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The effects of ablations on primary and secondary epileptic discharges in commissure-sectioned rhesus monkeys
Electroencephalography and Clinical Neurophysiology, 1978, 4 4 : 2 3 - - 3 6 © Elsevier/North-Holland Scientific Publishers, Ltd.
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THE EFFECTS OF ABLATIONS ON PRIMARY AND S E C O N D A R Y EPILEPTIC DISCHARGES IN COMMISSURE-SECTIONED R H E S U S MONKEYS * M.B. LOWRIE, J.J. MACCABE and G. ETTLINGER Institute o f Psychiatry, De Crespigny Park, London SE5 8 A F (England) (Accepted for publication: May 23, 1977)
Secondary discharges were observed in the contralateral hemisphere of rhesus monkeys with a unilateral aluminium hydroxide implant in the inferotemporal cortex by Gautrin et al. (1971) and Nie et al. (1973). These discharges survived ablation of the primary focus (Nie and Ettlinger 1974) although they became less clearly defined. Furthermore, Nie et al. (1974) reported the development of independent contralateral abnormal discharges in monkeys with total commissure section and unilateral parietal epileptogenic implants. In the present study we attempted to determine whether secondary abnormal discharges occurring despite commissure section were genuinely independent by observing the effects of ablation of the primary focus on the EEG. The effects of ablation of the contralateral cortex were also examined to define further the origin of the secondary focus and to control for possible non-specific interhemispheric effects of a unilateral ablation. Thirty monkeys underwent total commissure section and 27 of these were simultaneously given a unilateral parietal epileptogenic implant while three were controls. Ten of those receiving an implant and one control died or showed lasting behavioural impairment indicative of neurological damage additional to commissure section; nine failed to show consistent evidence of independent secondary discharges and one died after subse* This work was supported by the MRC.
quent ablation surgery. We report the EEG findings on the nine remaining monkeys; four with primary ablations, three with secondary ablations and two controls.
Methods
Subjects Nine immature monkeys (8 Macaca mulatta, 1 Macaca fascicularis) were randomly allocated for surgery: in seven all commissures were divided and aluminium hydroxide was implanted on the left posterior parietal cottex; in two controls (C1, C2) all commissures were divided b u t no aluminium hydroxide was applied to the cortex. When the experimental animals showed evidence of independent secondary discharges, four (EpP1--4) underwent ablation of the primary focus and three (EpS1--3) underwent ablation of the corresponding cortex contralateral to the primary focus. Surgery The methods of commissure section and implantation were similar to those used previously (Nie et al. 1974). In all animals a large bilateral bone flap was turned on the right temporal muscle, under pentobarbitone (Nembutal) anaesthesia. The dura was opened on the left side in a wide crescent based on the sagittal sinus. Gentle retraction was applied to both hemispheres in order to expose the corpus callosum; to achieve this,
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M.B. L O W R I E ET AL.
it was necessary for bridging vessels from the dura to the sagittal sinus to be cut in a few instances. With the aid of a Zeiss operating microscope the corpus callosum, posterior commissure, massa intermedia of the thalamus and anterior commissure were divided in the midline using a fine-gauge (No. 22) sucker, Implantation immediately followed commissure section. Four celluloid caps, each measuring 10 mm in total diameter, were placed over the left posterior parietal-preoccipital cortex, anterior to the lunate sulcus but posterior to the anterior end of the intraparietal sulcus, avoiding major blood vessels where possible. For the two control animals, C1 and C2, these caps were e m p t y but in the experimental animals, EpP1-4 and EpS1-3, the caps were first filled with boiled commercial aluminium hydroxide gel (Aludrox). Any excess gel was removed from the pial surface with a sucker and the dura was carefully repositioned over the caps. The dura was not sewn but gel-foam was placed over it and the bone flap and skin were tightly closed. After intervals varying from 4 to 22 months, all the experimental animals underwent wide ablation of the lateral posterior parietal-prestriate cortex: EpP1-4 on the left; EpS1-3 on the right,
Post-operative recovery All animals showed a transient right paresis lasting for 2--3 days or occasionally longer after commissure section. In addition rightsided epileptic convulsions were seen in animals EpP1, EpS1, EpS2, C1 and C2. In all cases except C1, the convulsions occurred within the first three days of surgery and lasted for a m a x i m u m of two days. In the case of C1 a single convulsion was seen nine days
after commissure section. This may have been caused by an infection as granulation tissue was found associated with the dura on the left lateral edge of the bone flap post mortem. All convulsions were successfully treated with Epanutin. Animals EpP3, EpP4 and EpS3 sustained a permanent paresis after their ablation on the side of the body contralateral to the cortex removed. This may be correlated with the extent of the lesion.
Verification o f lesions At termination all experimental animals were perfused with 10% formalin and their brains removed. Outline diagrams were made of the extent of the cortical ablations and/or the positions of caps (Fig. 1). The brains of EpP1, 2, 4, EpS1 and 2 were then embedded in celloidin and cut serially at 25 pm through a single block intended to extend from genu to the posterior commissure. Every 20th section was stained with cresyl violet. Examination of the sections did not reveal that any of the commissures (corpus callosum, anterior and posterior commissures or massa intermedia) remained undivided. In some animals, however, the available range of sections did not allow examination of the ends of the corpus callosum. Additional damage was found only in EpP4, namely dilatation of the left lateral ventricle and damage to the left cingular cortex and corpus striatum. The brains of EpP3, EpS3 and C1 were cut coronally into 5 mm slices and examined macroscopically. In animals EpP3 and C1 all commissures (corpus callosum, anterior and posterior commissure and massa intermedia) were found to be divided in the midline. In EpS3 the central and posterior part of the corpus callosum, the posterior commissure and massa intermedia were divided but 8.5
Fig. 1. Outline diagrams of the p o s i t i o n s o f the caps in animals EpS1-3, C1 and C2, and of the ablations in animals EpP1-4 and EpS1-3. In the case of ablations, medial as well as lateral aspects o f the brain are shown. The ablations are indicated in black; superficial tissue destruction resulting from the e x p o s u r e for commissure s e c t i o n is s h o w n by cross-hatching. A l t h o u g h the caps are of a p p r o x i m a t e l y similar size, their variation in shape is due to the m e t h o d o f representation: an a t t e m p t is made to r e p r o d u c e b o t h the brain and the caps in perspective, w h i c h results in an apparent foreshortening towards the medial surface. The m o s t lateral cap in EpS3 was f o u n d to be partially buried in the cortex.
