Literature Review

The Relevance of Kindling for Human Epilepsy

Article· Literature ReviewinEpilepsia 48 Suppl 2(s2):65-74 · February 2007with 335 Reads
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Abstract
Kindling is one of the most widely used models of seizures and epilepsy, and it has been used in its more than three decade history to provide many key insights into seizures and epilepsy. It remains a mainstay of epilepsy related research, but the question remains how the results from kindling experiments further our understanding of the underlying neurobiology of human epilepsy. In this article we compare the basic features of kindling and human epilepsy, especially human limbic or temporal lobe epilepsy. In this review we focus on a limited number of topics that may show areas in which kindling has been often cited as a tool for better understanding of human epilepsy. These areas include the underlying circuits, the importance of seizure spontaneity, the associated neuropathology, the contribution of genetics, seizure susceptibility, and the underlying pathophysiology of epilepsy. In the course of this article we will show that there are many features that kindling can teach us by direct comparison or implication about human temporal epilepsy. We will also see that not all findings associated with kindling may be applicable to the human condition. Ultimately we wish to encourage critical thinking about kindling and the similarities that it shares and does not share with the human epilepsy so the results from studies using this model are applied rationally to further our insights the mechanisms of human epilepsy.

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  • Article
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  • Article
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    The synchronization among the activities of neural populations in functional regions is one of the most important electrophysiological phenomena in epileptic brains. The spatiotemporal dynamics of phase synchronization was investigated to reveal the reciprocal interaction between different functional regions during epileptogenesis. Local field potentials (LFPs) were recorded simultaneously from the basolateral amygdala (BLA), the cornu ammonis 1 of hippocampus (CA1) and the mediodorsal nucleus of thalamus (MDT) in the mouse amygdala-kindling models during the development of epileptic seizures. The synchronization of LFPs was quantified between BLA, CA1 and MDT using phase-locking value (PLV). During amygdala kindling, behavioral changes (from stage 0 to stage 5) of mice were accompanied by after-discharges (ADs) of similar waveforms appearing almost simultaneously in CA1, MDT, as well as BLA. AD durations were positively related to the intensity of seizures. During seizures at stages 1~2, PLVs remained relatively low and increased dramatically shortly after the termination of the seizures; by contrast, for stages 3~5, PLVs remained a relatively low level during the initial period but increased dramatically before the seizure termination. And in the theta band, the degree of PLV enhancement was positively associated with seizure intensity. The results suggested that during epileptogenesis, the functional regions were kept desynchronized rather than hyper-synchronized during either the initial or the entire period of the seizures; so different dynamic patterns of phase synchronization may be involved in different periods of the epileptogenesis, and this might also reflect that during seizures at different stages, the mechanisms underlying the dynamics of phase synchronization were different.
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    We describe a patient with new onset temporal lobe epilepsy during prolonged maintenance electroconvulsive therapy. We suggest a possible causal relationship with maintenance electroconvulsive therapy through electrical kindling of the temporal lobe. This article is protected by copyright. All rights reserved.
  • Chapter
    Imaging Biomarkers in Epilepsy - edited by Andrea Bernasconi January 2019
  • Article
    Maintenance electroconvulsive therapy (ECT) is sometimes prescribed for refractory psychiatric conditions. We describe five patients who received maintenance ECT and developed florid temporal epileptiform abnormalities on electroencephalography (EEG) despite no history of epilepsy and normal neuroimaging. All patients had received regular ECT for at least 8 months. Three patients had clinical events consistent with epileptic seizures, and video-EEG monitoring captured electrographic seizures in two patients. After cessation of ECT the EEGs normalized in all patients, and no further clinical seizures occurred. Maintenance ECT may predispose to epilepsy with a seizure focus in the temporal lobe.
  • Chapter
    In this paper, we proposed a computational model of the limbic system in order to capture the spatio-temporal dynamics of abnormal/normal brain states. Power spectral density measurements of the abnormal seizure states are captured in order to differentiate from normal brain states. Electrical titration therapy is proposed through this model to demonstrate how the model can be utilized as an EEG simulator that demonstrates how external stimulation restores the model back to its normal chaotic operating state.
  • Chapter
    Animal models can afford useful insights into the mechanisms of neurobehavioral comorbidities of epilepsy. However, clinical relevance and value of the information that can be extracted from animal studies depend on many factors, including choice of proper models of epilepsy, choice of proper behavioral tasks, and accounting for the presence of multiple concurrent neurobehavioral disorders in the same epileptic animal. This chapter offers an overview of approaches used to examine selected neurobehavioral comorbidities in animal models of epilepsy. Assays used to study spatial and object memory, depression, anxiety, attention deficit/hyperactivity disorder, psychosis, and autism are described. First, the approaches are presented from a standpoint of single comorbidity, and mechanisms underlying respective epilepsy-associated neurobehavioral abnormalities are discussed. Further, examples are given as to how concurrent neurobehavioral perturbations may influence one another, and therefore how this may affect outcome measures and interpretation of the obtained data. It is suggested that systemic approach, rather than more commonly used isolated approach, offers more clinical-relevant and complete description of multifactorial systems that underlie neurobehavioral comorbidities of epilepsy.
  • Article
    Objective: Harmaline and other beta-carbolines act as an inverse agonist for GABA-A receptors and cause central nervous system stimulation and anxiety; thus, it may act hypothetically as a potential seizure augmenter. To examine the hypothesis, the effect of harmaline during the seizures induced by amygdala kindling is investigated here. Methods: Seven groups of male rats were kindled by daily electrical stimulation of the amygdala. After being kindled, Groups I–III, respectively, received 5, 15 and 50 mg/kg harmaline through intraperitoneal injection. The rats in Groups IV and V received vehicle daily (1 ml/kg) and harmaline (5 mg/kg) daily through intraperitoneal injection. Groups VI and VII received artificial cerebrospinal fluid and harmaline (50 mM) through intraventricular injection, respectively. Results: In addition to significant increase of some seizure parameters in the fully kindled groups, harmaline significantly increased cumulative afterdischarge duration (P < 0.05) and decreased stage 1 latency (P < 0.01) in the acquisition groups (Groups V and VII). In Group VII, seizure duration showed a significant increase (P < 0.01) while stage 1 latency and stage 4 latency decreased significantly (P < 0.01). Discussion: According to the results, it is suggested that harmaline may increase neuronal activity and the production of high-frequency action potentials by stimulating NMDA receptors and inhibiting GABA receptors. Overall, drugs and plants containing harmaline may be harmful to epileptic-susceptible people during some traditionally and costume treatments, so these should be avoided.
  • Article
    Temporal lobe epilepsy (TLE), the most common pharmacoresistant focal epilepsy disorder, remains a major unmet medical need. Propofol is used as short-acting medication for general anesthesia and refractory status epilepticus with issues of decreased consciousness and memory loss. Dipropofol, a derivative of propofol, has been reported to exert antioxidative and antibacterial activities. Here we report that dipropofol exerted anticonvulsant activity in mouse model of kainic acid-induced seizures. Whole-cell patch clamp recordings of brain slices from the medial entorhinal cortex (mEC) revealed that dipropofol hyperpolarized the resting membrane potential and reduced the number of action potential firings, resulting in suppression of cortical neuronal excitability. Furthermore, dipropofol activated native tonic GABAA currents of mEC layer II stellate neurons in dose-dependent manner with EC50 value of 9.3 {plus minus} 1.6 μM. Taken together, our findings showed that dipropofol activated GABAA currents and exerted anticonvulsant activities in mice, thus possessing developmental potential for new anticonvulsant therapy.
  • Article
    Cambridge Core - Medical Imaging - Imaging Biomarkers in Epilepsy - edited by Andrea Bernasconi
  • Article
    Full-text available
    Kindling is a phenomenon whereby repeated subthreshold stimulations for inducing a particular initial behavior, eventually produce that behavior and with further stimulations additional behaviors are observed.¹ It is a model of learning, memory and epileptogenesis/epilepsy; the latter is because the measured behavior is most often a seizure that becomes progressively more severe. This article is protected by copyright. All rights reserved.
