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Primary and “Transfer” Seizure Development in the Kindled Rat
Abstract
An investigation was made of both primary and "transfer" kindling as they occur in ipsilateral limbic sites. Primary kindling was found to involve progressive growth of afterdischarge (AD), propagation and convulsive behavior. It was noted that AD growth did not take place gradually but occurred in sudden, large increments. "Transfer" (a significant acceleration of secondary kindling) was found at every secondary limbic site. It was associated with the early appearance of full-blown AD's, super-normal propagation, and well-developed seizures. The post-transfer interference of primary site function previously reported by Goddard et al was also found, but it occurred in significant amounts only after transfer kindling of the amygdala. It is believed that the data offer some support for both of the hypothetical mechanisms of transfer which have been proposed.
... Convulsive behavior coincided with the brain wave changes in the frontal cortex. Burnham (1975) did a thorough analysis of afterdischarges in ipsilateral and contralateral structures during kindling with four structures: amygdala, septal area, ventral hippocampus, and dorsal hippocampus. Dur-ing stimulation of each structure unilaterally, progressive growth of afterdischarge occurred in each, similar to that noted by Goddard et al. (1969) and Racine (1972). ...
... A number of other individuals also indicated that stimulation of the amygdala provides the fastest kindling (Burnham, 1975;Racine, 1975). With the Royal Victoria Hooded strain (which kindles faster than Wistar strains) and a greater intensity of stimulation, Burnham (1975) reported the mean number of afterdischarges to first convulsion as follows: amygdala, 11; septal area, 17: ventral hippocampus, 21; dorsal hippo-campus, 37. ...
... A number of other individuals also indicated that stimulation of the amygdala provides the fastest kindling (Burnham, 1975;Racine, 1975). With the Royal Victoria Hooded strain (which kindles faster than Wistar strains) and a greater intensity of stimulation, Burnham (1975) reported the mean number of afterdischarges to first convulsion as follows: amygdala, 11; septal area, 17: ventral hippocampus, 21; dorsal hippo-campus, 37. With the intensity that Burnham used, afterdischarges occur on the first trial or within a few trials. ...
The kindling effect is described as involving a gradual change in behavior in response to periodic invariant electrical stimulation of specific brain sites, culminating in convulsions. Two premises are evaluated relative to kindling: (a) The kindling effect provides an excellent model of human epileptic conditions. (b) The amino acid taurine will act to suppress convulsions developed during kindling. Consideration of behavioral, electrophysiological, neurological, and chemical aspects of kindling suggest that behavioral aspects may model those of epilepsy, but it is probable that neurological mechanisms in some types of epilepsy are different from those underlying the kindling event. Although taurine appears to have an important role (e.g., as an inhibitory neurotransmitter) and has been successful in suppressing convulsions in humans and in some experimentally induced seizures, it has been found to have no effect on convulsions developed via kindling. (65 ref)
... The in vitro electrophysiological studies performed either on slices or on the whole hippocampus preparation, provide the most homogeneous and compelling body of evidence demonstrates the relatively higher network excitability of the ventral hippocampus versus the dorsal hippocampus. Also, most of the in vivo studies concluded that the ventral hippocampus plays a dominant role on the initiation and/or the intensity of induced epileptiform activity (145)(146)(147)(148)(149)(150)(151). A typical parameter in the studies of epileptiform activity in the intact animal is the strength of the particular stimulation pattern that is required to trigger an epileptiform afterdischarge, i.e. the induction threshold (152), which can be considered as an index of the excitability of the local neural circuitry (153). ...
... Analyzing the relative literature it was surprising to find rather conflicting results on which of the two hippocampal segments shows the lower afterdischarge threshold. Thus, four studies have shown that the dorsal hippocampus displays the lower threshold (27,(154)(155)(156) while two other studies found lower threshold in the ventral hippocampus (145,157). However, the kindling rate (i.e. the number of intermittent stimulations required before spontaneous epileptiform discharges are established) was most often found higher in the ventral than in the dorsal hippocampus (145,149,154), but in one study the kindling rate was higher in the dorsal hippocampus (155). ...
... Thus, four studies have shown that the dorsal hippocampus displays the lower threshold (27,(154)(155)(156) while two other studies found lower threshold in the ventral hippocampus (145,157). However, the kindling rate (i.e. the number of intermittent stimulations required before spontaneous epileptiform discharges are established) was most often found higher in the ventral than in the dorsal hippocampus (145,149,154), but in one study the kindling rate was higher in the dorsal hippocampus (155). ...
The elongated structure of the hippocampus is critically involved in brain functions of profound importance. The segregation of functions along the longitudinal (septotemporal or dorsoventral) axis of the hippocampus is a slowly developed concept and currently is a widely accepted idea. The segregation of neuroanatomical connections along the hippocampal long axis can provide a basis for the interpretation of the functional segregation. However, an emerging and growing body of data strongly suggests the existence of endogenous diversification in the properties of the local neural network along the long axis of the hippocampus. In particular, recent electrophysiological research provides compelling evidence demonstrating constitutively increased network excitability in the ventral hippocampus with important implications for the endogenous initiation and propagation of physiological hippocampal oscillations yet, under favorable conditions it can also drive the local network towards hyperexcitability. In addition, important specializations in the properties of dorsal and ventral hippocampal synapses may support an optimal signal processing that contributes to the effective execution of the distinct functional roles played by the two hippocampal segments.
... The "aftereffect" was able to suppress seizure activity in different parts of the nervous system, was proportional to the number of convulsions, and spontaneously dissipated over time; complete dissipation occurred in 2 weeks or so (McIntyre & Goddard, 1973). Burnham (1975) also suggested that two mechanisms were involved in these kindling events. One was a convulsion mechanism that had duration as its indicator; the other was a triggering mechanism which was expressed in terms of latency. ...
... On the other hand, of the 20 correlations involving duration, only 7 are significant, 2 for latency-duration relationships and 5 for criterionduration relationships. These results suggest that the latency-criterion dependent variables are different from the duration measure, as has been pointed out by Burnham (1975). ...
... This statement is supported by the intercorrelations between the three dependent variables, the factor structure determined for each of the three, and the factor structure determined over the 30 phases. These results are consistent with those of Burnham (1975) which lead him to suggest that latency was an indicator of a triggering mechanism, whereas duration values were concerned with a convulsion mechanism. ...
Data from a number of sequential alternation experiments were factor analyzed to determine the number of common factors present. Three dependent variables (latency of convulsion, number of trials to six convulsions, duration of convulsions) were evaluated by three procedures: principal components solution with 1s in main diagonals, principal axes solution with largest r in the diagonals, principal axes solution with R2 in the diagonals. The results were similar; the presence of two factors was suggested in the latency and criterion measures (primary site stimulation and secondary site stimulation) and one in the duration data. A principal components factor analysis over the three dependent variables showed the presence of three factors, those observed in each of the separate analyses.
... Careful morphological analyses have indicated that the effect is not due to edema, ion deposition, or any form of damage to the stimulated tissue (Goddard et aI., 1969;Goddard & Douglas, 1975;Racine, 1978). Although the amygdaloid complex appears to be particularly sensitive to kindling, the effect may be obtained from a number of different brain regions, especially those within the limbic system (Goddard et aI., 1969;Burnham, 1975). ...
... A few trials are required to reach the convulsion stage, thus indicating negative transfer. Similar results have been reported by a number of researchers (e.g., Burnham, 1975). Gaito (1976b) decided to extend the number of alternating stimulation phases to 10 or more (instead of just three) to determine the point where the transfer between hemispheres would disappear and the Copyright 1980 Psychonomic Society, Inc. 120 0090-5046/80/010120-06$00 .85/0 ...
... These two processes would be operating on one side or on two sides, depending on the stimulation conditions. Burnham (1975) also suggested that two mechanisms were involved in these kindling events. One was a convulsion mechanism that had duration as its indicator; the other was a triggering mechanism that was expressed in terms of latency. ...
There are three types of interference effects during kindling: that produced by alternate stimulation of homologous brain sites, by successive stimulation of one site, and by stimulation of one site by different frequencies. These three types of interference appear to be similar. Facilitation and interference effects during kindling seem to be generated by the operation of two factors: a “neurological trace” process, possibly involving synaptic changes, and an “aftereffect.” The latter process may be the main basis for these interference effects.
... A typical hippocampal kindling session initiates with triggering stimulus followed by the 1AD period, a relatively silent period, and the 2AD period (or rebound period). This electrophysiologic pattern is typical of hippocampal kindling and is not seen in perirhinal cortex stimulation and amygdala stimulation 16,[22][23][24] . This feature allows an electrophysiological evaluation of the electrode position even before histological analysis. ...
