Kindling of the Visual Cortex in Cats: Comparison with Amygdaloid Kindling

Abstract: Kindling of the primary visual cortex (VC) was compared with that of the amygdala in cats. VC kindling was basically similar to kindling of the amygdala in that daily electrical stimulation can lead to the development of a generalized convulsion in most subjects, a growth of afterdischarges in their configuration and duration, and a reduction of the afterdischarge threshold. The kindling response of the VC differed from that of the amygdala in a number of respects, i.e., a high afterdischarge threshold, a different pattern of behavioral seizure development, an abrupt growth of electroclinical seizures coincident with the onset of a generalized convulsion, an intersubject variability in seizure susceptibility, and a marked seizure instability. In VC kindling the afterdischarge propagation into the amygdala was not observed until the generalized convulsion developed, and the early involvement of afterdischarge was seen in the pulvinar, lateral geniculate body, and superior colliculus. These data suggest that a neural mechanism different from amygdaloid kindling may participate in VC kindling, and that the sub-cortical structures of the visual system are involved in the preferential pathway for a seizure generalization from the VC.     

Comparison between substantia innominata and amygdala kindling in rats

Kindling was induced in rats by electrical stimulation of the lateral portion of the substantia innominata (SI). The pattern of seizure development was similar to that of amygdala (AM) kindling. However, lateral SI kindling was associated with ipsilateral head turning as an initial manifestation. In addition, lateral SI kindling had a higher afterdischarge threshold than AM kindling, and the generalized seizure triggering threshold was more unstable in SI kindling than in AM kindling. These findings suggest that lateral SI participates in, but is not essential for, AM seizure development in rats.     

Effects of hypoglycemia on kindling seizures in suckling rats

The effects of insulin-induced hypoglycemia on epileptic disorders of suckling rats were examined using an amygdala kindling model. Kindling stimulations were conducted at 16 and 17 days of age with electrodes implanted in the amygdala 2 days earlier. In 18-day-old kindled rats, which acquired generalized behavioral seizures (stages 4 and 5; Moshé's score) by kindling stimulations, the duration of afterdischarge and behavioral seizures evoked by the stimulation at a threshold intensity to produce a generalized seizure was significantly prolonged after an injection of insulin (25 U/kg, i.p.). The prolongation was not observed in kindled rats that exhibited normal blood glucose concentrations after the application of saline or insulin together with glucose. There were no apparent changes in the amplitude of the afterdischarge, the score of behavioral seizure stages, or the generalized seizure threshold. A similar, marked prolongation of afterdischarge and behavioral seizures following the application of insulin, as in the kindled rats, was also observed during the course of the kindling acquisition without accelerating the development of kindling seizure scores. These results indicate that insulin-induced hypoglycemia easily increases the risk of prolonged seizures in immature brain without precipitating the secondarily generalizing mechanism.     

Kindling of the massa intermedia of the thalamus in rats

The kindling response of the massa intermedia (MI) was assessed in rats. Clinical manifestation of the MI kindling was generally similar to that of limbic kindling, and positive transfer to the amygdala (AM) was obtained following MI kindling. However, MI kindling showed (1) a relatively high afterdischarge threshold which sometimes increased during the course of kindling. (2) a seizure stage instability with frequent regression to earlier stages, (3) a failure to establish a generalized seizure triggering threshold with an ‘all-or-none’ property, and (4) a generalized tonic-clonic seizure, which was quite different from a kindledlimbic seizure, during early phase of kindling. Furthermore, the MI stimulation caused violent beating movement of the forelimbs, jumping, or running regardless of presence/absence of afterdischarge. The findings suggest that mechanisms other than a simple activation of limbic structures are involved in the process of MI kindling.     

Low-frequency kindling as a new experimental model of epilepsy

Ten cats were stimulated twice a day in the lateral amygdala with low-frequency stimulation of about 3 Hz until generalized convulsion occurred. After the completion of kindling, the longest interpulse interval required for provocation of generalized convulsion (pulse-interval threshold) was determined in each subject. The pulse-interval threshold was 1300 ms in five cats, and 900 ms in five other cats. Then the stability of pulse-interval threshold and of the number of stimulating pulses required for provocation of afterdischarge when the stimulation was delivered with the pulse-interval threshold (pulse-number threshold) was tested. The pulse-interval threshold, pulse-number threshold, and duration of afterdischarge in each stimulation did not change statistically at the interstimulation interval from 24 h to 7 days. Phenobarbital and diphenylhydantoin elevated the pulse-number threshold significantly. We propose that low-frequency kindling is a valuable experimental model of epilepsy in assessing simply and precisely the susceptibility of the epileptic focus itself and the severity of epileptic seizures.     

