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“Generalized” epileptic seizures elicited by electrical stimulation of the frontal lobe in man
Electroencephalography and Clinical Neurophysiology, 1974, 3 7 : 2 7 5 - 2 8 2 © Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
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" G E N E R A L I Z E D " EPILEPTIC SEIZURES ELICITED BY ELECTRICAL STIMULATION OF THE F R O N T A L LOBE IN MAN J. BANCAUD, J. TALAIRACH, P. MOREL, M. BRESSON, A. BONIS, S. GEIER, E. HEMON AND P. BUSER Unit( de Recherches I.N.S.E.R.M. U 97, 2 ter, rue d'Al~sia, 75014 Paris (France)
(Accepted for publication: March 20, 1974)
One major argument advanced by Penfield and Jasper (1954) in support of the centrencephalic origin of primary generalized epilepsies is the impossibility of a cortical epileptogenic lesion or electrical stimulation at any place in the cortex to determine a petit mal (PM) or grand mal (GM) seizure and to reproduce the electrographic patterns which characterize these attacks. Our findings with the stereotaxic methodology (stereoelectroencephalography,SEEG) have been rather different and do not coincide with the previous conclusions. When studying spontaneous seizures showing all the Characteristics of a PM absence, of a generalized tonic-clonic seizure or of a tonic axial attack, we observed that the discharges might initially be localized, first involving the cerebral cortex in the neighbourhood of an identified lesion (Bancaud et al. 1965, 1973; Bancaud and Talairacfi 1965; Bancaud 1969, 1971, 1972). In addition, such attacks could also be reproduced by electrical stimulation of the same cortical epileptogenic zone (Bancaud et al. 1965, 1973 ; Bancaud 1969, 1972; Niedermeyer 1970, 1972). In this paper we intend to show that it is possible to elicit generalized epileptic attacks "of the centrencephalic type" in man through electrical stimulation of the frontal lobe. The significance of these observations will be discussed. METHODS AND MATERIAL
The group of patients studied included 10 subjects who had severe epilepsies resistant to drug treatment and who were submitted to one or several SEEG explorations to determine
whether surgical intervention would be possible. The patients, 7 men and 3 women, ranged from 18 to 27 years of age at the time of the investigation. For each patient the attacks, which occurred several times daily (4 patients had status epilepticus), varied: they were characterized by simple absences or complex absences associated or not with tonic-clonic seizures generalized from onset. In 3 cases the attacks first appeared before the age of 5 years; in 4 cases they first occurred between the ages of 6 and 12 and in 3 cases between 13 and 16 years. Various examinations of these patients showed the existence of bilateral frontal epileptogenic zones in 8 cases and of a unilateral epileptogenic zone in the other 2. The clinical (psychologic, psychiatric, neurologic, etc.) examinations and the neuroradiologic assessment conducted under stereotaxic conditions (combining fractionated pneumoencephalography, light and heavy contrast ventriculography and bilateral carotid arteriography) showed a non-tumoural cerebral lesion in 5 patients. The EEG records were characterized in every case by discharges of spikes and waves and bilateral poly-spikes and waves of variable frequency (2-5 c/sec), which were bilaterally synchronous and symmetrical in 4 cases, asymmetrical in 3 cases, and clearly unilateral in 3 other cases. In all cases, these abnormalities predominated in the anterior regions, but it was impossible to demonstrate a localized "irritative" zone. The placement of the intracranial multilead electrodes was achieved by means of the stereotaxic method previously described on several occasions (Talairach et al. 1949, 1952, 1957,
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1958. 1967: Talairach and Bancaud 1973. 19741. The technical and methodological procedures used for these SEEG investigations have also been reported elsewhere (Bancaud and Dell 1959: Bancaud e t al. 1965. 1973: Buser and Bancaud 1967; Bancaud and Talairach 19741. In order to characterize the epileptogenic focus several multilead electrodes were introduced into the external and mesial cortex and the white matter at different sites of the cerebral hemisphere and in some subcortical structures. The patients were anaesthetized with 3--10 mg of dextromoramide with occasional addition of 40-60 mg of gallamine tri-iodoethylate (Flaxedil); these drugs were administered in the morning for electrode implantation. The patient awoke gradually towards noon. Depth recording and stimulation began at about 3 p.m. and were continued in the succeeding hours, The patients were therefore awake and conscious during the exploration itself. Unidirectional rectangular pulses from a conventional stimulator were delivered between two leads of the same electrode (separated by a distance of 1.5 mm). Their voltage, frequency and duration could be varied independently: voltages ranged from 2 to 12 V, frequencies between 1 and 50 c/sec and pulse durations from 1 to 3 msec: the overall durations of pulse trains usually employed ranged between 1 and 12 sec. while the most frequently used values were 6 V. 1 msec. 50 cisec, during 5 6 sec. /-"