... Different from amygdala kindling, the hippocampal features involve a faster progression to more advanced motor stages, leading to a fast ictal generalization affecting the motor area. The progressive duration increase of behavioral seizures and the presence of the stages 6, 7 and 8 (Pinel and Rovner Scale) are in conformance with previous descriptions that report a progressive complexity increase in both electrophysiological and behavioral features found in hippocampal kindling models 22,23 . ...
The kindling phenomenon is classically investigated in epileptology research. The present study aims to provide further information about hippocampal kindling through computational processing data. Adult Wistar rats were implanted with dorsal hippocampal and frontal neocortical electrodes to perform the experiment. The processing data was obtained using the Spike2 and Matlab softwares. An inverse relationship between the number of 'wet dog shakes' and the Racine's motor stages development was found. Moreover it was observed a significant increase in the afterdischarge (AD) duration and its frequency content. The highest frequencies were, however, only reached at the beginning of behavioral seizures. During the primary AD, fast transients (ripples) were registered in both hippocampi superimposed to slower waves. This experiment highlights the usefulness of computational processing applied to animal models of temporal lobe epilepsy and supports a relevant role of the high frequency discharges in temporal epileptogenesis.
... it might be that 3-Hz stimulation interferes with these synaptic changes, or possibly it sets up antagonistic synaptic changes. Burnham (1975) suggested that the kindling effect consisted of the development of a convulsion mechanIsm and the use of a triggering mechanism. In this framework one would say that the effect of 3-Hz stimulation is on the triggering mechanism. ...
These experiments investigated the effect of 3- Hz brain stimulation on behavior induced by 60- Hz stimulation.
... It was found that brain material from kindled rats retarded the development of the clonic convulsion in naive recipients but had no effect on rats which had attained the convulsion stage. Thus, the development of the convulsive mechanism and the triggering mechanism may represent two different processes (Burnham, 1975 Toronto. AprilS. ...
Five experiments were conducted in which taurine was administered to rats at various stages in the kindling process. Amygdaloid stimulation was at 100-microA intensity for 30 sec. Experiments 1, 2, and 3 evaluated the effects of taurine on rats at the clonic convulsion stage with various dosages (50, 100, 200, and 400 mg/kg weight). Experiments 4 and 5 were concerned with rats at the exploration and behavioral automatism stages (dosages: 50, 100, and 200 mg/kg weight). Rats at the initial stage (normal exploration) which received taurine intraperitoneally reached the convulsion stage later than did rats injected with physiological saline. Taurine administration had no effect when rats were at the behavioral automatism or clonic convulsion stage. A second set of four experiments were conducted which used 50, 100, and 200 mg/kg dosages and the duration of stimulation was just above latency threshold. The results were similar to the first set; however, the retardation with rats at Stage 1 was not as pronounced.
... Fewer stimuli are therefore required to kindle structures on the contralateral side (21,22). Interestingly, once this transfer effect has occurred, the ability of the original site to induce a motor seizure after stimulation is impaired (23,24). This ability to inhibit seizure development persists even after the secondary focus has been ablated. ...
The phenomenon of forced normalization and its clinical counterpart, alternative psychoses, is discussed. The historical origins are briefly noted before the clinical presentation, and some associated clinical findings are given. The main part of the article is devoted to the literature on chemical and electrical kindling, in an attempt to provide some heuristic model to understand the antithetical relationship between seizures and behavior disorders. We conclude that the use of the kindling model may provide further insights into these phenomena, particularly taking into account such key neurotransmitters as glutamate, dopamine, and GABA.
... Evidence for the dependence of enhanced extrafocal propagation on changes in widespread, extrafocal circuits was offered by the ''transfer'' phenomenon. ''Transfer'' refers to the fact that the kindling of secondary sites takes place much more rapidly in an animal that has already been kindled from a primary site (Goddard et al., 1969;Racine, 1972b;Burnham, 1975). This phenomenon occurs even when the primary site has been destroyed by a lesion (Racine, 1972b). ...
Racine's classic study suggested that after discharge thresholds were reduced in the primary stimulation site (amygdala) of kindled rats, but that that they were not reduced in secondary (nonstimulated) sites. However, recent reports of neurochemical changes related to excitation and inhibition in nonstimulated sites in kindled brains would be expected to cause reductions in afterdischarge thresholds in these sites. More recently Sanei et al. have reported a significant threshold reduction in the piriform cortex of amygdala- and hippocampus-kindled cats, but not in the entorhinal cortex. The present study was designed to determine whether the results of Sanei et al. in cats could be replicated in rats kindled in the amygdala-a model commonly used in studies of seizure mechanisms and anticonvulsant drug development.
Adult, male Long-Evans rats were kindled in the amygdala or given matched handling. Beginning 48 h following the last stimulation, afterdischarge thresholds were determined in the ipsilateral piriform and entorhinal cortices. Amygdala thresholds were determined 24 h later.
Afterdischarge thresholds were significantly reduced in both the amygdala and the ipsilateral entorhinal cortex of amygdala-kindled rats. Afterdischarge thresholds in the piriform cortex did not differ significantly between kindled and control subjects.
These data suggest that threshold reduction occurs outside the primary kindling site in rats as well as in cats. Extrafocal changes in afterdischarge threshold may be functionally important, and might possibly relate to extrafocal neurochemical changes and progressive generalization of seizure discharge from discrete focal sites.
... Compared to primary site kindling, the secondary site requires significantly fewer kindling sessions to elicit a motor seizure. For example, primary amygdaloid kindling requires a mean of 10.6 stimulations; however, subsequent to dHPC kindling, only 1.8 stimulations of the amygdala are required to induce a fully generalized seizure (Burnham, 1975). This represents an 84% savings. ...
Kindling involves the progressive development of epileptiform activity that culminates in generalized seizures in response to repeated electrical stimulation of the brain. Kindling induces widespread changes in synaptic sensitivity and neuronal reactivity. These neuroplastic changes are evident in altered memory and behavior. This research was designed to further our understanding of kindling-induced deficits in spatial cognition. Two questions were examined: 1)does entorhinal cortex kindling disrupt spatial cognition; and 2)can bilateral bifocal kindling, of two brain regions known to participate in spatial cognition, produce larger cognitive deficits than unifocal kindling? This research attempted to confirm the spatial cognitive effects produced by unifocal dorsal hippocampal (dHPC) kindling, as a positive control. In contrast, the spatial cognitive effects produce by unifocal entorhinal cortex (EC) and bifocal kindling (i.e., EC kindling with subsequent contralateral dHPC kindling) are unknown and were examined here. Rats were subjected to unifocal EC kindling, unifocal dHPC kindling, or bifocal kindling. Rats exhibited fully generalized seizures prior to Morris water maze training from days 2 to 31. Visible platform trials were used to examine escape motivation and gross motor coordination, and all groups performed adequately. Consistent with previous research, dHPC kindling disrupted performance during acquisition trials; however, EC and bifocal kindling failed to disrupt acquisition. During retention trials, the bifocal kindling group displayed a disruption in performance; however, dHPC and lateral EC kindling failed to affect retention. The bifocal kindled group failed to display larger deficits than the unifocal kindled groups. These data suggest that the number of kindling stimulations given to a particular site may play a critical role in site-dependent disruption of memory.
... Other structures, including the hippocampus, have been studied less thoroughly. Burnham (1975) has recently reported an interesting difference between the kindling response of the dorsal and ventral hippocampus. In his studies, the dorsal hippocampus required a greater number of stimulations than the ventral hippocampus before maximal seizure responses were developed. ...
Electrodes were implanted into dorsal hippocampus (CAI), ventral CAI, dorsal dentate gyrus or ventral dentate gyrus. Epileptiform afterdisvharge (AD) thresholds were lower in dorsal areas than in ventral areas. Dorsal areas, however, required a greater number of stimulations to develop (“kindle”) a fully generalized convulsion than did ventral areas. Thresholds and kindling rates in the dentate gyrus were intermediate between dorsal and ventral CAI, except for the ventral dentate which had higher AD thresholds than ventral CAI.
Secondary sites within the hippocampus subsequently kindled within a few stimulations following completion of kindling in the primary site, regardless of which hippocampal area served as the primary site.
... Accumulated evidence suggests that the amygdala is involved in temporal lobe epilepsy (Bruton 1988) and is one of the areas most sensitive to induce kindling regardless of the site of stimulation (Kairiss et al. 1984 ). Furthermore, the basolateral nucleus of the amygdala (BLA) is one of the areas most often selected to induce kindling (Burnham 1975; Le Gal La Salle 1981; Racine and McIntyre 1986). Hence, the amygdala kindling model of epilepsy allows the examination of long-term changes in neuronal excitability associated with epileptogenesis. ...