  • Chapter
    Full-text available
    Some women with epilepsy find a link between the premenstrual phase of their menstrual cycle and their tendency to have seizures. The present study is hence, an attempt to determine the alterations influencing the premenstrual exacerbation of seizures documented previously. The epileptic patients (n: 433), all women were categorized into two main groups: Group-I (with single seizure frequency pattern) and Group-II (with multiple seizure frequency pattern). Each group comprised catamenial (menstruation related) epileptics, non-catamenial (non-menstrual) epileptics and normal controls. Epileptic women with seizures related/unrelated to a menstruation related cycle phase were suggested to be further classified into three sub-types according to seizure severity/dispersion pattern as: Semi-Catamenial (Semi-menstrual), catamenial (menstrual) and non-catamenial (non-menstrual) epileptics. All patient groups showed significant decrease in plasma calcium. It thus seemed a common etiological factor in seizure disorders. Catamenial epileptic groups demonstrated significant rise in the premenstrual plasma levels of estradiol-17B, prolactin, cortisol, sodium, basal body temperature and fall in plasma calcium, all with concomitant significant exacerbation of seizures. Furthermore, plasma progesterone varied significantly only in catamenial epileptic patients with single seizure frequency pattern; whereas plasma LH was found to be altered in only catamenial epileptic patients with multiple seizure frequency pattern. The present study, thus suggests that the etiological role of both the disturbance in water metabolism and endocrine changes co-exists, in presently studied catamenial epileptic women. Probably these changes are either secondary to seizure exacerbations or some of them are altered, in turn changing the concentrations of other constituents and seizure activity and vice versa, the interpretation of which needs comprehensive studies to be conducted with integrative clinico-experimental approach. This book has been written primarily for clinical research workers and medical community. KEY WORDS: Menstruation, seizures, epilepsy patients, catamenial epilepsy, non-catamenial epilepsy, electrolytes, hormones, menstrual cycle, premenstrual epilepsy, estrogen, progesterone.
  • Chapter
    Full-text available
    INTRODUCTION ( Chapter 1) In : Menstrual Cycle and Epilepsy: premenstrual Reproductive Study (2010). P: 16-20. Germany (Printed in USA & UK).
  • Article
    Full-text available
    Aim: To evaluate the efficacy of non-invasive multichannel electrical stimulation (sympathetic correction) in patients with alcohol amnesic (Korsakoff's) psychosis. Material and methods: Thirty-seven men, aged 33-48 years, with Korsakoff's (amnestic) psychosis were studied. The duration of disease varied from 12 to 24 month. The device of electrical stimulation of neck nerve structures was used for neuroelectrostimulation. Treatment included 15 sessions within 3 weeks. During this period, patients did not receive pharmacological therapy. The Frontal Assessment Battery (FAB), the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) were used to determine changes in cognitive state of patients. Electroencephalography with qEEG analysis and spectral analysis of heart rate variability (HRV) were carried out as well. Results and conclusion: Positive effects of treatment were observed in all patients that suggested the high therapeutic potential of the neuroelectrostimulation method.
  • Article
    Full-text available
    Objective . Studies are ongoing to find appropriate low frequency stimulation (LFS) protocol for treatment of epilepsy. The present study aimed at assessing the antiepileptogenesis effects of LFS with the same protocol applied either just before or immediately after kindling stimulations. Method . This experimental animal study was conducted on adult Wistar rats (200 ± 20 g) randomly divided into kindle ( n=7 ), LFS + Kindle ( n=6 ), and Kindle + LFS groups ( n=6 ). All animals underwent rapid kindling procedure and four packages of LFS (1 Hz) with 5 min interval were applied either immediately before (LFS-K) or after kindling stimulation (K-LFS). The after discharge duration (ADD), daily stages of kindling, and kindling seizure stage and number of stimulations required to reach each stage were compared between the three groups using two-way analysis of variance (ANOVA) followed by Tukey post hoc and one-way ANOVA, and Kruskal-Wallis test, respectively. Results . LFS in both protocols significantly decreased the ADD ( p<0.05 ) and daily seizure stages ( p<0.05 ) and increased the number of stimulations required to achieve stage 3 and stages 4 and 5 of kindling compared with the kindle group (stage 2: p>0.05 , stages 3 to 5: p<0.05 ). Conclusion . Although LFS-K showed more inhibiting effect than K-LFS, the difference was not statistically significant.
  • Article
    Full-text available
    Simulations of EEG data provide the understanding of how the limbic system exhibits normal and abnormal states of the electrical activity of the brain. While brain activity exhibits a type of homeostasis of excitatory and inhibitory mesoscopic neuron behavior, abnormal neural firings found in the seizure state exhibits brain instability due to runaway oscillatory entrained neural behavior. We utilize a model of mesoscopic brain activity, the KIV model, where each network represents the areas of the limbic system, i.e., hippocampus, sensory cortex, and the amygdala. Our model initially demonstrates oscillatory entrained neural behavior as the epileptogenesis, and then by increasing the external weights that join the three networks that represent the areas of the limbic system, seizure activity entrains the entire system. By introducing an external signal into the model, simulating external electrical titration therapy, the modeled seizure behavior can be ‘rebalanced’ back to its normal state.
  • Article
    Full-text available
    The most common forms of acquired epilepsies arise following acute brain insults such as traumatic brain injury, stroke, or central nervous system infections. Treatment is effective for only 60%-70% of patients and remains symptomatic despite decades of effort to develop epilepsy prevention therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely inflammation, neuron loss, plasticity, and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to the development of successful epilepsy prevention or disease modification strategies. Risk factors for developing epilepsy that appear common to multiple acute injury etiologies include intracranial bleeding, disruption of the blood-brain barrier, more severe injury, and early seizures within 1 week of injury. In diverse human epilepsies and animal models, seizures appear to propagate within a limbic or thalamocortical/corticocortical network. Common histopathologic features of epilepsy of diverse and mostly focal origin are microglial activation and astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K⁺ conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from temporal lobe epilepsy patients. There is increasing evidence that epilepsy can be prevented or aborted in preclinical animal models of acquired epilepsy by interfering with processes that appear common to multiple acute injury etiologies, for example, in post–status epilepticus models of focal epilepsy by transient treatment with a trkB/PLCγ1 inhibitor, isoflurane, or HMGB1 antibodies and by topical administration of adenosine, in the cortical fluid percussion injury model by focal cooling, and in the albumin posttraumatic epilepsy model by losartan. Preclinical studies further highlight the roles of mTOR1 pathways, JAK-STAT3, IL-1R/TLR4 signaling, and other inflammatory pathways in the genesis or modulation of epilepsy after brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention therapy. Going forward, the identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.
  • Article
    Anxiety is one of the most common comorbidities of epilepsy, which has major detrimental effects on the quality of life. Generalized anxiety disorder (GAD) associated with epilepsy has been receiving most attention. However, several other forms of anxiety reportedly present in patients with epilepsy, including panic disorder (PD). In this study, using an animal model of limbic epilepsy, we examined the interplay between epilepsy and panic-like behavior (PLB). Further, considering the high degree of comorbidity between depression on the one hand, and both epilepsy and PD on the other hand, we studied whether and how the presence of PLB in animals with epilepsy would affect their performance in depression-relevant tests. Fifty-day-old male Wistar rats were subjected to repeated alternating electrical stimulations of the basolateral amygdala (BLA) to induce kindling of limbic seizures, and the dorsal periaqueductal gray (DPAG) to induce panic-like episodes. Seizure susceptibility and panic reaction threshold were examined before the first and 24h after the last stimulation. At the end of the stimulations, the rats were examined in depression-relevant tests: saccharin preference test (SPT) for anhedonia and forced swimming test (FST) for despair/hopelessness. With regard to kindling, BLA+DPAG stimulation induced more profound increase of seizure susceptibility than BLA stimulation alone (evident as the reduction of the afterdischarge threshold and the increase of the afterdischarge duration). With regard to PLB, the BLA+DPAG stimulation exacerbated the severity of panic-like episodes, as compared with the DPAG stimulation alone. Basolateral amygdala stimulation alone had no effects on panic-like reactions, and DPAG stimulation alone did not modify kindling epileptogenesis. Combined stimulation of BLA and DPAG induced depressive-like behavioral impairments. This is the first experimental study showing bidirectional, mutually exacerbating effect of epilepsy and PLB, and the precipitation of depressive-like state by the epilepsy-PLB comorbidity.