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mm of the corpus callosum anterior to the level of the interventricular foramina was intact: and a part of the anterior commissure (measuring 1 mm dorso-ventrally by 0.5 mm antero-posteriorly) was also intact. In this animal there was also severe dilatation of the third ventricle and moderate dilatation of the inferior horn of the left lateral ventricle. The depth of cortical damage beneath the celluloid caps was variable, sometimes extending through all cortical layers, sometimes involving only the more superficial layers. The tissue destruction rarely extended beyond the margins of the caps.
EEG recordings At least one pre-operative EEG recording was taken from all animals except EpP1, EpP4 and EpS3. After commissure section regular m o n t h l y recordings were taken from all experimental animals, either until 6 months after ablation, or, from C1 and C2, until 4 and 14 months respectively. During recording sessions each animal was seated comfortably in a primate chair in a dark room with outside noises masked by white noise, Eight silver/silver chloride cup electrodes were attached to the scalp according to the arrangement shown in Fig. 5 and bipolar recordings were made with a Polygraph. A time constant of 0.3 sec and a high frequency cut of 15% at 50 c/sec was used for all recordings. Correlation of EEG observations with behavioural changes in the animal was achieved by using an infra-red TV monitoring device,
guish between epileptic events and normally occurring waveforms such as muscle potentials, eyeblinks and vertex waves, as follows: (a) the wave should be distinguishable from background activity in both size and shape, and have the form of a spike or sharp wave as defined by the International Committee on EEG Terminology (Storm van Leeuwen et al. 1966); (b) there should be an electronegative phase-reversal at the parietal electrode. If this occurred in channels 3 and 4 it indicated a primary event; if in channels 1 and 2 it indicated a secondary event, either transmitted (if there was no detectable time-lag between it and the primary event), or independent (if not correlated in time with the primary) and (c) there should n o t be a corresponding electronegative phase-reversal at the vertex electrode (thereby excluding vertex waves). The epileptic events were consequently classified as primary, transmitted secondary or independent secondary. Additionally, because there is not always a clear distinction between epileptic and non-epileptic events, events were subclassified as: class I (definitely epileptic), class II (probably epileptic), class III (possibly epileptic). This classification is similar to that used in previous studies (Nie et al. 1974; Nie and Ettlinger 1974). The results from different animals were n o t pooled for statistical analysis because between-animal variance was large. Instead, the one-tailed Wilcoxon rank sum test was used to test the significance of any decrease in epileptic activity after ablation within each animal.
EEG analysis All m o n t h l y EEG recordings were quantitatively analysed by one of us (MBL). Those parts of the recordings which were marred by movement or other artefacts to the extent of precluding recognition of epileptic activity were discarded. Criteria for classification of epileptic events were based on the experience gained from comparison of pre- and postoperative records of both experimental and control animals. They were designed to distin-
Results No epileptic events were found in any of the pre-operative recordings, nor in the fourteen post-operative recordings of C2. Only three class III events were seen in any of the 4 post-operative records of C1. After surgery, all experimental animals gave evidence of primary and secondary interictal discharges. Seizure discharges were observed in the EEGs of
EPILEPTIC DISCHARGES AFTER COMMISSURE SECTION
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TJme (months) Fig. 2. The effect of ablating the primary focus on the incidence of primary interictal epileptic events. The adjusted total of epileptic events was calculated by summing 100% of class ! events, 75% of class [ I events and 50% of class I I I events for each EEG recording. The arrow indicates the time of the ablation operation. The decline in frequency after ablation was significant by the one-tailed Wilcoxon rank sum test (P < 0.01, EpP1, EpP2 and EpP4; P < 0.05, EpP3).
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EPILEPTIC DISCHARGES AFTER COMMISSURE SECTION
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30
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all experimental animals except EpS2. Although right-sided convulsions were seen several times in this animal while it was in its home cage, the overall level of epileptic activity in the EEG recordings remained low.
Effects of primary ablation As shown in Fig. 2 all primary interictal activity ceased (i.e., was significantly reduced) after ablation of the primary focus. Similarly all transmitted secondary activity ceased after ablation although the decline was statistically significant only for EpP1 and EpP4 (Fig. 3). No seizure discharges were observed in the EEGs of these animals after ablation, In contrast all 4 animals continued to have independent secondary interictal events after primary ablation (Fig. 4). Only one animal, EpP2, showed a significant decrease in this
activity. Examples of independent secondary discharges occurring after commissure section have been illustrated elsewhere (Nie et al. 1974). Fig. 5 shows EEG recordings taken from animals EpP3 and EpP4 at different times after ablation of the primary focus. Spikes can be seen only in the leads from the right {secondary)hemisphere.
Effects of secondary ablation Primary interictal epileptic events were seen in all 3 animals (EpS1-3) after removal of the contralateral secondary cortex (Fig. 6). The ablations were not associated with any significant difference in incidence. Transmitted secondary events were seen in EpS1 and EpS3 after ablation of the secondary cortex; the incidence was not significantly reduced by ablation (Fig. 7). The absence of
EPILEPTIC D I S C H A R G E S A F T E R C O M M I S S U R E S E C T I O N
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Fig. 6. The e f f e c t o f ablating the c o r t e x contralateral to the primary f o c u s on the incidence o f primary interictal epileptic events. There was n o statistically significant difference in f r e q u e n c y before and after ablation.
these events in EpS2 probably reflects the unusually low level of epileptic activity observed throughout in this animal. No independent secondary events were observed in the recordings of EpS1-3 after removal of the secondary cortex (Fig. 8). The decline in this activity was significant for EpS1 but failed to reach statistical significance in EpS2 and EpS3 because of the low preoperative frequency of this activity,
Discussion We have found, in agreement with Nie et al. (1974), that division of the forebrain commissures does not prevent ~he development of secondary epileptic discharges. Moreover we conclude that commissure section does not influence the persistence of secondary discharges after ablation of the primary focus; the incidence of secondary activity in the
32
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Fig. 7. T h e e f f e c t o f a b l a t i n g t h e c o r t e x c o n t r a l a t e r a l t o t h e p r i m a r y focus o n t h e i n c i d e n c e o f t r a n s m i t t e d seco n d a r y interictal epileptic events. T h e r e was n o statistically significant difference in f r e q u e n c y b e f o r e a n d a f t e r ablation.