Unidirectional interaction between flurothyl seizures and amygdala kindling

In this report, the interaction between flurothyl convulsions and electrical kindling of the amygdala was investigated. Three flurothyl convulsions decreased the afterdischarge threshold of the amygdala and enhanced the rate of development of electrical kindling without affecting the intensity of postictal refractoriness. On the other hand, 3 generalized kindled convulsions did not alter the flurothyl convulsive threshold. The data suggest that the influence of generalized convulsions on future seizure susceptibility may depend on the agents used to induce the convulsions.     

Facilitation of secondary site kindling in the dorsal hippocampus following forebrain bisection

Bisection of the corpus callosum and hippocampal commissure, after the kindling of one dorsal hippocampus (primary site), had no effect on the rate of generalized kindled seizure development in the contralateral dorsal hippocampus (secondary site). The rate of kindling in the secondary site was very rapid in both intact and commissure-bisected rats, resulting in a positive transfer between the two sites of approximately 90%. In addition, the afterdischarge threshold response of the secondary site, after commissurotomy but before secondary site kindling, revealed mature local epileptogenesis. These observations support the suggestion that the positive transfer observed between the dorsal hippocampi is based on bilateral epileptogenesis during primary site kindling. Bisection of the anterior corpus callosum lateralized the forelimb convulsion while the hippocampal commissure independently mediated the laterality of the hippocampal afterdischarge. Commissurotomy had no significant influence on the latency to onset or offset of these motor and electrographic responses. These results are compared with those from the amygdala, and their implication for the laterality of epileptogenesis is discussed.     

Kindling in the seizure-prone and seizure-resistant Mongolian gerbil

The kindling response in the amygdala of each of two strains of Mongolian gerbil bred for resistance to and suceptibility to stress-precipitated seizures was assessed. Seizure-prone gerbils had a lower afterdischarge threshold, a longer initial afterdischarge duration, and required fewer sessions to develop generalized kindled convulsions. Following kindling, the precipitated seizure pattern was exacerbated in both groups. These results suggest that the naturally occurring and kindled seizure states may depend in part on a common neural mechanism in this species.     

Electrical brain activity and cardiovascular function during amygdaloid kindling in the dog

Two lines of evidence converged to suggest that amygdaloid kindling would produce alterations in cardiovascular responsiveness. First, stimulation of the amygdala produces changes in heart rate and blood pressure. Second, the amygdala is the most sensitive region of the brain for kindling. Our objectives were to document the electrical brain activity, cardiovascular responses, and behavioral manifestations associated with the development of generalized convulsions during amygaloid kindling in the dog. Kindling in the dog was marked by its rapidity and lack of graded stages, resulting in two identifiable stages. The first, afterdischarge stage, was characterized by increased electrical brain activity in the stimulated amygdala but not in the ipsilateral anterior or posterior hypothalamus, or contralateral amygdala. Increased blood pressure was closely related to the activity of the stimulated amygdala, and a gradual increase in heart rate was unrelated to activity at any of the recording sites. Behavioral manifestations were confined to head and neck movements. The second, convulsion stage, was typified by increased activity in both amygdalae and in the anterior hypothalamic recording sites, indicating generalized involvement of both hemispheres. Blood pressure was significantly increased consistent with the behavioral manifestations of bilateral tonicclonic convulsion. Heart rate during the convulsion was not significantly different from that during the afterdischarge stage. This experiment, therefore, demonstrated that kindling in the dog follows a substantially different progression from that reported in other species and that kindled afterdischarges in the amygdala had a potent effect on blood pressure, even in the absence of generalized convulsions.     

"Saving-effect" of stimulating pulses at low-frequency limbic kindling in cats

To assess the development of kindling effect induced with low frequency electrical stimulations, we stimulated the lateral amygdala (AM group, 5 cats) and the dorsal hippocampus (HP group, 5 cats) bipolarly, once a day, with 2 mA base to peak, biphasic 1 msec square-wave pulses. In each stimulation we measured the longest inter-pulse interval required for the provocation of epileptic afterdischarge (AD), defined as the pulse-interval threshold; and the number of stimulating pulses required for the provocation of AD at this pulse-interval, defined as the pulse-number threshold. The observed behavioral seizures were classified into 6 stages in both the AM and HP group according to the conventional classification. In the AM group, an increase of the pulse-interval threshold and a decrease of the pulse-number threshold were observed during the kindling process. At the completion of kindling, a generalized convulsion was provoked with 1,200-1,600 msec pulse-intervals, and with 8-12 stimulating pulses. In the HP group an increase of the pulse-interval threshold and a decrease of the pulse-number threshold were observed in the early seizure stages, but not so significantly as the AM group. In the late seizure stages, a decrease of the pulse-interval threshold and an increase of the pulse-number threshold were observed. The observed behavioral stage of seizures in the two groups were similar to that of the conventional high-frequency kindling.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of low-intensity 50-Hz magnetic fields on kindling acquisition and fully kindled seizures in rats

