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Effect of motor cortical kindling on subsequent ventral hippocampal kindling and the role of the corpus callosum in the cat
Epilepsy Research 28 (1997) 1 – 10
Effect of motor cortical kindling on subsequent ventral hippocampal kindling and the role of the corpus callosum in the cat Tatsuya Kudo *, Kazuichi Yagi, Masakazu Seino National Epilepsy Center, Shizuoka Higashi Hospital, Urushiyama 886, Shizuoka 420, Japan Received 26 January 1997; received in revised form 1 February 1997; accepted 3 February 1997
Abstract The effect of bilateral motor cortical (MC) kindling on subsequent unilateral ventral hippocampal (VHIPP) kindling was studied in four cats with the corpus callosum (CC) intact and five cats with the CC bisected, compared with nine cats with unilateral VHIPP kindling. Subsequent VHIPP kindling in CC-intact cats resulted in the modified development of limbic seizures to ipsilateral, not contralateral, focal motor seizures in one of four cats, significantly greater seizure regressions from generalized convulsive seizure stage to earlier seizure stages and delayed onset of focal motor seizures and generalized convulsions in partial onset generalized convulsions. CC bisection reduced the degree of seizure regression from generalized convulsive seizure stage to earlier stages, facilitated the development of the last limbic seizure to the first generalized convulsive seizure, accentuated hemiconvulsions and asymmetrical generalized convulsions and delayed the onset of generalized convulsions in partial onset generalized convulsions. The modified seizure development was also induced in three of five CC-bisected cats. Results indicate that bilateral MC kindling induces inhibitory effects on subsequent unilateral VHIPP kindling and the modified ictal progress from the VHIPP to the contralateral hemispheric motor structures and also that CC bisection interferes with the bilateralization and synchronization of convulsions, but reduces the inhibition of previously established MC kindling against VHIPP kindling and facilitates the development of focal motor seizures to secondarily generalized convulsions. © 1997 Elsevier Science B.V. Keywords: Motor cortical kindling; Ventral hippocampal kindling; Callosal bisection; Facilitatory and inhibitory effects; Modified focal motor seizure; Cat
* Corresponding author. Tel.: +81 54 2455446; fax: +81 54 2479781. 0920-1211/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved. PII S 0 9 2 0 - 1 2 1 1 ( 9 7 ) 0 1 0 3 3 - 4
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1. Introduction The existence of interhemispheric positive transfer (facilitatory) and negative transfer (inhibitory or interference) effects is well known in limbic and neocortical kindling [6,13,19]. Regarding the effects of neocortical kindling on the subcortical structures, kindling in the temporal lobe and the suprasylvian association area has a positive transfer effect on subsequent hippocampal and amygdaloid kindling [8,13] and temporal lobe kindling induces a secondary epileptogenic focus in the hippocampus (HIPP) [3]. However, the effect of frontal lobe kindling on the limbic structures remains unknown in cats. In rats, frontal kindling suppressed seizure development with subsequent HIPP kindling [9] and, in contrast, facilitated seizure development with subsequent amygdaloid kindling [12]. Since the corpus callosum (CC) is known to play an important role in inhibiting seizure development with amygdaloid and motor cortical (MC) kindling [6,17], the CC may play an important role in the effect of MC kindling on the subcortical structures, as well as on the contralateral MC [6]. Callosotomy is performed in patients with frontal lobe epilepsy associated with multifocal epileptogenic discharges [4,15] and more intense and newly patterned focal seizures occur after callosotomy in patients with bilateral frontal EEG foci [15]. Therefore, it is meaningful to elucidate the secondary epileptogenic alteration in the ventral HIPP (VHIPP) induced by MC kindling and the effect of CC bisection on it.
2. Methods
2.1. Animals Nine adult cats (mean9 S.D. weight, 3.99 0.8 kg; control group) were used for unilateral VHIPP kindling and nine cats (mean weight, 3.5 9 0.6), four with intact CC (cats 1 – 4, CC-intact group) and five with the bisected CC (cats 5 – 9, CC-bisected group), were used for unilateral VHIPP kindling subsequent to bilateral MC kindling.
2.2. Control group
2.2.1. Electrode implantation Recording and stimulating electrodes were made from twisted stainless steel wire of 0.35 mm in diameter and insulated except for 1 mm at the tips. With the cats under sodium pentobarbital anesthesia, electrodes were implanted bilaterally into the hippocampus, midbrain reticular formation and anterior sigmoid gyrus (motor cortex) according to a stereotaxic atlas [14]. A stainless steel screw in the frontal bone was used as a reference.
2.2.2. VHIPP kindling Kindling began in the left VHIPP following a 2 week postoperative rest period. Electrical stimulation, given once a day with a 60 Hz sine wave lasting for 1 s, began at 100 mA and was subsequently increased by 100 mA steps until after-discharge (AD) was elicited. On each subsequent day, the stimulus intensity was reduced gradually by 50 mA stepwise until AD could no longer be elicited. The lowest intensity for inducing AD was arbitrarily named the after-discharge threshold (ADT), with which daily stimulation was done. Seizure stages were classified into stage 1, motionless stare; stage 2, autonomic manifestations like salivation and dilatation of pupils, facial twitching and mastication; stage 3, contralateral head turning and circling, tonic-clonic convulsion in the contralateral forepaw and extension of forepaws and stage 4, falling and partial onset generalized tonic-clonic convulsion [10]. Thus, stages 1 and 2 were limbic seizure stages, stage 3 was the focal motor stage and stage 4 was the generalized convulsive seizure stage. Following five daily consecutive elicitations of partial onset generalized convulsions, arbitrarily designated as a stable stage 4 generalized convulsive seizure state, the generalized convulsive triggering threshold (GST) with an ‘all-or-none’ property [16] was determined with stepwise reduction of the stimulus intensity by 50 mA.