present study is very similar to that found by Nie arid Ettlinger (1974) when the inferotemporal primary focus was removed in non-commissure-sectioned animals, Cortical ablation, whether in the primary or secondary hemisphere, abolishes EEG evidence of discharges from that cortex. However, one animal, EpP4, did show irregular jerking movements of the right arm and leg on several occasions during the 6 months fol-
lowing ablation of the primary (left) focus. Although these movements were different from the convulsions usually seen after application of aluminium hydroxide, and attempts to obtain EEG evidence of their neurological origin failed, it remains a possibility that an ipsilateral secondary focus had been spared from the otherwise extensive primary ablation. The results of ablations of the secondary
EPILEPTIC DISCHARGES A F T E R c o M M I S S U R E SECTION
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cortex show that removal of cortex in one hemisphere d o e s n o t s u p p r e s s e p i l e p t i c a c t i v i t y originating in the other hemisphere. Nor is there evidence that the lesion facilitated the primary activity. The raised post-ablation level of primary activity seen in EpS1 probably reflects the early date of ablation in this animal (four months) as most animals reach their peak of primary activity at 6 or 7 months,
The origin of transmitted secondary events Animals EpS1 and EpS3 showed evidence of transmitted secondary discharges after, and in spite of, removal of the contralateral cortex. Two possible reasons for this are discussed below, (1) Subcortical secondary focus. Ogden et al. (1956) have suggested that, in some cases of clinical epilepsy involving a unilateral lesion, a midline subcortical pacemaker might
subsequently be the source of the synchronized discharges to both hemispheres. It seems unlikely, however, that the present transmitted events are due to such a midline focus as no discharges were seen over the primary hemisphere after ablation of the primary cortex. The secondary hemisphere seems a more plausible site for a subcortical secondary focus, particularly in view of the observation by Wilder and Schmidt (1965) that propagation of epileptic discharges from a primary cortical focus to the contralateral cortex was always accompanied by involvement of one or more basal ganglia. However, if the source of transmitted secondary events is subcortical it is unlikely that it is also the source of independent secondary events as removal of the secondary cortex alone was sufficient to abolish the independent discharges. (2) Passive spread. By definition scalp EEG
34
recordings are dependent on passive spread of electrical potentials through overlying tissues to the electrode. As shown in studies on hemispherectomy (Cobb and Sears 1960) and the visual evoked response (Barrett et al. 1976), passive spread over several centimetres is possible, although some attenuation of the signal is to be expected. Although great caution is needed in interpretation of amplitude (particularly in monkeys which have a more mobile scalp than human subjects) it was noted that in the post-ablation records of EpS1 and EpS3 the transmitted events were never more than half the amplitude of the primary events. Pre-ablation records showed a variable attenuation. It is therefore possible that the transmitted events seen in the secondary hemisphere may have spread by volume conduction from the primary focus. To account for the variability in the occurrence of secondary transmitted events we suggest that spread can be recorded from the secondary hemisphere either when the primary events are large or when the orientation of the generators of the primary discharges has altered (e.g. by migrating into a sulcus),
The evidence for independent secondary discharges The type of events described here as independent secondary discharges were n o t seen in any of 42 recordings made from unoperated animals in the experience of one of us (MBL). Taken with the virtual absence of epileptic events in the 18 recordings of animals C1 and C2, it appears that these independent secondary discharges are genuinely epileptic manifestations, All f.our animals with primary ablations continued to show EEG evidence of secondary discharges in spite of the complete absence of primary events. This result, in agreement with earlier work on the inferotemporal cortex (Nie and Ettlinger 1974), argues strongly in favour of the independence of these discharges, One animal, EpP2, did show a significant
M.B. L O W R I E E T AL.
decrease in the frequency of independent secondary discharges after a primary ablation, suggesting partial dependence on the primary focus. However, a decline in secondary activity with time might be expected to occur in the absence of ablation, as indicated by EpS3 in Fig. 8.
The origin of secondary independent discharges In the past it has been proposed that the forebrain commissures play a major role in the evolution of a secondary (mirror) focus (Morrell 1960). In the light of the present study and the earlier work of Nie et al. (1974) an alternative explanation other than transcommissural b o m b a r d m e n t must be sought for the origin of the secondary focus in the monkey. Several explanations relating to experimental methods have already been discussed by Nie et al. (1974). Like these authors we consider such explanations to be possible but unlikely. Another interpretation is that discharges are propagated along interhemispheric pathways below the level of the massa intermedia. Several workers have commented upon the widespread involvement of subcortical structures during propagation of epileptic discharges from a primary cortical focus (Wilder and Schmidt 1965; Wada and Cornelius 1960). Wilder and Schmidt (1965) recording from non-commissure-sectioned monkeys with a unilateral aluminium hydroxide focus on the sensorimotor cortex, state that propagation to the contralateral cortex was never seen without involvement of one or more subcortical structures. It is possible that a similar pathway could be involved in the spread of activity from a posterior parietal focus. French etal. (1955) have demonstrated posterior parietal cortico-reticular pathways in the monkey. However, Walker and Rivera (1964) failed to observe subcortical involvement during spread of epileptic activity from a parietal aluminium hydroxide focus to the contralaterai cortex in the monkey, although propaga-
EPILEPTIC DISCHARGES AFTER COMMISSURE SECTION