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Depth recordings were always performed bipolarly between two adjacent leads of the same electrode. These were displayed, together with some conventional scalp recordings, on a 23 channel ink-writer (Alvar) and controlled on a 4 channel oscilloscope. RESULTS
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During the 16 SEEG explorations of the l0 patients 634 electrical stimulations were delivered. of which 509 were directed to various structures in the two frontal lobes (Fig. l). Out of these 509 local stimulations of the frontal lobes. 150 induced electrical or electro-clinical events that can be characterized as either: (a) simple absences (accompanied by spikes and waves) in 67 cases (Fig. 2 and 3); (b) complex absences (accompanied by spikes and waves) in
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ELECTRICAL STIMULATION OF FRONTAL LOBE
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29 cases; (c) generalized tonic-clonic seizures in 17 cases; or (d)"sub-clinical" spike and wave discharges in 37 cases. In all patients these elicited seizures were practically identical to their spon-
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taneous attacks; they started soon after onset of the stimuli and ended with them, except for the tonic--clonic seizures which continued after cessation of stimulation• All electrodes eliciting clinical responses were located in the cortex of the frontal lobes. As shown in Fig. 4 and 5, the electrodes whose stimulation provoked electro-clinical absences were almost always located in the mesial frontal cortex (118 times), extending from the rolandic region to the frontal pole, sometimes in the cingulate gyrus (16 times) and in corona radiata or external frontal cortex (16 times). a. Stimulation of a limited portion of the mesial frontal cortex on one side (Fig. 6), induced electro-clinical absences in only 2 of the 10 patients. In fact, this occurred precisely in the 2 patients whose epileptogenic zone was located where the deep electrodes had been introduced. b. In the other 8 cases, absences were pro-
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was prolonged. With the same stimulus locations in the same patients, we noticed that, with increased voltage or duration of the trains, the response was modified: consisting of "sub-clinical" spikes and waves with weak stimuli, the response typically became an absence for high intensities and a generalized tonic-clonic seizure with even higher intensities. Finally it seemed to us that, in a given subject, the responses were all the more easy to obtain the closer the frequency of stimulation was to that of spontaneous paroxysmal discharges (spikes and waves at 2-5 c/see).
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voked by stimulation of the mesial cortex of the two frontal lobes over a very extensive area (Fig. 7). Moreover it must be stressed that in these patients the zones of "positive" response were practically symmetrical (Fig. 8). A study of the relationship between the stimulation frequency and the type of attack showed that absences were generally induced by low frequencies, at about 3 c/sec, while tonic-clonic seizures were induced by higher frequencies. On the other hand, stimuli at 1 c/sec never produced a tonic-ctonic attack, even when stimulation
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ELECTRICAL STIMULATION OF FRONTAL LOBE DISCUSSION
To summarize our findings briefly, the stimulation of a limited portion of one frontal cortex in man, especially its mesial aspect, could induce either paroxysmal discharges of bilateral spikes and waves, most often synchronous and sometimes accompanied by simple or complex typical absences, or discharges of apparently diffuse spikes accompanied by generalized tonic-clonic attacks. These attacks induced by electrical stimulation could not be differentiated in our series from those spontaneously appearing or chemically induced in the same patient. The very fast propagation and wide extension of the discharge also yielded EEG pictures identical to those characterizing spontaneous attacks of the patient, whether spikes and waves or fast spikes were involved. Moreover, these electrical paroxysms were related to a clinical semiology which closely resembled that of absences or of tonic-clonic seizures generalized from the onset. In other words, localized stimulation of the frontal cortex, most often of its mesial aspect, can elicit electro-clinical absences or typical generalized convulsive seizures. The