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2.3. CC-intact group 2.3.1. Electrode implantation Electrodes were implanted in the same procedure as that of the control group except that electrodes were also implanted bilaterally in the substantia innominata. 2.3.2. MC and VHIPP kindling Following a 2 week postoperative rest period, primary site MC kindling began at the left MC of three cats (cats 1, 2 and 4) and the right MC of cat 3 in a procedure similar to that of VHIPP kindling. Generalized convulsions were elicited at least five times. Daily contralatral MC stimulation (secondary site MC kindling) began on the day 15 following completion of primary site MC kindling in order to compare with previously published papers [8,13,19]. Restimulation of the primary site MC (primary site MC retest) began 24 h following completion of secondary site MC kindling at the previously established ADT. In MC kindling, a focal motor seizure in the contralateral limb developed to a contralateral hemiconvulsion and culminated in a generalized convulsion [6]. VHIPP kindling began in the site ipsilateral to the primary site of MC kindling on the day 7 after the completion of MC kindling in a procedure similar to that of the control group. 2.4. CC-bisected group 2.4.1. CC bisection and electrode implantation With the cats under sodium pentobarbital anesthesia, the dura mater was exposed and then reflected following a craniotomy. The CC was bisected stereotaxically between A20.0 and P1.5 with a cut knife. After a postoperative rest period ranging from 2 to 4 weeks, electrodes were implanted as in the CC-intact group. 2.4.2. MC and VHIPP kindling Two weeks after electrode implantation, MC kindling began in the same procedure as that in the CC-intact group. The left MC of four cats (cats 5, 7, 8 and 9) and the right MC of cat 6 were chosen for primary site MC kindling. On day 7 following the completion of MC kindling, VHIPP
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kindling of the ipsilateral site to the primary site of MC kindling began in the same procedure as that of the control group.
2.5. Histology and data analysis Upon completion of the study, all animals were sacrificed by an overdose of sodium pentobarbital and their brains were perfused with saline and 10% formaline and then surgically removed. The brains were serially sectioned and stained with cresyl violet and hematoxylin eosin. Histological examination showed that all electrodes were located in the intended structures. The Mann– Whitney U test and the x 2-test were used for statistical analysis. Group values are mean 9S.D.
3. Results Results are summarized in Table 1.
3.1. Control group In the control group, seizures developed gradually from limbic seizures (stages 1 and 2) to contralateral focal motor seizures (stage 3) and then to a partial onset, symmetrical generalized tonic-clonic convulsion (stage 4), as reported previously [10], without seizure stage regression. As seizures developed from stage 1 to 4, AD propagated from the stimulated VHIPP to the contralateral VHIPP, bilateral midbrain reticular formation, and bilateral MC. Seizure development from stage 3 to 4 is consistent with self-sustained AD showing an earlier onset in the ipsilateral MC or a simultaneous onset in the bilateral MC. Table 1 shows the number of stimulations required for attaining the first seizure of each stage and the stable stage 4 generalized convulsive seizure state and for developing from the last limbic seizure to the first stage 4 seizure. After attaining the first stage 4 seizure, seizure regressed occasionally from stage 4 to 3 or 2 in five of the nine cats. After attaining the first stage 4 seizure, the mean number of stimulations required to reach the stable stage 4 generalized convulsive seizure state was 6.992.0, the mean
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Table 1 Summary of ventral hippocampal kindling subsequent to motor cortical kindling
ADT, after-discharge threshold; GST, generalized convulsion triggering threshold; CC, corpus callosum. Stages 1 and 2 seizures are limbic seizures. The former shows motionless stare and the latter shows autonomic manifestations, facial twitching and mastication. Stages 3 and 4 seizures show a focal motor seizure and a partial onset generalized convulsion, respectively. Five daily consecutive elicitations of generalIzed convulsions is designated as a stable stage 4 generalized convulsive state.
number of seizure regressions was 1.1 9 1.3 and the ratio of the total number of seizure regressions to the total number of stimulations was 10/62 in all nine cats.
3.2. CC-intact group 3.2.1. Seizure de6elopment In the CC-intact group, seizures developed electroclinically in the same way as that of the control group, except that cat 2 had a modified pattern of seizure development in which the limbic seizure evolved to an ipsilateral, not contralateral, focal motor seizure, with ipsilateral head turning and circling and a tonic-clonic convulsion in the ipsi-
lateral forepaw. The contralateral focal motor seizure development of three cats coincided with the earlier onset of self-sustained AD in the ipsilateral MC. In contrast, the ipsilateral, modified, focal motor seizure development of cat 2 corresponded with the earlier onset in the contralateral MC. The number of stimulations required for attaining the first stage 4 seizure and the stable stage 4 generalized convulsive seizure state and for developing from the last limbic seizure to the first stage 4 seizure in this group showed no significant difference from those of the control group (Table 1). There existed frequent seizure regressions from stage 4 or 3 to stage 2 in cats 2 and 4, and from stage 4 to 3 in all four cats (Fig.
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Fig. 1. The profile of seizure development in CC-intact cats. Seizures often regress from stage 4 or 3 to stage 2 in cats 2 and 4 and from stage 4 to 3 in all four cats. Finally, the stable stage 4 generalized convulsive seizure state is established.
1). After the first stage 4 seizure was reached, the mean number of stimulations required for the stable stage 4 generalized seizure state (17.0 9 12.2, PB 0.05), the mean number of seizure regressions (8.89 8.1, P B 0.05) and the ratio of the total number of seizure regressions to the total number of stimulations (32/68, P B 0.01) in all cats of the CC-intact group were all significantly greater than those in the control group. Finally, the stable stage 4 generalized convulsive seizure state (Fig. 1) and GST with an ‘all-or-none’ property was established.
3.2.2. Latencies to onset of focal motor seizures and generalized con6ulsions and AD durations in stage 4 seizures Latencies (s) from stimulation to the onset of
focal motor seizures and generalized convulsions and AD durations in stage 4 partial onset generalized convulsive seizures are, respectively, 72.89 16.5, 81.69 17.0 and 118.69 22.8 s in the CC-intact group and 35.7910.6, 47.29 17.4 and 78.39 26.4 s in the control group. Those are significantly greater (PB 0.001) in the CC-intact group than in the control group (Fig. 2).
3.3. CC-bisected group 3.3.1. Extent of CC lesion The common denominator area of the lesion was in the anterior half of the CC (Table 1). Cat 5 showed the total bisection of the CC. The hippocampal commissure was intact in all cats of the CC-bisected group.