1. Intracellular current-clamp recordings were obtained from neurons of the basolateral amygdala (BLA) in an in vitro slice preparation from control and kindled animals. Postsynaptic potentials, elicited by stimulation of the stria terminalis (ST) or lateral amygdaloid nucleus (LA), were used to investigate the role of excitatory and inhibitory amino acid transmission in kindling-induced epileptiform activity. The contributions of glutamatergic and GABAergic receptor subtypes were analyzed by use of the non-N-methyl-D-aspartate (non-NMDA) antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), the NMDA antagonist DL-2-amino-5-phosphonovaleric acid (APV), and the GABAA antagonist bicuculline methiodide (BMI). 2. The synaptic waveform evoked in control neurons consisted of an excitatory postsynaptic potential (EPSP), a fast inhibitory postsynaptic potential (f-IPSP), and a slow inhibitory postsynaptic potential (s-IPSP). Stimulation of the ST or LA pathways evoked a burst-firing response in BLA neurons contralateral from the site of stimulation of kindled animals. 3. APV (50 microM) reduced, but CNQX (10 microM) completely blocked, the burst-firing response in BLA neurons from kindled animals and bicuculline-induced bursting in control neurons. 4. Kindling significantly increased the amplitude of both the slow NMDA- and the fast non-NMDA-receptor-mediated components of synaptic transmission (s- and f-EPSPs, respectively). Furthermore, the stimulus intensities required to evoke EPSPs just subthreshold for action potential generation were significantly lower in slices from kindled animals. 5. In kindled neurons no significant change was observed in the membrane input resistance and resting membrane potential or in the number of action potentials elicited in response to depolarizating current injection. 6. Kindling resulted in a pathway-specific loss of ST- and LA-evoked feedforward GABAergic synaptic transmission and of spontaneous IPSPs. In the same BLA neurons, direct GABAergic inhibition via stimulation of the LA was not affected by kindling. 7. The enhanced glutamatergic transmission was not due to disinhibition, because, in the presence of BMI (and CNQX to prevent BMI-induced bursting), the s-EPSP amplitude was still greater in kindled than in control neurons. 8. These results provide evidence that the epileptiform activity observed in BLA neurons after kindling results from an increase in excitatory NMDA- and non-NMDA-receptor-mediated glutamatergic transmission and a decrease in inhibitory gamma-aminobutyric acid (GABA)-receptor-mediated transmission; the enhanced excitatory transmission cannot be accounted for by reduced inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)
... One area particularly sensitive to kindling and most often used to induce kindling is the basolateral nucleus of the amygdala (BLA). (Burnham, 1975; Kairiss et al. 1984; Le Gal La Salle 1981; Racine and McIntyre 1986). Anatomically, the BLA resembles the neocortex (Hall 1972a,b; Millhoru:e and de Olmos 1983). ...
1. Intracellular current-clamp recordings obtained from neurons of the basolateral nucleus of the amygdala (BLA) were used to characterize postsynaptic potentials elicited through stimulation of the stria terminalis (ST) or the lateral amygdala (LA). The contribution of glutamatergic receptor subtypes to excitatory postsynaptic potentials (EPSPs) were analyzed by the use of the non N-methyl-D-aspartate (non-NMDA) antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), and the NMDA antagonist, (DL)-2-amino-5-phosphonovaleric acid (APV). 2. Basic membrane properties of BLA neurons determined from membrane responses to transient current injection showed that at the mean resting membrane potential (RMP; -67.2 mV) the input resistance (RN) and time constant for membrane charging (tau) were near maximal, and that both values were reduced with membrane hyperpolarization, suggesting an intrinsic regulation of synaptic efficacy. 3. Responses to stimulation of the ST or LA consisted of an EPSP followed by either a fast inhibitory postsynaptic potential (f-IPSP) only, or by a fast- and subsequent slow-IPSP (s-IPSP). The EPSP was graded in nature, increasing in amplitude with increased stimulus intensity, and with membrane hyperpolarization after DC current injection. Spontaneous EPSPs were also observed either as discrete events or as EPSP/IPSP waveforms. 4. In physiological Mg2+ concentrations (1.2 mM), at the mean RMP, the EPSP consisted of dual, fast and slow, glutamatergic components. The fast-EPSP (f-EPSP) possessed characteristics of kainate/quisqualate receptor activation, namely, the EPSP increased in amplitude with membrane hyperpolarization, was insensitive to the NMDA receptor antagonist, APV (50 microM), and was blocked by the non-NMDA receptor antagonist, CNQX (10 microM). In contrast, the slow-EPSP (s-EPSP) decreased in amplitude with membrane hyperpolarization, was insensitive to CNQX (10 microM), and was blocked by APV (50 microM), indicating mediation by NMDA receptor activation. 5. In the presence of CNQX (10 microM), ST stimulation evoked an APV-sensitive s-EPSP. In contrast, LA stimulation evoked a f-IPSP, which when blocked by subsequent addition of bicuculline methiodide (BMI; 30 microM) revealed a temporally overlapping APV-sensitive s-EPSP. These data suggest that EPSP amplitude and duration are determined, in part, by the shunting of membrane conductance caused by a concomitant IPSP. 6. Superfusion of either CNQX or APV in BLA neurons caused membrane hyperpolarization and blockade of spontaneous EPSPs and IPSPs, suggesting that these compounds may act to block tonic excitatory amino acid (EAA) release within the nucleus, and that a degree of feed-forward inhibition occurs within the nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)
The excitation/inhibition (E/I) balance is a critical feature of neural circuits, which is crucial for maintaining optimal brain function by ensuring network stability and preventing neural hyperexcitability. The hippocampus exhibits the particularly interesting characteristics of having different functions and E/I profiles between its dorsal and ventral segments. Furthermore, the hippocampus is particularly vulnerable to epilepsy and implicated in Fragile X Syndrome (FXS), disorders associated with heightened E/I balance and possible deficits in GABA-mediated inhibition. In epilepsy, the ventral hippocampus shows heightened susceptibility to seizures, while in FXS, recent evidence suggests differential alterations in excitability and inhibition between dorsal and ventral regions. This article explores the mechanisms underlying E/I balance regulation, focusing on the hippocampus in epilepsy and FXS, and emphasizing the possible mechanisms that may confer homeostatic flexibility to the ventral hippocampus in maintaining E/I balance. Notably, the ventral hippocampus in adult FXS models shows enhanced GABAergic inhibition, resistance to epileptiform activity, and physiological network pattern (sharp wave-ripples, SWRs), potentially representing a homeostatic adaptation. In contrast, the dorsal hippocampus in these FXS models is more vulnerable to aberrant discharges and displays altered SWRs. These findings highlight the complex, region-specific nature of E/I balance disruptions in neurological disorders and suggest that the ventral hippocampus may possess unique compensatory mechanisms. Specifically, it is proposed that the ventral hippocampus, the brain region most prone to hyperexcitability, may have unique adaptive capabilities at the cellular and network levels that maintain the E/I balance within a normal range to prevent the transition to hyperexcitability and preserve normal function. Investigating the mechanisms underlying these compensatory responses in the ventral hippocampus and their developmental trajectories may offer novel insights into strategies for mitigating E/I imbalances in epilepsy, FXS, and potentially other neuropsychiatric and neurodevelopmental disorders.
Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder characterized by intellectual disability and is related to autism. FXS is caused by mutations of the fragile X messenger ribonucleoprotein 1 gene (Fmr1) and is associated with alterations in neuronal network excitability in several brain areas including hippocampus. The loss of fragile X protein affects brain oscillations, however, the effects of FXS on hippocampal sharp wave-ripples (SWRs), an endogenous hippocampal pattern contributing to memory consolidation have not been sufficiently clarified. In addition, it is still not known whether dorsal and ventral hippocampus are similarly affected by FXS. We used a Fmr1 knock-out (KO) rat model of FXS and electrophysiological recordings from the CA1 area of adult rat hippocampal slices to assess spontaneous and evoked neural activity. We find that SWRs and associated multiunit activity are affected in the dorsal but not the ventral KO hippocampus, while complex spike bursts remain normal in both segments of the KO hippocampus. Local network excitability increases in the dorsal KO hippocampus. Furthermore, specifically in the ventral hippocampus of KO rats we found an increased effectiveness of inhibition in suppressing excitation and an upregulation of α1GABAA receptor subtype. These changes in the ventral KO hippocampus are accompanied by a striking reduction in its susceptibility to induced epileptiform activity. We propose that the neuronal network specifically in the ventral segment of the hippocampus is reorganized in adult Fmr1-KO rats by means of balanced changes between excitability and inhibition to ensure normal generation of SWRs and preventing at the same time derailment of the neural activity toward hyperexcitability.