  • Chapter
    Of all treatment modalities available, medical management using drugs will be the most common and effective approach. Proper management improves the pet's quality of life (cats, dogs) and the owner's quality of life, helps to reduce the chances of seizure progression, helps to prevent sudden death or debilitation secondary to epileptic seizures, and gives the clinician time to elucidate the underlying etiology of the epileptic seizures. Chronic, maintenance, or prophylactic therapy forms the foundation for successful antiseizure management. When considering dosing of an antiseizure medication, the goal is to use as little medication as possible but as much as necessary. Formulating an effective treatment strategy is as important as identification of the underlying cause of seizures and choosing the right antiseizure medication. The treatment strategies can be defined by Prophylactic treatment, Bridge therapy, and Pulse therapy.
  • Chapter
    Kindling was first recognized in 1968 by Graham Goddard during experiments investigating whether learning in rats was disrupted by repeated hippocampal electrical stimulation. Goddard observed that repeated electrical stimulation of a variety of brain pathways unexpectedly evoked gradually evolving seizures and permanent progressive increases in seizure susceptibility that he described as “kindling,” and recognized as potentially significant for epilepsy.
  • Article
    Full-text available
    The random nature of seizures poses difficult challenges for epilepsy research. There is great need for a reliable method to control the pathway to seizure onset, which would allow investigation of the mechanisms of ictogenesis and optimization of treatments. Our hypothesis is that increased random afferent synaptic activity (i.e. synaptic noise) within the epileptic focus is one endogenous method of ictogenesis. Building upon previous theoretical and in vitro work showing that synaptic noise can induce seizures, we developed a novel in vivo model of ictogenesis. By increasing the excitability of afferent connections to the hippocampus, we control the risk of temporal lobe seizures during a specific time period. The afferent synaptic activity in the hippocampus was modulated by focal microinjections of potassium chloride into the nucleus reuniens, during which the risk of seizure occurrence increased substantially. The induced seizures were qualitatively and quantitatively indistinguishable from spontaneous ones. This model thus allows direct control of the temporal lobe seizure threshold via endogenous pathways, providing a novel tool in which to investigate the mechanisms and biomarkers of ictogenesis, test for seizure threshold, and rapidly tune antiseizure treatments.
  • Chapter
    This chapter reviews the remarkable genetic overlap emerging between human migraine with aura and various monogenic ion channel epilepsies. It also describes new insights into mechanisms linking spreading depolarization (SD) in the brainstem to a novel “aura” comorbidity phenotype, sudden unexpected death, the most common cause of premature lethality in epilepsy. In models of this syndrome, two genes for hemiplegic migraine (CACNA1A, SCN1A) lead to SD-linked postictal collapse of cardiorespiratory homeostasis in experimental models, and in vitro studies reveal a lower SD threshold in the mutant brainstem. The chapter draws attention to microtubule-associated protein tau (MAPT), a shared protective gene for epilepsy and SD. Ablation of MAPT, the gene encoding Tau, a microtubule binding protein, corrects the SD threshold and prolongs survival in sudden unexpected death in epilepsy (SUDEP) mutant mouse models.
Literature Review
  • Article
    The effect of intermittent seizures on the pyramidal neurons of the hippocampus is largely unknown. To determine whether recurrent seizures centered in the hippocampus can produce neuronal loss in this region, a morphometric analysis was performed from standardized sections of hippocampus using 5 groups of animals: (1) surgical control subjects, (2) rats kindled by the rapidly recurring hippocampal seizure (RRHS) paradigm, (3) kindled rats with a few additional limbic seizures (528 +/- 66 seizures), (4) kindled rats with many limbic seizures (1,523 +/- 130 seizures), and (5) rats experiencing limbic status epilepticus (SE) induced by "continuous" hippocampal stimulation. The RRHS and SE protocols induced significant neuronal loss in the CA1 region, but no evidence was found for additional cell loss with increasing numbers of intermittent seizures. These intermittent seizures were, however, associated with a significant thickening of the basal and apical dendritic fields of the CA1 region. These findings indicate that intermittent seizures produce no significant hippocampal neuronal loss and may result in a hypertrophy of CA1 dendritic fields.
  • Article
    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.
  • Article
    The piriform and perirhinal cortices are parahippocampal structures with strong connections to limbic structures, including the amygdala and hippocampus, as well as other parahippocampal structures such as the entorhinal cortex. In this paper, we present results, based on anatomical, physiological, and kindling studies, that suggest that the perirhinal and piriform cortices might be very important in the secondary generalization of limbic seizures, particularly those with convulsive expression. These kindling data further suggest that the progressive lowering of afterdischarge thresholds in the parahippocampal structures, due to insult and/or genetic predisposition, might provide the neural basis for the clinical presentation of temporal lobe epilepsy.
  • Article
    Human beings with partial epilepsy and demonstrable cerebral lesions show, in addition to ipsilateral epileptiform EEG discharges, apparently independent epileptiform discharges from the opposite hemisphere. Patients with apparent unilateral focal onset of their partial seizures but without demonstrable lesions also frequently display what appear to be bilaterally independent EEG foci. When surgical treatment or medical prognosis is considered and there is no demonstrable lesion, the decision of which of the two apparent foci is primarily responsible for the seizures is often difficult. Even with a known structural lesion the question arises whether, following its removal, the contralateral focus will persist and will be epileptogenic. Two related experimental phenomena bear directly on these questions—kindling and the mirror focus. This presentation looks critically at existing evidence and finds that it fails to support the idea that kindling and the mirror focus have roles in human epilepsy that currently should influence clinical decisions.
  • Article
    Purpose: To examine whether simultaneous kindling of bilateral hippocampi [bilateral kindling (BK)] could accelerate the achievement of seizures by the breakdown of kindling antagonism or decelerate the achievement of seizures by its enhancement. Methods: The hippocampi of 17 adult rabbits were simultaneously kindled bilaterally according to Goddard's method. Results: All animals developed stage 5 convulsions after a mean of 28 stimulations. Six animals showed spontaneous seizure discharges. Afterdischarge duration increased abruptly during the early period of kindling, but thereafter it gradually progressed. Chronological analyses of interictal discharges (HDs) demonstrated that simple as well as complex types of IIDs increased their frequencies during BK. Conclusions: Compared with unilaterally kindled animals, the BK procedure significantly increased the percentage of animals that successfully kindled (100% vs. 59%; p < 0.01), whereas it significantly decelerated the kindling progression (28 days vs. 19 days; p < 0.02). We conclude that the BK procedure represents potentiation of both excitatory and inhibitory mechanisms. Although the reason why such an antagonistic relationship between them breaks down is still unknown, the BK provides an advanced animal model to study the pathogenic mechanisms of kindling and to screen anticonvulsants.
  • Chapter
    Determining the circuitry of a seizure has been of interest for many years. The primary goals have been to define the regions that are involved in the seizures and to determine the roles that these different regions play in the course of a seizure. Kindling has been used over the years to examine this issue, and it has many advantages for this purpose. Some of the advantages include the ability to determine exactly where to stimulate, when to stimulate and to time the stimulation so that potentially modifying treatments can be given at predetermined points around the seizure inducing stimulation. Over the years a number of observations have been made regarding the potential roles of the different regions of the brain based on seizure thresholds, speed of kindling, ability to alter established seizure patterns or to slow the rate of kindling.9, 15, 16, 22 These observations have been interpreted in terms of presumed or known anatomical connections, and our understanding of the significance of findings has evolved with our improving understanding of the anatomical relationships among the different regions. In this paper we will re-examine the issue of seizure circuitry through a series of experiments that were designed around past observations and evolving information about neural networks in the limbic system.