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3.3.2. Seizure de6elopment In the CC-bisected group, seizures developed abruptly from the limbic seizure stage 1 or 2 to the generalized convulsive seizure stage 4 without remaining in stage 2 or 3 in four cats (Table 1 and Fig. 3). Seizures progressed from limbic seizures to either contralateral (cats 8 and 9) or ipsilateral (cats 5, 6 and 7) focal motor seizures culminating in generalized convulsions. The ictal progression to contralateral focal motor seizure was associated with the earlier onset of self-sustained AD in the ipsilateral MC to the stimulated VHIPP. On the other hand, the ipsilateral focal motor seizure development corresponded with the earlier onset in the contralateral MC (Fig. 4). Hemiconvulsions were accentuated markedly in the CC-bisected group. The stage 4 partial onset generalized convulsions were asymmetrical, showing either marked contralateral (cat 9) or marked ipsilateral (cats 5, 6 and 7) dominance, except that cat 8 had symmetrical generalized convulsions. Seizures of-
Fig. 2. Latencies for the onset of focal motor seizures and generalized convulsions and AD durations in stage 4 partial onset generalized convulsive seizures. Latencies from stimulation to the onset of focal motor seizures and generalized convulsions and AD durations in stage 4 partial onset generalized convulsive seizures of the CC-intact and CC-bisected groups are significantly greater (PB 0.001) than those of the control group. Latency for the onset of generalized convulsions and AD duration in stage 4 partial onset generalized convulsive seizures of the CC-bisected group are significantly greater (P B 0.001) than those of the CC-intact group. Hatched portion of bars indicates stages 1 and 2 limbic seizures, stippled portion indicates stage 3 focal motor seizure and the unshaded portion indicates stage 4 generalized convulsive seizure. AD durations are shown with the time during from the onset of stage 1 seizures until the end of stage 4 seizures.
ten regressed from stage 4 or 3 to stage 2 in cats 5 and 7 and from stage 4 to 3 in cats 6, 7 and 9 and regressed once from stage 2 to 1 in cat 5 (Fig. 3). As shown in Table 1, the number of stimulations required for the first seizure of each stage in the CC-bisected cats was not significantly different from that of the CC-intact group. The number of stimulations required for development from the last limbic seizure to the first stage 4 seizure in the CC-bisected group (1.69 1.2) was significantly (PB 0.05) fewer than those in the control group (4.19 2.0) and the CC-intact group (10.5 9 6.8). The mean number of stimulations required to reach the stable stage 4 generalized convulsive seizure state (17.29 12.0) and the mean number of seizure regressions (7.89 9.5) after attaining the first stage 4 seizure in the CC-bisected group have no significant difference from those in both control and CC-intact groups. The ratio of the total number of seizure regressions to the total number of stimulations after attaining the first stage 4 seizure of all five cats in the CC-bisected group (39/86) was significantly (P B 0.01) different from that in the control group (10/62), but not significantly different from that in the CC-intact group (32/68). Finally, the stable stage 4 seizure state and GST with an ‘all-or-none’ property was established in all cats except cat 5, in which the reduction of stimulus intensity resulted in seizure stage regression. Latencies to onset of focal motor seizures and generalized convulsions and AD durations in stage 4 partial onset generalized convulsive seizures. As shown in Fig. 2, latencies from stimulation to the onset of focal motor seizures and generalized convulsions and AD durations in partial onset stage 4 generalized convulsions of the CC-bisected group are, respectively, 73.09 21.9, 93.59 19.3 and 152.59 22.3 s. These values are all significantly (PB 0.001) greater than those of the control group (35.7 910.6, 47.29 17.4 and 78.39 26.4 s). Latencies to the onset of generalized convulsions and AD durations in partial onset stage 4 generalized convulsions of the CCbisected group (93.59 19.3 and 152.5922.3 s) were also significantly (P B 0.001) greater than those of the CC-intact group (81.69 17.0 and 118.69 22.8 s). But the latency to the onset of
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Fig. 3. The profile of seizure development in CC-bisected group. Seizures develop abruptly from limbic seizure stage 1 or 2 to stage 4 without remaining in stages 2 or 3 in cats 5, 6, 8 and 9. Seizures often regress from stages 4 or 3 to stage 2 in cats 5 and 7 and from stage 4 to 3 in cats 6, 7 and 9 and regress once from stage 2 to 1 in cat 5. Finally, the stable stage 4 seizure state is established.
focal motor seizure has no significant difference between the CC-bisected group (73.09 21.9 s) and the CC-intact group (72.8916.5 s).
4. Discussion
4.1. Effect of MC kindling on subsequent VHIPP kindling VHIPP kindling of the control group showed a preferential pathway by which hippocampal seizures access to the ipsilateral hemispheric motor structures, producing contralateral focal motor seizures. But previously established MC
kindling induced a modified pattern of seizure development, which progressed from limbic seizures to ipsilateral focal motor seizures, in subsequent VHIPP kindling of one CC-intact and three CC-bisected cats. Since the ipsilateral focal motor seizure was associated with the contralateral MC self-sustained discharge, the VHIPP seizure probably accessed to the contralateral MC before the ipsilateral MC was activated in cats with a modified patten of seizure development. Kindling effect is reported to persist in the MC after MC kindling [6]. Therefore, both MCs were made susceptible to epileptic seizures with bilateral MC kindling in the CC-intact and CC-bisected groups before VHIPP kindling began. It
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Fig. 4. EEG of stage 4 seizure in cat 7 with the CC bisected. After the stimulation of the left ventral hippocampus (VHIPP) indicated by the arrow, seizure discharge propagated soon to the left midbrain reticular formation (MRF) (A), then to the right motor cortex (MC) (C) and to the right MRF and VHIPP (C and D). Seizure discharge is of low amplitude and appear last in the left MC. Notably, self-sustained spike discharges appear earlier in the right (contralateral) MC, not in the left (ipsilateral) MC expected as in the control group and continue in the right MC with higher amplitude than that in the left MC. The development of a left, not right as expected in the control group, focal motor seizure (D and E) from a limbic seizure (A, B and C) is consistent with earlier onset and dominant continuation of self-sustained discharges in the right MC. The left partial motor seizure develops to an accentuated left hemiconvulsion (F) and finally culminates in asymmetrical generalized convulsion with left dominance (G). Parts 1, 2 and 3 of EEG are shown in enlarged figures to show seizure discharges clearly. A, motionless stare; B, facial twitching; C, mastication and salivation; D, circling to the left; E, rotation of the body axis to the left side; F, left hemiconvulsion; G, asymmetrical generalized convulsion; L, left; R, right; MC, motor cortex; HIPP, hippocampus; MRF, midbrain reticular formation.
