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Secondary generalization of seizures from a cortical penicillin focus following stimulation of the basal forebrain
EXPERIMENTAL
NEUROLOGY
109,237-242
(1990)
Secondary Generalization of Seizures from a Cortical Penicillin Focus following Stimulation of the Basal Forebrain R. S. MCLACHLAN’ Department
of Clinical
Neurological
Sciences,
University
Hospital,
Many subcortical areas have been implicated in the pathophysiological mechanisms involved in generalized seizures (12). Structures with widespread cortical connections such as the nonspecific thalamic nuclei and reticular formation have been particularly associated with seizure generalization (2, 13, 16, 31). During the course of studies of the effect of electrical stimulation of subcortical regions on interictal cortical EEG spike activity (23) it was found that seizures also occurred upon stimulation of the substantia innominata-ventral pallida1 area (SI-VP). This subpallidal region in the basal forebrain has widely distributed efferents (7, 10, 18, 20-22,41) and is a regulatory area involved in the modulation of attention, arousal, cognition, and motor function (1). Electrolytic lesions of SI are associated with a profound decrease in the intensity of generalized convulsions induced by amygdala kindling (15). Furthermore, activation of y-aminobutyric acid (GABA) terminals in SI-VP by intracerebral injection of muscimol or gabaculine also suppresses convulsive seizure generalization from amygdala kindling (26, 27). These studies concentrated on the motor component of the clinical seizure and suggested that SI-VP may play a role in
and
correspondence
should
Road,
London,
Ontario,
Canada
N6A
5A5
Experiments were carried out on 20 Wistar rats weighing between 200 and 350 g. Animals were anesthetized with urethane, 1.15 g/kg body wt, ip before being placed in a Kopf stereotaxic frame. Body temperature was maintained at 37°C using a heating pad controlled by feedback from a rectal probe. Following incision of the scalp along the sagittal ‘plane, bilateral generous craniectomies were made to expose the dura over both hemispheres. The dura was then reflected over the left hemisphere while that over the right hemisphere was left intact. A concentric bipolar stimulating electrode (Rhodes NElOO) was stereotaxically placed in the left basal forebrain in the area of the substantia innominata-ventral pallidal complex 0.3 to 1.4 mm posterior to bregma, 2.0 to 3.5 mm lateral to the midline, and 7.0 to 8.5 mm deep to the cortical surface (29). The electrocorticogram (ECoG) from both hemispheres was recorded from two to six platinum ball electrodes (impedance less than 20K ohm) connected to a Grass electroencephalograph. Monopoiar recordings were referred to a needle electrode inserted into the neck muscles. Following baseline recording, l-mm’ pieces of filter paper soaked in sodium penicillin G solution (100,000 IU/ml) were applied to the left frontal parietal cortex. One recording electrode was always placed on the focus. Electrical stimulation of SI-VP (0.4-0.8 mA, 0.2 ms, 40-50 Hz biphasic square-wave pulses) for 2-15 s was carried out following the establishment of an active cor-
INTRODUCTION
reprints
339 Windermere
linking the amygdala with the motor pathways that are responsible for generalized convulsions. Our preliminary observations suggested the hypothesis that SI-VP was not only involved in seizure generalization from limbic structures as suggested by the kindling experiments but also from neocortex. We therefore investigated electroencephalographically the transition from interictal to ictal activity during electrical stimulation of SI-VP in urethane anesthetized rats. Since previous studies (33,35) and our own early investigations showed that seizures do not occur with SI-VP stimulation alone, we examined the effect of stimulation on a previously established interictal neocortical spike focus. METHODS
The basal forebrain has been implicated in the regulation of generalized motor convulsive activity particularly from amygdala kindling. The effect of electrical stimulation of the substantia innominata and ventral pallidal regions of the basal forebrain in rats with acute interictal penicillin foci in the frontal parietal neocortex was determined. Stimulation of this area resulted in generalized cortical EEG synchronization, an inconsistent effect on interictal spike frequency, and generalized seizures that were not prevented by atropine. The results support a role for these basal forebrain structures in the regulation of generalized seizures from a cortical focus mediated primarily through influences on thalamocortical pathways. @ 1990 Academic Press, Inc.