tion to subcortical structures was observed when the focus was made in m o t o r or other areas of cortex. A final possibility relates to the immunological hypotheses of Bowen (1968); Ettlinger and Lowrie {1976); Cazzullo et al. (1976). According to such proposals an antigen would be released by tissue destruction at the primary focus and the resultant antibodies could be responsible for the development of both primary and secondary discharges,
Summary Nine monkeys underwent division of the corpus callosum, anterior commissure, massa intermedia, and posterior commissure. At the same operation, in seven of these animals aluminium hydroxide was applied to the left posterior parietal-prestriate cortex. Monthly EEG recordings were taken from all animals, All seven animals with epileptogenic implants gave evidence of primary abnormal discharges {i.e. from the ipsilateral hemisphere) and secondary (i.e. from the contralateral hemisphere) discharges. The secondary events were of two types: transmitted, i.e. synchronous with primary events; independent, i.e. asynchronous with primary events, After intervals varying from 4 to 22 months all seven monkeys underwent wide ablation of the posterior parietal cortex: on the left in four animals, on the right in three animals. EEG recordings were taken for a further 6 months. All recordings were quantitatively analysed, the number of primary, transmitted secondary and independent secondary events being counted separately. This analysis indicated the following: (1) Primary and transmitted secondary discharges ceased after primary ablations b u t were unaffected by removal of the secondary cortex. (2) Independent secondary discharges persisted after removal of the primary focus but were abolished by secondary ablations. of
Possible m e c h a n i s m s for the d e v e l o p m e n t transmitted and independent secondary
discharges are considered,
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R~sum~ Effets d'ablations sur les ddcharges primaires et secondaires chez des Macaques aprds commissurotomie Sur neuf Macaques (rhesus) on a procddd la section du corps calleux, de la commissure antdrieure, de la massa intermedia, et de la commissure postdrieure. Au cours de la m~me intervention, on a appliqud, ~ sept de ces animaux, de l'alumine sur la r~gion corticale pari~tale post~rieure--prdstride gauche. Des enregistrements EEG mensuels ont ~t~ effectu~s sur t o u s l e s animaux. Les sept animaux porteurs d'implants dpileptog~nes d~velopp~rent des ddcharges anormales primaires (c.-~-d. sur l'hdmisph~re ipsilateral), et secondaires (c.-~-d. sur l'hdmisphere contralatdral). Les dv~nements secondaires ~taient de deux types, soit transmis, c'est-~-dire synchrones des ~v~nements primaires, soit ind~pendants, c'est-~-dire nonsynchrones de ces derniers. Apr~s un laps de temps de 4 ~ 22 mois, les sept singes ont subi une ablation du cortex paridtal postdrieur, ~ gauche chez quatre animaux, ~ droite chez trois animaux. Les enregistrements EEG ont dtd poursuivis pendant 6 mois encore. T o u s l e s trac~s on ~td analys~s quantitativement, en comptant s~par~ment le nombre d'~v~nements primaires, secondaires transmis et secondaires ind~pendants. L'analyse a donn~ les rdsultats suivants: (1) Les d~charges primaires et secondaires transmises ont dtd dlimindes par les ablations primaires; en revanche, elles ne furent pas supprim~es par ~limination du cortex secondaire. (2) Les ddcharges secondaires ind~pendantes ont persist~ apr~s ablation du foyer primaire mais furent abolies par des ablations secondaires. Les m~canismes ~ventuellement impliquds dans le d~veloppement des d~charges secondaires transmises et ind~pendantes sont examin~s. We thank Dr. J.B. Brierley for the histological processing of some of the brains; and Dr. I. Janota for cutting the remaining brains and interpreting the find-
ings.
36
References Barrett, G., Blumhardt, L., Halliday, A.M., Halliday, E. and Kriss, A. A paradox in the lateralisation of the visual evoked response. Nature (Lond.), 1976, 261 : 253--255. Bowen, F.P. Immunologic reactions after cortical lesions in rabbits. Arch. Neurol.~ 1968, 19: 398-402. Cazzullo, C.L., Altamura, A.C., Canger, R. and Penati, G. Cobalt-induced experimental epilepsy in cats pharmacologically immunodepressed. Arzneim.-Forsch., 1976, 26: 1387--1393. Cobb, W. and Sears, T.A. A study of the transmission of potentials after hemispherectomy. Electroenceph. clin. Neurophysiol., 1960, 12: 371--383. Ettlinger, G. and Lowrie, M.B. An immunological factor in epilepsy. Lancet, 1976, i: 1386. French, J.D., Hern~indez-P~on, R. and Livingston, R.B. Projections from cortex to cephalic brain stem (reticular formation) in monkey. J. Neurophysiol., 1955, 18: 74--95. Gautrin, D., Fenton, G. and Ettlinger, G. Aluminium hydroxide implants on the inferotemporal cortex of the monkey: their mode of influencing visual discrimination performance. Exp. Neurol., 1971, 33: 459--474. Morrell, F. Secondary epileptogenic lesions. Epilepsia (Amst.), 1960, 1: 538--560. Nie, V. and Ettlinger, G. Ablation of the primary inferotemporal epileptogenic focus in rhesus monkeys with independent secondary spike discharges. Brain Res., 1974, 69: 149--152.
M.B. LOWRIE ET AL. Nie, V., Maccabe, J.J., Ettlinger, G. and Driver, M.V. The development of secondary discharges in the rhesus monkey after commissure section. Electroenceph, clin. Neurophysiol., 1974, 37: 473--481. Nie, V., Upton, A. and Ettlinger, G. Behavioral impairment in the monkey following implantation of aluminum hydroxide on the temporal cortex: the role of cortical destruction. Exp. Neurol., 1973, 40: 632--651. Ogden, T.E., Aird, R.B. and Garoutte, B.C. The nature of bilateral and synchronous cerebral spiking. Acta psychiat, neurol, scand., 1956, 31: 273-284. Storm van Leeuwen, W., Bickford, R., Brazier, M., Cobb, W.A., Dondey, M., Gastaut, H., Gloor, P., Henry, C.E., Hess, R., Knott, J.R., Kugler, J., Laity, G.C., Loeb, C., Magnus, O., Oiler Daurella, L., Petsche, H., Schwab, R., Walter, W.G. and Widen, L. Proposals for an EEG terminology by the Terminology committee of the international federation for electroencephalography and clinical neurophysiology. Electroenceph. clin. Neurophysiol., 1966, 20: 293--320. Wada, J.A. and Cornelius, L.R. Functional alteration of deep structures in cats with chronic focal cortical irritative lesions. Arch. Neurol., 1960, 3: 425-447. Walker, A.E. and Rivera, J.F. Subcortical recording in experimental focal chronic epilepsy. Trans. Amer. neurol. Ass., 1964, 89: 37--39. Wilder, B.J. and Schmidt, R.P. Propagation of epileptic discharge from chronic neocortical loci in monkey. Epilepsia (Amst.), 1965, 6: 297--309.