  • Chapter
    Neural mechanisms underlying convulsive events are believed to be distinctly different from those of absence seizures.1 Typical absence epilepsy has been suggested to be related to a predominance of inhibitory activity, in contrast to generalized or focal convulsive seizures where an excess of excitatory activity is present.2 Likewise, drugs that exacerbate seizure activity, clinically and in animal models, support the hypothesis concerning distinct differences between convulsive and non-convulsive epileptic events. It has long been known that carbamazepine, oxcarbazepine and phenytoin are successfully used in the treatment of partial and secondary generalized seizures, whereas typical absence seizures are clearly exacerbated by carbamazepine and phenytoin.3, 4 Similarly, despite the fact that vigabatrin is a highly effective anticonvulsive agent against partial seizures,5 two patients with idiopathic generalized absence epilepsy in whom vigabatrin increased the frequency and severity of absence and absence status were reported by Panayiotopoulos et al.6 On the other hand, absence seizures in both animal models and humans respond to ethosuximide and trimethadion, which are ineffective against partial seizures.3, 7 Models of convulsive events as well as non-convulsive seizures offer several unique opportunities to understand the pathophysiology of epileptogenesis in animals and perhaps, by extrapolation, in humans.
  • Daily electrical stimulation of the amygdala or hippocampus via implanted electrodes results in the development of a potentiality to trigger motor seizures in those areas. Arguments against several possible mechanisms underlying this development are discussed. Experiments are described which are intended to decide between increases in the strength of limbic-“motor system” connections or limbic-limbic connections as events underlying motor seizure development. It was found that stimulation of more than one area increases the rate of seizure development, whereas disrupting inter-limbic connections retards seizure development. It is concluded that motor seizure development is dependent upon the increased strength of limbic-limbic connections.RésuméLa stimulation électrique quotidienne de l'amygdale ou de l'hippocampe au moyen d'électrodes implantées provoque le développement d'une aptitude à déclencher des crises motrices dans ces aires. Des arguments contre plusieurs mécanismes possibles soustendant ce développement sont discutés. Les auteurs décrivent des expériences qui ont été effectuées afin de choisir entre l'hypothèse d'une augmentation de la force des connexions système limbique-système moteur ou des connexions inter-limbiques comme événements soustendant le développement des crises motrices. Les auteurs observent que la stimulation de plus d'une aire augmente la vitesse de développement des crises, tandis que l'interruption des connexions interlimbiques retarde le développement des crises. Ils concluent que le développement des crises motrices dépend d'une augmentation de la force des connexions inter-limbiques.
  • 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.
  • Article
    Amygdaloid kindling in rhesus monkeys resulted in development of secondarily generalized convulsive seizures in an average of 196 days. Prior pharmacologic (bemegride) kindling accelerated this seizure development in one animal. None of the animals reached the stage 5 primary generalized seizure of baboons (Papio papio), even after 400 daily amygdaloid stimulations. Seizure stage instability, with frequent regression to an earlier stage, and the difficulty of establishing a generalized seizure triggering threshold in most of the rhesus monkeys, contrasts with our experiences in Papio papio. Thus, differences in the speed of kindling and in the quality of kindled convulsion between rhesus monkeys and epileptic baboons probably reflect the presence or absence of an epileptogenic predisposition in these two species. The difficulty of developing convulsive seizure in rhesus monkeys suggests that this species is particularly suited for the study of partial complex seizure. These studies indicate that the abrupt onset of human epilepsy with a fully developed convulsive seizure must represent and overwhelming central pathophysiologic event resulting from an endogenous, exogenous or a combined insult interacting with a genetically predisposed seizure susceptibility.
  • Article
    When electrical stimulation is periodically applied to any one of a number of forebrain sites, there is a progressive development and intensification of elicited motor seizures which can culminate in the development of an epileptic syndrome characterized by spontaneously recurring motor seizures; however, spontaneous motor seizures have been observed in relatively few kindled animals. In the present experiment rats received amygdaloid stimulation about 300 times during a 134-day period. The initial development and intensification of elicited clonic motor seizures progressed as others have described it; however, with continued stimulation running fits were eventually elicited in most of the subjects, and seizures with a tonic component were elicited in a few. Spontaneous motor seizures similar to those elicited by stimulation were observed in 16 of the 18 kindled subjects. Thus, rather than being an idiosyncratic response of a few kindled rats, spontaneous motor seizures appear to be a reliable manifestation of long-term amygdaloid kindling.
  • Article
    Daily electrical stimulation of the amygdala in Senegalese baboons (Papio papio) resulted in the development of generalized convulsive seizures focal onset through five distinct clinical stages in an average of 72 days. The chronologic pattern of electroclinical features suggested that vertical intrahemispheric ictal dissemination was of primary importance in the progressive seizure development. Some animals developed spontaneous recurrence of both partial complex and primary generalized seizures. The kindling preparation in P. papio represents a unique model of human epilepsy with its secondary generalized convulsive seizure development, spontaneously recurrent partial and primary generalized seizures in the background of predisposed epileptogenic susceptibility.
  • Article
    Seizures are known to induce dramatic alterations in neuronal gene expression. These changes may play a role in the genesis of an epileptic state. The present report describes another consequence of seizures-a dramatic induction of glial fibrillary acidic protein (GFAP) expression in astrocytes. Using a hippocampal kindling model, we demonstrate that kindled seizures lead to many fold increases in mRNA for GFAP in structures which experience electrographic seizures. The increases can be detected 1 day following a single seizure. If seizures are induced repetitively (every other day for many days), levels of GFAP mRNA remain elevated. However, when kindled seizures are not induced, levels of GFAP mRNA return to near control levels within a few days. The increases in GFAP mRNA levels are not in response to decreases in neuronal activity (as a result of postictal depression), because GFAP mRNA levels are unaffected when neuronal activity is decreased by blocking afferent drive (with tetrodotoxin). The induction of GFAP expression by seizures may reflect the first step in a process in which seizures induce astrocytic hypertrophy. The changes in astrocytes could in turn modify the way in which astrocytes maintain homeostasis in the extracellular microenvironment in ways that could contribute to the development of an epileptic state.
  • Article
    We previously described a model of spontaneous "sleep epilepsy" in kindled kittens with temporal lobe epilepsy (TLE). We now describe the postkindling course of this model from preadolescence to maturity and suggest pathophysiologic mechanisms. Spontaneous epilepsy, particularly generalized tonic-clonic convulsions (GTCs), developed 1h to 4 months after amygdala kindling and persisted to adulthood. At first, GTCs were detected only in sleep; later, convulsions also occurred during wakefulness. Two factors were consistently associated with the sequential onset of sleep and waking GTCs: seizure clusters and anatomic seizure localization. (1) Seizure clusters. Cats with infrequent or unclustered GTCs continued to exhibit "sleep epilepsy," defined by convulsions occurring exclusively during sleep. In contrast, cats with frequent seizure clusters developed recurrent or terminal convulsive status in conjunction with GTCs during waking and sleep. Severe seizure manifestations therefore appeared to contribute to the dissociation of convulsions from the sleep-wake cycle. (2) Anatomical seizure localization. Focal seizure origin appeared to differentiate sleep from waking GTCs. Onset during sleep was first recorded in the kindled amygdala, whereas onset during waking was initially detected outside the temporal lobe. Findings thus suggest secondary "kindling" of multifocal epilepsy. Secondary epileptogenesis is consistent with "transsynaptic" kindling effects. This phenomenon is defined in mature animals by rapid secondary site kindling (transfer) and subtle morphologic changes distal to the stimulating electrode. Transfer may be accentuated by youth, because kittens developed spontaneous seizure foci in previously unstimulated tissue. Moreover, multifocal interactions and diffuse cell loss were implicated as possible mechanisms. Collectively, the findings indicate complications with early onset TLE in kindled cats. Onset during youth can have an unfavorable prognosis, reflected by recurrent status epilepticus and multifocal epilepsy with convulsions distributed throughout the sleep-wake cycle.