’ To whom
AND F. BIHARI
be addressed.
237 Copyright 0 1990 All rights of reproduction
0014-4886/90 $3.00 by Academic Press, Inc. in any form reserved.
238
MCLACHLAN
AND
BIHAR1
15min. POST FENICILUN
FIG. 2. Typical cruiting type rhythm then clonic activity. FIG. 1. Electrical stimulation of S-VP (0.6 mA, 0.2 ms, 40 Hz) before and at various times after application of focal penicillin. Bihemispheric synchrony of the cortical ECoG gradually increases until seizures develop. L, left hemisphere; R, right hemisphere. Time bar = 2 6.
tical spike focus in all animals and before application of penicillin in six animals. In the former group, if no electrographic change appeared during two trials of stimulation separated by 5 to 10 min, the stimulating electrode was moved until a response was obtained. The deepest point of penetration of the stimulating electrode was marked by passing a dc current. In six animals a second electrode was placed in the right LX-VP contralateral to the side with the penicillin focus and stimulation was carried out in the manner described. In 10 rats with stimulation-induced seizures, atropine sulfate (0.6 mg/ml) was applied topically to the cortex or given intravenously (2.5 mg/kg) and the same areas were immediately stimulated again. Following completion of the experiment, the anesthetized animals were perfused through the heart with saline followed by 10% formalin. The brains were removed and fixed in 10% formalin. Electrode positions were determined using thioninestained 60-pm sections of brain cut on a freezing microtome. RESULTS The ECoG of the urethane-anesthetized rat consists of diffuse low voltage desynchronized fast activity with occasional superimposed low voltage ~-HZ slow waves. Electrical stimulation of SI-VP before application of penicillin in six animals induced, in three of these, immediate 3.5 to ~-HZ low voltage diffuse synchronized rhythmic slow waves which persisted 5-30 s following the end of stimulation (Fig. 1, Control). No epileptiform potentials were seen. No change in background activity occurred in the other three animals. Focal application of penicillin to the left hemisphere induced localized high voltage brief duration interictal spikes within 2-10 min that persisted for 20-45 min at a frequency of 20-60 spikes/min (Fig. 2) In some animals,
progression of electrographic with reduction in interictal Time bar = 2 s.
seizure from refocal spikes to tonic
slight spread occurred to homologous cortex in the opposite hemisphere where low voltage spikes synchronous with those at the focus were seen. Stimulation of SI-VP following penicillin application resulted in a stereotyped alteration in the ECoG (Table 1) consisting of diffuse 4 to ~-HZ synchronous rhythmic waves which gradually augmented in amplitude and slowed in frequency (Fig. 1, Postpenicillin). This recruiting or augmenting rhythm which occurred in all 20 rats never outlasted the stimulus and was found before focal penicillin spikes appeared in some animals but never before penicillin was applied. Figure 3 shows the effect of stimulation at various sites in SI-VP and the surrounding area including part of the amygdala. In 12 of the 20 rats, generalized bilaterally symmetric electrographic seizure activity appeared during or at the offset of stimulation and persisted from 3 to 100 s (X = 16 s) following the end of stimulation (Figs. 1 and 2). Associated bilateral clonic twitching of the vibrissae occurred in 5 of the 12 rats with electrographic seizures but no other behavior changes were seen in these anesthetized animals. However, the ECoG activity resembled that which would appear with a generalized tonicclonic motor convulsion in a nonanesthetized animal. Seizures occurred only after the penicillin focus was well established and spike frequency exceeded 25/min.
TABLE
1
Effect of Electrical Stimulation of SI-VP Prepenicillin Ipsi Recruiting rhythm Electrographic seizure
(6) 0 0
Postpenicillin Ipsi
(20) 20 12”
Note. Total number of animals is in parentheses. Ipsi, of SI-VP on same side as penicillin focus; Contra, opposite lation. n Atropine pretreatment in 10 animals.