23
THE EFFECTS OF ABLATIONS ON PRIMARY AND S E C O N D A R Y EPILEPTIC DISCHARGES IN COMMISSURE-SECTIONED R H E S U S MONKEYS * M.B. LOWRIE, J.J. MACCABE and G. ETTLINGER Institute o f Psychiatry, De Crespigny Park, London SE5 8 A F (England) (Accepted for publication: May 23, 1977)
Secondary discharges were observed in the contralateral hemisphere of rhesus monkeys with a unilateral aluminium hydroxide implant in the inferotemporal cortex by Gautrin et al. (1971) and Nie et al. (1973). These discharges survived ablation of the primary focus (Nie and Ettlinger 1974) although they became less clearly defined. Furthermore, Nie et al. (1974) reported the development of independent contralateral abnormal discharges in monkeys with total commissure section and unilateral parietal epileptogenic implants. In the present study we attempted to determine whether secondary abnormal discharges occurring despite commissure section were genuinely independent by observing the effects of ablation of the primary focus on the EEG. The effects of ablation of the contralateral cortex were also examined to define further the origin of the secondary focus and to control for possible non-specific interhemispheric effects of a unilateral ablation. Thirty monkeys underwent total commissure section and 27 of these were simultaneously given a unilateral parietal epileptogenic implant while three were controls. Ten of those receiving an implant and one control died or showed lasting behavioural impairment indicative of neurological damage additional to commissure section; nine failed to show consistent evidence of independent secondary discharges and one died after subse* This work was supported by the MRC.
quent ablation surgery. We report the EEG findings on the nine remaining monkeys; four with primary ablations, three with secondary ablations and two controls.
Methods
Subjects Nine immature monkeys (8 Macaca mulatta, 1 Macaca fascicularis) were randomly allocated for surgery: in seven all commissures were divided and aluminium hydroxide was implanted on the left posterior parietal cottex; in two controls (C1, C2) all commissures were divided b u t no aluminium hydroxide was applied to the cortex. When the experimental animals showed evidence of independent secondary discharges, four (EpP1--4) underwent ablation of the primary focus and three (EpS1--3) underwent ablation of the corresponding cortex contralateral to the primary focus. Surgery The methods of commissure section and implantation were similar to those used previously (Nie et al. 1974). In all animals a large bilateral bone flap was turned on the right temporal muscle, under pentobarbitone (Nembutal) anaesthesia. The dura was opened on the left side in a wide crescent based on the sagittal sinus. Gentle retraction was applied to both hemispheres in order to expose the corpus callosum; to achieve this,
24
M.B. L O W R I E ET AL.
it was necessary for bridging vessels from the dura to the sagittal sinus to be cut in a few instances. With the aid of a Zeiss operating microscope the corpus callosum, posterior commissure, massa intermedia of the thalamus and anterior commissure were divided in the midline using a fine-gauge (No. 22) sucker, Implantation immediately followed commissure section. Four celluloid caps, each measuring 10 mm in total diameter, were placed over the left posterior parietal-preoccipital cortex, anterior to the lunate sulcus but posterior to the anterior end of the intraparietal sulcus, avoiding major blood vessels where possible. For the two control animals, C1 and C2, these caps were e m p t y but in the experimental animals, EpP1-4 and EpS1-3, the caps were first filled with boiled commercial aluminium hydroxide gel (Aludrox). Any excess gel was removed from the pial surface with a sucker and the dura was carefully repositioned over the caps. The dura was not sewn but gel-foam was placed over it and the bone flap and skin were tightly closed. After intervals varying from 4 to 22 months, all the experimental animals underwent wide ablation of the lateral posterior parietal-prestriate cortex: EpP1-4 on the left; EpS1-3 on the right,
Post-operative recovery All animals showed a transient right paresis lasting for 2--3 days or occasionally longer after commissure section. In addition rightsided epileptic convulsions were seen in animals EpP1, EpS1, EpS2, C1 and C2. In all cases except C1, the convulsions occurred within the first three days of surgery and lasted for a m a x i m u m of two days. In the case of C1 a single convulsion was seen nine days
after commissure section. This may have been caused by an infection as granulation tissue was found associated with the dura on the left lateral edge of the bone flap post mortem. All convulsions were successfully treated with Epanutin. Animals EpP3, EpP4 and EpS3 sustained a permanent paresis after their ablation on the side of the body contralateral to the cortex removed. This may be correlated with the extent of the lesion.
Verification o f lesions At termination all experimental animals were perfused with 10% formalin and their brains removed. Outline diagrams were made of the extent of the cortical ablations and/or the positions of caps (Fig. 1). The brains of EpP1, 2, 4, EpS1 and 2 were then embedded in celloidin and cut serially at 25 pm through a single block intended to extend from genu to the posterior commissure. Every 20th section was stained with cresyl violet. Examination of the sections did not reveal that any of the commissures (corpus callosum, anterior and posterior commissures or massa intermedia) remained undivided. In some animals, however, the available range of sections did not allow examination of the ends of the corpus callosum. Additional damage was found only in EpP4, namely dilatation of the left lateral ventricle and damage to the left cingular cortex and corpus striatum. The brains of EpP3, EpS3 and C1 were cut coronally into 5 mm slices and examined macroscopically. In animals EpP3 and C1 all commissures (corpus callosum, anterior and posterior commissure and massa intermedia) were found to be divided in the midline. In EpS3 the central and posterior part of the corpus callosum, the posterior commissure and massa intermedia were divided but 8.5
Fig. 1. Outline diagrams of the p o s i t i o n s o f the caps in animals EpS1-3, C1 and C2, and of the ablations in animals EpP1-4 and EpS1-3. In the case of ablations, medial as well as lateral aspects o f the brain are shown. The ablations are indicated in black; superficial tissue destruction resulting from the e x p o s u r e for commissure s e c t i o n is s h o w n by cross-hatching. A l t h o u g h the caps are of a p p r o x i m a t e l y similar size, their variation in shape is due to the m e t h o d o f representation: an a t t e m p t is made to r e p r o d u c e b o t h the brain and the caps in perspective, w h i c h results in an apparent foreshortening towards the medial surface. The m o s t lateral cap in EpS3 was f o u n d to be partially buried in the cortex.