morphology, the frequency and the topographical distribution of the discharges, which occurred soon after the onset of, and lasted as long as, the stimuli, were related to the type of the given electrical pulses and not to the site where they were delivered. In fact, stimulation with different parameters applied to the same area could induce either "sub-clinical" discharges of spikes and waves, or absences, or generalized tonic-clonic attacks. This possibility of transforming an absence into a convulsive seizure is well-known in epileptology and was previously considered by Penfield and Jasper (1954). On the other hand we were never able to provoke absences in a subject who had not previously had them spontaneously (Bancaud et al. 1965). With respect to localization, it is interesting to note that in our series it was only stimulation of the frontal cortex which enabled us to provoke absences. In our observations the mesial cortex generally seemed much more sensitive than the external cortex, but this may only be a matter of stimulus threshold. A topographical study of the effective sites did not indicate the presence of a
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privileged place in the frontal lobe and the zone responsible for the cortical discharges varied from one subject to another. This zone rarely covered a restricted territory and was only unilateral in a limited number of cases..On the contrary, in most cases the effective areas were distributed in the two frontal regions and were practically symmetrical. It is impossible to know if these bilateral epileptogenic zones were present from the beginning or if we were dealing with the gradual building up of a mirror focus, as has been suggested by various animal (Mutani et al. 1973) and human (Bancaud et al. 1965) studies. We believe that our observations raise the question of the origin and mechanism of extension of generalized epileptic attacks. Tiikel and Jasper (1952) have already claimed that in patients with unilateral lesions of the parasagittal cortex bilateral spike and wave type attacks could be observed; these patterns would correspond to "secondary synchrony" as distinct from "primary synchrony" of centrencephalic origin, spike and waves of the first type being more irregular than those of the second type. At variance with this opinion, we find that no distinction can be made between the electrographic epileptic patterns described in our cases here and typical bilateral synchronous spikes and waves most usually considered as originating from deep structures. We tend to assume that more or less restricted zones of the cerebral cortex play an essential role as regions of origin in these types of epilepsies. Although the theory of the centrencephalic origin of primary generalized epilepsies (Penfield and Jasper 1954) is based on numerous clinical, EEG and experimental data, a considerable number of other arguments and/or observations have been raised against it. The localizing value of synchronous bilateral EEG abnormalities has been questioned and the presence of multiple generators in the cortex explaining these abnormalities has been suggested (Petsche et al. 1970; Scarpelezos et al. 1973). Moreover, the results from stimulating various cerebral structures or from creating experimental epiteptogenic foci in animals also seem to favour this essential role of the cerebral cortex (Kaada 1951 ; Lennox and Robinson 1951; Ingvar 1959; Ralston 1961; Marcus and Watson 1964; Naquet
280 et al. t968; Marcus and Jacobson 1969; Mutani et al. 1973). The modes of action of sedatives or
convulsant drugs introduced into the brain through various routes were also considered to favour the cortical origin of diffuse discharges in animals by Shimizu et al. (1952) and Starzl et al. (1953) and in man by Bennett and Gibbs (1952). Loiseau and Cohadon (1970) quoted 19 cases from the literature in whom mostly frontal hemispheric cerebral tumours were responsible for a petit mal; we were also able to find (Pruvot et al. 1972) 11 cases of generalized epilepsies due to localized, generally frontal, cortical trauma. Finally, other stereotaxic investigations have also led to consideration of the primary role of the cerebral cortex in eliciting generalized attacks (Bancaud I971: Goldring 1972: Niedermeyer 19721. The mechanism of the bilateral extension of seizure starting from a restricted cortical zone also remains a matter of discussion. Regarding the thalamus, none of our data as yet really suggest its possible role in either triggering the attack or operating the bilateral transfer (at variance with other data, see Rossi 1973 I. On the other hand. we have data indicating that the interhemispheric pathways, in particular the corpus callosum, could play an essential role in the process of bilateralization. Oscilloscopic analyses (to be published elsewhere) of the responses evoked in one hemisphere through single shock electrical stimulation of the homonymous, contralateral area have brought up some interesting facts in connection with the present discussion: (al the threshold tor eliciting such (presumably transcallosal) contralateral responses is significantly lower in patients with frontal epileptogenic loci: (b) the latency of such responses is rather short ( ~ 10 msec) and remains very constant over several successive shocks: (c) these transcaUosal responses remain closely restricted to the homonymous area, without spreading to other even neighbouring electrodes. In other words, the short connections with few synapses between the two mesial cortices seem to become very excitable in patients with parasagittal lesion, the latency of transfer being sufficient to