The possibility that chronic exposure to power-line frequency (50 Hz) magnetic fields (MFs) might affect the acquisition or characteristics of focal and generalized seizures in amygdala kindled rats was studied. Acute, short-lasting 50-Hz MF exposure of fully kindled rats at either 1 or 100 μT had no effect on afterdischarge threshold (ADT) or seizure parameters recorded at ADT. In the chronic experiments, rats with electrodes implanted in the basolateral amygdala were exposed to a 50-Hz, 100-μT (1 Gauss) MF or to a sham field condition before and after onset of daily electrical stimulations over the whole period of kindling development. The focal seizure threshold (ADT) was determined before and after kindling development in MF exposed and sham exposed rats. Pre-kindling ADT was significantly increased by MF exposure. Exposed rats needed about the same number of stimulations to kindle than sham exposed rats, but the cumulative afterdischarge duration to reach criterion (i.e., a stage 5 seizure) was significantly reduced in MF exposed animals. Post-kindling ADT was similar in the two groups, but MF exposed rats showed a significantly higher threshold for generalized seizures. The data indicate that chronic exposure of rats to a 50-Hz, 100-μT MF exerts weak inhibitory effects on some seizure parameters of the kindling model.     

Lateral geniculate kindling and long-lasting photosensitivity in cats

The kindling response of the lateral geniculate body (GL) was compared with that of the amygdala, using cats. Daily electrical stimulation in the GL group led to the generalized tonic-clonic convulsion in most subjects and the resulting state of seizure susceptibility was long-lasting, as in the amygdala group. The kindling response of the GL differed from that of the amygdala in some respects, i.e., rapid kindling, short latency for seizure generalization, a different pattern of behavioral seizure development, and seizure regression during the course of kindling. The effects of photic stimulation with pentylenetetrazol administration were also examined before and after kindling in both groups. This study revealed that the photically induced myoclonus, at times proceeding to the generalized tonic-clonic convulsion, was provoked repeatedly as a result of GL kindling, whereas none of the amygdala-kindled cats showed such marked photosensitivity. These photically induced seizures were invariably observed for at least 4 weeks after GL kindling. Our results suggest that a neural mechanism participating in GL kindling is different from that in amygdala kindling, and that there might be cross-sensitization between seizure susceptibility resulting from GL kindling and photosensitivity.     

Frontal kindling in rabbits and its influence on visual and auditory evoked response

Frontal kindling in rabbits, prolongation of the duration of afterdischarge concomitant and clinical manifestations and the epileptic foci (primary and independent secondary foci) were revealed. Auditory and visual evoked responses were recorded after completion of the kindling phenomenon. 1. Electrical stimulations, 300 microA, 60 Hz. 1 msec in duration, 2 sec train, were applied once a day. Clinical manifestations were divided into five stages: 1) the arrest of behavior or no response, 2) the adversive movement with a tonic and/or clonic convulsion of left paw, 3) the adversive movement following mastication, facial spasms and postictal stupor, 4) falling down abruptly and generalized convulsive seizure, and 5) generalized seizure followed by rotatory movement, vocalization and myoclonus. The appearance of five generalized convulsions was defined as a completion of the kindling phenomenon. 2. The duration of afterdischarge increased stepwisely from 2--3 sec to more than 400 sec. However, there was no constant duration of AD even though the animal showed generalized convulsion after completion of the kindling phenomenon. 3. Visual and auditory evoked responses were recorded after completion of kindling. There was a change in the auditory evoked response but not in the visual. A shortening of the latency of P2 component (73.3 msec in peak latency), N2 component (146.7 msec in peak latency) and amplification of the amplitude of N2 component were noticed. Thus, the intermittent weak electrical stimulation on the frontal cortex in rabbits induced generalized convulsion and produced primary and independent secondary epileptic focus on EEG, and the change of auditory evoked response was recognized in kindled animals.     