Patients with focal temporal lobe seizures often experience transient episodes of impaired awareness with behavioral arrest, but the precise mechanism remains unknown. The Network Inhibition Hypothesis attributes these deficits to a loss of cholinergic input to the cortex. This is presumed to result from increased activation of inhibitory regions that suppress subcortical arousal, giving rise to cortical delta wave activity. Recently, this hypothesis has been tested in animal experiments, where triggering dorsal hippocampal seizures is associated with behavioral arrest. To further test this hypothesis in animals – and, more specifically, to characterize the relationship between propagated discharge, cortical delta waves and behavioral arrest – we performed partial kindling studies in three different limbic sites in rats. We found that seizure discharge took longer to spread from the amygdala than the hippocampus, and took more stimulations to elicit behavioral arrest. In addition, the onset of propagated discharge in subcortical and cortical sites did not always match with the onset of behavioral arrest. Importantly, the activity seen in the cortex did not resemble the slow waves seen in deep sleep. Together, these findings suggest that limbic discharge triggers epileptic discharge in downstream pacemakers, including the cortex, and that these secondarily cause behavioral arrest.
Kindling is a neuroplastic process that appears to involve the lasting alteration of synaptic function. This implies that kindling may require a neural growth process for some aspect of its establishment. The fact that inhibition of protein synthesis blocks kindling without affecting the epileptiform afterdischarge (AD) that normally leads to its development [8] is consistent with that suggestion, as are reports of kindling-induced neural alterations and sprouting at the ultrastructural level [17,18,51].
There is convincing evidence that excitatory amino acids, particularly glutamate (GLU) and aspartate (ASP), are involved in basic mechanism of epilepsy (for reviews see refs. 1,2,26). Thus, enhanced release, and reduced tissue levels, of excitatory amino acids have been reported in various animal models of epilepsy (9,13,20,24,34,41,44). Reduced levels of both GLU and ASP have also been demonstrated in tissue excised from human epileptic foci (42,43). In addition, excitatory amino acid antagonists have been shown to block epileptic seizures and epileptiform activity in both rodent and primate models of epilepsy (4,5,6,26,34,39,40).
The amygdala, an almond-shaped area of the limbic brain, is particularly sensitive to kindling.10,29,66 One nucleus of the amygdala, the basolateral nucleus, is most often used to induce kindling.9,20,28,47 Basolateral amygdala (BLA) neurons are divided morphologically31,32 and electrophysiologically51,63 into two major classes of neurons: the principal class is comprised of pyramidal and stellate cells, and the smaller proportion of cells are interneurons. Glutamatergic cells are found throughout the nucleus34 and the stria terminalis (ST), a major bidirectional pathway of the amygdala, contains glutamatergic afferent fibers projecting to the BLA.42 The BLA also receives input from the lateral amygdala (LA) and is reported to have recurrent projections.26,58 The BLA contains moderate amounts of γ-aminobutyric acid (GABA)8 and GABA immunoreactivity.11,43 Morphologically, interneurons comprising ~ 5% of the cells31 have been classified as GABAergic33 and form synapses with the principal cell types. Lesioning the afferent ST pathway did not reduce GABA content, suggesting GABA neurons in the BLA are intrinsic.8
What is the nature of the kindling process? “Kindling” was coined by Goddard and his colleagues [20] to describe an observed phenomenon — the progressively increasing seizure generalization seen with repeated, temporally spaced stimulations of certain brain structures. From this phenomenological point of view, kindling is well named, since it appears to be a self-perpetuating process which once started continues inexorably to completion.
Interest in the contribution of the pyriform cortex to complex partial seizures is not new. In the 1890s Hughlings Jackson and colleagues (9, 10) described a lesion limited to the human uncus, the homologue of the rodent pyriform cortex (2), which they believed initiated ‘uncinate fits’. The development of elaborate behavioral symptoms during the uncinate seizure was presumed to be a result of seizure spread beyond this area, perhaps to the frontal cortex via the uncinate fasciculus (25). Occasionally these spontaneous uncinate seizures developed secondarily into full generalized convulsions, an outcome frequently observed after electrical stimulation of the uncus (21). Thus, it seems that provocation of the uncus is able to directly trigger, or gain access to mechanisms necessary to trigger, secondarily generalized convulsions.
Agents with the potential to induce seizure-like discharge in the limbic system also have the potential to induce permanent alteration in that system. The most dramatic set of alterations have been called, collectively, the kindling effect (Goddard, McIntyre & Leech, 1969). Kindling is observed when an agent is applied mildly, repeatedly, usually once per day, and the response to that agent progressively changes until it includes a major clinical convulsion. If the treatments are discontinued, the system does not return to normal, but remains in a state of readiness even for a year or more. It will respond with convulsions to unusually low doses or gentle application of a wide range of the known epileptogenic agents (Pinel & Van Oot, 1976). When sufficient time is allowed between treatments, the sensitivity of the convulsive response may continue to increase; and, in some cases after many repetitions, the convulsions may recur spontaneously (Wada, Sato & Corcoran, 1974; Wada, Osawa & Mizoguchi, 1976; Pinel, Mucha & Phillips, 1975).
Psychiatric illness is very commonly associated with epilepsy, both in adults as well as in children and adolescents; however, the etiology of psychiatric conditions in persons with epilepsy is still controversial. Although the understanding of psychiatric comorbidity has vastly improved over the past century, in many cases, it is difficult to resolve whether psychiatric illness is coincidental or associated with the underlying seizure disorder. Despite numerous reports confirming an overrepresentation of psychiatric illness associated with epilepsy, many patients do not receive mental health treatment. Unfortunately, in some cases, the psychiatric comorbidity may be more impairing to quality of life than the seizure themselves.The consistently high level of psychiatric comorbidity suggests that epilepsy is a complicated illness that may have neuropsychiatric symptoms well beyond discrete seizures.Epileptologists and advocacy groups have raised awareness of the need for an interdisciplinary approach to management of epilepsy. The existing literature tends to focus upon one of three potential explanations for psychiatric comorbidity: symptoms related to psychosocial stress of chronic disease, symptoms related to medication side effects, and symptoms directly related to epilepsy pathophysiology. Although the evidence base is limited regarding treatment for the most common comorbidities of depression, anxiety, attention and cognitive disorders, recent studies have been encouraging in terms of outlining practical treatment approaches in the context of specific epilepsy factors.This chapter addresses historical and theoretical characteristics of psychiatric illness associated with epilepsy as well as strategies for managing the most common psychiatric comorbidities.
For many of us who work on the kindling phenomenon, there is often some ambiguity about our intentions. Are we investigating a learning model or an epilepsy model? Most neuroscientists would agree that claims of a relationship between epilepsy and learning are risky, to say the least. Consequently, we usually play it safe by using terms such as neural plasticity, or we focus on kindling as an epilepsy model. There is at least a little psychologist in all of us however, and that part of us would like to “solve” learning. We have been rather disappointed by recent data that seemed to us to be inconsistent with a learning model view of the kindling. In this paper we will review some of the work that led to an increasing skepticism about the validity of kindling as a learning model, and then we will describe some of our most recent work. This work, we believe, suggests that it may be premature to give up on the relevance of kindling to learning.
Much of the early work on kindling was done in the rat using limbic, and especially amygdaloid sites for stimulation (Goddard et al, 1969; Racine, 1972a and b). It was known that brief convulsions could also be elicited from the anterior neocortex (Goddard et al, 1969; Racine, 1975), but these differed from limbic-kindled seizures both in their motor pattern and in their course of development, and they were considered a special “cortical” seizure type.
Kindling is a powerful model of epilepsy.11,29 It is the best model we have of mesial temporal lobe epilepsy (MTLE), which is the most devastating type of human epilepsy, accounting for the vast majority of people with medically intractable epilepsy. More than 0.5 million people in the USA are afflicted with MTLE and continue to have seizures despite the best available medical treatment. It has been the hope of investigators that understanding the mechanisms underlying kindling will provide insight into treatment for MTLE. In nearly thirty years of research, however, kindling has yet to give up its most fundamental secrets.
Three groups of rats were subjected to a sequence of electrical stimulations alternating from one amygdala to the contralateral one. In Group 1 each stimulation was for one convulsion prior to stimulation of the opposite side. Rats in Group 2 had six convulsions per phase. Twelve convulsions per phase were provided for Group 3 rats. The oscillation tendency (high values for one side, low values for the other side) was prominent with all groups, but seemed less prevalent for the rats in the one convulsion per phase group.