was reported that the susceptible parts, which were not a primary epileptogenic zone, developed an independent electrographical seizure pattern and also had potential to initiate seizure [5]. When both contralateral MC and ipsilateral MC are susceptible to epileptic seizures, the contralateral MC is possibly activated in the seizure development originating from the VHIPP before the ipsi-
lateral MC is involved, in contrast to the preferential pathway shown in VHIPP seizures of the control group. Since the modified pattern of seizure development was also observed in CC-bisected cats, modified ictal progression from the stimulated VHIPP to the contralateral subcortical and cortical motor structures may be induced via structures other than the CC. It is well known
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that the HIPP projects to other limbic structures and the diencephalon and to the contralateral hemisphere through the HIPP and anterior commissures [11] and these structures play a critical role in HIPP seizure development and propagation to the contralateral hemisphere [2,7]. Therefore, previously established MC kindling facilitates the propagation of VHIPP seizures to the contralateral hemispheric motor structures via the subcortical structures in cats. In the CC-intact group with VHIPP kindling subsequent to MC kindling, there were frequent seizure regressions of stage 3 to 2 in cat 2, which was not observed in the control group. After attaining the first stage 4 seizure, the number of stimulations required to reach the stable stage 4 generalized convulsive seizure state, the number of seizure regressions and the ratio of the total number of seizure regressions to the total number of stimulations in the CC-intact group were all significantly greater than those of the control group. These findings show that the previously established MC kindling induced an inhibitory effect against the seizure development from limbic seizure stage to stable stage 4 generalized convulsive seizure state in VHIPP kindling. The latencies from stimulations to the onset of focal motor seizures and generalized convulsions during stage 4 generalized convulsive seizures were significantly greater in the CC-intact group than the control group. Therefore, previously established MC kindling has an inhibitory effect not only on the development of seizure stage but also on the evolvement of partial onset generalized stage 4 seizure in VHIPP kindling. The VHIPP seizure development was not facilitated by previously established MC kindling. This is in contrast with earlier findings that the suprasylvian association area and temporal lobe kindling have a facilitatory effect on subsequent amygdaloid and HIPP kindling in cats [8,13].
4.2. Effect of CC bisection on seizure de6elopment with subsequent VHIPP kindling During VHIPP kindling, the CC-bisected group had seizure stage regressions before attaining the first stage 4 seizure. The CC-bisected group also
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had a significantly greater ratio of the total number of seizure regressions to the total number of stimulations after attaining the first stage 4 seizure than the control group. But, in VHIPP kindling, the CC-bisected group did not show a significantly greater difference than the control group in the number of stimulations required to reach the stable stage 4 generalized convulsive seizure state and the number of stage regressions from stage 4 to earlier stages after attaining the first stage 4 seizure. As previously mentioned, the CC-intact group showed a significantly greater difference than the control group in these numbers of VHIPP kindling. Thus, previously established MC kindling inhibited the seizure development of VHIPP kindling, but CC bisection seemed to reduce the degree of the inhibition. Furthermore, CC-bisection resulted in abrupt seizure development from the limbic seizure stage to the generalized convulsive seizure stage 4, without remaining in limbic stage 2 or focal motor seizure stage 3 in four or five cats and significantly fewer stimulations were required for development from the last limbic seizure to the first generalized convulsive seizure in VHIPP kindling. Therefore, CC bisection facilitated the seizure development from the limbic seizure stage through focal motor seizure stage to generalized convulsive seizure stage. Our speculation is that CC bisection reduces the inhibition induced by previously established MC kindling and facilitates the seizure development of limbic seizure to generalized convulsive seizure in VHIPP kindling. This is consistent with previous papers, which report that electrical stimulation of the CC induces long-lasting inhibitory effects on pyramidal cells in the pericruciate cortex of cats [1] and the CC has inhibitory effects on the mechanism of cortical motor seizure propagation in MC kindling of cats [6] and in amygdaloid kindled seizures of Papio papio baboons [18]. Our results show that CC bisection induces accentuated hemiconvulsions, asymmetrical generalized convulsions and increases the latency to the onset of generalization of convulsions, but not the latency to the onset of focal motor seizure stage, during stage 4 seizures. These findings indicate that the CC plays an important role in generalization and synchronization of convulsive seizures, as reported previously [6,17,18].
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In summary, previously established bilateral MC kindling causes an inhibitory effect on subsequent unilateral VHIPP kindling. MC kindling also modifies ictal progress from the VHIPP, so that VHIPP seizures propagate to the contralateral hemispheric motor mechanism. CC-bisection interferes with generalization and synchronization of convulsive seizures, but reduces the degree of the inhibitory effect MC kindling has on subsequent VHIPP kindling and facilitates the development of limbic seizure to generalized convulsions once limbic seizures reaches the motor mechanism.
