsia (Amst.), 1972, 13: 4 0 1 4 0 8 . ITO, M. Neurophysiological aspects of the cerebellar motor control system. Int. J. Neurol., 1970, 7:162 176. I~VATA, K. and SNIDER, R. S. Cerebello-hippocampal influences on the electroencephalogram. Electroeneeph. clin. Neurophysiol., 1959, 11:439 446. JULIEN, R. M. Cerebellar involvement in the antiepileptic action of diazepam. Ncuropharmacolo~ly, 1972, l l: 683 691. JULIEN, R. M. Lidocaine in experimental epilepsy: Correlation of anticonvulsant effect with blood concentrations. Electroenceph. clin. Neurophysiol., 1973, 34 : 639-645. JUL1EN, R. M. and HALPER~, L. M. Effects ofdiphenylhydantoin and other antiepileptic drugs on epileptiform activity and Purkinje cell dischargc rates. Epilepsia (Amst.), 1972, 13: 387-400. JUNG, R. Hirnelektrische Untersuchungen fiber den Electrokrampf, die Erregungsablaufe in corticalen Hirn regionen bei Katz und Hund. Arch. Psychiat. Nervenkr., 1949, 183:206 244. KREINDLER, A. Experimental epilepsy. In Proglress m Brain Research, Elsevier, Amsterdam, 1964, 19:160 167. KUSSKE, J., OJEMANN, G. A. and WARD, A. A. The effects of lesions in ventral anterior thalamus on experimental focal epilepsy. Exp. Neurol., 1972, 3 4 : 2 7 9 290. LAGRUTTA, V., AMATO, G. and ZAGAMI,M. T. The importance of the caudate nucleus in the control of convulsive activity on the amygdaloid complex and the temporal cortex of the cat. Electroenceph. olin. Neurophl,siol.. 1971, 31 : 57-69. MAHNKE, J. H., BABB, T. L. and VERZEANO, M. The action of cholinergic agents on the electrical activity of the nonspecific nuclei of the thalamus. Proc. Amcr. Ass. Neurol. Sur#., 1971. MASSION, J. and RISPAL-PADEL, L. Spatial organization of the cerebello-thalamo-cortical pathway. Brabt Res., 1972, 40:61 65. MUTANI,R., BERGAMIN1,L. and DoRl(iUZZl, T. Experimental evidence for the existence of an extrarhinencephalic control of the activity of the cobalt rhinencephalic epileptogenie focus. Part 2: Effects of the paleocerebellar stimulation. Epilepsia (Amst.), 1969, 9:351 362. POMPE1ANO, 0. Sleep mechanisms. In J. JASPER, A. WARD and A. PoPE (Eds.), Brah7 mechanisms (~/"the epih, psies. Little, Brown and Co., Boston, 1969: 453-473. PURPURA, D. M., PENRY, J. K., TOWER, D. B., WOODBURY, D. M. and WALTER, R. D. Experimental mode& o[" epilep.s3' A manual fi)r the laboratory worker. Raven Press, New York, 1972. SN1DER, R. S., MITRE, D. J. and SUD,,OUSKY, A. Cerebellar effects on the cerebrum. Int. J. Neurol., 1970, 2:141 151. THACH, W. T. Cerebellar output: properties, synthesis and uses. Brain Res., 1972, 40:89 97.