Deep prepyriform cortex kindling and its relation to amygdala kindling in the rat

Kindling of the deep prepyriform cortex (DPC), a recently identified sensitive site to chemoconvulsants, was compared to kindling of the amygdala in rats. Although the two kindled sites were very similar in their initial responses, electroencephalographic changes during kindling stimulation, kindling seizure development, and growth of afterdischarge, they differed in that the deep prepyriform cortex showed a significantly lower final threshold, a significantly higher frequency of afterdischarge and a significantly shorter latency to bilateral forelimb clonus than the amygdala. Significant bidirectional transfer was found during secondary kindling of either of the two sites, suggesting a close interrelation between them. Rhythmic synchronous discharge was directly induced in the deep prepyriform cortex by ipsilateral amygdala stimulation, but not in the amygdala by ipsilateral cortical stimulation. Local application of both muscimol (0.45 nM) and 2-amino-5-phosphonovaleric acid (25 nM) into the cortical site reduced the afterdischarge duration of amygdala-kindled seizures by approximately 20% without changing the type or duration of the motor seizure. We suggest that the deep prepyriform cortex is “downstream” from the amygdala in the preferential routes of afterdischarge propagation, and that, although the deep prepyriform cortical neurocircuits of GABA and excitatory amino acids may be involved in the maintenance of amygdala-kindled, self-sustained afterdischarge, they are not essential in the expression of amygdala-kindled motor convulsions.     

Contrasting effects of zonisamide and acetazolamide on amygdaloid kindling in rats

PURPOSE: Zonisamide (ZNS) and acetazolamide (AZM) are two antiepileptic drugs (AEDs) that differ in clinical efficacy. To elucidate the mechanisms of action of these compounds, we investigated their therapeutic and prophylactic effects in rats by using a kindling model of partial epilepsy. METHODS: Electrodes were implanted into the left amygdala of adult male Wistar rats. The animals were stimulated at the afterdischarge threshold until five stage 5 seizures were induced. The generalized seizure threshold was then determined. Therapeutic effects were examined in rats manifesting successive convulsions with near-threshold stimulation. To test prophylactic effects, drugs were administered intraperitoneally before daily kindling stimulation until the animal had a stage 5 seizure or reached day 18. RESULTS: ZNS (10-40 mg/kg; n=6) suppressed kindled seizures in a dose-dependent manner. Repeated administration for 7 days produced tolerance to anticonvulsive effects. AZM (25-200 mg/kg; n=7) showed limited therapeutic effect, alleviating only the clonic convulsion in stage 5 seizures and reducing afterdischarge duration. Secondary generalization was not significantly suppressed during repeated treatment (50-200 mg/kg; n=6). ZNS, 25 or 40 mg/kg (n=8), significantly retarded seizure development; 15.0 or 17.0 daily stimulations were required to produce a stage 5 seizure. AZM, 50-200 mg/kg (n=6), also retarded seizure development, with 14.0-14.8 stimulations required. CONCLUSIONS: ZNS exhibited modest therapeutic and prophylactic effects, whereas AZM showed mainly prophylactic effects. Hypotheses are presented that may explain the mechanisms of action of these drugs.     

The anticonvulsant effects of progesterone and 5alpha-dihydroprogesterone on amygdala-kindled seizures in rats

PURPOSE: Progesterone has been shown to be anticonvulsant in several animal seizure models. The purpose of the present study was to investigate the anticonvulsant actions of progesterone and its primary metabolite 5alpha-dihydroprogesterone in the amygdala kindling model. METHODS: Female Wistar rats were implanted in the right basolateral amygdala with a long-term, bipolar electrode. The subjects were kindled to 30 stage 5 seizures and stability tested. Multiple doses of progesterone and 5alpha-dihydroprogesterone were then tested for anticonvulsant activity against focal electrographic and generalized convulsive kindled seizures. The time course of progesterone's anticonvulsant action also was examined. RESULTS: Progesterone had a median effective dose (ED50) of 103 mg/kg against generalized convulsions at 15 min after injection. Subjects were not sedated at the time of seizure testing, although sedation developed later (40-60 min after injection). In time-course experiments, it was found that 120 mg/kg of progesterone caused complete suppression of the generalized convulsion from 20 to 160 min after injection. Suppression of the focal discharge also was seen in some animals between 20 and 160 min. 5alpha-dihydroprogesterone had an ED50 of 2.9 mg/kg against generalized kindled convulsions and an ED50 of 4.3 mg/kg against focal afterdischarge 15 min after injection. 5alpha-dihydroprogesterone did not produce sedation 15 min after injection, or at any later time interval. CONCLUSIONS: Progesterone is anticonvulsant only at high doses when tested against amygdala kindled seizures. 5alpha-dihydroprogesterone is considerably more potent than progesterone. At low, nonsedative doses, it was effective against both the kindled amygdala focal afterdischarge and the generalized convulsion.     