References [1] Asanuma H, Okamoto K. Unitary study on evoked activity of callosal neurons and its effect on pyramidal tract cell activity on cats. Jpn J Physiol 1959;9:473–83. [2] Collins RC, Tearse RG, Lothman EW. Functional anatomy of limbic seizures: Focal discharges from medial entorhinal cortex in rat. Brain Res 1983;280:25–40. [3] Ehara Y. Prolonged sylvian and ectosylvian gyrus kindling in cats and the secondary epileptogenic change in the limbic system. J Jpn Epil Soc 1988;6:28–38. [4] Huck FR, Radvany J, Avila OJ, Pires de Camargo CH, Marino R Jr., Ragazzo PC, Riva D, Arlant P. Anterior callosotomy in epileptics with multiform seizures and bilateral synchronous spike and wave EEG pattern. Acta Neurochir Suppl 1980;30:127–35. [5] Jayakar P, Duchowny M, Alvarez L, Resnick T. Intraictal activation in the neocortex: A marker of the epileptogenic region. Epilepsia 1994;35:489–94. [6] Kudo T, Amano K, Tanaka M, Yagi K, Seino M. Effect of callosal bisection on motor cortical kindling. Jpn J Psychiatry Neurol 1994;48:433–5. [7] Mayanagi Y, Walker AE. Experimental temporal lobe
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epilepsy. Brain 1974;97:423 – 46. [8] Okamoto M. An experimental study of temporal cortical kindling in cats: The effects of midline-bisection on seizure generalization mechanism. Psychiat Neurol Jap 1982;84:48 – 67. [9] Ono K, Baba H, Mori K, Wada JA. Premotor cortical kindling interferes with subsequent hippocampal kindling. Brain Res 1988;475:182 – 6. [10] Rondouin G, Baldy-Moulinier M, Passouant P. The influence of hippocampal kindling on sleep organization in cats. Effect of alpha – methylparatyrosine. Brain Res 1980;181:413 – 24. [11] Schwerdtfeger WK. Structure and fiber connections of the hippocampus. A comparative study, Springer-Verglag, Berlin, 1984. [12] Seidel W, Corcoran M. Relations between amygdaloid and anterior neocortical kindling. Brain Res 1986;385:375 – 8. [13] Seki K, Wada JA. Kindling of cortical association area 5 in the cat. In: Wada JA, editor. Kindling 3. New York: Raven Press, 1986:429 – 446. [14] Snider RS, Niemer WT. A stereotaxic atlas of the cat brain, The University of Chicago Press, Chicago, 1961. [15] Spencer SS, Spencer DD, Glaser GH, Williamson PD, Mattson RH. More intense focal seizure types after callosal section: The role of inhibition. Ann Neurol 1984;16:686 – 93. [16] Wada JA, Sato M. Generalized convulsive seizures induced by daily electrical stimulation of the amygdala in cats. Correlative electrographic and behavioral features. Neurology 1974;24:565 – 74. [17] Wada JA, Sato M. The generalized convulsive seizure state induced by daily electrical stimulation of the amygdala in split brain cats. Epilepsia 1975;16:417 – 30. [18] Wada JA, Komai S. Effect of anterior two-thirds callosal bisection upon bisymmetrical and bisynchronous generalized convulsions kindled from amygdala in epileptic baboon, Papio papio. In: Reeves AG, editor. Epilepsy and the corpus callosum. New York: Plenum Press, 1985:75 – 97. [19] Wake A, Wada JA. Transfer and interference in amygdaloid kindling in cats. Can J Neurol Sci 1977;4:5 – 11.
Effect of motor cortical kindling on subsequent ventral hippocampal kindling and the role of the corpus callosum in the cat Tatsuya Kudo *, Kazuichi Yagi, Masakazu Seino National Epilepsy Center, Shizuoka Higashi Hospital, Urushiyama 886, Shizuoka 420, Japan Received 26 January 1997; received in revised form 1 February 1997; accepted 3 February 1997
Abstract The effect of bilateral motor cortical (MC) kindling on subsequent unilateral ventral hippocampal (VHIPP) kindling was studied in four cats with the corpus callosum (CC) intact and five cats with the CC bisected, compared with nine cats with unilateral VHIPP kindling. Subsequent VHIPP kindling in CC-intact cats resulted in the modified development of limbic seizures to ipsilateral, not contralateral, focal motor seizures in one of four cats, significantly greater seizure regressions from generalized convulsive seizure stage to earlier seizure stages and delayed onset of focal motor seizures and generalized convulsions in partial onset generalized convulsions. CC bisection reduced the degree of seizure regression from generalized convulsive seizure stage to earlier stages, facilitated the development of the last limbic seizure to the first generalized convulsive seizure, accentuated hemiconvulsions and asymmetrical generalized convulsions and delayed the onset of generalized convulsions in partial onset generalized convulsions. The modified seizure development was also induced in three of five CC-bisected cats. Results indicate that bilateral MC kindling induces inhibitory effects on subsequent unilateral VHIPP kindling and the modified ictal progress from the VHIPP to the contralateral hemispheric motor structures and also that CC bisection interferes with the bilateralization and synchronization of convulsions, but reduces the inhibition of previously established MC kindling against VHIPP kindling and facilitates the development of focal motor seizures to secondarily generalized convulsions. © 1997 Elsevier Science B.V. Keywords: Motor cortical kindling; Ventral hippocampal kindling; Callosal bisection; Facilitatory and inhibitory effects; Modified focal motor seizure; Cat
* Corresponding author. Tel.: +81 54 2455446; fax: +81 54 2479781. 0920-1211/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved. PII S 0 9 2 0 - 1 2 1 1 ( 9 7 ) 0 1 0 3 3 - 4
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1. Introduction The existence of interhemispheric positive transfer (facilitatory) and negative transfer (inhibitory or interference) effects is well known in limbic and neocortical kindling [6,13,19]. Regarding the effects of neocortical kindling on the subcortical structures, kindling in the temporal lobe and the suprasylvian association area has a positive transfer effect on subsequent hippocampal and amygdaloid kindling [8,13] and temporal lobe kindling induces a secondary epileptogenic focus in the hippocampus (HIPP) [3]. However, the effect of frontal lobe kindling on the limbic structures remains unknown in cats. In rats, frontal kindling suppressed seizure development with subsequent HIPP kindling [9] and, in contrast, facilitated seizure development with subsequent amygdaloid kindling [12]. Since the corpus callosum (CC) is known to play an important role in inhibiting seizure development with amygdaloid and motor cortical (MC) kindling [6,17], the CC may play an important role in the effect of MC kindling on the subcortical structures, as well as on the contralateral MC [6]. Callosotomy is performed in patients with frontal lobe epilepsy associated with multifocal epileptogenic discharges [4,15] and more intense and newly patterned focal seizures occur after callosotomy in patients with bilateral frontal EEG foci [15]. Therefore, it is meaningful to elucidate the secondary epileptogenic alteration in the ventral HIPP (VHIPP) induced by MC kindling and the effect of CC bisection on it.
2. Methods
2.1. Animals Nine adult cats (mean9 S.D. weight, 3.99 0.8 kg; control group) were used for unilateral VHIPP kindling and nine cats (mean weight, 3.5 9 0.6), four with intact CC (cats 1 – 4, CC-intact group) and five with the bisected CC (cats 5 – 9, CC-bisected group), were used for unilateral VHIPP kindling subsequent to bilateral MC kindling.
2.2. Control group
2.2.1. Electrode implantation Recording and stimulating electrodes were made from twisted stainless steel wire of 0.35 mm in diameter and insulated except for 1 mm at the tips. With the cats under sodium pentobarbital anesthesia, electrodes were implanted bilaterally into the hippocampus, midbrain reticular formation and anterior sigmoid gyrus (motor cortex) according to a stereotaxic atlas [14]. A stainless steel screw in the frontal bone was used as a reference.