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M.B. L O W R I E E T AL.
mm of the corpus callosum anterior to the level of the interventricular foramina was intact: and a part of the anterior commissure (measuring 1 mm dorso-ventrally by 0.5 mm antero-posteriorly) was also intact. In this animal there was also severe dilatation of the third ventricle and moderate dilatation of the inferior horn of the left lateral ventricle. The depth of cortical damage beneath the celluloid caps was variable, sometimes extending through all cortical layers, sometimes involving only the more superficial layers. The tissue destruction rarely extended beyond the margins of the caps.
EEG recordings At least one pre-operative EEG recording was taken from all animals except EpP1, EpP4 and EpS3. After commissure section regular m o n t h l y recordings were taken from all experimental animals, either until 6 months after ablation, or, from C1 and C2, until 4 and 14 months respectively. During recording sessions each animal was seated comfortably in a primate chair in a dark room with outside noises masked by white noise, Eight silver/silver chloride cup electrodes were attached to the scalp according to the arrangement shown in Fig. 5 and bipolar recordings were made with a Polygraph. A time constant of 0.3 sec and a high frequency cut of 15% at 50 c/sec was used for all recordings. Correlation of EEG observations with behavioural changes in the animal was achieved by using an infra-red TV monitoring device,
guish between epileptic events and normally occurring waveforms such as muscle potentials, eyeblinks and vertex waves, as follows: (a) the wave should be distinguishable from background activity in both size and shape, and have the form of a spike or sharp wave as defined by the International Committee on EEG Terminology (Storm van Leeuwen et al. 1966); (b) there should be an electronegative phase-reversal at the parietal electrode. If this occurred in channels 3 and 4 it indicated a primary event; if in channels 1 and 2 it indicated a secondary event, either transmitted (if there was no detectable time-lag between it and the primary event), or independent (if not correlated in time with the primary) and (c) there should n o t be a corresponding electronegative phase-reversal at the vertex electrode (thereby excluding vertex waves). The epileptic events were consequently classified as primary, transmitted secondary or independent secondary. Additionally, because there is not always a clear distinction between epileptic and non-epileptic events, events were subclassified as: class I (definitely epileptic), class II (probably epileptic), class III (possibly epileptic). This classification is similar to that used in previous studies (Nie et al. 1974; Nie and Ettlinger 1974). The results from different animals were n o t pooled for statistical analysis because between-animal variance was large. Instead, the one-tailed Wilcoxon rank sum test was used to test the significance of any decrease in epileptic activity after ablation within each animal.
EEG analysis All m o n t h l y EEG recordings were quantitatively analysed by one of us (MBL). Those parts of the recordings which were marred by movement or other artefacts to the extent of precluding recognition of epileptic activity were discarded. Criteria for classification of epileptic events were based on the experience gained from comparison of pre- and postoperative records of both experimental and control animals. They were designed to distin-
Results No epileptic events were found in any of the pre-operative recordings, nor in the fourteen post-operative recordings of C2. Only three class III events were seen in any of the 4 post-operative records of C1. After surgery, all experimental animals gave evidence of primary and secondary interictal discharges. Seizure discharges were observed in the EEGs of
EPILEPTIC DISCHARGES AFTER COMMISSURE SECTION
27
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TJme (months) Fig. 2. The effect of ablating the primary focus on the incidence of primary interictal epileptic events. The adjusted total of epileptic events was calculated by summing 100% of class ! events, 75% of class [ I events and 50% of class I I I events for each EEG recording. The arrow indicates the time of the ablation operation. The decline in frequency after ablation was significant by the one-tailed Wilcoxon rank sum test (P < 0.01, EpP1, EpP2 and EpP4; P < 0.05, EpP3).
28
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EPILEPTIC DISCHARGES AFTER COMMISSURE SECTION
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30
M.B. LOWRIE ET AL.
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all experimental animals except EpS2. Although right-sided convulsions were seen several times in this animal while it was in its home cage, the overall level of epileptic activity in the EEG recordings remained low.
Effects of primary ablation As shown in Fig. 2 all primary interictal activity ceased (i.e., was significantly reduced) after ablation of the primary focus. Similarly all transmitted secondary activity ceased after ablation although the decline was statistically significant only for EpP1 and EpP4 (Fig. 3). No seizure discharges were observed in the EEGs of these animals after ablation, In contrast all 4 animals continued to have independent secondary interictal events after primary ablation (Fig. 4). Only one animal, EpP2, showed a significant decrease in this
activity. Examples of independent secondary discharges occurring after commissure section have been illustrated elsewhere (Nie et al. 1974). Fig. 5 shows EEG recordings taken from animals EpP3 and EpP4 at different times after ablation of the primary focus. Spikes can be seen only in the leads from the right {secondary)hemisphere.
Effects of secondary ablation Primary interictal epileptic events were seen in all 3 animals (EpS1-3) after removal of the contralateral secondary cortex (Fig. 6). The ablations were not associated with any significant difference in incidence. Transmitted secondary events were seen in EpS1 and EpS3 after ablation of the secondary cortex; the incidence was not significantly reduced by ablation (Fig. 7). The absence of
EPILEPTIC D I S C H A R G E S A F T E R C O M M I S S U R E S E C T I O N
31
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these events in EpS2 probably reflects the unusually low level of epileptic activity observed throughout in this animal. No independent secondary events were observed in the recordings of EpS1-3 after removal of the secondary cortex (Fig. 8). The decline in this activity was significant for EpS1 but failed to reach statistical significance in EpS2 and EpS3 because of the low preoperative frequency of this activity,
Discussion We have found, in agreement with Nie et al. (1974), that division of the forebrain commissures does not prevent ~he development of secondary epileptic discharges. Moreover we conclude that commissure section does not influence the persistence of secondary discharges after ablation of the primary focus; the incidence of secondary activity in the
32
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Fig. 7. T h e e f f e c t o f a b l a t i n g t h e c o r t e x c o n t r a l a t e r a l t o t h e p r i m a r y focus o n t h e i n c i d e n c e o f t r a n s m i t t e d seco n d a r y interictal epileptic events. T h e r e was n o statistically significant difference in f r e q u e n c y b e f o r e a n d a f t e r ablation.