  • Article
    In adult rats, concurrent kindling of two limbic sites, alternating stimulation to each site, often results in the retarding of kindling at one or both sites. This inhibitory interaction between two limbic kindling foci is termed kindling antagonism and occurs irrespective of whether the sites are contralateral or ipsilateral. We have previously shown that kindling antagonism does not occur when 16- to 17-day-old rat pups are concurrently kindled in the hippocampus and contralateral amygdala or between the two amygdalae. In this study, adult and 16- to 17-day-old rats were concurrently kindled in the hippocampus and ipsilateral amygdala to determine if the local intrahemispheric mechanisms suppressing multiple kindled foci are age-dependent. Kindling antagonism occurred in 7 out of 10 adult rats. In contrast, in rat pups, kindling development was not suppressed. Concurrent kindling of the two limbic sites enhanced the development of severe seizures. Two 16- to 17-day-old rats receiving alternating stimulations exhibited spontaneous seizures. The age-specific failure of both inter- and intrahemispheric mechanisms to suppress the development of multiple kindling foci may explain the high incidence of multifocal seizures in the immature CNS.
  • Article
    Eleven months after the completion of primary site amygdaloid (AM) kindling, three cats experienced kindling of the secondary site AM. At the secondary site, animals developed kindled seizure with a mean of eight stimulations, which was significantly fewer than the 29 required at the primary site, indicating a presence of a positive transfer effect. However, the ictal architecture of the secondary site-kindled seizure was significantly different from that of the primary site: in the former, there was a marked delay in secondary generalization, with individual kindled seizure having a significantly prolonged seizure duration. Both the transhemispheric positive and negative transfer effects observed with the secondary site AM kindling reflect the lasting nature of the neural remodeling induced by the primary site AM kindling. This finding may have clinical relevance.
  • Article
    Structural damage of the human brain (perinatal damage, cerebral trauma, head injury, cerebrovascular and degenerative diseases, intracranial tumor, metabolic diseases, toxins, drug-induced seizures) may lead to chronic epilepsy in survivors. Epidemiologic analyses show that a considerable time-delay occurs between the exposure of the brain to injury and the appearance of seizures. Such seizures are usually partial or mixed, may develop at any age, and are difficult to treat. In rats subjected to structural damage of the brain induced by sustained convulsions triggered by systemic administration of the cholinergic agent pilocarpine, spontaneous seizures may develop after a mean latency of 14-15 days. The mean frequency of spontaneous recurrent convulsions remains constant for several months. Evolution of these convulsions proceeds through several electrographic and behavioral stages resembling kindling. Kindling may be otherwise induced in rodents by repeated systemic administration of convulsants or by repeated electrical stimulation of sensitive brain regions. These observations demonstrate that structural damage of the brain may lead to spontaneously recurrent convulsions (chronic epilepsy) in rats and that kindling may be involved in the evolution of such a condition. This finding suggests that kindling mechanisms underlie the development of epileptic foci from structural brain lesions. Such mechanisms may be involved in the etiology of some forms of epilepsy in humans.
  • Article
    In order to study spatial interactions during low magnesium induced epileptiform activity, changes in extracellular potassium concentration ([K+]0) and associated slow field potentials (f.p.'s) were recorded in thin rat temporal cortex slices (400 microns) containing the neocortical temporal area 3 (Te3), the entorhinal cortex (EC) and the hippocampal formation with the dentate gyrus, area CA3 and CA1 and the subiculum (Sub). The epileptiform activity was characterized by short recurrent epileptiform discharges (40 to 80 ms, 20/min) in areas CA3 and CA1 and by interictal discharges and tonic and clonic seizure like events (SLE's) (13-88s) in the EC, Te3 and Sub. While interictal discharges occurred independent of each other in the different subfields, the three areas became synchronized during the course of a SLE. The EC, Te3 and Sub all could represent the "focus" for generation of the SLE's. This initiation site for SLE's sometimes changed from one area to another. The characteristics of the rises in [K+]0 and subsequent undershoots were comparable to previous observations in in vivo preparations. Interestingly, rises in [K+]0 could start before actual onset of seizure like activity in secondarily recruited areas. The epileptiform activity could change its characteristics to either a state of recurrent tonic discharge episodes or to a continuous clonic discharge state reminiscent of various forms of status epilepticus. We did not observe, in any of these states, active participation by area CA3 in the epileptiform activity of the EC in spite of clear projected activity to the dentate gyrus. Even after application of picrotoxin (20 microM), area CA3 did not actively participate in the SLE's generated in the entorhinal cortex. When baclofen (2 microM) was added to the picrotoxin containing medium, SLE's occurred both in the entorhinal cortex and in area CA3, suggesting that inhibition of inhibitory interneurons by baclofen could overcome the "filtering" of projected activity from the entorhinal cortex to the hippocampus.
  • Article
    Full-text available
    Neuronal gene expression is known to be modulated by functional activity. This modulation is thought to play a key role in determining the differentiation of developing neurons and regulating the operation of mature neurons. Here we describe a regulation of astroglial gene expression by neuronal activity. We report that intense neuronal activity (electrically induced seizures) in rat hippocampus leads to rapid and dramatic increases in mRNA for glial fibrillary acidic protein (GFAP), an astroglia-specific intermediate filament protein. GFAP mRNA levels increased at sites of stimulation as well as in areas that were synaptically activated by the resultant seizures. When seizures were induced repetitively for many days, levels of GFAP mRNA remained chronically elevated. However, GFAP mRNA returned to control levels within a few days after the cessation of stimulation. The coupling between astroglial gene expression and neuronal activity may be a mechanism through which neuronal activity modulates the function of supporting cells that are responsible for regulating the extracellular microenvironment of the brain.
  • Article
    Full-text available
    Recent studies have revealed that mossy fiber axons of granule cells in the dentate gyrus undergo reorganization of their terminal projections in both animal models of epilepsy and human epilepsy. This synaptic reorganization has been demonstrated by the Timm method, a histochemical technique that selectively labels synaptic terminals of mossy fibers because of their high zinc content. It has been generally presumed that the reorganization of the terminal projections of the mossy fiber pathway is a consequence of axonal sprouting and synaptogenesis by mossy fibers. To evaluate this possibility further, the time course for development of Timm granules, which correspond ultrastructurally to mossy fiber synaptic terminals, was examined in the supragranular layer of the dentate gyrus at the initiation of kindling stimulation with an improved scoring method for assessment of alterations in Timm histochemistry. The progression and permanence of this histological alteration were similarly evaluated during the behavioral and electrographic evolution of kindling evoked by perforant path, amygdala, or olfactory bulb stimulation. Mossy fiber synaptic terminals developed in the supragranular region of the dentate gyrus by 4 d after initiation of kindling stimulation in a time course compatible with axon sprouting. The induced alterations in the terminal projections of the mossy fiber pathway progressed with the evolution of behavioral kindled seizures, became permanent in parallel with the development of longlasting susceptibility to evoked seizures, and were observed as long as 8 months after the last evoked kindled seizure. The results demonstrated a strong correlation between mossy fiber synaptic reorganization and the development, progression, and permanence of the kindling phenomenon.
  • Article
    We describe the ontogeny of feline temporal lobe epilepsy after amygdala kindling in 24 cats, aged 2.5 months to over 1 year. In so doing, we report the first experimental model of spontaneous epilepsy in immature animals. Preadolescent kittens (n = 12 less than or equal to 6.5 months) are far more likely to develop epilepsy, indexed by spontaneous seizures, than are adult cats (n = 12 greater than 1 year). Moreover, youth accelerated the development of epilepsy. The younger the kitten at the beginning of kindling, the more probable and rapid the onset of spontaneous seizures. Failed postictal depression was the most reliable precursor of spontaneous seizures in immature cats. However, spontaneous epilepsy continued after postictal refractory periods stabilized and was still present when kittens matured to adulthood. Collectively, the results suggest that failed inhibition contributes to the onset of spontaneous epilepsy in immature animals but that other morphologic, physiological and/or chemical changes might sustain epilepsy afterwards.
  • Article
    Kindling of limbic structures induces synaptic reorganization of the mossy fiber pathway in the dentate gyrus. To evaluate the hypothesis that kindling stimulation may also cause neuronal loss in the hilus of the dentate gyrus that could play a role in this synaptic reorganization, neuron counts were obtained using quantitative stereological methods in the hilar polymorphic region of rats kindled by perforant path stimulation. After 3 kindled generalized tonic clonic seizures, there was 12.7% neuronal loss in the hilar polymorphic region compared to controls, but there was no visually apparent lesion. After 30 generalized kindled seizures, the neuronal loss was 40.1%, was visually apparent, and resembled one aspect of the pattern of hilar neuronal loss observed in human hippocampal sclerosis. The results demonstrate that brief sporadic seizures can induce neuronal loss in the hippocampal formation, a brain region implicated in epilepsy, memory, and cognition.