2.2.2. VHIPP kindling Kindling began in the left VHIPP following a 2 week postoperative rest period. Electrical stimulation, given once a day with a 60 Hz sine wave lasting for 1 s, began at 100 mA and was subsequently increased by 100 mA steps until after-discharge (AD) was elicited. On each subsequent day, the stimulus intensity was reduced gradually by 50 mA stepwise until AD could no longer be elicited. The lowest intensity for inducing AD was arbitrarily named the after-discharge threshold (ADT), with which daily stimulation was done. Seizure stages were classified into stage 1, motionless stare; stage 2, autonomic manifestations like salivation and dilatation of pupils, facial twitching and mastication; stage 3, contralateral head turning and circling, tonic-clonic convulsion in the contralateral forepaw and extension of forepaws and stage 4, falling and partial onset generalized tonic-clonic convulsion [10]. Thus, stages 1 and 2 were limbic seizure stages, stage 3 was the focal motor stage and stage 4 was the generalized convulsive seizure stage. Following five daily consecutive elicitations of partial onset generalized convulsions, arbitrarily designated as a stable stage 4 generalized convulsive seizure state, the generalized convulsive triggering threshold (GST) with an ‘all-or-none’ property [16] was determined with stepwise reduction of the stimulus intensity by 50 mA.
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2.3. CC-intact group 2.3.1. Electrode implantation Electrodes were implanted in the same procedure as that of the control group except that electrodes were also implanted bilaterally in the substantia innominata. 2.3.2. MC and VHIPP kindling Following a 2 week postoperative rest period, primary site MC kindling began at the left MC of three cats (cats 1, 2 and 4) and the right MC of cat 3 in a procedure similar to that of VHIPP kindling. Generalized convulsions were elicited at least five times. Daily contralatral MC stimulation (secondary site MC kindling) began on the day 15 following completion of primary site MC kindling in order to compare with previously published papers [8,13,19]. Restimulation of the primary site MC (primary site MC retest) began 24 h following completion of secondary site MC kindling at the previously established ADT. In MC kindling, a focal motor seizure in the contralateral limb developed to a contralateral hemiconvulsion and culminated in a generalized convulsion [6]. VHIPP kindling began in the site ipsilateral to the primary site of MC kindling on the day 7 after the completion of MC kindling in a procedure similar to that of the control group. 2.4. CC-bisected group 2.4.1. CC bisection and electrode implantation With the cats under sodium pentobarbital anesthesia, the dura mater was exposed and then reflected following a craniotomy. The CC was bisected stereotaxically between A20.0 and P1.5 with a cut knife. After a postoperative rest period ranging from 2 to 4 weeks, electrodes were implanted as in the CC-intact group. 2.4.2. MC and VHIPP kindling Two weeks after electrode implantation, MC kindling began in the same procedure as that in the CC-intact group. The left MC of four cats (cats 5, 7, 8 and 9) and the right MC of cat 6 were chosen for primary site MC kindling. On day 7 following the completion of MC kindling, VHIPP
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kindling of the ipsilateral site to the primary site of MC kindling began in the same procedure as that of the control group.
2.5. Histology and data analysis Upon completion of the study, all animals were sacrificed by an overdose of sodium pentobarbital and their brains were perfused with saline and 10% formaline and then surgically removed. The brains were serially sectioned and stained with cresyl violet and hematoxylin eosin. Histological examination showed that all electrodes were located in the intended structures. The Mann– Whitney U test and the x 2-test were used for statistical analysis. Group values are mean 9S.D.
3. Results Results are summarized in Table 1.
3.1. Control group In the control group, seizures developed gradually from limbic seizures (stages 1 and 2) to contralateral focal motor seizures (stage 3) and then to a partial onset, symmetrical generalized tonic-clonic convulsion (stage 4), as reported previously [10], without seizure stage regression. As seizures developed from stage 1 to 4, AD propagated from the stimulated VHIPP to the contralateral VHIPP, bilateral midbrain reticular formation, and bilateral MC. Seizure development from stage 3 to 4 is consistent with self-sustained AD showing an earlier onset in the ipsilateral MC or a simultaneous onset in the bilateral MC. Table 1 shows the number of stimulations required for attaining the first seizure of each stage and the stable stage 4 generalized convulsive seizure state and for developing from the last limbic seizure to the first stage 4 seizure. After attaining the first stage 4 seizure, seizure regressed occasionally from stage 4 to 3 or 2 in five of the nine cats. After attaining the first stage 4 seizure, the mean number of stimulations required to reach the stable stage 4 generalized convulsive seizure state was 6.992.0, the mean
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Table 1 Summary of ventral hippocampal kindling subsequent to motor cortical kindling
ADT, after-discharge threshold; GST, generalized convulsion triggering threshold; CC, corpus callosum. Stages 1 and 2 seizures are limbic seizures. The former shows motionless stare and the latter shows autonomic manifestations, facial twitching and mastication. Stages 3 and 4 seizures show a focal motor seizure and a partial onset generalized convulsion, respectively. Five daily consecutive elicitations of generalIzed convulsions is designated as a stable stage 4 generalized convulsive state.
number of seizure regressions was 1.1 9 1.3 and the ratio of the total number of seizure regressions to the total number of stimulations was 10/62 in all nine cats.
3.2. CC-intact group 3.2.1. Seizure de6elopment In the CC-intact group, seizures developed electroclinically in the same way as that of the control group, except that cat 2 had a modified pattern of seizure development in which the limbic seizure evolved to an ipsilateral, not contralateral, focal motor seizure, with ipsilateral head turning and circling and a tonic-clonic convulsion in the ipsi-
lateral forepaw. The contralateral focal motor seizure development of three cats coincided with the earlier onset of self-sustained AD in the ipsilateral MC. In contrast, the ipsilateral, modified, focal motor seizure development of cat 2 corresponded with the earlier onset in the contralateral MC. The number of stimulations required for attaining the first stage 4 seizure and the stable stage 4 generalized convulsive seizure state and for developing from the last limbic seizure to the first stage 4 seizure in this group showed no significant difference from those of the control group (Table 1). There existed frequent seizure regressions from stage 4 or 3 to stage 2 in cats 2 and 4, and from stage 4 to 3 in all four cats (Fig.
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Fig. 1. The profile of seizure development in CC-intact cats. Seizures often regress from stage 4 or 3 to stage 2 in cats 2 and 4 and from stage 4 to 3 in all four cats. Finally, the stable stage 4 generalized convulsive seizure state is established.