Contra
(6) 3 0
stimulation side stimu-
GENERALIZED
FIG. rhythm;
3. Stimulation sites shown on coronal section Triangles, no effect; SI, substantia innominata;
SEIZURES
AND
BASAL
239
FOREBRAIN
in mm posterior to bregma (Br). Open circles, VP, ventral pallidurn; GP, globus pallidus.
Figure 1 shows the progression of the effect of SI-VP stimulation as the penicillin focus matured and the spike frequency increased. A recruiting type rhythm appeared first, then a brief afterdischarge, and finally a sustained seizure. Seizures were obtained only from the immediate subpallidal region when the electrode tip was located within SI-VP (Fig. 3, open circles). If the penicillin focus was well established, seizures appeared during the initial stimulation in an appropriate anatomical area. Pretreatment with either topical or intravenous atropine in 10 of the 12 animals with seizures did not alter the effect of stimulation except that the current required to produce seizures was increased in three rats. Stimulation of the right SI-VP contralateral to the side of the penicillin focus induced generalized synchronization of the ECoG maximum in the posterior cortex in 3 of 6 animals (Fig. 4) but no seizures even when these had occurred with ipsilateral stimulation. There was no consistent effect of electrical stimulation in the absence of a seizure on interictal penicillin spike frequency or amplitude during and after stimulation as compared to before stimulation. Mean spike frequency was 30 +- G/min in all animals in the minute before stimulation and 28 + 8/min during the minute after stimulation. However, in individual animals, a decrease in spike frequency of greater than 20% occurred in 6 (18 f lO/min) compared to an increase of more than 20% in only 2 (42 f S/min). If a seizure developed, then
seizures;
interictal spikes were suppressed period after the seizure.
closed
circles,
during
recruiting
type
and for a brief
DISCUSSION
The results support the hypothesis that SI-VP participates in the regulation of seizure generalization not only from limbic areas but also from neocortex. Electrical stimulation of S&-VP produced the following effects on the cortical ECoG in these experiments: (i) diffuse synchronization of background activity, (ii) secondarily
LT. Fr. ly
PAR
SI STlM.
1
FIG. 4. Stimulation of SI-VP contralateral to penicillin focus resulted in a recruiting type rhythm but no seizures. The effect is generalized but maximum in the posterior head. Fr, frontal; Par, parietal; Occ, occipital. Time bar = 2 s.
240
MCLACHLAN
generalized bilaterally synchronous electrocorticographic seizures from a cortical focus, and (iii) a decrease more often than an increase in focal interictal spike frequency. Previous studies have examined the effects of electrical stimulation of other subcortical areas but only a few described generalized seizures. Stimulation of both rostra1 and caudal reticular formation results in both electrographic and clinical tonicclonic seizures (2, 16) and more recently Piredda and Gale have demonstrated bilaterally synchronous cortical seizures from electrical and chemical stimulation of a small area in the prepiriform cortex of rats (31). The pars reticulata of the substantia nigra also plays a facilitory role in the regulation of the spread of generalized seizures since both lesions of the area or application of drugs that suppress nigral function attenuate generalized seizures in several experimental models (8). This study indirectly demonstrates from electroencephalographic observations that SI-VP is another area at the base of the brain which may be involved in the propagation of or the modulation of generalized tonicclonic seizures, particularly when they are secondarily generalized from a cortical focus. The results concur with the finding of suppression of amygdala kindled generalized convulsions by enhancing GABAergic transmission in and therefore presumably suppressing the activity of SI-VP of rats and cats (27). Since electrographic as well as motor components of the seizures are affected and similar facilitation occurs from both amygdala and neocortical foci, SI-VP appears to act at a more complex level than as a limbic motor interface as suggested by Wada and co-workers (26). Increases in cortical cholinergic activity have been shown to augment epileptiform potentials (17), suggesting that facilitation of seizures by SI-VP stimulation in this model could involve activation of the widely distributed cholinergic efferents from SI-VP to cortex (20). This argument is further supported by