J. BANCAUDet al. account for quasi-synchrony (especially with routine low-speed inkwriter recordings). This of course points to the possible role of the neurones which constitute the corpus catlosum. To sum up, although it is not intended here to claim that subcortical structures do not play any role in the elaboration of typical absences or generalized tonic-clonic seizures, we believe that our data point to the essential role that is played by the cerebral cortex, particularly the frontal lobes, in triggering such attacks. SUMMARY
Five hundred and nine electrical stimulations were performed in the frontal lobes of 10 epileptic patients presenting "'generalized" spontaneous attacks. These stimulations were carried out by means of stereotaxically implanted electrodes. Of these 509 stimulations. 150 induced either simple electro-clinical absences (67), complex absences (29), generalized tonic-clonic seizures [17), or only bilaterally synchronous, symmetrical spike and wave paroxysms (37). These responses, which in each case reproduced the spontaneous attacks of the patient. occurred from the beginning of stimulation and ended with it, except for the tonic-clonic seizures. The active electrodes were always located in the frontal lobe, particularly in the mesial cortex. Although the bilateral responses were related to stimulation of a restricted unilateral zone. most often they could be obtained from stimulation of either frontal lobe. in q uasi-symmetrical regions. The type of electro-clinical response obtained was largely related to the parameters of stimulation: thus. in the same patient, a discharge of sub-clinical spikes and waves could become an absence and subsequently a "generalized" tonic clonic seizure, when increasing the intensity or duration of the shocks. These results point to the preponderant role of the cerebral cortex, particularly that of its frontal portion, in elaboration of generalized epileptic attacks.
ELECTRICAL STIMULATIONOF FRONTAL LOBE RESUME
CRISES EPILEPTIQUES "GENERALISEES" PAR STIMULATION ELECTRIQUE DU LOBE FRONTAL CHEZ L'HOMME Les a u t e u r s o n t rapport6 l'incidence de 509 s t i m u l a t i o n s 61ectriques port6es au n i v e a u des lobes f r o n t a u x chez l0 m a l a d e s 6pileptiques pr6s e n t a n t s p o n t a n 6 m e n t des acc~s "g6n6ralis6s". Ces s t i m u l a t i o n s 6taient pratiqu6es au m o y e n d'61ectrodes implant6es scion u n e technique st6r6otaxique particuli6re. Sur ces 509 s t i m u l a t i o n s 150 o n t i n d u i t soit des absences 61ectro-cliniques simples (67 fois) ou complexes (29 lois) soit des crises t o n i c o - c l o n i ques g6n6ralis6es (17 lois) soit seulement des p a r o x y s m e s de p o i n t e s - o n d e s bilat6raux, synchrones et sym6triques (37 fois). Ces r6ponses qui r e p r o d u i s a i e n t les acc+s s p o n t a n 6 s de c h a q u e m a l a d e s u r v e n a i e n t d6s le d 6 b u t de l'excitation et cessaient avec elle except6 les crises t o n i c o - c l o n i q u e s . Les 61ectrodes actives si6geaient t o u j o u r s au n i v e a u d u lobe frontal, en particulier d a n s le cortex de la face interne. Bien q u e des r6ponses bilat6rales aient p u &re suscit6es p a r la s t i m u l a t i o n d ' u n e z o n e unilat6rale restreinte, le plus s o u v e n t elles 6taient obtenues fi partir des deux lobes f r o n t a u x d a n s des r6gions p r a t i q u e m e n t sym6triques. Le type de r6ponses 61ectro-cliniques o b t e n u e s 6tait en g r a n d e partie f o n c t i o n des p a r a m & r e s de s t i m u l a t i o n en sorte q u e l ' o n p o u v a i t passer chez le m ~ m e m a l a d e d ' u n e d6charge de pointeso n d e s i n f r a - c l i n i q u e s ~ u n e absence puis fi u n e crise t o n i c o - c l o n i q u e "g6n6ralis6e". Ces r6sultats p e r m e t t e n t aux auteurs de discuter d u r61e p r 6 p o n d 6 r a n t du cortex c6r6bral, en particulier frontal, d a n s l'61aboration des acc6s 6pileptiques g6n6ralis6s. REFERENCES BANCAUD,J. Physiopathogenesis of generalized epilepsiesof organic nature (SEEG study). In H. GASTAUTet al. (Eds.), The physiopathogenesis of the epilepsies. Thomas, Springfield, Ill., 1969, 316 p. BANCAUD, J. R61e du cortex c6r6bral dans les 6pilepsies "g6n6ralis6es" d'origine organique. Presse M~d., 1971, 79 : 669-673. BANCAUD,J. Mechanisms of cortical discharges in "genera-