  • Article
    A period of continuous hippocampal stimulation (CHS) establishes an acute condition of self-sustaining limbic status epilepticus (SSLSE) which is followed by chronic neuropathological changes reminiscent of hippocampal sclerosis encountered in epileptic patients. In the chronic (greater than or equal to 1 month) condition following CHS-induced SSLSE, extended electrographic monitoring in the hippocampus revealed spontaneous recurrent paroxysmal discharges. All 6 animals studied had persistent interictal spiking; 3 had multiple fully developed electrographic seizures. There was a marked diminution of paired pulse inhibition, demonstrated by a protocol known to reflect the potency of inhibition mediated by GABAA receptors. Hippocampal slices from animals that had previously experienced CHS-induced SSLSE demonstrated an increased excitability relative to slices from control animals as evidenced by epileptiform bursting in increased extracellular potassium ([K+]0) and decreased extracellular calcium ([Ca2+]0). These studies establish that CHS-induced SSLSE in rats provides an experimental model with recurrent spontaneous hippocampal seizures. Based on electrophysiological data we suggest that a decrease in GABA-mediated inhibition and/or altered sensitivity to extracellular ions may play roles in the development of such seizures.
  • Article
    This article has three goals: (1) to review the evidence that bears upon the occurrence of secondary epileptogenesis in man, (2) to set forth the criteria that distinguish secondary epileptogenesis from multifocal epilepsy--both clinically and by pharmacologic means--and (3) to indicate the importance of an understanding of the pathophysiology of secondary epileptogenesis to clinical decision making in the care of epileptic patients. In Section I, the three different developmental stages of secondary epileptogenesis defined in experimental preparations are outlined, and particular emphasis is placed on the remarkable similarity in the electrographic manifestations reported from animal species ranging from reptile to baboon. The clinical manifestations differ depending, within species, on exactly where in the brain the primary focus is situated and, between species, on the different organizations of the neural substrate within which epileptiform discharge is engendered. Section II is devoted to a review of three separate series of patients whose presenting symptom was epilepsy and in whom the etiology proved to be a histologically verified brain tumor or malformation. The choice of patient material was dictated by the conclusion that the main barrier to acceptance of human secondary epileptogenesis is the difficulty of distinguishing between multiple primary lesions maturing at different rates and those secondarily induced by an already existing single one. In the vast majority of patients where trauma, infection, anoxia, and vascular disease represent the most common etiologies, multiple primary structural injury is an ever-present possibility. Restricting our analysis to tumors of neural, glial, or vascular origin eliminates, as far as practicable, the issue of multiple primary lesions. A significant number of patients with focal epilepsy develop secondary epileptogenic lesions. The evidence presented shows that a primary epileptogenic lesion in man may induce a trans-synaptic and long-lasting alteration in nerve cell behavior characterized by paroxysmal electrographic manifestations and clinical seizures. Furthermore, the more frequent the seizures, the more likely is a secondary focus to become permanent. These observations underscore the importance of rigorous seizure control (electrographic as well as behavioral) and raise the question of earlier surgical intervention where medicinal therapy fails.
  • Article
    The distribution of the mossy fiber synaptic terminals was examined using the Timm histochemical method in surgically excised hippocampus and dentate gyrus from patients who underwent lobectomy of the anterior part of the temporal lobe for refractory partial complex epilepsy. The dentate gyrus of epileptic patients demonstrated intense Timm granules and abundant mossy fiber synaptic terminals in the supragranular region and the inner molecular layer. In contrast, the dentate gyrus of presenescent nonepileptic primates demonstrated no Timm granules in the supragranular region. In nonepileptic senescent primates, occasional very sparse supragranular Timm granules were results are morphological evidence of mossy fiber synaptic reorganization in the temporal lobe of epileptic humans, and suggest the intriguing possibility that mossy fiber sprouting and synaptic reorganization induced by repeated partial complex seizures may play a role in human epilepsy.
  • Article
    Bath application of 4-aminopyridine (4-AP) to hippocampal slices taken from rats on postnatal days 10-15 produced prolonged synchronized epileptiform discharges in the CA3 subfield. Extracellular field recordings obtained from the pyramidal cell body layer recorded repetitive synchronized afterdischarges which were often 30 sec in duration. These ictal-like events were interspersed with variable amplitude positive-going interictal burst-like discharges. The afterdischarges consisted of a sustained negative field potential, upon which were superimposed negative-going population spikes. Simultaneous recordings from areas CA3 and CA1 indicated that the afterdischarge activity originated in CA3 since population spikes recorded there preceded and were time locked to spikes in CA1 pyramidal neurons. The burst-like interictal events recorded in CA3 were not all-or-none and had 2 clearly identifiable phases, the first being a smooth positive wave of relatively constant amplitude and duration. A second and subsequent excitatory phase was also positive going but more variable in size. This latter phase was accompanied by multiple population spikes. Intracellular events recorded simultaneously were most often excitatory, depolarized potentials. These varied in size and duration with coincident field potentials. Thus variations of the extracellular burst-like discharges recorded are more likely to be produced by changes from time to time in excitatory synaptic drive to CA3 pyramidal neurons than by alterations in the number of these pyramidal cells discharging in an all-or-none manner. The 4-AP-induced epileptiform discharge occurred in the presence of inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
  • Article
    The concurrent, alternate electrical stimulation of the entorhinal cortex and septal nucleus results in the development of fully generalized seizures at one electrode site and the suppression of seizure development at the other. We have labeled this phenomenon kindling antagonism. Selective, whole-brain depletion of norepinephrine (NE) virtually eliminates the development of kindling antagonism such that fully generalized seizures develop at both sites in a majority of animals. This effect occurs in the absence of appreciable changes in kindling characteristics of these animals compared with either untreated or vehicle-treated controls. These results suggest that the suppression of seizure development observed in the kindling antagonism model is normally maintained by a NE-dependent mechanism. Our results support those of earlier studies using single-site kindling paradigms in which NE depletion facilitates the rate of kindled seizure development. We suggest that the NE-dependent mechanism responsible for the seizure suppression observed to follow concurrent, alternate stimulation and the suppression of seizure development using single-site kindling paradigms may be the same. The nature of this NE-dependent seizure suppression mechanism and the anatomic locus or loci critical for this effect remain questions for future research.
  • Article
    The ability of increases in extracellular potassium ([K+]o) and/or decreases in extracellular calcium ([Ca2+]o) to induce epileptiform activity in hippocampal slices was studied by systematically varying [K+]o and [Ca2+]o. Slices prepared from kindled rats, both 1 week and 1 month after the last kindled seizure, showed an increased sensitivity to perturbations of both ions. Stimulus-locked epileptiform discharges occurred with small displacements of [K+]o and/or [Ca2+]o. The ionic threshold for spontaneous epileptiform discharges was not significantly affected. This long-lasting change in sensitivity to the ionic environment produced by the kindling process had important implications for epileptogenesis in chronically epileptic tissue.
  • Article
    Reduction of [Mg2+]o induced spontaneous epileptiform activity consisting of 40-100-ms bursts of population spikes in hippocampal slices. This activity disappeared from area CA1 when the connections to area CA3 were cut, but persisted in isolated minislices of area CA3. Spontaneous activity was also observed in the dentate gyrus, provided that the connections to the subiculum and entorhinal cortex (EC) were intact. In the parasubiculum and EC longer lasting epileptiform events were observed which resembled seizure-like behaviour. The epileptiform activity was completely suppressed by 2-aminophosphonovalerate (30 microM) suggesting that N-methyl-D-aspartate receptors for excitatory amino acid transmitters participate in the generation of this activity. These findings show that the EC possesses properties which permit the generation of seizure-like activity in contrast to the hippocampus where the activity resembled recurrent interictal events.