the fact that the majority of neurons in the area of basal forebrain from which seizures or synchronization of the ECoG was obtained with electrical stimulation are choline acetyltransferase-positive cholinergic efferents to cortex (20, 22, 41). However, pretreatment with atropine did not influence the results. Furthermore, the inconsistent effect of SI-VP stimulation on interictal spike frequency does not support a role of direct cholinergic efferents to cortex. Acetylcholine release in the cortex is associated with a marked increase in excitability (37) so that any increase in choline&c neurotransmission in the cortex would be expected to considerably augment existing interictal spike activity (9). In addition, cholinergic stimulation of the cortex is generally associated with arousal and ECoG desynchronization (14, 30). The predominantly synchronizing effect of SI-VP stimulation and the inability of atropine to block it favor an alternative mechanism, possibly involving direct or indirect non-
AND
BIHAR1
cholinergic efferents to cortex. Direct noncholinergic efferents from basal forebrain to neocortex have been demonstrated in the rat (41) and these have been shown in the cat to be GABAergic (6). Since ictal discharge was obtained only with stimulation ipsilateral to the cortical focus, a primarily unilateral pathway such as that directly from SI-VP to cortex may be involved. However, activation of this pathway alone is unlikely to result in the bilateral synchrony of ECoG rhythms observed with unilateral ST-VP stimulation. This observation is more parsimoniously explained by activation of thalamic or other subcortical pathways (5). Indirect efferents to the thalamus (10, 11, 19, 28, 38) may constitute the main pathway by which cortical activity is modulated with SI-VP stimulation. There is considerable evidence that secondary generalization from a cortical focus occurs after activation of thalamic circuits, particularly those involving nonspecific midline thalamic nuclei (3,39,40). Further enhancement of the activity within these intrathalamic circuits by input from SI-VP could result in the achievement of threshold for seizure generalization. The rhythmic bilaterally synchronized recruiting rhythm that results from unilateral basal forebrain stimulation from either side in these animals also suggests that thalamic pathways are activated since such rhythms have long been known to occur with unilateral thalamic stimulation (4,5). In addition, this synchronizing effect of basal forebrain stimulation, which has been noted before (33,36), is greatly enhanced after a cortical interictal spike focus has been established, supporting the concept of an excitatory corticofugal influence of such a cortical focus on subcortical structures (25). A further possible explanation for the bilaterally synchronous ECoG changes is activation of the rostra1 midbrain reticular formation to which efferents from the subpallidal region also project (2834). Against such,an interpretation is the absence of cortical desynchronization which is typically seen with stimulation of this area (16). Another pathway through which widespread synchronization might appear is via the prepiriform cortex, an exceptionally sensitive area for stimulation-induced seizure generalization (8, 31) which also receives input from SI-VP (32). This is not likely to be the case since lesions of that area do not affect the ability of SI-VP stimulation to induce seizures (24). Finally, as might occur with any electrical stimulation study, activation of fibers traversing the basal forebrain primarily from amygdala to hypothalamus and thalamus could also contribute to the synchronizing and seizure activating effect. We conclude that the subpallidal region of the basal forebrain is another subcortical area which, although not directly involved in the generalization of seizures, participates in the regulation of the sensitivity of the
GENERALIZED
SEIZURES
brain to generalized seizure activity primarily direct or indirect influences on thalamocortical
AND
through circuits.
15.
BASAL
241
FOREBRAIN
KIMURA, H., Y. KANEKO, AND J. A. WADA. 1981. Catecholamine and choline@ systems and amygdaloid kindling. In Kindling (J. A. Wada, Ed.), pp. 265-287. Raven Press, New York. A., E. ZUCKERMANN, M. STERIADE, AND D. CHIMION. 1958. Electroclinical features of convulsions induced by stimulation of brain stem. J. Neurophysiol. 21: 430-436.
16. KREINDLER, ACKNOWLEDGMENTS This Ontario
research Ministry
was supported by a Career Scientist of Health and the PSI Foundation.