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" G E N E R A L I Z E D " EPILEPTIC SEIZURES ELICITED BY ELECTRICAL STIMULATION OF THE F R O N T A L LOBE IN MAN J. BANCAUD, J. TALAIRACH, P. MOREL, M. BRESSON, A. BONIS, S. GEIER, E. HEMON AND P. BUSER Unit( de Recherches I.N.S.E.R.M. U 97, 2 ter, rue d'Al~sia, 75014 Paris (France)
(Accepted for publication: March 20, 1974)
One major argument advanced by Penfield and Jasper (1954) in support of the centrencephalic origin of primary generalized epilepsies is the impossibility of a cortical epileptogenic lesion or electrical stimulation at any place in the cortex to determine a petit mal (PM) or grand mal (GM) seizure and to reproduce the electrographic patterns which characterize these attacks. Our findings with the stereotaxic methodology (stereoelectroencephalography,SEEG) have been rather different and do not coincide with the previous conclusions. When studying spontaneous seizures showing all the Characteristics of a PM absence, of a generalized tonic-clonic seizure or of a tonic axial attack, we observed that the discharges might initially be localized, first involving the cerebral cortex in the neighbourhood of an identified lesion (Bancaud et al. 1965, 1973; Bancaud and Talairacfi 1965; Bancaud 1969, 1971, 1972). In addition, such attacks could also be reproduced by electrical stimulation of the same cortical epileptogenic zone (Bancaud et al. 1965, 1973 ; Bancaud 1969, 1972; Niedermeyer 1970, 1972). In this paper we intend to show that it is possible to elicit generalized epileptic attacks "of the centrencephalic type" in man through electrical stimulation of the frontal lobe. The significance of these observations will be discussed. METHODS AND MATERIAL
The group of patients studied included 10 subjects who had severe epilepsies resistant to drug treatment and who were submitted to one or several SEEG explorations to determine
whether surgical intervention would be possible. The patients, 7 men and 3 women, ranged from 18 to 27 years of age at the time of the investigation. For each patient the attacks, which occurred several times daily (4 patients had status epilepticus), varied: they were characterized by simple absences or complex absences associated or not with tonic-clonic seizures generalized from onset. In 3 cases the attacks first appeared before the age of 5 years; in 4 cases they first occurred between the ages of 6 and 12 and in 3 cases between 13 and 16 years. Various examinations of these patients showed the existence of bilateral frontal epileptogenic zones in 8 cases and of a unilateral epileptogenic zone in the other 2. The clinical (psychologic, psychiatric, neurologic, etc.) examinations and the neuroradiologic assessment conducted under stereotaxic conditions (combining fractionated pneumoencephalography, light and heavy contrast ventriculography and bilateral carotid arteriography) showed a non-tumoural cerebral lesion in 5 patients. The EEG records were characterized in every case by discharges of spikes and waves and bilateral poly-spikes and waves of variable frequency (2-5 c/sec), which were bilaterally synchronous and symmetrical in 4 cases, asymmetrical in 3 cases, and clearly unilateral in 3 other cases. In all cases, these abnormalities predominated in the anterior regions, but it was impossible to demonstrate a localized "irritative" zone. The placement of the intracranial multilead electrodes was achieved by means of the stereotaxic method previously described on several occasions (Talairach et al. 1949, 1952, 1957,
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1958. 1967: Talairach and Bancaud 1973. 19741. The technical and methodological procedures used for these SEEG investigations have also been reported elsewhere (Bancaud and Dell 1959: Bancaud e t al. 1965. 1973: Buser and Bancaud 1967; Bancaud and Talairach 19741. In order to characterize the epileptogenic focus several multilead electrodes were introduced into the external and mesial cortex and the white matter at different sites of the cerebral hemisphere and in some subcortical structures. The patients were anaesthetized with 3--10 mg of dextromoramide with occasional addition of 40-60 mg of gallamine tri-iodoethylate (Flaxedil); these drugs were administered in the morning for electrode implantation. The patient awoke gradually towards noon. Depth recording and stimulation began at about 3 p.m. and were continued in the succeeding hours, The patients were therefore awake and conscious during the exploration itself. Unidirectional rectangular pulses from a conventional stimulator were delivered between two leads of the same electrode (separated by a distance of 1.5 mm). Their voltage, frequency and duration could be varied independently: voltages ranged from 2 to 12 V, frequencies between 1 and 50 c/sec and pulse durations from 1 to 3 msec: the overall durations of pulse trains usually employed ranged between 1 and 12 sec. while the most frequently used values were 6 V. 1 msec. 50 cisec, during 5 6 sec. /-"