1). After the first stage 4 seizure was reached, the mean number of stimulations required for the stable stage 4 generalized seizure state (17.0 9 12.2, PB 0.05), the mean number of seizure regressions (8.89 8.1, P B 0.05) and the ratio of the total number of seizure regressions to the total number of stimulations (32/68, P B 0.01) in all cats of the CC-intact group were all significantly greater than those in the control group. Finally, the stable stage 4 generalized convulsive seizure state (Fig. 1) and GST with an ‘all-or-none’ property was established.
3.2.2. Latencies to onset of focal motor seizures and generalized con6ulsions and AD durations in stage 4 seizures Latencies (s) from stimulation to the onset of
focal motor seizures and generalized convulsions and AD durations in stage 4 partial onset generalized convulsive seizures are, respectively, 72.89 16.5, 81.69 17.0 and 118.69 22.8 s in the CC-intact group and 35.7910.6, 47.29 17.4 and 78.39 26.4 s in the control group. Those are significantly greater (PB 0.001) in the CC-intact group than in the control group (Fig. 2).
3.3. CC-bisected group 3.3.1. Extent of CC lesion The common denominator area of the lesion was in the anterior half of the CC (Table 1). Cat 5 showed the total bisection of the CC. The hippocampal commissure was intact in all cats of the CC-bisected group.
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3.3.2. Seizure de6elopment In the CC-bisected group, seizures developed abruptly from the limbic seizure stage 1 or 2 to the generalized convulsive seizure stage 4 without remaining in stage 2 or 3 in four cats (Table 1 and Fig. 3). Seizures progressed from limbic seizures to either contralateral (cats 8 and 9) or ipsilateral (cats 5, 6 and 7) focal motor seizures culminating in generalized convulsions. The ictal progression to contralateral focal motor seizure was associated with the earlier onset of self-sustained AD in the ipsilateral MC to the stimulated VHIPP. On the other hand, the ipsilateral focal motor seizure development corresponded with the earlier onset in the contralateral MC (Fig. 4). Hemiconvulsions were accentuated markedly in the CC-bisected group. The stage 4 partial onset generalized convulsions were asymmetrical, showing either marked contralateral (cat 9) or marked ipsilateral (cats 5, 6 and 7) dominance, except that cat 8 had symmetrical generalized convulsions. Seizures of-
Fig. 2. Latencies for the onset of focal motor seizures and generalized convulsions and AD durations in stage 4 partial onset generalized convulsive seizures. Latencies from stimulation to the onset of focal motor seizures and generalized convulsions and AD durations in stage 4 partial onset generalized convulsive seizures of the CC-intact and CC-bisected groups are significantly greater (PB 0.001) than those of the control group. Latency for the onset of generalized convulsions and AD duration in stage 4 partial onset generalized convulsive seizures of the CC-bisected group are significantly greater (P B 0.001) than those of the CC-intact group. Hatched portion of bars indicates stages 1 and 2 limbic seizures, stippled portion indicates stage 3 focal motor seizure and the unshaded portion indicates stage 4 generalized convulsive seizure. AD durations are shown with the time during from the onset of stage 1 seizures until the end of stage 4 seizures.
ten regressed from stage 4 or 3 to stage 2 in cats 5 and 7 and from stage 4 to 3 in cats 6, 7 and 9 and regressed once from stage 2 to 1 in cat 5 (Fig. 3). As shown in Table 1, the number of stimulations required for the first seizure of each stage in the CC-bisected cats was not significantly different from that of the CC-intact group. The number of stimulations required for development from the last limbic seizure to the first stage 4 seizure in the CC-bisected group (1.69 1.2) was significantly (PB 0.05) fewer than those in the control group (4.19 2.0) and the CC-intact group (10.5 9 6.8). The mean number of stimulations required to reach the stable stage 4 generalized convulsive seizure state (17.29 12.0) and the mean number of seizure regressions (7.89 9.5) after attaining the first stage 4 seizure in the CC-bisected group have no significant difference from those in both control and CC-intact groups. The ratio of the total number of seizure regressions to the total number of stimulations after attaining the first stage 4 seizure of all five cats in the CC-bisected group (39/86) was significantly (P B 0.01) different from that in the control group (10/62), but not significantly different from that in the CC-intact group (32/68). Finally, the stable stage 4 seizure state and GST with an ‘all-or-none’ property was established in all cats except cat 5, in which the reduction of stimulus intensity resulted in seizure stage regression. Latencies to onset of focal motor seizures and generalized convulsions and AD durations in stage 4 partial onset generalized convulsive seizures. As shown in Fig. 2, latencies from stimulation to the onset of focal motor seizures and generalized convulsions and AD durations in partial onset stage 4 generalized convulsions of the CC-bisected group are, respectively, 73.09 21.9, 93.59 19.3 and 152.59 22.3 s. These values are all significantly (PB 0.001) greater than those of the control group (35.7 910.6, 47.29 17.4 and 78.39 26.4 s). Latencies to the onset of generalized convulsions and AD durations in partial onset stage 4 generalized convulsions of the CCbisected group (93.59 19.3 and 152.5922.3 s) were also significantly (P B 0.001) greater than those of the CC-intact group (81.69 17.0 and 118.69 22.8 s). But the latency to the onset of
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Fig. 3. The profile of seizure development in CC-bisected group. Seizures develop abruptly from limbic seizure stage 1 or 2 to stage 4 without remaining in stages 2 or 3 in cats 5, 6, 8 and 9. Seizures often regress from stages 4 or 3 to stage 2 in cats 5 and 7 and from stage 4 to 3 in cats 6, 7 and 9 and regress once from stage 2 to 1 in cat 5. Finally, the stable stage 4 seizure state is established.
focal motor seizure has no significant difference between the CC-bisected group (73.09 21.9 s) and the CC-intact group (72.8916.5 s).