Award
from
the
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WOOLF, N. J., M. C. HERNITT, AND L. L. BUTCHER. 1986. Cholinergic and non-choline@ projections from the rat basal forebrain revealed by combined choline acetyltransferase and phaseolus vulgaris leucoagglutinin immunohistochemistry. Neurosci. Lett. 66: 281-286.
NEUROLOGY
109,237-242
(1990)
Secondary Generalization of Seizures from a Cortical Penicillin Focus following Stimulation of the Basal Forebrain R. S. MCLACHLAN’ Department
of Clinical
Neurological
Sciences,
University
Hospital,
Many subcortical areas have been implicated in the pathophysiological mechanisms involved in generalized seizures (12). Structures with widespread cortical connections such as the nonspecific thalamic nuclei and reticular formation have been particularly associated with seizure generalization (2, 13, 16, 31). During the course of studies of the effect of electrical stimulation of subcortical regions on interictal cortical EEG spike activity (23) it was found that seizures also occurred upon stimulation of the substantia innominata-ventral pallida1 area (SI-VP). This subpallidal region in the basal forebrain has widely distributed efferents (7, 10, 18, 20-22,41) and is a regulatory area involved in the modulation of attention, arousal, cognition, and motor function (1). Electrolytic lesions of SI are associated with a profound decrease in the intensity of generalized convulsions induced by amygdala kindling (15). Furthermore, activation of y-aminobutyric acid (GABA) terminals in SI-VP by intracerebral injection of muscimol or gabaculine also suppresses convulsive seizure generalization from amygdala kindling (26, 27). These studies concentrated on the motor component of the clinical seizure and suggested that SI-VP may play a role in
and
correspondence
should
Road,
London,
Ontario,
Canada
N6A
5A5
Experiments were carried out on 20 Wistar rats weighing between 200 and 350 g. Animals were anesthetized with urethane, 1.15 g/kg body wt, ip before being placed in a Kopf stereotaxic frame. Body temperature was maintained at 37°C using a heating pad controlled by feedback from a rectal probe. Following incision of the scalp along the sagittal ‘plane, bilateral generous craniectomies were made to expose the dura over both hemispheres. The dura was then reflected over the left hemisphere while that over the right hemisphere was left intact. A concentric bipolar stimulating electrode (Rhodes NElOO) was stereotaxically placed in the left basal forebrain in the area of the substantia innominata-ventral pallidal complex 0.3 to 1.4 mm posterior to bregma, 2.0 to 3.5 mm lateral to the midline, and 7.0 to 8.5 mm deep to the cortical surface (29). The electrocorticogram (ECoG) from both hemispheres was recorded from two to six platinum ball electrodes (impedance less than 20K ohm) connected to a Grass electroencephalograph. Monopoiar recordings were referred to a needle electrode inserted into the neck muscles. Following baseline recording, l-mm’ pieces of filter paper soaked in sodium penicillin G solution (100,000 IU/ml) were applied to the left frontal parietal cortex. One recording electrode was always placed on the focus. Electrical stimulation of SI-VP (0.4-0.8 mA, 0.2 ms, 40-50 Hz biphasic square-wave pulses) for 2-15 s was carried out following the establishment of an active cor-
INTRODUCTION
reprints
339 Windermere
linking the amygdala with the motor pathways that are responsible for generalized convulsions. Our preliminary observations suggested the hypothesis that SI-VP was not only involved in seizure generalization from limbic structures as suggested by the kindling experiments but also from neocortex. We therefore investigated electroencephalographically the transition from interictal to ictal activity during electrical stimulation of SI-VP in urethane anesthetized rats. Since previous studies (33,35) and our own early investigations showed that seizures do not occur with SI-VP stimulation alone, we examined the effect of stimulation on a previously established interictal neocortical spike focus. METHODS
The basal forebrain has been implicated in the regulation of generalized motor convulsive activity particularly from amygdala kindling. The effect of electrical stimulation of the substantia innominata and ventral pallidal regions of the basal forebrain in rats with acute interictal penicillin foci in the frontal parietal neocortex was determined. Stimulation of this area resulted in generalized cortical EEG synchronization, an inconsistent effect on interictal spike frequency, and generalized seizures that were not prevented by atropine. The results support a role for these basal forebrain structures in the regulation of generalized seizures from a cortical focus mediated primarily through influences on thalamocortical pathways. @ 1990 Academic Press, Inc.
