C. Menini

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.

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.

The kinetics and displacement of [11C]flunitrazepam in the brain of the living baboon

The distribution and kinetics of [11C]flunitrazepam in the brain were studied by positron emission tomography in the living baboon. Flunitrazepam was labelled on the methyl group with the 20 min positron emitter carbon 11. Fifteen to 25 mCi corresponding to 15-30 nmol were injected i.v. and sequential tomographic pictures of the brain were obtained. In some experiments, therapeutic doses of various benzodiazepines were injected i.v. subsequently in order to study the displacement of the radioactive ligand from brain structures. Lorazepam was shown to displace [11C]flunitrazepam from brain tissue, although other benzodiazepines (chlordiazepoxide, Ro 116896 and Ro 116893) led to a redistribution of the radioactive ligand in the body accompanied by an increase of brain radioactivity.

Electroencephalographic Study of the GAB A-Withdrawal Syndrome in Rats

Summary: The spatial and temporal EEG features of the epileptogenic syndrome induced by cessation of chronic intracortical GABA infusion in normal rats are described. In the initial stages, the paroxysmal discharges (PDs) induced by withdrawal from unilateral GABA application may appear either unilaterally or bilaterally, although with greater amplitude on the infused side. PDs are transitorily accompanied by behavioral signs of distal myoclonus of the body territory corresponding to the infused area (contralateral hindlimb). Later, the paroxysmal activity becomes more localized, circumscribed to the can‐nula‐infused site and with ipsilateral propagation to anterior cortical areas. The amplitude of PDs decreases progressively while their frequency increases, reaching its maximal value at about 4 h after the first PDs have appeared. In the final stages of the syndrome, which may last several days, clinical manifestations are absent and PDs are activated by slow‐wave sleep and reduced during REM sleep and waking. Chronic intracortical applications of taurine failed to induce any electroclinical changes on withdrawal and were unable to inhibit the focus elicited by GABA withdrawal, whereas reinstatement of GABA infusion into the epileptogenic area was effective in blocking the paroxysmal activity. Intracortical infusion of baclofen induced the appearance of an epileptogenic focus that waned on withdrawal. The GABA‐withdrawal syndrome appears to be a new model of focal status epilepticus; it may be useful as an experimental model of human partial epilepsy to investigate the role of GABAergic neurotransmission.

Cholinergic system disturbance in the West syndrome

The effects of drug on the cholinergic system (atropine and physostigmine) were evaluated in acute tests in 12 infant patients with the West syndrome (WS) and in 12 older ones who had suffered from WS at typical ages, displaying various types of epileptic symptoms. In both groups paroxysmal EEG activity was inhibited by physostigmine and enhanced by atropine. In two infants who had frequent clinical seizures, the seizures were temporarily blocked by physostigmine. These effects in WS are different from those reported in some other experimental and clinical epilepsies, where physostigmine has a proepileptic and atropine often an antiepileptic effect, thus indicating that a cholinergic system disturbance may occur in patients with WS.

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.

The Influence of Light Stimulation on Subcortical Potentials Evoked by Single Flashes in Photosensitive Papio papio

Summary: Visual evoked potentials (VEPs) from the fron‐torolandic (FR) cortex and from subcortical nuclei (colliculi superioris, pulvinar, corpori geniculati lateralis, centrum medianum, ventralis lateralis) and from pontine reticular formation were analyzed in Papio papio monkeys rendered photosensitive by a subconvulsant dose of allylglycine. The VEPs induced by single flashes were compared statistically with those induced by flashes preceded by trains of intermittent light stimulation (ILS). This latter mode of stimulation provoked the appearance of paroxysmal VEPs (PVEPs) in the FR cortex with the same morphology as the spikes and waves induced in this area by the ILS. The aim of our research was to provide evidence for the possible implication of the subcortical structures which we have studied in the elaboration of PVEPs and thus of spikes and waves. The VEPs recorded at the thalamic and pontine levels were modified when PVEPs were present. These modifications varied according to the site, but subcortical VEPs were never paroxysmal. In structures with visual functions (colliculi superioris, corpori geniculati lateralis), the VEPs were modified by the ILS, but showed more marked changes when PVEPs were present. Thus, these structures may contribute to the genesis of PVEPs. In the other structures (centrum medianum, ventralis lateralis, and pontine reticular formation), modifications of the VEPs occurred only when PVEPs were present. Thus, these structures would be only secondarily involved. We also present preliminary results concerning the effects of lesioning the pulvinar and the ventralis lateralis on the susceptibility of the FR cortex to produce spikes and waves during ILS. Since this susceptibility returned fully a week after a bilateral lesion of the pulvinar, this nucleus does not appear to exercise a direct action in the elaboration of FR PVEPs. A lesion of the ventralis lateralis diminished the epileptogenic susceptibility of the FR cortex without blocking it completely. This effect probably arises because the nucleus ventralis lateralis projects to a cortical area (area 4) where PVEPs and spikes and waves predominate.