present study is very similar to that found by Nie arid Ettlinger (1974) when the inferotemporal primary focus was removed in non-commissure-sectioned animals, Cortical ablation, whether in the primary or secondary hemisphere, abolishes EEG evidence of discharges from that cortex. However, one animal, EpP4, did show irregular jerking movements of the right arm and leg on several occasions during the 6 months fol-
lowing ablation of the primary (left) focus. Although these movements were different from the convulsions usually seen after application of aluminium hydroxide, and attempts to obtain EEG evidence of their neurological origin failed, it remains a possibility that an ipsilateral secondary focus had been spared from the otherwise extensive primary ablation. The results of ablations of the secondary
EPILEPTIC DISCHARGES A F T E R c o M M I S S U R E SECTION
33
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cortex show that removal of cortex in one hemisphere d o e s n o t s u p p r e s s e p i l e p t i c a c t i v i t y originating in the other hemisphere. Nor is there evidence that the lesion facilitated the primary activity. The raised post-ablation level of primary activity seen in EpS1 probably reflects the early date of ablation in this animal (four months) as most animals reach their peak of primary activity at 6 or 7 months,
The origin of transmitted secondary events Animals EpS1 and EpS3 showed evidence of transmitted secondary discharges after, and in spite of, removal of the contralateral cortex. Two possible reasons for this are discussed below, (1) Subcortical secondary focus. Ogden et al. (1956) have suggested that, in some cases of clinical epilepsy involving a unilateral lesion, a midline subcortical pacemaker might
subsequently be the source of the synchronized discharges to both hemispheres. It seems unlikely, however, that the present transmitted events are due to such a midline focus as no discharges were seen over the primary hemisphere after ablation of the primary cortex. The secondary hemisphere seems a more plausible site for a subcortical secondary focus, particularly in view of the observation by Wilder and Schmidt (1965) that propagation of epileptic discharges from a primary cortical focus to the contralateral cortex was always accompanied by involvement of one or more basal ganglia. However, if the source of transmitted secondary events is subcortical it is unlikely that it is also the source of independent secondary events as removal of the secondary cortex alone was sufficient to abolish the independent discharges. (2) Passive spread. By definition scalp EEG
34
recordings are dependent on passive spread of electrical potentials through overlying tissues to the electrode. As shown in studies on hemispherectomy (Cobb and Sears 1960) and the visual evoked response (Barrett et al. 1976), passive spread over several centimetres is possible, although some attenuation of the signal is to be expected. Although great caution is needed in interpretation of amplitude (particularly in monkeys which have a more mobile scalp than human subjects) it was noted that in the post-ablation records of EpS1 and EpS3 the transmitted events were never more than half the amplitude of the primary events. Pre-ablation records showed a variable attenuation. It is therefore possible that the transmitted events seen in the secondary hemisphere may have spread by volume conduction from the primary focus. To account for the variability in the occurrence of secondary transmitted events we suggest that spread can be recorded from the secondary hemisphere either when the primary events are large or when the orientation of the generators of the primary discharges has altered (e.g. by migrating into a sulcus),
The evidence for independent secondary discharges The type of events described here as independent secondary discharges were n o t seen in any of 42 recordings made from unoperated animals in the experience of one of us (MBL). Taken with the virtual absence of epileptic events in the 18 recordings of animals C1 and C2, it appears that these independent secondary discharges are genuinely epileptic manifestations, All f.our animals with primary ablations continued to show EEG evidence of secondary discharges in spite of the complete absence of primary events. This result, in agreement with earlier work on the inferotemporal cortex (Nie and Ettlinger 1974), argues strongly in favour of the independence of these discharges, One animal, EpP2, did show a significant
M.B. L O W R I E E T AL.
decrease in the frequency of independent secondary discharges after a primary ablation, suggesting partial dependence on the primary focus. However, a decline in secondary activity with time might be expected to occur in the absence of ablation, as indicated by EpS3 in Fig. 8.
The origin of secondary independent discharges In the past it has been proposed that the forebrain commissures play a major role in the evolution of a secondary (mirror) focus (Morrell 1960). In the light of the present study and the earlier work of Nie et al. (1974) an alternative explanation other than transcommissural b o m b a r d m e n t must be sought for the origin of the secondary focus in the monkey. Several explanations relating to experimental methods have already been discussed by Nie et al. (1974). Like these authors we consider such explanations to be possible but unlikely. Another interpretation is that discharges are propagated along interhemispheric pathways below the level of the massa intermedia. Several workers have commented upon the widespread involvement of subcortical structures during propagation of epileptic discharges from a primary cortical focus (Wilder and Schmidt 1965; Wada and Cornelius 1960). Wilder and Schmidt (1965) recording from non-commissure-sectioned monkeys with a unilateral aluminium hydroxide focus on the sensorimotor cortex, state that propagation to the contralateral cortex was never seen without involvement of one or more subcortical structures. It is possible that a similar pathway could be involved in the spread of activity from a posterior parietal focus. French etal. (1955) have demonstrated posterior parietal cortico-reticular pathways in the monkey. However, Walker and Rivera (1964) failed to observe subcortical involvement during spread of epileptic activity from a parietal aluminium hydroxide focus to the contralaterai cortex in the monkey, although propaga-
EPILEPTIC DISCHARGES AFTER COMMISSURE SECTION