’ To whom
AND F. BIHARI
be addressed.
237 Copyright 0 1990 All rights of reproduction
0014-4886/90 $3.00 by Academic Press, Inc. in any form reserved.
238
MCLACHLAN
AND
BIHAR1
15min. POST FENICILUN
FIG. 2. Typical cruiting type rhythm then clonic activity. FIG. 1. Electrical stimulation of S-VP (0.6 mA, 0.2 ms, 40 Hz) before and at various times after application of focal penicillin. Bihemispheric synchrony of the cortical ECoG gradually increases until seizures develop. L, left hemisphere; R, right hemisphere. Time bar = 2 6.
tical spike focus in all animals and before application of penicillin in six animals. In the former group, if no electrographic change appeared during two trials of stimulation separated by 5 to 10 min, the stimulating electrode was moved until a response was obtained. The deepest point of penetration of the stimulating electrode was marked by passing a dc current. In six animals a second electrode was placed in the right LX-VP contralateral to the side with the penicillin focus and stimulation was carried out in the manner described. In 10 rats with stimulation-induced seizures, atropine sulfate (0.6 mg/ml) was applied topically to the cortex or given intravenously (2.5 mg/kg) and the same areas were immediately stimulated again. Following completion of the experiment, the anesthetized animals were perfused through the heart with saline followed by 10% formalin. The brains were removed and fixed in 10% formalin. Electrode positions were determined using thioninestained 60-pm sections of brain cut on a freezing microtome. RESULTS The ECoG of the urethane-anesthetized rat consists of diffuse low voltage desynchronized fast activity with occasional superimposed low voltage ~-HZ slow waves. Electrical stimulation of SI-VP before application of penicillin in six animals induced, in three of these, immediate 3.5 to ~-HZ low voltage diffuse synchronized rhythmic slow waves which persisted 5-30 s following the end of stimulation (Fig. 1, Control). No epileptiform potentials were seen. No change in background activity occurred in the other three animals. Focal application of penicillin to the left hemisphere induced localized high voltage brief duration interictal spikes within 2-10 min that persisted for 20-45 min at a frequency of 20-60 spikes/min (Fig. 2) In some animals,
progression of electrographic with reduction in interictal Time bar = 2 s.
seizure from refocal spikes to tonic
slight spread occurred to homologous cortex in the opposite hemisphere where low voltage spikes synchronous with those at the focus were seen. Stimulation of SI-VP following penicillin application resulted in a stereotyped alteration in the ECoG (Table 1) consisting of diffuse 4 to ~-HZ synchronous rhythmic waves which gradually augmented in amplitude and slowed in frequency (Fig. 1, Postpenicillin). This recruiting or augmenting rhythm which occurred in all 20 rats never outlasted the stimulus and was found before focal penicillin spikes appeared in some animals but never before penicillin was applied. Figure 3 shows the effect of stimulation at various sites in SI-VP and the surrounding area including part of the amygdala. In 12 of the 20 rats, generalized bilaterally symmetric electrographic seizure activity appeared during or at the offset of stimulation and persisted from 3 to 100 s (X = 16 s) following the end of stimulation (Figs. 1 and 2). Associated bilateral clonic twitching of the vibrissae occurred in 5 of the 12 rats with electrographic seizures but no other behavior changes were seen in these anesthetized animals. However, the ECoG activity resembled that which would appear with a generalized tonicclonic motor convulsion in a nonanesthetized animal. Seizures occurred only after the penicillin focus was well established and spike frequency exceeded 25/min.
TABLE
1
Effect of Electrical Stimulation of SI-VP Prepenicillin Ipsi Recruiting rhythm Electrographic seizure
(6) 0 0
Postpenicillin Ipsi
(20) 20 12”
Note. Total number of animals is in parentheses. Ipsi, of SI-VP on same side as penicillin focus; Contra, opposite lation. n Atropine pretreatment in 10 animals.