Kindling of the Interpeduncular Nucleus and Its Influence on Subsequent Amygdala Kindling in Rats

Summary We examined the effect of interpeduncular nucleus (IPN) kindling on subsequent amygdala (AM) kindling in rats (n = 9). Eleven to 15 daily IPN stimulations at an afterdischarge (AD)-inducing threshold (40CL1000 PA, biphasic sine waves, 1–3 s) produced progressive AD growth (9 of 9 rats) and recruitment of behavioral seizures (7 of 9 rats). The final form of the latter was generalized tonic-clonic seizures with or without a limbic seizure component. The latter was associated with ictal involvement of AM and sensorimotor cortex. Subsequent AM kindling resulted not only in more rapid kindling, but also in tonic seizure associated with a protracted loss of postural control (5–20 s) not observed in animals undergoing AM kindling without previous IPN kindling (n = 5).These findings indicate that the IPN can be kindled and that subsequent AM kindling utilizes the proconvulsant neuroplastic changes that have been already established by IPN kindling.     

Facilitation of Amygdala Kindling Development and Kindled Seizures by Metaphit

Summary: The effect of metaphit (a phencyclidine analogue with an acylating isothiocyanate) on kindling development and kindled seizures from amygdala was investigated in rats pretreated once with metaphit. Administration of a single dose of metaphit (10 or 20 mg/kg intraperitoneally i.p.) 4 h before the first electrical stimulation of the amygdala did not in itself induce seizures, but greatly facilitated development of behavioral seizures during kindling. This effect persisted throughout the whole process of electrical amygdala kindling without further dosing. In contrast, metaphit only transiently and modestly increased the growth of afterdischarge (AD) duration. In kindled rats, pretreatment with a single dose of metaphit (20 mg/kg) 8 h before the test stimulation reduced the threshold current required to elicit a stage 5 seizure and shortened the latency for bilateral forelimb clonus (BFC) without changing AD duration or BFC duration. The facilitation of kindling development and kindled seizures may be due to an excessive excitatory transmission by metaphit in the limbic seizure circuitry.     

The Role of Interhemispheric Pathways in Generalization of Kindled Seizures in Cats and Subhuman Primates

Abstract: The role of interhemispheric pathways in generalization of partial seizures was evaluated in the kindling model of epilepsy. The generalized seizure kindled from the amygdala was asymmetrical in cats with callosal bisection, destruction of massa intermedia of the thalamus or bilateral ventral hippocampus. The generalized convulsion of amygdala kindled cats became asymmetrical or changed into partial seizures by callosal bisection. The fully-kindled amygdala seizure of a split-brain epileptic baboon and rhesus monkey was a hemiconvulsion or an asymmetrical generalized convulsion. The amygdala-kindled bisymmetrical generalized convulsion of the epileptic baboon was changed into a hemiconvulsion or an asymmetrical generalized convulsion. These results indicate that the corpus callosum plays an imoprtant, although not exclusive, role in bilateralization of epileptic activity, and its role becomes more important when the animal ascends the phylogenetic scale.     

Development of amygdaloid kindling in histidine decarboxylase-deficient and histamine H1 receptor-deficient mice

PURPOSE: This study attempted to clarify the role of histamine or histamine H1 receptors in the development of amygdaloid kindling by using histidine decarboxylase (HDC)-deficient and histamine H1 receptor (H1R)-deficient mice. METHODS: Under pentobarbital anesthesia, mice were fixed to a stereotaxic apparatus, and bipolar electrodes were implanted into the right amygdala. Electrodes were connected to a miniature receptacle, which was embedded in the skull with dental cement. A bipolar electroencephalogram was recorded; bipolar stimulation of the amygdala was applied every day with a constant-current stimulator and continued until a generalized convulsion was obtained. RESULTS: The development of amygdaloid kindling in HDC-deficient and H1R-deficient mice was significantly accelerated compared with that in their respective wild-type mice. In addition, the afterdischarge (AD) duration and generalized seizure duration in HDC-deficient and H1R-deficient mice were prolonged. Intraperitoneal injection of histidine resulted in an inhibition of amygdaloid kindled seizures in wild-type mice at doses that caused an increase in the histamine contents of the brain. However, no significant effect was observed with histidine in H1R-deficient mice at the same dose. CONCLUSIONS: These findings suggest that histaminergic mechanisms through H1 receptors play a crucial role not only in amygdaloid kindled seizures but also in the development of amygdaloid kindling.