Kindling and status epilepticus models of epilepsy: rewiring the brain.

Electrographic, clinical and pathological alterations following systemic administration of kainic acid, bicuculline or pentetrazole: metabolic mapping using the deoxyglucose method with special reference to the pathology of epilepsy

Animal models of the epilepsies

Summary: Purpose: We describe an algorithm for rapid realtime detection, quantitation, localization of seizures, and prediction of their clinical onset.

Methods: Advanced digital signal processing techniques used in time-frequency localization, image processing, and identification of time-varying stochastic systems were used to develop the algorithm, which operates in generic or adaptable “modes.” The “generic mode” was tested on (a) 125 partial seizures (each contained in a 10-min segment) involving the mesial temporal regions and recorded using depth electrodes from 16 subjects, and (b) 205 ten-minute segments of randomly selected interictal (nonseizure) data. The performance of the algorithm was compared with expert visual analysis, the current “gold standard.”

Results: The generic algorithm achieved perfect sensitivity and specificity (no false-positive and no false-negative detections) over the entire data set. Seizure intensity, a novel measure that seems clinically relevant, ranged between 35.7 and 6129. Detection was sufficiently rapid to allow prediction of clinical onset in 92% of seizures by a mean of 15.5 s.

Conclusions: This algorithm, which was implemented with a personal computer, represents a definitive step toward rapid and accurate detection and prediction of seizures. It may also enable development of intelligent devices for automated seizure warning and treatment and stimulate new study of the dynamics of seizures and of the epileptic brain.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1528-1157.1998.tb01430.x

Real-Time Automated Detection and Quantitative Analysis of Seizures and Short-Term Prediction of Clinical Onset

Functional anatomy of hippocampal seizures.

Experimental epileptogenesis: kindling-induced epilepsy in rats.

The periodic administration of convulsive agents, even at doses or intensities that initially have no convulsive effect, can lead to a progressive and enduring increase in the susceptibility to subsequent convulsive stimulation. This kindling effect has contributed to the understanding of the convulsive effects of alcohol withdrawal in three ways. First, rats kindled by the periodic application of electroconvulsive shock, local brain stimulation, or pentylenetetrazol were found to be hypersusceptible to the convulsive effects of subsequent alcohol withdrawal, thus raising the possibility that some forms of electrical or pharmacological therapy can potentiate the alcohol withdrawal syndrome in humans. Second, the duration of seizures elicited in kindled rats has been used as a sensitive index of convulsive withdrawal effects; increases in the duration of kindled motor seizures and afterdischarges can be detected following the metabolism of a single intoxicating injection of ethanol. Third, it was suggested that the potentiation of the convulsive effects of alcohol exposure and withdrawal by prior episodes of alcohol withdrawal may reflect a kindling-like process rather than an increase in physical dependence.

Alcohol withdrawal seizures: Implications of kindling

SUMMARY

Rats subjected'jb daily electrical stimulation of the amygdala at current levels that were too low to produce a behavioral response initially, eventually displayed stimulus-induced bilateral, clonic convulsions. This change in epileptic activity progressed through two stages. The first stage was characterized by an increase in the duration of both motor seizures and after-discharges, and the second by a gradual increase in the uniformity of seizures produced by successive stimulations. Footshock administered prior to brain stimulation shortened and in some cases completely blocked both motor seizures and after-discharges without producing any change in the pattern of the seizure.



RESUME

Des rats soumis chaque jour a des stimulations electriques de l'amygdala avec des courants initialement d'intensite trop basse pour produire des reponses cordportementales, presentaient a la fin des convulsions toniques bilaterales, provoquees par des stimuli. Ces modifications de l'activiteepileptique progressaient en deux etapes. La premiere etait caracterisee par une augmentation de la duree de la crise motrice et de la post-decharge, et la seconde etait caracterisee par une augmentation graduelle de l'uniformite des crises produites par des stimulations successives. Chez les animaux qui presentaient une activiteepileptique uniforme, un choc sur les pattes, precedant la stimulation cerebrale, diminuait et dans quelques cas bloquait completement les crises motrices.



ZUSAMMENFASSUNG

Ratten, bei denen taglich die Corpora amygdaloidea mit Stromstarken gereizt wurden, die zu niedrig waren, urn initial eine Verhaltensantwort auszulosen, zeigten gelegentlich reizinduzierte, bilaterale clonische Krampfe. Diese Anderung der epileptischen Aktivitat durchlief zwei Stadien. Das erste Stadium war durch eine verlangerte Dauer sowohl der motorischen Krampfe als auch der Nachentladungen gekennzeichnet, das zweite durch eine allmahlich zunehmende Gleichformigkeit der durch wiederholte Reizung ausgelosten Krampfe. Wurden Extremitatenreize (footshocks) fruher als die Hirnreizung gesetzt, so kurzten sie sowohl die motorischen Krampfe als auch die Nachentladungen ab oder blockierten beide in einigen Fallen vollstandig; dabei erfolgte jedoch keine Anderung des Krampfmusters.

Blockage of Highly‐stable “Kindled” Seizures in Rats by Antecedent Footshock

The effect of convulsive stimulation during periods of drug exposure on the development of tolerance to the anticonvulsant effects of carbamazepine (CBZ), diazepam (DZP), or sodium valproate (VPA) was studied in three similar experiments. In each experiment, amygdala-kindled rats were assigned to one of three groups: one group received a drug injection (CBZ, 70 mg/kg, IP; DZP, 2 mg/kg, IP; VPA, 250 mg/kg, gavage) 1 h before each of a series of 10 bidaily (one every 48 h) convulsive stimulations, a second group received the same dose of the drug 1 h after each of the 10 stimulations, and a third group served as a vehicle control. The drug tolerance test occurred in each experiment 48 h after the 10th tolerance-development trial; every rat received the appropriate dose of CBZ, DZP, or VPA 1 h before being stimulated. In each experiment, only the rats from the drug-before-stimulation group displayed a significant amount of tolerance to the drug's anticonvulsant effect. Thus the development of tolerance to the anticonvulsant effects of CBZ, DZP, and VPA was not an inevitable consequence of drug exposure; the development of tolerance was contingent upon the occurrence of convulsive stimulation during the periods of drug exposure. These results support the idea that functional drug tolerance is an adaptation to a drug's effects on ongoing patterns of neural activity, rather than to drug exposure per se.

Contingent tolerance to the anticonvulsant effects of carbamazepine, diazepam, and sodium valproate in kindled rats.

Ethanol (1.5 g/kg, IP) administered to kindled rats blocked the seizures normally elicited in these subjects by electrical stimulation of the amygdala. Tolerance to this anticonvulsant effect developed following a series of ethanol injections only when the amygdaloid stimulation was administered during the periods of ethanol intoxication. Control subjects stimulated each day prior to ethanol administration displayed no tolerance to ethanol's anticonvulsant effects. Such findings emphasize the important role of learning in the development of alcohol tolerance and support the view that tolerance develops more rapidly for responses that are affected by the alcohol exposure.

John P.J. Pinel

Papers

Experimental epileptogenesis: kindling-induced epilepsy in rats.

Alcohol withdrawal seizures: Implications of kindling

Blockage of Highly‐stable “Kindled” Seizures in Rats by Antecedent Footshock

Contingent tolerance to the anticonvulsant effects of carbamazepine, diazepam, and sodium valproate in kindled rats.

Learned tolerance to the anticonvulsant effects of alcohol in rats