4. Discussion
4.1. Effect of MC kindling on subsequent VHIPP kindling VHIPP kindling of the control group showed a preferential pathway by which hippocampal seizures access to the ipsilateral hemispheric motor structures, producing contralateral focal motor seizures. But previously established MC
kindling induced a modified pattern of seizure development, which progressed from limbic seizures to ipsilateral focal motor seizures, in subsequent VHIPP kindling of one CC-intact and three CC-bisected cats. Since the ipsilateral focal motor seizure was associated with the contralateral MC self-sustained discharge, the VHIPP seizure probably accessed to the contralateral MC before the ipsilateral MC was activated in cats with a modified patten of seizure development. Kindling effect is reported to persist in the MC after MC kindling [6]. Therefore, both MCs were made susceptible to epileptic seizures with bilateral MC kindling in the CC-intact and CC-bisected groups before VHIPP kindling began. It
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Fig. 4. EEG of stage 4 seizure in cat 7 with the CC bisected. After the stimulation of the left ventral hippocampus (VHIPP) indicated by the arrow, seizure discharge propagated soon to the left midbrain reticular formation (MRF) (A), then to the right motor cortex (MC) (C) and to the right MRF and VHIPP (C and D). Seizure discharge is of low amplitude and appear last in the left MC. Notably, self-sustained spike discharges appear earlier in the right (contralateral) MC, not in the left (ipsilateral) MC expected as in the control group and continue in the right MC with higher amplitude than that in the left MC. The development of a left, not right as expected in the control group, focal motor seizure (D and E) from a limbic seizure (A, B and C) is consistent with earlier onset and dominant continuation of self-sustained discharges in the right MC. The left partial motor seizure develops to an accentuated left hemiconvulsion (F) and finally culminates in asymmetrical generalized convulsion with left dominance (G). Parts 1, 2 and 3 of EEG are shown in enlarged figures to show seizure discharges clearly. A, motionless stare; B, facial twitching; C, mastication and salivation; D, circling to the left; E, rotation of the body axis to the left side; F, left hemiconvulsion; G, asymmetrical generalized convulsion; L, left; R, right; MC, motor cortex; HIPP, hippocampus; MRF, midbrain reticular formation.
was reported that the susceptible parts, which were not a primary epileptogenic zone, developed an independent electrographical seizure pattern and also had potential to initiate seizure [5]. When both contralateral MC and ipsilateral MC are susceptible to epileptic seizures, the contralateral MC is possibly activated in the seizure development originating from the VHIPP before the ipsi-
lateral MC is involved, in contrast to the preferential pathway shown in VHIPP seizures of the control group. Since the modified pattern of seizure development was also observed in CC-bisected cats, modified ictal progression from the stimulated VHIPP to the contralateral subcortical and cortical motor structures may be induced via structures other than the CC. It is well known
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that the HIPP projects to other limbic structures and the diencephalon and to the contralateral hemisphere through the HIPP and anterior commissures [11] and these structures play a critical role in HIPP seizure development and propagation to the contralateral hemisphere [2,7]. Therefore, previously established MC kindling facilitates the propagation of VHIPP seizures to the contralateral hemispheric motor structures via the subcortical structures in cats. In the CC-intact group with VHIPP kindling subsequent to MC kindling, there were frequent seizure regressions of stage 3 to 2 in cat 2, which was not observed in the control group. After attaining the first stage 4 seizure, the number of stimulations required to reach the stable stage 4 generalized convulsive seizure state, the number of seizure regressions and the ratio of the total number of seizure regressions to the total number of stimulations in the CC-intact group were all significantly greater than those of the control group. These findings show that the previously established MC kindling induced an inhibitory effect against the seizure development from limbic seizure stage to stable stage 4 generalized convulsive seizure state in VHIPP kindling. The latencies from stimulations to the onset of focal motor seizures and generalized convulsions during stage 4 generalized convulsive seizures were significantly greater in the CC-intact group than the control group. Therefore, previously established MC kindling has an inhibitory effect not only on the development of seizure stage but also on the evolvement of partial onset generalized stage 4 seizure in VHIPP kindling. The VHIPP seizure development was not facilitated by previously established MC kindling. This is in contrast with earlier findings that the suprasylvian association area and temporal lobe kindling have a facilitatory effect on subsequent amygdaloid and HIPP kindling in cats [8,13].
4.2. Effect of CC bisection on seizure de6elopment with subsequent VHIPP kindling During VHIPP kindling, the CC-bisected group had seizure stage regressions before attaining the first stage 4 seizure. The CC-bisected group also
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had a significantly greater ratio of the total number of seizure regressions to the total number of stimulations after attaining the first stage 4 seizure than the control group. But, in VHIPP kindling, the CC-bisected group did not show a significantly greater difference than the control group in the number of stimulations required to reach the stable stage 4 generalized convulsive seizure state and the number of stage regressions from stage 4 to earlier stages after attaining the first stage 4 seizure. As previously mentioned, the CC-intact group showed a significantly greater difference than the control group in these numbers of VHIPP kindling. Thus, previously established MC kindling inhibited the seizure development of VHIPP kindling, but CC bisection seemed to reduce the degree of the inhibition. Furthermore, CC-bisection resulted in abrupt seizure development from the limbic seizure stage to the generalized convulsive seizure stage 4, without remaining in limbic stage 2 or focal motor seizure stage 3 in four or five cats and significantly fewer stimulations were required for development from the last limbic seizure to the first generalized convulsive seizure in VHIPP kindling. Therefore, CC bisection facilitated the seizure development from the limbic seizure stage through focal motor seizure stage to generalized convulsive seizure stage. Our speculation is that CC bisection reduces the inhibition induced by previously established MC kindling and facilitates the seizure development of limbic seizure to generalized convulsive seizure in VHIPP kindling. This is consistent with previous papers, which report that electrical stimulation of the CC induces long-lasting inhibitory effects on pyramidal cells in the pericruciate cortex of cats [1] and the CC has inhibitory effects on the mechanism of cortical motor seizure propagation in MC kindling of cats [6] and in amygdaloid kindled seizures of Papio papio baboons [18]. Our results show that CC bisection induces accentuated hemiconvulsions, asymmetrical generalized convulsions and increases the latency to the onset of generalization of convulsions, but not the latency to the onset of focal motor seizure stage, during stage 4 seizures. These findings indicate that the CC plays an important role in generalization and synchronization of convulsive seizures, as reported previously [6,17,18].
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In summary, previously established bilateral MC kindling causes an inhibitory effect on subsequent unilateral VHIPP kindling. MC kindling also modifies ictal progress from the VHIPP, so that VHIPP seizures propagate to the contralateral hemispheric motor mechanism. CC-bisection interferes with generalization and synchronization of convulsive seizures, but reduces the degree of the inhibitory effect MC kindling has on subsequent VHIPP kindling and facilitates the development of limbic seizure to generalized convulsions once limbic seizures reaches the motor mechanism.
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