Contra
(6) 3 0
stimulation side stimu-
GENERALIZED
FIG. rhythm;
3. Stimulation sites shown on coronal section Triangles, no effect; SI, substantia innominata;
SEIZURES
AND
BASAL
239
FOREBRAIN
in mm posterior to bregma (Br). Open circles, VP, ventral pallidurn; GP, globus pallidus.
Figure 1 shows the progression of the effect of SI-VP stimulation as the penicillin focus matured and the spike frequency increased. A recruiting type rhythm appeared first, then a brief afterdischarge, and finally a sustained seizure. Seizures were obtained only from the immediate subpallidal region when the electrode tip was located within SI-VP (Fig. 3, open circles). If the penicillin focus was well established, seizures appeared during the initial stimulation in an appropriate anatomical area. Pretreatment with either topical or intravenous atropine in 10 of the 12 animals with seizures did not alter the effect of stimulation except that the current required to produce seizures was increased in three rats. Stimulation of the right SI-VP contralateral to the side of the penicillin focus induced generalized synchronization of the ECoG maximum in the posterior cortex in 3 of 6 animals (Fig. 4) but no seizures even when these had occurred with ipsilateral stimulation. There was no consistent effect of electrical stimulation in the absence of a seizure on interictal penicillin spike frequency or amplitude during and after stimulation as compared to before stimulation. Mean spike frequency was 30 +- G/min in all animals in the minute before stimulation and 28 + 8/min during the minute after stimulation. However, in individual animals, a decrease in spike frequency of greater than 20% occurred in 6 (18 f lO/min) compared to an increase of more than 20% in only 2 (42 f S/min). If a seizure developed, then
seizures;
interictal spikes were suppressed period after the seizure.
closed
circles,
during
recruiting
type
and for a brief
DISCUSSION
The results support the hypothesis that SI-VP participates in the regulation of seizure generalization not only from limbic areas but also from neocortex. Electrical stimulation of S&-VP produced the following effects on the cortical ECoG in these experiments: (i) diffuse synchronization of background activity, (ii) secondarily
LT. Fr. ly
PAR
SI STlM.
1
FIG. 4. Stimulation of SI-VP contralateral to penicillin focus resulted in a recruiting type rhythm but no seizures. The effect is generalized but maximum in the posterior head. Fr, frontal; Par, parietal; Occ, occipital. Time bar = 2 s.
240
MCLACHLAN
generalized bilaterally synchronous electrocorticographic seizures from a cortical focus, and (iii) a decrease more often than an increase in focal interictal spike frequency. Previous studies have examined the effects of electrical stimulation of other subcortical areas but only a few described generalized seizures. Stimulation of both rostra1 and caudal reticular formation results in both electrographic and clinical tonicclonic seizures (2, 16) and more recently Piredda and Gale have demonstrated bilaterally synchronous cortical seizures from electrical and chemical stimulation of a small area in the prepiriform cortex of rats (31). The pars reticulata of the substantia nigra also plays a facilitory role in the regulation of the spread of generalized seizures since both lesions of the area or application of drugs that suppress nigral function attenuate generalized seizures in several experimental models (8). This study indirectly demonstrates from electroencephalographic observations that SI-VP is another area at the base of the brain which may be involved in the propagation of or the modulation of generalized tonicclonic seizures, particularly when they are secondarily generalized from a cortical focus. The results concur with the finding of suppression of amygdala kindled generalized convulsions by enhancing GABAergic transmission in and therefore presumably suppressing the activity of SI-VP of rats and cats (27). Since electrographic as well as motor components of the seizures are affected and similar facilitation occurs from both amygdala and neocortical foci, SI-VP appears to act at a more complex level than as a limbic motor interface as suggested by Wada and co-workers (26). Increases in cortical cholinergic activity have been shown to augment epileptiform potentials (17), suggesting that facilitation of seizures by SI-VP stimulation in this model could involve activation of the widely distributed cholinergic efferents from SI-VP to cortex (20). This argument is further supported by the fact that the majority of neurons