This paper describes in kindled rats an increment in wheat germ agglutinin-horseradish peroxidase labeling in anterior commissure, bed nuclei of stria terminalis and amygdala. Three groups of animals were analyzed: control, sham-operated and kindled animals with ten convulsive generalized seizures. Results show that kindled animals have an increase in fiber labeling in anterior commissure and in the bed nuclei of stria terminalis, as well as a greater number of labeled neurons in amygdala. This label enhancement is related to the hyperexcitability of neurons produced by epilepsy, and could be associated to the propagation and formation of secondary foci and related plastic changes occurring during kindling.
The present study was aimed at evaluating an extended kindling model of spontaneous epilepsy. Behavioral and electrographic responses to repeated kindling of either the perforant path or amygdala were monitored for up to 300 trials. Kindling initially led to generalized convulsions equivalent to the level 5 seizure on the rating scale developed by Racine. The evoked seizures became progressively more complex with additional kindling, which was described by a 10-stage classification system. The highest stage (stage 10) was achieved when the kindling stimulation evoked two or more bouts of level 5 seizures combined with running and jumping fits. These more complex seizures developed over the course of amygdala, but not perforant path kindling. Electrographic seizures from both the amygdala and dentate gyrus increased in duration and amplitude during the early phase of kindling, but did not correlate with motor seizure development beyond level 5. During the late phase of kindling, the dentate gyrus afterdischarge amplitude decreased and became dissociated from the behavioral seizures. Manifestations of spontaneously recurring seizures were seen in the majority of animals, but spontaneous seizures of level 4 or greater were observed in only five rats. The second part of this study examined kindling transfer effects, the efficacy of kindling a new site after the completion of the initial (in this case extended) kindling protocol. The effect depended on both primary and secondary site location. When the amygdala served as primary site, perforant path transfer was complete in some animals but absent in others. No transfer occurred in the opposite direction, from the perforant path to the amygdala. Finally, transfer effects in the dentate gyrus, which was tested as tertiary site, were complete. Previous studies have found weaker transfer effects in the dentate when kindling to the standard stage 5 level.
We sought to describe quantitatively the morphological and functional changes that occur in the dentate gyrus of kainate-treated rats, an experimental model of temporal lobe epilepsy. Adult rats were treated systemically with kainic acid, and, months later, after displaying spontaneous recurrent motor seizures, their dentate gyri were examined. Histological, immunocytochemical, and quantitative stereological techniques were used to estimate numbers of neurons per dentate gyrus of various classes and to estimate the extent of granule cell axon reorganization along the septotemporal axis of the hippocampus in control rats and epileptic kainate-treated rats. Compared with control rats, epileptic kainate-treated rats had fewer Nissl-stained hilar neurons and fewer somatostatin-immunoreactive neurons. There was a correlation between the extent of hilar neuron loss and the extent of somatostatin-immunoreactive neuron loss. However, functional inhibition in the dentate gyrus, assessed with paired-pulse responses to perforant-pathway stimulation, revealed enhanced, and not the expected reduced, inhibition in epileptic kainate-treated rats. Numbers of parvalbumin- and cholecystokinin-immunoreactive neurons were similar in control rats and in most kainate-treated rats. A minority (36%) of the epileptic kainate-treated rats had fewer parvalbumin- and cholecystokinin-immunoreactive neurons than control rats, and those few (8%) with extreme loss in these interneuron classes showed markedly hyperexcitable dentate gyrus field-potential responses to orthodromic stimulation. Compared with control rats, epileptic kainate-treated rats had larger proportions of their granule cell and molecular layers infiltrated with Timm stain. There was a correlation between the extent of abnormal Timm staining and the extent of hilar neuron loss. Granule cell axon reorganization and dentate gyrus neuron loss were more severe in temporal vs. septal hippocampus. These findings from the dentate gyrus of epileptic kainate-treated rats are strikingly similar to those reported for human temporal lobe epilepsy, and they suggest that neuron loss and axon reorganization in the temporal hippocampus may be important in epileptogenesis. J. Comp. Neurol. 385:385–404, 1997. © 1997 Wiley-Liss, Inc.
The amygdala is a critical brain region for limbic seizure activity, but the mechanisms underlying its epileptic susceptibility are obscure. Several lines of evidence implicate GluR5 (GLUK5) kainate receptors, a type of ionotropic glutamate receptor, in the amygdala's vulnerability to seizures and epileptogenesis. GluR5 mRNA is abundant in temporal lobe structures including the amygdala. Brain slice recordings indicate that GluR5 kainate receptors mediate a portion of the synaptic excitation of neurons in the rat basolateral amygdala. Whole-cell voltage-clamp studies demonstrate that GluR5 kainate receptor-mediated synaptic currents are inwardly rectifying and are likely to be calcium permeable. Prolonged activation of basolateral amygdala GluR5 kainate receptors results in enduring synaptic facilitation through a calcium-dependent process. The selective GluR5 kainate receptor agonist ATPA induces spontaneous epileptiform bursting that is sensitive to the GluR5 kainate receptor antagonist LY293558. Intra-amygdala infusion of ATPA in the rat induces limbic status epilepticus; in some animals, recurrent spontaneous seizures occur for months after the ATPA treatment. Together, these observations indicate that GluR5 kainate receptors have a unique role in triggering epileptiform activity in the amygdala and could participate in long-term plasticity mechanisms that underlie some forms of epileptogenesis. Accordingly, GluR5 kainate receptors represent a potential target for antiepileptic and antiepileptogenic drug treatments. Most antiepileptic drugs do not act through effects on glutamate receptors. However, topiramate at low concentrations causes slow inhibition of GluR5 kainate receptor-mediated synaptic currents in the basolateral amygdala, indicating that it may protect against seizures, at least in part, through suppression of GluR5 kainate receptor responses.
Repeated electrical stimulation of the brain can produce many epileptogenic effects including those which characterize the kindling model. Kindling stimulation, by definition, changes the brain in such a way that formerly subconvulsive stimuli can elicit electrographic and convulsive seizure activity. In addition, the kindled animal becomes more susceptible to many, but not all, other types of seizures. These facts suggest that kindling produces brain changes which may selectively model some types of epileptiform excitability. In order to understand the basis for such changes, numerous neurochemical studies have been attempted in the last few years. Although many changes have been demonstrated to be produced by kindling, few studies have been designed to specifically examine the long-lasting (permanent) neurochemical correlates of kindling stimulation. In this review, neurochemical data relevant to kindling are presented and discussed in terms of their possible significance to the seizure susceptibility changes produced by kindling.
Pollock, Daniel C. : Models for Understanding the Antagonism Between Seizures and Psychosis. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1987, : 483–504 1.1. The relationship between seizures and psychosis is reviewed using incidence and association studies, and experimental models of kindling and behavioral sensitization.2.2. While there are conflicting data on the association of psychopathology with epilepsy, studies illustrating the antagonism between seizures and psychosis are examined along with the phenomenon of “Forced Normalization”.3.3. Electrical kindling of the amygdala provides a model of temporal lobe epilepsy while pharmacologic kindling/behavioral sensitization or dopaminergic kindling provides a model for psychosis.4.4. A model explaining both the etiology and the reciprocal nature of seizures and psychosis in temporal lobe epilepsy is developed. Preictal and interictal spikes kindle both proconvulsive and inhibitory pathways of seixure expression and behaviorally relevant limbic systems. That system currently expressive, either seizure or psychosis, while under high synchronous drive would tend to fail allowing for the emergence of the opposing system.
Audiogenic seizures in genetically susceptible rodents are provoked by intense acoustic stimulations which result in a tonic seizure associated with a short flattening of the EEG. These seizures have been shown to involve primarily brainstem structures. Daily exposure to sound for 30–40 days produced a permanent change in the evoked seizure with development of facial myoclonias, rearing and falling, or of tonic-clonic seizures accompanied by high amplitude cortical spike-and-wave discharges. Kindled audiogenic seizures appear similar to seizures kindled from amygdala or hippocampus, suggesting that repeated auditory stimulations cause a progressive propagation of the epileptic discharge toward limbic structures. To verify this hypothesis, the behavioral and EEG development of electrical hippocampal kindling has been studied in 7 non epileptic controls (NE), 8 acoustic susceptible (AS), and 8 audiogenic kindled rats (KAS). The behavioral and EEG development of the electrical hippocampal kindling was similar in the AS and the NE rats. However, 2 animals in the AS group but no controls exhibited behavioral running and bouncing during the course of hippocampal kindling. In the KAS group, the hippocampal kindling was clearly facilitated as compared to NE and AS: behavioral stage ⩾ 5 was reached in a mean of 4 stimulations in KAS versus 30 and 22 stimulations respectively in NE and AS groups. This positive transfer phenomenon suggests that during kindling of audiogenic seizures, epileptic discharge spreads from the brainstem to the forebrain and progressively involves the hippocampus.