  • Article
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    In the rat hippocampal formation, degeneration of CA4-derived afferent fibers provokes the growth of mossy fiber collaterals into the fascia dentata. These aberrant fibers subsequently form granule cell-granule cell synapses. The hippocampal slice preparation was employed to determine whether these recurrent connections are electrophysiologically functional. Hippocampal slices were prepared 12 to 21 days after the bilateral destruction of CA4 neurons with either intracerebroventricular or intravenous kainic acid (KA). In slices from control rats, antidromic stimulation of the mossy fibers elicited a single population spike in the granular layer of the fascia dentata. In contrast, when slices from some KA-treated rats were similarly tested, antidromic stimulation elicited multiple population spikes. This effect was not reproduced by blocking inhibitory transmission with bicuculline methiodide. Slices from other KA-treated rats fired a single population spike, but an antidromic conditioning volley increased the amplitude of a subsequent antidromic population spike by 5 to 15%. In slices from control rats, on the other hand, an antidromic conditioning volley always either decreased or failed to alter the amplitude of an antidromic test response. Superfusion with Ca2+-free medium containing 3.8 mM Mg2+ reversibly abolished all effects of KA administration. Abnormal responses to antidromic stimulation correlated with the loss of CA4 neurons and the growth of supragranular mossy fiber collaterals in the same animals. These results suggest that supragranular mossy fiber collateral sprouts form a functional recurrent excitatory circuit. These aberrant connections may further compromise hippocampal function already disrupted by neuronal degeneration, such as by facilitating seizure activity.
  • Article
    This report documents a unique case, in which over 1,250 ECTs produced no observable gross or histological sign of brain damage. The patient was an 89 year-old female with chronic psychiatric illness; neuropathological examination revealed a healthy CNS, in spit of the massive ECT exposure, and there was no sign of oxygen deficiency in spite of numerous, repeated anaesthesia inductions and seizures for each of the many courses of treatment.
  • Article
    Antagonists of gamma-aminobutyric acid (GABA)- or glycine-mediated neurotransmission, muscarinic cholinergic agonists, and excitatory amino acids and their analogues are all considered to be potent chemoconvulsant agents. However, although systemic injections of these agents have been used to create experimental models of generalized epilepsy, there has been no identification of a specific locus at which any of these drugs act to initiate generalized seizures. We recently located a forebrain region from which seizures can be elicited by the GABA antagonist bicuculline, and now report that manipulations of excitatory amino acid transmission and cholinergic transmission can also elicit seizures from this site. Bilateral clonic seizures can be elicited after unilateral application of picomole amounts of bicuculline, kainic acid or carbachol and micromole amounts of glutamate. Local application of the GABA agonist muscimol prevents the appearance of seizures on subsequent microinjection of all convulsant agents examined, whereas local application of the muscarinic antagonist, atropine, only prevents seizures induced by carbachol. This region is therefore a site of action for the epileptogenic effects of neuroactive agents with diverse mechanisms of action; it may also represent a site at which GABA agonists could function therapeutically to control epileptogenesis.
  • Article
    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.
  • Article
    AN ANALYSIS OF THE CASE HISTORIES OF NINE PATIENTS WHO DEVELOPED EPILEPTIC FITS SHORTLY AFTER STARTING TRICYCLIC ANTIDEPRESSANT DRUGS SHOWED THAT ALL OF THEM HAD ONE OR MORE OF THE FOLLOWING FACTORS: previous or family history of epilepsy, pre-existing brain damage, cerebral arteriosclerosis, alcoholism, withdrawal of barbiturates, and history of previous electric convulsive therapy. Before prescribing antidepressant drugs these factors should be sought for in the history, and if any are present prophylactic anticonvulsant medication is indicated. From a limited experience we do not think that chlordiazepoxide is adequate to counteract the convulsant effect of antidepressant drugs.
  • Article
    Findings in children seen between 1955 and 1965 during the year of onset of typical absence seizures (90 patients) or rolandic epilepsy (79 patients) were analyzed by actuarial methods. One hundred and eighteen patients were followed for more than 15 years. Rolandic epilepsy is a true benign epilepsy ending with puberty. Although school and family problems are common during the acute stage of the disease, the social adaptability of such patients is excellent. We considered only typical absences occurring as a first epileptic sign in normal children. Myoclonic or atonic absences have a poor prognosis. Many patients with simple and automatic absences experience remission 15 years after withdrawal of medication. The overall cessation rate in those experiencing absences was only 57.5%, however, and 36% of patients developed tonic-clonic seizures. Social adaptability was often inadequate. Simple and automatic absences (constituting a homogeneous group) are not truly a benign form of epilepsy, even though prognosis for those afflicted is better than that for those with other forms of primary generalized epilepsy.
  • Article
    Human beings with partial epilepsy and demonstrable cerebral lesions show, in addition to ipsilateral epileptiform EEG discharges, apparently independent epileptiform discharges from the opposite hemisphere. Patients with apparent unilateral focal onset of their partial seizures but without demonstrable lesions also frequently display what appear to be bilaterally independent EEG foci. When surgical treatment or medical prognosis is considered and there is no demonstrable lesion, the decision of which of the two apparent foci is primarily responsible for the seizures is often difficult. Even with a known structural lesion the question arises whether, following its removal, the contralateral focus will persist and will be epileptogenic. Two related experimental phenomena bear directly on these questions- kindling and the mirror focus. This presentation looks critically at existing evidence and finds that it fails to support the idea that kindling and the mirror focus have roles in human epilepsy that currently should influence clinical decisions.
  • Article
    The evolution of untreated partial epilepsy is unknown. This study uses a newly developed model of chronic limbic epilepsy to determine whether seizures inexorably worsen in duration, frequency and behavioral accompaniment. The seizures begin following an episode of limbic status epilepticus induced by continuous electrical stimulation of the hippocampus, and they persist for more than a year (longest duration followed). We monitored 10 rats continuously with combined EEG and closed circuit television for 24 weeks following the first recorded spontaneous seizure. Seizure duration, behavioral accompaniment and frequency all intensified during the early stages, but the last 12-16 weeks of the study were characterized by a plateau for all measures. The results showed significant increases that occurred over the first 12 weeks only (P < 0.01 for duration and behavioral accompaniment, P < 0.05 for seizure frequency). These findings suggest that untreated epilepsy will undergo an early maturation process, but that once the seizures mature they remain stable over a prolonged period. It was also noted that 67% (P < 0.00001) of the seizures occurred during the day, suggesting that the sleep-wake cycle has a strong influence on the occurrence of seizures in this model of limbic epilepsy.
  • Article
    Repetitive synchronized neuronal discharging that lasts for seconds and even minutes in in vitro brain slice preparations are important new models in experimental epilepsy. In hippocampal slices from 1-2-week-old rats, individual CA3 pyramidal cells undergo a sustained depolarization during such electrographic seizures, induced by GABAA receptor antagonists. In experiments reported here these events were produced in small isolated segments of the CA3 subfield, measuring only 400-500 microns along the cell body layer. In such minisclices local application of either kynurenic acid or 6-cyano-7-nitroquinoxaline-2-3-dione (CNQX) to the proximal basilar dendrites abolished the synchronized discharges of electrographic seizures. Interictal spikes appeared unaffected by this treatment. Application of these excitatory amino acid receptor antagonists to distal basilar dendrites or apical dendrites was ineffective. In "larger" minislices, measuring 700-1000 microns along the cell body layer, application of kynurenic acid, CNQX, or TTX to the proximal basilar dendrites did not abolish electrographic seizures but instead selectively suppressed the intracellularly recorded sustained depolarization and the coincident slow negative field potential recorded in proximal basilar dendrites. Results of several experiments suggest that electrographic seizures recorded under these conditions were produced by a remote network of "generator cells." Since the remote neurons were unaffected by local application of the drugs, it seemed likely that they continued to undergo a sustained depolarization. Simultaneous blockade of basilar dendritic synapses in the "generator" population abolished electrographic seizures throughout these larger minislices. These results suggest that the sustained depolarization plays a central role in seizure generation and that it does not have to be generated in every neuron, only in a critical number of "generator cells" for a seizure to occur. Taken together, results presented here suggest that the sustained depolarization of electrographic seizures is a separate physiological process from the more rapid repetitive depolarizations of the seizure discharges and is required if electrographic seizures are to occur. This slow depolarization appears to be synaptically mediated and generated exclusively in proximal basilar dendrites. Therefore, in addition to the excitatory synaptic potentials involved in paroxysmal depolarization shift generation, a second form of recurrent excitation may exist in immature hippocampus. Not only is this physiological process critical for the genesis of seizures, but it also appears to be highly partitioned within the hippocampal laminae.
