Ch. Menini

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.

Cortical unit activity during intermittent photic stimulation in Papio Papio. Relationship with paroxysmal fronto-rolandic activity☆

Extracellular records have been made in the fronto-rolandic (FR), parietal and occipital cortical areas in Papio papio injected with allylglycine and paralysed with a synthetic curarizing agent. The organization of the unit discharges in the absence of intermittent light stimulation (ILS) is normal. During ILS, unit discharges in the FR cortex are organized in bursts of high frequency that are synchronous with the spikes of the EEG paroxysmal discharges (PD) in the same territory; this burst-organized FR activity is reversible, and bursts disappear when the ILS stops. In addition, in the FR cortex, triple or single flashes induced paroxysmal visual evoked potentials (PVEP) whose spikes were accompanied by bursts identical to the preceding ones. The slow waves which constituted the PD and the PVEP corresponded to a transitory inhibition of the FR neuronal activity. From the unit discharge patterns, no difference was observed between the two EEG paroxysmal activities recorded. No pattern of discharge in bursts was ever observed in the parietal and occipital cortex. The synchronizing role of the light stimulation in the FR cortex in Papio papio under allylglycine is discussed and the results are used to compare the experimental model with the naturally highly photosensitive animal. The particular reactivity of the FR cortex with respect to other regions is also discussed. Finally, the results bring forth new information in favour of a similarity between PD and PVEP.

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.

Paroxysmal visual evoked potentials (PVEPs) in Papio papio. I. Morphological and topographical characteristics. Comparison with paroxysmal discharges

This study describes a method of stimulation capable of inducing fronto-rolandic (FR) visual evoked potentials of very large amplitude (up to an even greater than 1000 μV) to isolated flashes in the naturally photosensitive Papio papio and in those made photosensitive by an injection of allylglycine. The morphological and topographical characteristics of these FR paroxysmal visual evoked potentials (PVEPs) are described in two experimental situations: the animals either awake and placed in a restraining chair, or paralysed with a synthetuc curare agent and ventilated artificially. During thes study, the following observations were made: 1. (1) The morphology of the PVEPs is similar to that of the paroxysmal discharges (PD) induced by intermittent light stimulation (ILS) in photosensitive animals. 2. (2) The PVEPs are observed in the FR cortex; those of maximal amplitude are located in the precentral area. Simultaneously, the specific occipital responses retain their usual characteristics and never become paroxysmal. 3. (3) PVEPs have never been observed in non-photosensitive animals in the absence of allyglycine. In non-paralysed photosensitive or allyglycine-injected animals the PVEPs are hard to obtain, while the PDs and seizures on the contrary are easily induced by the ILS. Conversely, in paralysed and allyglycine-injected animals, the PDs and seizures are difficult to obtain whereas the PVEPs occur with increased amplitude and frequency. Several questions arise from these observations concerning the origin of the visual afferents to the FR cortex which induce the PVEPs, and concerning the possible relationships between the PVEPs and the PDs induced by ILS. In response to the latter question, it seems that despite the similarities of morphological and topographical characteristics, the PVEPs and PDs evolve differently after curaruzation of the animal.

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.

Local asymptomatic status epilepticus induced by withdrawal of GABA infusion into limbic structures

Abstract Most of the experimental models of status epilepticus result either from administration of a variety of excitatory neurotoxins or repeated electrical stimulation. Here we propose a new model based on the withdrawal of chronic γ-aminobutyric acid (GABA) infusion into limbic structuresvia osmotic minipumps. Appearing with a latency of about 50 min, continuous pseudo-rhythmic EEG epileptic spiking was elicited for about 12–24 h after removal of GABA infusion in hippocampus or amygdala. No apparent distant brain damage was observed. This model differs from many others by several features and could result from different mechanisms.

Characteristics and origin of frontal paroxysmal responses induced by light stimulation in the Papio papio under allylglycine

In the Papio papio, curarized and rendered photosensitive by injection of a subconvulsant dose of DL-allylglycine, single flashes induce frontal paroxysmal evoked responses on condition that they be preceded by trains of intermittent light stimulation (ILS). The characteristics of these responses have been compared to those of non-paroxysmal responses induced in the same cortical area by isolated flashes (not preceded by trains of ILS). The paroxysmal responses resemble spikes and waves and consist of one or two positive spikes followed by a slow negative wave. The intracortical distribution of these responses has been studied in the motor cortex. The non-paroxysmal responses are probably not generated at this level. On the other hand, observations made during paroxysmal responses show the existence of two cortical responses; this demonstration follows from the existence of an inversion in some response components, linked to a negativity and a local cellular activation. A generator, situated in the pyramidal cell layer, is active during the positive surface spikes; the other generator, situated in the more superficial cortical layers, is active at the beginning of the slow negative surface wave. The cortical and subcortical afferents likely to bring these generators into play are discussed.

Les crises induites — Ou non — Par la stimulation lumineuse intermittente chez le « Papio papioaprès injection d'allylglycine

Summary Allylglycine, an inhibitor of GABA synthesis, produces increased sensitivity to photic stimulation and in convulsant doses spontaneous seizures arising occipitally in the baboon ( Horton and Meldrum, 1973 ). In this study, convulsant doses of allylglycine induced either sharp wave and polyspike fronto-rolandic discharges (FR) or critical posterior discharges which then reinforce the fronto-rolandic spikes. A seizure may then arise from the fronto-rolandic region and secondarily spread to the rest of the cerebral cortex. Intermittent photic stimulation produces a reinforcement of the fronto-rolandic sharp waves and can also induce self-maintaining mechanisms similar to those just described. In this situation, however, and with the animals paralysed with Flaxedil no seizures arising occipitally have been observed. The role of the occipital cortex as the sensory visual and somatic afferent in photosensitive epilepsy in the baboon is discussed in the light of these results.

Loss of phase synchrony in an animal model of partial status epilepticus

Interrupting a focal, chronic infusion of GABA to the rat motor cortex initiates the progressive emergence of a sustained spiking electroencephalographic (EEG) activity, associated with myoclonic jerks of the corresponding body territory. This activity is maintained over several hours, has an average frequency of 1.5 Hz, is localized to the infusion site and never generalizes. The GABA withdrawal syndrome (GWS) has therefore features of partial status epilepticus. Changes in EEG signals associated with the GWS were studied in freely moving rats by measuring the phase synchrony between bilateral epidural records from the neocortex. Our results showed (i) epileptic activity was associated with a striking decrease in phase synchrony between all pairs of electrodes including the focus, predominantly in the 1-6 Hz frequency range. There was a mean decrease of 75.34+/-5.26% in phase synchrony levels between the period before GABA interruption and the period after epileptic activity appeared. (ii) This reduction in synchrony contrasted with an increase of power spectral density in the corresponding EEG channels over the same 1-6 Hz frequency range, (iii) neither changes in synchrony nor in nonlinear dynamics were detected before the first EEG spikes, (iv) systemic injection of ketamine, an antagonist of N-methyl-d-aspartic acid (NMDA) receptors, modified transiently both epileptic activity and the synchrony profile. (v) Spiking activity and synchrony changes were suppressed by reperfusion of GABA. Our data suggest that, during a partial status epilepticus, interactions between the epileptic focus and connected neocortical neuronal populations are dramatically decreased in low frequencies.