C. Silva-Barrat

The GABA-withdrawal syndrome: a new model of focal epileptogenesis.

A novel model of focal, cortical epilepsy is described. Chronic (6 h to 14 days), localized application of gamma-aminobutyric acid (GABA) into the somatomotor cortex of rats induces, upon withdrawal, the appearance of epileptogenic activity with maximal electrographic expression circumscribed to the infused site. This GABA-withdrawal syndrome (tested for a 100 micrograms/microliter/h dose) lasted from 24 to 168 h (mean values). A significant correlation was found between infusion time and duration of the excitability rebound, with the longer duration corresponding to the shorter infusion time. A distant lesion effect was observed in the thalamic area of cortical projection. The potential use of this neurotransmitter-induced phenomenon in the study of brain plasticity in general, and of epilepsy in particular, is discussed.

Epileptogenic γ-aminobutyric acid-withdrawal syndrome after chronic, intracortical infusion in baboons

We studied the effects of chronic (7 days) infusion of GABA (100 micrograms/microliter) applied intracortically into the fronto-rolandic (FR) area of baboons, via osmotic minipumps. In photosensitive animals, bilateral GABA application produced a complete blockade of the paroxysmal discharges and associated clinical signs induced by intermittent light stimulation. Unilateral administration had similar effects, although these developed more gradually. At the end of the infusion period, both photosensitive and non-photosensitive animals showed a transitory state (3-4 days) of cortical hyperexcitability (spontaneous epileptogenic activity) localized to the infused area. The data indicate a role of GABA both in the natural photosensitivity of the epileptic baboon and in the withdrawal syndrome consecutive to the sudden interruption of chronically enhanced GABA levels in the FR territories of this monkey.

Multiunitary activity naalysis of cortical and subcortical structures in paroxysmal discharges and grand mal seizures in photosensitve baboons

Abstract Cortical and subcortical multiunitary activities (MUA) and EEG were s0imultaneously recorded in baboons made photosensitive bu a subconvulsant does of dl -allglycine. Intermittent light stimulation (ILS) trains induced in these animals fronto-rolandic (FR) paroxysmal discharges (PDs, constituted as spikes and waves) and grand mal seizures. During the induction of FR PDs by ILS trains, the visual structures (occipital cortex, colliculi superiors, pulvinar) showed a significant MUA increase which was not related to teh PD spike or wave but correlated with the flashes. The first structure showing bursts of MUA that frequently preceded the PD appearance was the FR cortex. When PDs appeared, the brusts were related to the spikes of PDs and were followed by an inhibition during the slow wave. The pontine and mesencephalic formations and the facial nuclei were activated in bursts after the FR PDs had reached a certain amplitude. The thalamic nuclei ventralis lateralis, centrum medianum and lateralis posterior were activated only later, when the FR PDs had reached an even greater amplitude. It is suggested that the activation of visual structures is necessary for FR PD appearance. The secondary pontine and mesencephalic activation could reinforce that of the FR cortex and then the thalamus, and could determine the myoclonus observed in unparalysed animals. When the ILS is continued, grand mal seizures appear. The onset of the seizures could be linked to the loss of FR cortical control of the subcortical structures. The resulting reticular activation would be responsible for the vasomotor modifications which constitute the first clinical signs of a seizures.

Effects of localized, chronic GABA infusions into different cortical areas of the photosensitive baboon, Papio papio

The effects of chronic (7 days) intracortical GABA infusions were investigated in both naturally photosensitive and non-photosensitive baboons. Bilateral and unilateral infusions into motor and occipital regions blocked photosensitivity, while premotor and prefrontal cortex infusions had no effect on the electro-clinical manifestations of this type of reflex epilepsy; the monkeys with prefrontal GABA infusions, however, showed selective attention deficits, detected with the delayed response test. In all cases a GABA withdrawal syndrome, appearing as epileptogenic spontaneous activity localized to the infused sites, was found at the cessation of GABA application. We conclude that GABAergic systems localized at discrete cortical areas play an important role in photosensitivity and in the modulation of cognitive processes in the monkey.