  • Article
    We report a characteristic pattern of neuropathological change in the entorhinal cortex (EC) from four patients with temporal lobe epilepsy. Specimens of the EC were obtained during the surgical treatment of intractable partial seizures and were studied by light microscopy in Nissl-stained sections. A distinct loss of neurons was observed in the anterior portion of the medial EC in the absence of apparent damage to temporal neocortical gyri. Cell loss was most pronounced in layer III, but also noticed in layer II, particularly in the rostral field. A similar pattern of neurodegeneration in the EC was found in all specimens examined though the degree of neuronal loss varied between cases. These observations provide neuropathological evidence for an involvement of the EC in temporal lobe epilepsy. Since the EC occupies a pivotal position in gating hippocampal input and output, our results further support previous suggestions that dysfunction of this region may contribute, either independently or in concert with Ammon's horn sclerosis, to epileptogenesis in humans.
  • Article
    Full-text available
    Repeated kindled seizures induce long-lasting physiological and morphological alterations in the hippocampal formation. In the dentate gyrus (DG), the morphological alterations induced by kindled seizures include loss of polymorphic neurons in the hilus, mossy fiber axon sprouting, and synaptic reorganization of the mossy fiber pathway. In this study, quantitative stereological methods were used to determine the distribution and time course of neuronal loss induced by 3, 30, or 150 kindled generalized tonic-clonic seizures in hippocampal, limbic, and neocortical pathways. Neuronal loss was observed in the hilus of the DG and CA1 after three generalized tonic-clonic seizures, and progressed in these sites to 49% and 44% of controls after 150 seizures. Neuronal loss was also observed in CA3, entorhinal cortex, and the rostral endopyriform nucleus after 30 seizures, and was detected in the granule cell layer and CA2 after 150 seizures. There was no evidence of neuronal loss in the somatosensory cortex after 150 seizures. The time course of the neuronal loss demonstrated selective vulnerability of hippocampal neuronal populations to seizure-induced injury, and suggests that even brief seizures may induce excitotoxic injury in vulnerable neuronal populations. Repeated brief seizures induced neuronal loss in a distribution that resembled hippocampal sclerosis, the most common lesion observed in human epilepsy. The results demonstrated that kindling induces alterations in neural circuitry in a variety of locations in the limbic system, and suggest that hippocampal sclerosis may be acquired in human epilepsy as a consequence of repeated seizures.
  • Article
    The kynurenine pathway metabolites quinolinic acid and kynurenic acid have been hypothetically linked to the occurrence of seizure phenomena. The present immunohistochemical study reports the activation of astrocytes containing three enzymes responsible for the metabolism of quinolinic acid and kynurenic acid in a rat model of chronic epilepsy. Rats received 90 min of patterned electrical stimulation through a bipolar electrode stereotaxically positioned in one hippocampus. This treatment induces non-convulsive limbic status epilepticus that leads to chronic, spontaneous, recurrent seizures. One month after the status epilepticus, the rats showed neuronal loss and gliosis in the piriform cortex, thalamus, and hippocampus, particularly on the side contralateral to the stimulation. Astrocytes containing the kynurenic acid biosynthetic enzyme (kynurenine aminotransferase) and the enzymes for the biosynthesis and degradation of quinolinic acid (3-hydroxyanthranilic acid oxygenase and quinolinic acid phosphoribosyltransferase, respectively) became highly hypertrophied in brain areas where neurodegeneration occurred. Detailed qualitative and quantitative analyses were performed in the hippocampus. In CA1 and CA3 regions, the immunostained surface area of reactive astrocytes increased up to five-fold as compared to controls. Enlarged cells containing the three enzymes were mainly observed in the stratum radiatum, whereas the stratum pyramidale, in which neuronal somata degenerated, showed relatively fewer reactive glial cells. Hypertrophied kynurenine aminotransferase- and 3-hydroxyanthranilic acid oxygenase-immunoreactive cells were comparable in their morphology and distribution pattern. In contrast, reactive quinolinic acid phosphoribosyl transferase-positive glial cells displayed diversified sizes and shapes. Some very large quinolinic acid phosphoribosyl transferase-immunoreactive cells were noticed in the molecular layer of the dentate gyrus. In the hippocampus, the number of immunoreactive glial cells increased in parallel to the hypertrophic responses. In addition, pronounced increases in immunoreactivities, associated with hypertrophied astrocytes, occurred around lesioned sites in the thalamus and piriform cortex. These findings indicate that kynurenine metabolites derived from glial cells may play a role in chronic epileptogenesis.
  • Article
    The effect of recurrent seizures on the hippocampus has been controversial for many years. To determine the effect different seizure paradigms had on the structure of the dentate gyrus, we conducted histological studies on the dentate gyrus (DG) from three groups of rats: (1) those that had experienced 1500 intermittent kindled seizures; (2) those that had experienced a single episode of limbic status epilepticus (SE); and (3) control rats that had been implanted with electrodes. When compared to controls the DG of SE rats was overall slightly, but non-significantly, smaller, but the DG of rats with 1500 kindled seizures was significantly larger. The decrease of size following SE was attributable to a significant atrophy of the molecular layer. The increase in area associated with kindling was the result of an enlargement of the molecular layer and the hilus. Absolute neuronal counts showed a decrease in the hilus after SE but no change following kindling, but both groups had decreased neuronal densities in the hilus when compared to controls. The decreased density after SE was secondary to neuronal loss, but the decrease in neuronal density following kindling was the result of the expansion of the hilar neuropil without change in the number of neurons. This study extends our previous findings in Ammon's horn and indicates that SE induces significant neuronal loss, but numerous intermittent kindled seizures have no effect on neuronal numbers in the DG.
  • Article
    Kindling is a widely used model of epilepsy. While intriguing hypotheses have recently emerged about how kindling occurs, the mechanisms behind kindling remain to be elucidated. In order to test whether certain anatomical changes that have been detected in the brains of animals that have completed kindling are necessary for the expression of kindled seizures, means to achieve kindling over a time course too rapid for the anatomical changes to take place were sought. Stimulus trains of various durations (2 and 10 s) and frequencies (20, 50, and 100 Hz) were given every 30 min, 12 times a day for 4 consecutive days to rats through bipolar electrodes stereotactically positioned in the ventral hippocampus. Responses were monitored with conventional kindling behavioral seizure scores and afterdischarge durations. The frequencies studied were chosen to survey the range that has been previously used to determine the optimal frequency for eliciting maximal dentate activation. Maximal dentate activation is a paroxysmal process that has been postulated to play both a role in regulating epileptiform activity in the hippocampus and adjacent regions that are coupled in a functional hippocampal-parahippocampal loop and a role in kindling. All types of trains resulted in rapid kindling in which kindled motor seizures emerged after several stimuli and then were consistently elicited with each stimulus; there was also retention of the kindled state after periods of 18 h of withholding the stimuli. Thus, the overall response profile of the rapid kindling demonstrated in this study was phenomenologically similar to the profile of traditional kindling. Yet rapid kindling developed more quickly than did mossy fiber sprouting, determined in prior work, thereby excluding the latter as a necessary factor in rapid kindling. Stimulus frequency significantly influenced the rate of rapid kindling. Trains of 20 Hz, the optimal frequency for eliciting maximal dentate activation, yielded the fastest kindling. This finding supports the proposed role of maximal dentate activation and the hippocampal-parahippocampal loop in kindling. Longer (10 s) trains consistently triggered shorter afterdischarge durations. We postulate that this may reflect a tighter linkage between seizure-terminating processes with the 10 s trains than with 2 s trains.