tion to subcortical structures was observed when the focus was made in m o t o r or other areas of cortex. A final possibility relates to the immunological hypotheses of Bowen (1968); Ettlinger and Lowrie {1976); Cazzullo et al. (1976). According to such proposals an antigen would be released by tissue destruction at the primary focus and the resultant antibodies could be responsible for the development of both primary and secondary discharges,
Summary Nine monkeys underwent division of the corpus callosum, anterior commissure, massa intermedia, and posterior commissure. At the same operation, in seven of these animals aluminium hydroxide was applied to the left posterior parietal-prestriate cortex. Monthly EEG recordings were taken from all animals, All seven animals with epileptogenic implants gave evidence of primary abnormal discharges {i.e. from the ipsilateral hemisphere) and secondary (i.e. from the contralateral hemisphere) discharges. The secondary events were of two types: transmitted, i.e. synchronous with primary events; independent, i.e. asynchronous with primary events, After intervals varying from 4 to 22 months all seven monkeys underwent wide ablation of the posterior parietal cortex: on the left in four animals, on the right in three animals. EEG recordings were taken for a further 6 months. All recordings were quantitatively analysed, the number of primary, transmitted secondary and independent secondary events being counted separately. This analysis indicated the following: (1) Primary and transmitted secondary discharges ceased after primary ablations b u t were unaffected by removal of the secondary cortex. (2) Independent secondary discharges persisted after removal of the primary focus but were abolished by secondary ablations. of
Possible m e c h a n i s m s for the d e v e l o p m e n t transmitted and independent secondary
discharges are considered,
35
R~sum~ Effets d'ablations sur les ddcharges primaires et secondaires chez des Macaques aprds commissurotomie Sur neuf Macaques (rhesus) on a procddd la section du corps calleux, de la commissure antdrieure, de la massa intermedia, et de la commissure postdrieure. Au cours de la m~me intervention, on a appliqud, ~ sept de ces animaux, de l'alumine sur la r~gion corticale pari~tale post~rieure--prdstride gauche. Des enregistrements EEG mensuels ont ~t~ effectu~s sur t o u s l e s animaux. Les sept animaux porteurs d'implants dpileptog~nes d~velopp~rent des ddcharges anormales primaires (c.-~-d. sur l'hdmisph~re ipsilateral), et secondaires (c.-~-d. sur l'hdmisphere contralatdral). Les dv~nements secondaires ~taient de deux types, soit transmis, c'est-~-dire synchrones des ~v~nements primaires, soit ind~pendants, c'est-~-dire nonsynchrones de ces derniers. Apr~s un laps de temps de 4 ~ 22 mois, les sept singes ont subi une ablation du cortex paridtal postdrieur, ~ gauche chez quatre animaux, ~ droite chez trois animaux. Les enregistrements EEG ont dtd poursuivis pendant 6 mois encore. T o u s l e s trac~s on ~td analys~s quantitativement, en comptant s~par~ment le nombre d'~v~nements primaires, secondaires transmis et secondaires ind~pendants. L'analyse a donn~ les rdsultats suivants: (1) Les d~charges primaires et secondaires transmises ont dtd dlimindes par les ablations primaires; en revanche, elles ne furent pas supprim~es par ~limination du cortex secondaire. (2) Les ddcharges secondaires ind~pendantes ont persist~ apr~s ablation du foyer primaire mais furent abolies par des ablations secondaires. Les m~canismes ~ventuellement impliquds dans le d~veloppement des d~charges secondaires transmises et ind~pendantes sont examin~s. We thank Dr. J.B. Brierley for the histological processing of some of the brains; and Dr. I. Janota for cutting the remaining brains and interpreting the find-
ings.
36
References Barrett, G., Blumhardt, L., Halliday, A.M., Halliday, E. and Kriss, A. A paradox in the lateralisation of the visual evoked response. Nature (Lond.), 1976, 261 : 253--255. Bowen, F.P. Immunologic reactions after cortical lesions in rabbits. Arch. Neurol.~ 1968, 19: 398-402. Cazzullo, C.L., Altamura, A.C., Canger, R. and Penati, G. Cobalt-induced experimental epilepsy in cats pharmacologically immunodepressed. Arzneim.-Forsch., 1976, 26: 1387--1393. Cobb, W. and Sears, T.A. A study of the transmission of potentials after hemispherectomy. Electroenceph. clin. Neurophysiol., 1960, 12: 371--383. Ettlinger, G. and Lowrie, M.B. An immunological factor in epilepsy. Lancet, 1976, i: 1386. French, J.D., Hern~indez-P~on, R. and Livingston, R.B. Projections from cortex to cephalic brain stem (reticular formation) in monkey. J. Neurophysiol., 1955, 18: 74--95. Gautrin, D., Fenton, G. and Ettlinger, G. Aluminium hydroxide implants on the inferotemporal cortex of the monkey: their mode of influencing visual discrimination performance. Exp. Neurol., 1971, 33: 459--474. Morrell, F. Secondary epileptogenic lesions. Epilepsia (Amst.), 1960, 1: 538--560. Nie, V. and Ettlinger, G. Ablation of the primary inferotemporal epileptogenic focus in rhesus monkeys with independent secondary spike discharges. Brain Res., 1974, 69: 149--152.
M.B. LOWRIE ET AL. Nie, V., Maccabe, J.J., Ettlinger, G. and Driver, M.V. The development of secondary discharges in the rhesus monkey after commissure section. Electroenceph, clin. Neurophysiol., 1974, 37: 473--481. Nie, V., Upton, A. and Ettlinger, G. Behavioral impairment in the monkey following implantation of aluminum hydroxide on the temporal cortex: the role of cortical destruction. Exp. Neurol., 1973, 40: 632--651. Ogden, T.E., Aird, R.B. and Garoutte, B.C. The nature of bilateral and synchronous cerebral spiking. Acta psychiat, neurol, scand., 1956, 31: 273-284. Storm van Leeuwen, W., Bickford, R., Brazier, M., Cobb, W.A., Dondey, M., Gastaut, H., Gloor, P., Henry, C.E., Hess, R., Knott, J.R., Kugler, J., Laity, G.C., Loeb, C., Magnus, O., Oiler Daurella, L., Petsche, H., Schwab, R., Walter, W.G. and Widen, L. Proposals for an EEG terminology by the Terminology committee of the international federation for electroencephalography and clinical neurophysiology. Electroenceph. clin. Neurophysiol., 1966, 20: 293--320. Wada, J.A. and Cornelius, L.R. Functional alteration of deep structures in cats with chronic focal cortical irritative lesions. Arch. Neurol., 1960, 3: 425-447. Walker, A.E. and Rivera, J.F. Subcortical recording in experimental focal chronic epilepsy. Trans. Amer. neurol. Ass., 1964, 89: 37--39. Wilder, B.J. and Schmidt, R.P. Propagation of epileptic discharge from chronic neocortical loci in monkey. Epilepsia (Amst.), 1965, 6: 297--309.