Epileptic discharges induced by intermittent light stimulation in photosensitive baboons: a current source density study.

The current source density (CSD) method was applied to the study of paroxysmal discharges (PDs) induced by intermittent light stimulation (ILS) in Papio papio baboons made photosensitive by a subconvulsant dose of allylglycine. CSD was studied in the motor and premotor areas (4 and 6). Laminar profiles of sinks and sources are similar in both areas. Nevertheless, the motor area seems to become involved first since it shows the earliest and most prominent sink in layer III. Such a sink, correlated with the PD spike, moves progressively upward to the cortical surface. The localization and other experimental arguments obtained by the same method suggest that this sink could be mainly of dendritic origin. The cortico-cortical afferents to the superficial layers of the motor area might thus determine the generation of this sink. A smaller sink, detected at the same latency between layers V and VI could correspond to synaptic activations due to thalamo-cortical afferents probably arriving on the pyramidal cells which project to the spinal cord. Intense sinks correlated with the PD wave in layer V could be passive, due to active sources lying just above and/or below, because in previous studies an inhibition of the cellular discharges was always observed in correlation with the wave. It is suggested that ILS triggered PDs involve visual cortico-cortical afferents directed mainly to the superficial layers of the motor area provoking an intense synaptic activation of the cellular elements situated at this level.

Physostigmine antagonizes benzodiazepine-induced myoclonus in the baboon, Papio papio.

The antagonism of some benzodiazepine (Bz) actions by physostigmine was investigated in 4 Papio papio baboons. As a model of these actions, the myoclonus induced in this species by clonazepam i.m. administration was used. The baboon develops, 20-30 min after Bz i.m. injection, a non-epileptic myoclonus characterized by clinical symptomatology (jerks involving mainly the neck and the trunk bilaterally), by the absence of any correlative EEG discharge, and by its facilitation during movement. This Bz-induced myoclonus resembles the intention myoclonus of human patients, as seen for example after anoxia. In the present series, the effect of physostigmine i.v. injection on the frequency of clonazepam-induced myoclonus was tested. Physostigmine produces a rapid and total abolition of the myoclonus, and this effect lasts for a period which corresponds to the pharmacological activity of physostigmine. On the contrary, atropine i.v. injection considerably increases the amount of Bz-induced myoclonus. These results allow the existence of an anticholinergic action of benzodiazepines, reversed by physostigmine, and the theory that the myoclonus would be the consequence of a cholinergic system depression to be hypothesized.

Anticonvulsant effects of localized chronic infusions of GABA in cortical and reticular structures of baboons

We studied the effects of chronic (7 day) infusions of GABA (100 and 20 micrograms/microliter, 10 microliter/h) applied in different cerebral structures of baboons made photosensitive by a subconvulsant dose of allylglycine. The GABA infusion has partial anticonvulsant effects when applied to the motor cortex, reticular magnocellular nucleus (RMC), or substantia nigra (SN), but when directed to the prefrontal cortex (area 8) it has no effect. These anticonvulsant effects of GABA infusion are more important when GABA is infused into the motor cortex, where paroxysmal discharges (PDs) originate, than when it is infused into the RMC. In contrast, the anticonvulsant effects on light-induced generalized seizures are more pronounced when GABA is infused into the RMC than when it is infused into the motor cortex. GABA infusion into the SN has no effect on PDs and myoclonia and blocks seizures less effectively than the RMC infusion. These results are in accordance with the role of the motor cortex as a generator of PDs and of RMC in the generalization of seizures. Focal paroxysmal EEG and clinical activities, previously reported to appear at the end of the motor cortex GABA infusion, were not observed after RMC or SN infusions. However, behavioral hyperactivity occurring at the end of subcortical GABA infusions was observed. These behavioral signs could correspond to the clinical expression of a GABA withdrawal syndrome.

The GABA-withdrawal syndrome: a model of local status epilepticus.