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Depth recordings were always performed bipolarly between two adjacent leads of the same electrode. These were displayed, together with some conventional scalp recordings, on a 23 channel ink-writer (Alvar) and controlled on a 4 channel oscilloscope. RESULTS
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During the 16 SEEG explorations of the l0 patients 634 electrical stimulations were delivered. of which 509 were directed to various structures in the two frontal lobes (Fig. l). Out of these 509 local stimulations of the frontal lobes. 150 induced electrical or electro-clinical events that can be characterized as either: (a) simple absences (accompanied by spikes and waves) in 67 cases (Fig. 2 and 3); (b) complex absences (accompanied by spikes and waves) in
277
ELECTRICAL STIMULATION OF FRONTAL LOBE
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29 cases; (c) generalized tonic-clonic seizures in 17 cases; or (d)"sub-clinical" spike and wave discharges in 37 cases. In all patients these elicited seizures were practically identical to their spon-
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taneous attacks; they started soon after onset of the stimuli and ended with them, except for the tonic--clonic seizures which continued after cessation of stimulation• All electrodes eliciting clinical responses were located in the cortex of the frontal lobes. As shown in Fig. 4 and 5, the electrodes whose stimulation provoked electro-clinical absences were almost always located in the mesial frontal cortex (118 times), extending from the rolandic region to the frontal pole, sometimes in the cingulate gyrus (16 times) and in corona radiata or external frontal cortex (16 times). a. Stimulation of a limited portion of the mesial frontal cortex on one side (Fig. 6), induced electro-clinical absences in only 2 of the 10 patients. In fact, this occurred precisely in the 2 patients whose epileptogenic zone was located where the deep electrodes had been introduced. b. In the other 8 cases, absences were pro-
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was prolonged. With the same stimulus locations in the same patients, we noticed that, with increased voltage or duration of the trains, the response was modified: consisting of "sub-clinical" spikes and waves with weak stimuli, the response typically became an absence for high intensities and a generalized tonic-clonic seizure with even higher intensities. Finally it seemed to us that, in a given subject, the responses were all the more easy to obtain the closer the frequency of stimulation was to that of spontaneous paroxysmal discharges (spikes and waves at 2-5 c/see).
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voked by stimulation of the mesial cortex of the two frontal lobes over a very extensive area (Fig. 7). Moreover it must be stressed that in these patients the zones of "positive" response were practically symmetrical (Fig. 8). A study of the relationship between the stimulation frequency and the type of attack showed that absences were generally induced by low frequencies, at about 3 c/sec, while tonic-clonic seizures were induced by higher frequencies. On the other hand, stimuli at 1 c/sec never produced a tonic-ctonic attack, even when stimulation
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ELECTRICAL STIMULATION OF FRONTAL LOBE DISCUSSION
To summarize our findings briefly, the stimulation of a limited portion of one frontal cortex in man, especially its mesial aspect, could induce either paroxysmal discharges of bilateral spikes and waves, most often synchronous and sometimes accompanied by simple or complex typical absences, or discharges of apparently diffuse spikes accompanied by generalized tonic-clonic attacks. These attacks induced by electrical stimulation could not be differentiated in our series from those spontaneously appearing or chemically induced in the same patient. The very fast propagation and wide extension of the discharge also yielded EEG pictures identical to those characterizing spontaneous attacks of the patient, whether spikes and waves or fast spikes were involved. Moreover, these electrical paroxysms were related to a clinical semiology which closely resembled that of absences or of tonic-clonic seizures generalized from the onset. In other words, localized stimulation of the frontal cortex, most often of its mesial aspect, can elicit electro-clinical absences or typical generalized convulsive seizures. The morphology, the frequency and the topographical distribution of the discharges, which occurred soon after the onset of, and lasted as long as, the stimuli, were related to the type of the given