To identify specific genes involved with epileptogenesis kindling was examined in mice carrying mutations engineered by gene targeting. Amygdala kindling was tested in mice with a null-mutation in the Fyn tyrosine kinase gene, a mutation that raises the threshold for the induction of long-term potentiation in the hippocampus. The fyn mutants had a normal threshold, duration and stability of epileptiform after-discharge, which is crucial for kindling. Despite the normal after-discharge, fyn mutants showed a striking retardation in the rate of kindling. Once the kindled state was established in fyn mutants it remained stable. This implicates a Fyn-dependent biochemical pathway in the induction but not the maintenance of normal amygdala kindling. fyn is the first gene identified to be required for normal epileptogenesis.
Male Holtzman rats stimulated through a right medial septal electrode displayed prominent hippocampal afterdischarges and the progressive development of kindled seizures. Hippocampal synaptic plasma membranes of kindled rats showed a reduction of32P incorporation into a protein of approximately 50,000 daltons. This change was not present in controls that received twice as many stimulations as kindled rats with a timing that did not lead to kindling. In kindled rats, reduction of32P incorporation persisted at least 2 months without further stimulation.
Joubert syndrome (JBTS) is an autosomal recessive disorder characterized by cerebellum and brainstem malformations. Individuals with JBTS have abnormal breathing and eye movements, ataxia, hypotonia, and cognitive difficulty, and they display mirror movements. Mutations in the Abelson-helper integration site-1 gene (AHI1) cause JBTS in humans, suggesting that AHI1 is required for hindbrain development; however AHI1 may also be required for neuronal function. Support for this idea comes from studies demonstrating that the AHI1 locus is associated with schizophrenia. To gain further insight into the function of AHI1 in both the developing and mature central nervous system, we determined the spatial and temporal expression patterns of the gene products of AHI1 orthologs throughout development, in human, mouse, and zebrafish. Murine Ahi1 was distributed throughout the cytoplasm, dendrites, and axons of neurons, but was absent in glial cells. Ahi1 expression in the mouse brain was observed as early as embryonic day 10.5 and persisted into adulthood, with peak expression during the first postnatal week. Murine Ahi1 was observed in neurons of the hindbrain, midbrain, and ventral forebrain. Generally, the AHI1/Ahi1/ahi1 orthologs had a conserved distribution pattern in human, mouse, and zebrafish, but mouse Ahi1 was not present in the developing and mature cerebellum. Ahi1 was also observed consistently in the stigmoid body, a poorly characterized cytoplasmic organelle found in neurons. Overall, these results suggest roles for AHI1 in neurodevelopmental processes that underlie most of the neuroanatomical defects in JBTS, and perhaps in neuronal functions that contribute to schizophrenia.
The effects of cortically kindled seizure responses of procaine hydrochloride, diazepam and combinations of these two drugs were tested in this study. The cortex was stimulated until seizure responses developed past the focal stage (accompanied primarily by brief tonic convulsions) to the cortico-generalized stage (accompanied, typically, by an early brief tonus followed by a longer clonic seizure that is characteristic of subcortically triggered seizures). Diazepam was found to block the generalized component of the cortico-generalized electrographic and motor seizure leaving the tonus only slightly suppressed. Procaine blocked the tonus leaving the clonic seizure and discharge that is characteristic of the generalized response relatively intact. Combinations of half doses of the two drugs completely blocked all electrographic and motor seizure responses in about half the animals. The remaining animals had a very brief discharge with no convulsive responses.
Previous research has suggested that brain serotonin (5-hydroxytryptamine or 5-HT) neurons inhibit epileptiform seizure activity. To test further this possibility, experiments were performed to determine if brain 5-HT depletion would enhance the occurrence and/or magnitude of seizures "kindled" from the amygdala or neocortex of rats. Two modes of 5-HT depletion were used: (1) radiofrequency heat lesions of the midbrain dorsal and median raphe nuclei, and (2) systemic injection of the 5-HT synthesis inhibitor, p-chlorophenylalanine (pCPA). Both modes of 5-HT depletion reliably enhanced the strength of motor convulsions kindled from the cortex. Systemic pCPA also reduced the duration of after-discharges (ADs) in cortically-stimulated rats. However, pCPA reduced rather than enhanced convulsions kindled from the amygdala. In contrast to this, raphe lesions appeared to sensitize rats to the effects of amygdaloid kindling, i.e., lesions lowered AD thresholds, AD durations and number of ADs to elicit motor convulsions. Viewed together, these data support the hypothesis that 5-HT neurons can serve to inhibit seizures. However, the lack of robustness across parameters of epileptogenesis as well as discrepant findings related to 5-HT depletion mode additionally suggest that kindled seizures affect other neuronal populations in addition to those under serotonergic influence.
It is confirmed that administration of atropine sulfate retards the development of amygdala-kindled seizures in the rat; no significant strain differences were found.
Unilateral amygdala electrodes were implanted in male Sprague-Dawley rats stimulated once daily with a 200 μamp pulse of 500 millisecond duration to produce kindling. Forty-six percent (12 of 26) of the animals that eventually developed after-discharges demonstrated rhythmic oscillations in after-discharge duration. The presence or absence of generalized bilateral clonic seizures also showed rhythmic oscillations in close association with after-discharge duration. It is suggested that during kindling some animals, independent of electrode placement, develop rhythmic oscillations in excitability of the amygdala. This model may represent a means of experimentally eliciting or uncovering neuronal substrates which show regular alterations in excitability and may be relevant to the oscillations in mood and behavior observed in the affective disorders.
Anatomical structures demonstrating increased glucose uptake during the various stages of amygdaloid kindling in rats were identified by the 14C-2-deoxyglucose (DG) autoradiographic technique. Partial (stages 1 and 2) seizures were correlated with increased DG uptake in the ipsilateral amygdala and its direct projection fields. The appearance of generalized motor (stages 3,4, and 5) seizures was accompanied by less limbic involvement and recruitment of a bilateral system including substantia nigra, specific and nonspecific thalamic nuclei, globus pallidus, and neocortex. Increased hippocampal DG uptake was correlated with prolonged amygdaloid after discharge duration but not with the behavioral seizure stage. This study does not reveal which of these structures are responsible for the observed behavioral and electrical events and which are activated by them. It does suggest, however, that three discrete anatomical systems underlie the generation of partial seizures, generalized motor seizures, and local after discharge.
The pharmacological properties of synaptic responses in rat basolateral amygdaloid (BLA) neurons were studied using intracellular recording techniques. Three distinct types of synaptic potential were evoked by stimulation of the adjacent ventral endopyriform nucleus: 1) a fast excitatory postsynaptic potential (f-EPSP); 2) a late EPSP (1-EPSP) following the f-EPSP; and 3) a multiphasic hyperpolarization following the initial depolarizing potential. Superfusion of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a selective non-N-methyl-D-aspartate (non-NMDA) receptor antagonist, blocked the f-EPSP in a concentration-dependent manner. The ED50 for this effect was around 4 microM. In the presence of CNQX, however, a small depolarizing potential remained. This residual depolarizing component was markedly enhanced on removing Mg++ from the perfusing medium and could subsequently be abolished by DL-2-amino-5-phosphonovaleate (DL-APV, 50 microM) indicating its mediation via NMDA receptor-coupled ionophore. The l-EPSP was reversibly blocked by DL-APV. These results suggest that the pyriform cortex-amygdala pathway is mediated through excitatory amino acids acting on non-NMDA as well as NMDA receptors located on the BLA neurons.
Intraperitoneally (i.p.) administered L-aspartate (Asp) (20 mmol/kg) produced no behavioral or EEG change in nonkindled rats. Nonkindled rats that received 18, 19, or 20 mmol/kg Asp, dissolved in 10 or 15% dimethylsulfoxide (DMSO), i.p. developed masticatory movement, head nodding, and myoclonic jerks of the limbs, followed by wild running and subsequent tonic extension of the whole body. In contrast to the effects in nonkindled rats, i.p. injection of Asp 20 mmol/kg in 15% DMSO in amygdala-kindled rats precipitated electroclinical generalized seizures identical to kindled ones. When the kindled amygdala was pretreated with 2-amino-7-phosphonoheptanoic acid (2-APH), a potent and specific antagonist of N-methYl-D-aspartate (NMDA) receptors, the Asp/DMSO-induced generalized convulsion identical to kindled amygdala seizure was suppressed. 2-APH treatment of the contralateral amygdala was without such suppression. The results suggest that (a) Asp is ineffective when given alone (when given with DMSO, however, Asp evokes generalized seizures identical to kindled ones in amygdala-kindled rats, while it induces a qualitatively different generalized seizure in nonkindled rats; (b) NMDA receptors of the kindled amygdala play an important role in activation of the transsynaptic neurocircuit underlying the expression of kindled amygdala seizure; and (c) DMSO is useful in assessing potential central effects of compounds that do not readily penetrate the blood-brain barrier (BBB).