The GABA-withdrawal syndrome (GWS) is a model of local status epilepticus following the interruption of a chronic GABA infusion into the rat somatomotor cortex. GWS is characterized by focal epileptic electroencephalographic discharges and associated contralateral myoclonus. In neocorticai slices obtained from GWS rats, most neurons recorded in the GABA-infused area are pyramidal neurons presenting bursting properties. The bursts are induced by white-matter stimulation and/or intracellular depolarizing current injection and correlate with a decrease of cellular sensitivity to GABA, caused by its prolonged infusion. This effect is related to a calcium influx that may reduce the GABAA receptormediated inward current and is responsible for the bursting properties. Here we present evidence for the involvement of calcium- and NMDA-induced currents in burst genesis. We also report modulatory effects of noradrenaline appearing as changes on firing patterns of bursting and nonbursting cells. Complementary histochemical data reveal the existence of a local noradrenergic hyperinnervation and an ectopic expression of tyrosine hydroxylase mRNAs in the epileptic zone.

Stimulus-sensitive myoclonus of the baboon Papio papio: pharmacological studies reveal interactions between benzodiazepines and the central cholinergic system.

The baboon Papio papio develops a nonepileptic myoclonus 20 to 30 min after i.m. benzodiazepine injection. It is characterized by bilateral jerks involving mainly the neck and the trunk, by the absence of any correlative EEG paroxysmal discharge, and by its facilitation during movement or agitation. This myoclonus resembles the intention myoclonus of human patients as seen, for example, after anoxia. We found in experiments on 10 adolescent baboons that atropine alone induced the myoclonus for several hours, that physostigmine completely antagonized the benzodiazepine-induced as well as the atropine-induced myoclonus, and that the peripherally acting cholinergic antagonist, methyl-QNB, and agonist prostigmine had no action on the myoclonus, suggesting that the benzodiazepine-induced myoclonus in this species depends on a strong depression of the central cholinergic system by benzodiazepine. The benzodiazepine-induced myoclonus was mediated by benzodiazepine receptors as it was blocked by the specific benzodiazepine receptor antagonist, Ro 15-1788, which did not block atropine-induced myoclonus; latency to myoclonus after benzodiazepine was longer than after atropine. These facts suggest that benzodiazepines, by an as yet unknown mechanism, induce a depression of the cholinergic system which in turn leads to the development of myoclonus. Finally, the benzodiazepine-induced myoclonus of the baboon can be considered as a good model for testing drugs that act on the muscarinic cholinergic system and also for testing benzodiazepine-acetylcholine interactions.

The influence of intermittent light stimulation of potentials evoked by single flashes in photosensitive and non-photosensitive Papio papio ☆

The effects of intermittent light stimulation (ILS) on visual potentials (VEPs), evoked in different cortical areas, were statistically studied in baboons either naturally photosensitive or made photosensitive by allylglycine at a subconvulsant dose, as well as in non-photosensitive animals. VEPs were induced by single flashes (paradigm a) or by flashes preceded by trains of ILS (paradigm b). In every baboon, photosensitive or not, the VEPs induced by paradigm b in the striate area show a decrease of amplitude compared to VEPs induced by paradigm a. The ERG evolves in the same way. Therefore, these effects do not depend on photosensitivity; they depend on the intensity of stimulation. In photosensitive animals the single flash in paradigm b can induce a paroxysmal VEP in the fronto-rolandic (FR) area. In parietal and peristriate areas the VEPs induced by paradigm b show new late components when compared to those induced by paradigm a. These changes are observed even if no FR paroxysmal VEP is induced; they depend on the presence of a train of ILS preceding the single flash and on the predisposition to epilepsy (both natural and due to allylglycine); in the non-photosensitive animals the VEPs recorded in the same areas do not show such differences. We consider that among afferents which could act in inducing FR paroxysmal activities some cortico-cortical visual afferents can come from non-specific cortical areas (parietal or peristriate), but would not directly originate in the striate cortex; anatomical data in this species may support such a hypothesis.