electrical pulses and not to the site where they were delivered. In fact, stimulation with different parameters applied to the same area could induce either "sub-clinical" discharges of spikes and waves, or absences, or generalized tonic-clonic attacks. This possibility of transforming an absence into a convulsive seizure is well-known in epileptology and was previously considered by Penfield and Jasper (1954). On the other hand we were never able to provoke absences in a subject who had not previously had them spontaneously (Bancaud et al. 1965). With respect to localization, it is interesting to note that in our series it was only stimulation of the frontal cortex which enabled us to provoke absences. In our observations the mesial cortex generally seemed much more sensitive than the external cortex, but this may only be a matter of stimulus threshold. A topographical study of the effective sites did not indicate the presence of a
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privileged place in the frontal lobe and the zone responsible for the cortical discharges varied from one subject to another. This zone rarely covered a restricted territory and was only unilateral in a limited number of cases..On the contrary, in most cases the effective areas were distributed in the two frontal regions and were practically symmetrical. It is impossible to know if these bilateral epileptogenic zones were present from the beginning or if we were dealing with the gradual building up of a mirror focus, as has been suggested by various animal (Mutani et al. 1973) and human (Bancaud et al. 1965) studies. We believe that our observations raise the question of the origin and mechanism of extension of generalized epileptic attacks. Tiikel and Jasper (1952) have already claimed that in patients with unilateral lesions of the parasagittal cortex bilateral spike and wave type attacks could be observed; these patterns would correspond to "secondary synchrony" as distinct from "primary synchrony" of centrencephalic origin, spike and waves of the first type being more irregular than those of the second type. At variance with this opinion, we find that no distinction can be made between the electrographic epileptic patterns described in our cases here and typical bilateral synchronous spikes and waves most usually considered as originating from deep structures. We tend to assume that more or less restricted zones of the cerebral cortex play an essential role as regions of origin in these types of epilepsies. Although the theory of the centrencephalic origin of primary generalized epilepsies (Penfield and Jasper 1954) is based on numerous clinical, EEG and experimental data, a considerable number of other arguments and/or observations have been raised against it. The localizing value of synchronous bilateral EEG abnormalities has been questioned and the presence of multiple generators in the cortex explaining these abnormalities has been suggested (Petsche et al. 1970; Scarpelezos et al. 1973). Moreover, the results from stimulating various cerebral structures or from creating experimental epiteptogenic foci in animals also seem to favour this essential role of the cerebral cortex (Kaada 1951 ; Lennox and Robinson 1951; Ingvar 1959; Ralston 1961; Marcus and Watson 1964; Naquet
280 et al. t968; Marcus and Jacobson 1969; Mutani et al. 1973). The modes of action of sedatives or
convulsant drugs introduced into the brain through various routes were also considered to favour the cortical origin of diffuse discharges in animals by Shimizu et al. (1952) and Starzl et al. (1953) and in man by Bennett and Gibbs (1952). Loiseau and Cohadon (1970) quoted 19 cases from the literature in whom mostly frontal hemispheric cerebral tumours were responsible for a petit mal; we were also able to find (Pruvot et al. 1972) 11 cases of generalized epilepsies due to localized, generally frontal, cortical trauma. Finally, other stereotaxic investigations have also led to consideration of the primary role of the cerebral cortex in eliciting generalized attacks (Bancaud I971: Goldring 1972: Niedermeyer 19721. The mechanism of the bilateral extension of seizure starting from a restricted cortical zone also remains a matter of discussion. Regarding the thalamus, none of our data as yet really suggest its possible role in either triggering the attack or operating the bilateral transfer (at variance with other data, see Rossi 1973 I. On the other hand. we have data indicating that the interhemispheric pathways, in particular the corpus callosum, could play an essential role in the process of bilateralization. Oscilloscopic analyses (to be published elsewhere) of the responses evoked in one hemisphere through single shock electrical stimulation of the homonymous, contralateral area have brought up some interesting facts in connection with the present discussion: (al the threshold tor eliciting such (presumably transcallosal) contralateral responses is significantly lower in patients with frontal epileptogenic loci: (b) the latency of such responses is rather short ( ~ 10 msec) and remains very constant over several successive shocks: (c) these transcaUosal responses remain closely restricted to the homonymous area, without spreading to other even neighbouring electrodes. In other words, the short connections with few synapses between the two mesial cortices seem to become very excitable in patients with parasagittal lesion, the latency of transfer being sufficient to