in the area of basal forebrain from which seizures or synchronization of the ECoG was obtained with electrical stimulation are choline acetyltransferase-positive cholinergic efferents to cortex (20, 22, 41). However, pretreatment with atropine did not influence the results. Furthermore, the inconsistent effect of SI-VP stimulation on interictal spike frequency does not support a role of direct cholinergic efferents to cortex. Acetylcholine release in the cortex is associated with a marked increase in excitability (37) so that any increase in choline&c neurotransmission in the cortex would be expected to considerably augment existing interictal spike activity (9). In addition, cholinergic stimulation of the cortex is generally associated with arousal and ECoG desynchronization (14, 30). The predominantly synchronizing effect of SI-VP stimulation and the inability of atropine to block it favor an alternative mechanism, possibly involving direct or indirect non-
AND
BIHAR1
cholinergic efferents to cortex. Direct noncholinergic efferents from basal forebrain to neocortex have been demonstrated in the rat (41) and these have been shown in the cat to be GABAergic (6). Since ictal discharge was obtained only with stimulation ipsilateral to the cortical focus, a primarily unilateral pathway such as that directly from SI-VP to cortex may be involved. However, activation of this pathway alone is unlikely to result in the bilateral synchrony of ECoG rhythms observed with unilateral ST-VP stimulation. This observation is more parsimoniously explained by activation of thalamic or other subcortical pathways (5). Indirect efferents to the thalamus (10, 11, 19, 28, 38) may constitute the main pathway by which cortical activity is modulated with SI-VP stimulation. There is considerable evidence that secondary generalization from a cortical focus occurs after activation of thalamic circuits, particularly those involving nonspecific midline thalamic nuclei (3,39,40). Further enhancement of the activity within these intrathalamic circuits by input from SI-VP could result in the achievement of threshold for seizure generalization. The rhythmic bilaterally synchronized recruiting rhythm that results from unilateral basal forebrain stimulation from either side in these animals also suggests that thalamic pathways are activated since such rhythms have long been known to occur with unilateral thalamic stimulation (4,5). In addition, this synchronizing effect of basal forebrain stimulation, which has been noted before (33,36), is greatly enhanced after a cortical interictal spike focus has been established, supporting the concept of an excitatory corticofugal influence of such a cortical focus on subcortical structures (25). A further possible explanation for the bilaterally synchronous ECoG changes is activation of the rostra1 midbrain reticular formation to which efferents from the subpallidal region also project (2834). Against such,an interpretation is the absence of cortical desynchronization which is typically seen with stimulation of this area (16). Another pathway through which widespread synchronization might appear is via the prepiriform cortex, an exceptionally sensitive area for stimulation-induced seizure generalization (8, 31) which also receives input from SI-VP (32). This is not likely to be the case since lesions of that area do not affect the ability of SI-VP stimulation to induce seizures (24). Finally, as might occur with any electrical stimulation study, activation of fibers traversing the basal forebrain primarily from amygdala to hypothalamus and thalamus could also contribute to the synchronizing and seizure activating effect. We conclude that the subpallidal region of the basal forebrain is another subcortical area which, although not directly involved in the generalization of seizures, participates in the regulation of the sensitivity of the
GENERALIZED
SEIZURES
brain to generalized seizure activity primarily direct or indirect influences on thalamocortical
AND
through circuits.
15.
BASAL
241
FOREBRAIN
KIMURA, H., Y. KANEKO, AND J. A. WADA. 1981. Catecholamine and choline@ systems and amygdaloid kindling. In Kindling (J. A. Wada, Ed.), pp. 265-287. Raven Press, New York. A., E. ZUCKERMANN, M. STERIADE, AND D. CHIMION. 1958. Electroclinical features of convulsions induced by stimulation of brain stem. J. Neurophysiol. 21: 430-436.
16. KREINDLER, ACKNOWLEDGMENTS This Ontario
research Ministry
was supported by a Career Scientist of Health and the PSI Foundation.
Award
from
the
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