Kindling is a permanent form of brain change that results from repeated elicitation of epileptiform neural activity. c-fos has been proposed as the gene responsible for turning on molecular events that might underlie the long-term neural changes that occur during kindling. This study investigated the enhancement of c-fos levels following kindled seizures and the role of c-fos in the plastic changes underlying kindling. Male hooded rats were electrically kindled in the amygdala and the resulting c-fos and c-Ha-ras gene expression was quantified using Northern blot hybridization analysis. The results indicated that c-fos was constitutively expressed in forebrain and cerebellum, and that basal levels of c-fos were equivalent in naive and in fully kindled rats that have been seizure-free for 3 weeks. Following an amygdala-piriform kindled seizure there was a massive and transient increase in c-fos levels throughout forebrain and cerebellum. Although enhanced c-fos levels were correlated with afterdischarge (AD) duration in the kindled site, enhanced c-fos levels were also observed in the amygdala-piriform contralateral to the kindled site, and the enhancement did not depend on the occurrence of AD in the contralateral amygdala-piriform. Furthermore, electrical stimulations not resulting in AD as well as other forms of control stimulation also increased c-fos levels. We conclude that c-fos was expressed simply as a consequence of neural activity and not exclusively due to the specific neural activity or underlying plastic change required for kindling. This does not preclude a role for c-fos in the long-term response to external stimuli, but it does suggest that c-fos is not the crucial 'master switch' in turning on a molecular program that might underlie kindling.
In order to test the GABA hypothesis of kindling, GABA-complex antagonists were administered in a dose-response paradigm to rats that had been implanted with indwelling forebrain electrodes, but not kindled. Focal seizures were then elicited from either the cortex or the amygdala to see whether kindling-like secondary generalization would occur. Norharmane, a benzodiazepine inverse agonist, failed to promote secondary generalization from either the cortex or the amygdala. Bicuculline, a GABAA receptor antagonist, and picrotoxin, a chloride ionophore antagonist, enhanced generalization from both sites and, in amygdala-implanted subjects, appeared to produce a significant acceleration of kindling as well. Aminophylline, an adenosine antagonist tested for purposes of comparison, also enhanced secondary generalization from both sites, and in amygdala-implanted subjects produced long electrographic discharges which sometimes developed into status epilepticus.
Written primarily for students and research workers in the area of the behavioral sciences, this book is meant to provide a text and comprehensive reference source on statistical principles underlying experimental design. Particular emphasis is given to those designs that are likely to prove useful in research in the behavioral sciences. The book primarily emphasizes the logical basis of principles underlying designs for experiments rather than mathematical derivations associated with relevant sampling distributions. The topics selected for inclusion are those covered in courses taught by the author during the past several years. Students in these courses have widely varying backgrounds in mathematics and come primarily from the fields of psychology, education, economics, sociology, and industrial engineering. It has been the intention of the author to keep the book at a readability level appropriate for students having a mathematical background equivalent to freshman college algebra. From experience with those sections of the book which have been used as text material in dittoed form, there is evidence to indicate that, in large measure, the desired readability level has been attained. Admittedly, however, there are some sections in the book where this readability goal has not been achieved. The first course in design, as taught by the author, has as a prerequisite a basic course in statistical inference. The contents of Chaps. 1 and 2 review the highlights of what is included in the prerequisite material. These chapters are not meant to provide the reader with a first exposure to these topics. They are intended to provide a review of terminology and notation for the concepts which are more fully developed in later chapters. By no means is all the material included in the book covered in a one semester course. In a course of this length, the author has included Chaps. 3, 4, parts of 5, 6, parts of 7, parts of 10, and parts of 11. Chapters 8 through 11 were written to be somewhat independent of each other. Hence one may read, with understanding, in these chapters without undue reference to material in the others. In general, the discussion of principles, interpretations of illustrative examples, and computational procedures are included in successive sections within the same chapter. However, to facilitate the use of the book as a reference source, this procedure is not followed in Chaps. 5 and 6. Basic principles associated with a large class of designs for factorial experiments are discussed in Chap. 5. Detailed illustrative examples of these designs are presented in Chap. 6. For teaching purposes, the author includes relevant material from Chap. 6 with the corresponding material in Chap. 5. Selected topics from Chaps. 7 through 11 have formed the basis for a second course in experimental design. Relatively complete tables for sampling distributions of statistics used in the analysis of experimental designs are included in the Appendix. Ample references to source materials having mathematical proofs for the principles stated in the text are provided. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
This book brings to date the reports and conclusions from the Montreal Neurological Institute's clinical, physiological, and neuro-surgical studies of epilepsy, and is, in a sense, a sequal to "Epilepsy and cerebral localization," published in 1941. There is extensive addition of new material on subcortical mechanisms, functional cortical localization, surgical and medical treatment and electroencephalography. The book is illustrated with 8 color plates and 314 black and white illustrations. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
1. 1. A comparative study of the projections of the dorsal and ventral hippocampus in the cat was made by evoked potentials and by spread of hippocampal after-discharges. 2. 2. Evoked potentials with short latency (less than 5 msec) were found in many subcortical centers, and over a large cortical area. The distribution of the responses to dorsal and ventral hippocampal shocks, and their latencies, showed marked differences. 3. 3. A great number of subcortical structures was activated by hippocampal after-discharge, and specific patterns of spread to the cortex and subcortex from the ventral and dorsal regions were noted (Fig. 4 and 5). Dorsal after-discharges spread mainly to the dorsal thalamus and to the posterior suprasylvian gyrus; ventral after-discharges to autonomic centers and to the temporal cortex. 4. 4. Previous evidence for connections of the dorsal and ventral regions of the hippocampus is reviewed, and some physiological and functional corollaries considered.
In unanesthetized cats, with permanent intracerebral electrodes, as many as 100 repeated hippocampal after-discharges (HAD's) were evoked during a period of 15–30 days. In addition, four cats were trained in conditioned avoidance, and the tests were repeated during HAD's. In other cats, after several HAD's had been evoked, ablations were made of the motor areas, fornix and amygdala, and then the HAD's were studied. Results were as follows: 1.1. Repetition of HAD's did not modify local thresholds, but considerably increased the behavioral disturbances according to a pattern which was repeated in different animals.2.2. Conditioned avoidance response was very little impaired during the first 10 sec of the evoked HAD, but was considerably disturbed at the height of the HAD. Repetition of the HAD's decreased the responses even during the first 10 sec of each HAD, with responses dropping to zero at the height of the HAD. Controls, however, showed that repetition of the HAD's did not produce lasting deficits in avoidance performance. Hippocampal stimulations which were not followed by HAD's did not modify the conditioned responses.3.3. During HAD's, thresholds and effects evoked by stimulation of the reticular mesencephalic substance were not modified. Hypothalamic thresholds were also kept constant. The septum excitability increased with a drop in threshold to about half of the control values, without modification of the pattern of response.4.4. Ablation of the motor areas had no effect on the electrical or clinical pattern of the HAD. Bilateral destruction of the fornix did not modify the clinical symptomatology, but affected the electrical pattern of the HAD's. After unilateral destruction of the amygdala, the ipsilateral facial motor manifestation which accompanied the HAD's disappeared, and did not return even during the generalized seizure produced after many repeated HAD's.5.5. Repetition of the seizures increased the duration of the HAD's two to five times, producing also an increase in the duration of “clonic” activity and short, irregular spikes. In general, however, the configuration of each pattern was not modified.6.6. A clear correlation was established between motor participation of the face and 4–6 c/sec activity of the amygdala. Other possible clinical EEG correlations are discussed in this paper.7.7. Two different classes of spread from the hippocampus to the amygdala are considered: (a) propagated: in which the pattern of the amygdala after-discharge corresponds to and seems to depend on the pattern of the hippocampal seizure; (b) reactive: in which the amygdala showed 4–6 c/sec waves, which were independent of, but triggered by HAD's.The propagated spread was asymptomatic while the reactive spread was associated with ipsilateral motor manifestations of the face. Similar examples have previously been recorded in other parts of the limbic system of the monkey, and the distinction between the two kinds of spread may have functional and perhaps diagnostic implications.