J. BANCAUDet al. account for quasi-synchrony (especially with routine low-speed inkwriter recordings). This of course points to the possible role of the neurones which constitute the corpus catlosum. To sum up, although it is not intended here to claim that subcortical structures do not play any role in the elaboration of typical absences or generalized tonic-clonic seizures, we believe that our data point to the essential role that is played by the cerebral cortex, particularly the frontal lobes, in triggering such attacks. SUMMARY
Five hundred and nine electrical stimulations were performed in the frontal lobes of 10 epileptic patients presenting "'generalized" spontaneous attacks. These stimulations were carried out by means of stereotaxically implanted electrodes. Of these 509 stimulations. 150 induced either simple electro-clinical absences (67), complex absences (29), generalized tonic-clonic seizures [17), or only bilaterally synchronous, symmetrical spike and wave paroxysms (37). These responses, which in each case reproduced the spontaneous attacks of the patient. occurred from the beginning of stimulation and ended with it, except for the tonic-clonic seizures. The active electrodes were always located in the frontal lobe, particularly in the mesial cortex. Although the bilateral responses were related to stimulation of a restricted unilateral zone. most often they could be obtained from stimulation of either frontal lobe. in q uasi-symmetrical regions. The type of electro-clinical response obtained was largely related to the parameters of stimulation: thus. in the same patient, a discharge of sub-clinical spikes and waves could become an absence and subsequently a "generalized" tonic clonic seizure, when increasing the intensity or duration of the shocks. These results point to the preponderant role of the cerebral cortex, particularly that of its frontal portion, in elaboration of generalized epileptic attacks.
ELECTRICAL STIMULATIONOF FRONTAL LOBE RESUME
CRISES EPILEPTIQUES "GENERALISEES" PAR STIMULATION ELECTRIQUE DU LOBE FRONTAL CHEZ L'HOMME Les a u t e u r s o n t rapport6 l'incidence de 509 s t i m u l a t i o n s 61ectriques port6es au n i v e a u des lobes f r o n t a u x chez l0 m a l a d e s 6pileptiques pr6s e n t a n t s p o n t a n 6 m e n t des acc~s "g6n6ralis6s". Ces s t i m u l a t i o n s 6taient pratiqu6es au m o y e n d'61ectrodes implant6es scion u n e technique st6r6otaxique particuli6re. Sur ces 509 s t i m u l a t i o n s 150 o n t i n d u i t soit des absences 61ectro-cliniques simples (67 fois) ou complexes (29 lois) soit des crises t o n i c o - c l o n i ques g6n6ralis6es (17 lois) soit seulement des p a r o x y s m e s de p o i n t e s - o n d e s bilat6raux, synchrones et sym6triques (37 fois). Ces r6ponses qui r e p r o d u i s a i e n t les acc+s s p o n t a n 6 s de c h a q u e m a l a d e s u r v e n a i e n t d6s le d 6 b u t de l'excitation et cessaient avec elle except6 les crises t o n i c o - c l o n i q u e s . Les 61ectrodes actives si6geaient t o u j o u r s au n i v e a u d u lobe frontal, en particulier d a n s le cortex de la face interne. Bien q u e des r6ponses bilat6rales aient p u &re suscit6es p a r la s t i m u l a t i o n d ' u n e z o n e unilat6rale restreinte, le plus s o u v e n t elles 6taient obtenues fi partir des deux lobes f r o n t a u x d a n s des r6gions p r a t i q u e m e n t sym6triques. Le type de r6ponses 61ectro-cliniques o b t e n u e s 6tait en g r a n d e partie f o n c t i o n des p a r a m & r e s de s t i m u l a t i o n en sorte q u e l ' o n p o u v a i t passer chez le m ~ m e m a l a d e d ' u n e d6charge de pointeso n d e s i n f r a - c l i n i q u e s ~ u n e absence puis fi u n e crise t o n i c o - c l o n i q u e "g6n6ralis6e". Ces r6sultats p e r m e t t e n t aux auteurs de discuter d u r61e p r 6 p o n d 6 r a n t du cortex c6r6bral, en particulier frontal, d a n s l'61aboration des acc6s 6pileptiques g6n6ralis6s. REFERENCES BANCAUD,J. Physiopathogenesis of generalized epilepsiesof organic nature (SEEG study). In H. GASTAUTet al. (Eds.), The physiopathogenesis of the epilepsies. Thomas, Springfield, Ill., 1969, 316 p. BANCAUD, J. R61e du cortex c6r6bral dans les 6pilepsies "g6n6ralis6es" d'origine organique. Presse M~d., 1971, 79 : 669-673. BANCAUD,J. Mechanisms of cortical discharges in "genera-
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