Daily electrical stimulations of the amygdala and hippocampus at intensities sufficient to evoke after-discharges (ADs) resulted in the development of motor seizures, which could not initially be evoked by these stimulations. The triggering of ADs was critical for this development, as well as for the development of permanent changes in the characteristics of the AD. The wave form of the AD "spikes" became more complex. The frequency of these spikes and the duration of AD increased. The amplitude of the AD spikes increased in the structure stimulated as well as in secondary structures to which the AD was "projected". This increase in amplitude of "projected" spikes often correlated with the appearance of motor seizures. Other electrographic developments are discussed including the appearance of spontaneous "inter-ictal" spiking in the amygdala. It was found that the development of motor seizures by stimulation of the amygdala resulted in an increased ability of the contralateral amygdala, and the septal area, but not of the hippocampus, to drive motor seizures when stimulated ("transfer"). Motor seizure development in the hippocampus transferred to the contralateral hippocampus. These developments were shown, by means of control subjects, with lesions in the primary focus to involve changes outside the primary focus. The implications of these developments with respect to seizure development are discussed.
Rats with multiple recording and stimulating electrodes were stimulated electrically in the amygdala, hippocampus and reticular formation. Intensity of stimulation was varied in a systematic way to determine the threshold at which after-discharges (ADs) were produced in the vicinity of the stimulating electrode. AD thresholds were permanently reduced by 40–60% in the amygdala and 25% in the hippocampus by daily 1 sec bursts of stimulation. The reduction took place with subthreshold as well as suprathreshold stimulation, but not in the absence of stimulation.It was found that the reduction of AD thresholds in the amygdala had no effect on AD thresholds in the contralateral amygdala, septal area or hippocampus. Reduction of AD thresholds in the hippocampus, however, resulted in an increase in the AD threshold in the contralateral hippocampus.RésuméDes rats porteurs d'électrodes de stimulation et d'enregistrement multiples ont subi une stimulation électrique de l'amygdale, de l'hippocampe et de la formation réticulaire. L'intensité de la stimulation varie de façon systématique afin de déterminer le seuil auquel les post-décharges sont produites dans le voisinage de l'électrode de stimulation. Les seuils de post-décharge sont en permanence abaissés de 40 à 60% dans l'amygdale et de 25% dans l'hippocampe par des bouffées quotidiennes de stimulation durant une seconde. Cet abaissement survient aussi bien pour des stimulations sous-liminaires que sus-liminaires, mais non en l'absence de stimulation.L'auteur observe que la réduction des seuils de post-décharges dans l'amygdale n'a aucum effet sur les seuils de post-décharge dans l'amygdale controlatérale, la région septale ou l'hippocampe. L'abaissement des seuils de post-décharges dans l'hippocampe, par contre, provoque une augmentation du seuil de post-décharge dans l'hippocampe controlatéral.
This report presents studies which relate limbic epileptic excitability to behavioral measures of defensive suppression of predatory attack in cats. Correlated with heightened defensiveness to environmental stimuli among non-killer cats is a heightened amygdaloid epileptic excitability, as well as a heightened conduction of amygdaloid epileptic activity to thalamic and hypothalamic substrates of predatory response in the amygdala to the complex visual stimuli presented by rat prey. These neurosensory responses correlate well with measures of epileptic excitability. Brain and behavior measures appear related since enhancement of excitability in the amygdala and of projection of epileptic activity by repeated electrical stimulation of predatory attacks. Furthermore, the ventral hippocampus seems capable of antagonizing the behaviorally suppressive effects of heightened amygdaloid excitability perhaps at points of convergence of amygdaloid and hippocampal output.
Rats were subjected to varying degrees of commissurotomy, followed by implantation of a bipolar electrode into each amygdala. After the kindling of six convulsions at one electrode (primary site), the procedure was applied to the contralateral amygdala (secondary site). Convulsions were observed to develop more rapidly, independent of the degree or kind of transection. After 6 secondary site convulsions, the primary site was re-tested and convulsion-triggering was blocked, except in animals with transection of the rostral portion of the corpus callosum (CC).
Collectively, the data indicate: (i) amygdala kindling develops a lasting trace which operates through the midbrain or brainstem; (ii) kindling from a second site utilizes this trace; (iii) a series of 6 convulsions produces negative after-effect which manifests itself at the convulsion level via the anterior CC; (iv) the anterior CC is important in determining the laterality of the forelimb clonus; and (v) the inter-amygdala propagation of after-discharge is blocked by the combined sectioning of the anterior CC and the anterior commissure.
Several different patterns of electrical stimulation were applied to the amygdala of the rat for 10 min in order to determine: (1) if first trial generalized convulsions could be triggered; and (2) which parameters were most effective for triggering first trial convulsions. It was found that motor seizures could be triggered and that low frequencies (16-24 p/sec) were most effective, whether presented in the form of continuous pulses or pulse trains. The pattern of stimulation did not appear to affect the amount of seizure susceptibility subsequently shown by these subjects. They were, however, more susceptible to seizures than a previously nonstimulated group as shown by their faster rate of seizure development during repeated stimulation (kindling). It was also shown that the range of stimulation frequencies that were found to be most effective for triggering first trial seizures was similar to the range of frequencies which produced "recruiting" in the hippocampus during amygdala stimulation. Possible mechanisms were discussed.
Three rat strains were tested at 4 inter-stimulation intervals for the development of motor seizures by repeated amygdaloid stimulation. Wistar rats required a significantly greater number of stimulations to develop motor seizures than did Sprague-Dawley or RVH-hooded rats. There were no significant differences between 24 h, 2 h, or 1 h inter-stimulation intervals with respect to number of stimulations required to develop seizures. There was, however, a significant increase in the number of stimulations required when the inter-stimulation interval was 0.5 h.
Bipolar electrodes were implanted into the amygdala of each hemisphere of adult male rats. A short burst of low-intensity stimulation was applied to one of these electrodes once each day. Initially there was little response. With repetition, epileptiform responses progressively developed until each daily stimulus triggered a behavioral convulsion (kindling effect). Following six convulsions, the procedure was applied to the contralateral hemisphere. Convulsions were observed to kindle more rapidly, especially if a rest interval of 2 weeks followed the last primary site convulsion. When stimulation was reapplied to the primary site, convulsions were not triggered. This was associated with failure to evoke local after-discharge and/or failure of the after-discharge to propagate. Several trials were necessary to re-establish convulsion, unless a 2 week rest preceded testing, in which case convulsions were triggered on the first trial. Following a series of convulsions triggered from either hemisphere, the contralaterally triggered convulsions, when they appeared, showed consistently longer onset lattencies. These latency shifts were attentuated when rest intervals preceded the testing. Latency shifts and seizures failures were not observed if the preceeding series of convulsions was reduced from six to one. Lesions at the tip of either electrode had little effect on the results obtained in the contralateral hemisphere. Together, the results imply that: kindling establishes a lasting trace which is both transynaptic and widespread, kindling from a second location establishes a second trace utilizing parts of the existing trace, a series of convulsions leaves a less durable after-effect with a decay time of about 2 weeks and which interferes with various aspects of seizure activity, and the trace which activates the convulsions is less susceptible to interference from the after-effect.
Brief bursts of nonpolarizing electrical brain stimulation were presented once each day at constant intensity. At first the stimulation had little effect on behavior and did not cause electrographic afterdischarge. With repetition the response to stimulation progressively changed to include localized seizure discharge, behavioral automatisms and, eventually, bilateral clonic convulsions. Thereafter, the animal responded to each daily burst of stimulation with a complete convulsion. The effect was obtained from bipolar stimulation of loci associated with the limbic system, but not from stimulation of many other regions of the brain. Parametric studies and control observations revealed that the effect was due to electrical activation and not to tissue damage, poison, edema, or gliosis. The changes in brain function were shown to be both permanent and trans-synaptic in nature. Massed-trial stimulation, with short inter-burst intervals, rarely led to convulsions. The number of stimulation trials necessary to elicit the first convulsion decreased as the interval between trials approached 24 hours. Further increase in the inter-trial interval had little effect on the number of trials to first convulsion. High-intensity stimulation studies revealed that the development of convulsions was not based simply on threshold reduction, but involved complex reorganization of function. Experiments with two electrodes in separate parts of the limbic system revealed that previously established convulsions could facilitate the establishment of a second convulsive focus, but that the establishment of this second convulsive focus partially suppressed the otherwise permanent convulsive properties of the original focus.
Generalized convulsive seizure state induced by daily electrical stimulation of the amygdala in split-brain cats. Delivered at Annual Convention of Am
- J A Wada
- M Sato
WADA, J. A. and SATO, M. Generalized
convulsive seizure state induced by daily
electrical stimulation of the amygdala in
split-brain cats. Delivered at Annual Convention of Am. EEG Assn., June 15, 1973
(Boston, Mass.).
A stereotaxic atlas of the rat brain
- L Pellegrino
- A Cushman
PELLEGRINO, L. and CUSHMAN, A.
(1967). A stereotaxic atlas of the rat brain.
New York: Appleton-Century-Crofts.