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A strain of chicken, called here FEpi (for Fayoumi epileptic), bearing an autosomal recessive mutation, exhibits a form of reflex epilepsy with EEG interictal paroxysmal manifestations and generalized seizures in response to either light or sound stimulations. By using the brain chimera technology, we demonstrate here that the epileptic phenotype can be partially or totally transferred from an FEpi to a normal chick by grafting specific regions of the embryonic brain. The mesencephalon contains the generator of all epileptic manifestations whether they involve visual or auditory neuronal circuits, with the exception of the abnormal EEG which is transmitted exclusively by telencephalic grafts. This analysis supports the hypothesis that certain forms of human and mammalian epilepsies have a brainstem origin. Trends Neurosci . (1996) 19, 246–252

Interruption of a chronic GABA infusion into the rat somatosensory cortex induces the appearance of focal epileptic manifestations, known as the 'GABA withdrawal syndrome' (GWS). The aim of the present study was to determine, by immunocytochemistry, if neurotransmitters other than GABA are involved in GWS, namely: noradrenaline (NA), serotonin, choline acetyltransferase (CAT), cholecystokinin, neuropeptide Y, somatostatin and glial fibrillary acid protein (GFAP). Immunocytochemical data were compared in three animal groups: GABA-, saline- and L-aspartate (L-Asp)-infused rats. Only GABA-infused rats presented epileptic manifestations after interruption of the infusion. Saline- and L-Asp-infused rats served as controls. Observations were limited to the region surrounding the cortical infusion site. GABA-infused rats showed in the zone of the epileptic focus a number of cell bodies strongly immunoreactive to NA antibodies much larger than control rats. In addition, NA-immunoreactive fibers formed a dense plexus and some of them were observed around perikarya. In saline- and L-Asp-infused rats, the NA-immunolabelled fibers were sparse and NA immunolabelling was rarely observed in cell bodies. These results contrast to those obtained for the serotonergic system, where no significant difference was observed among the three groups of rats. CAT immunolabelling was observed in cell bodies, but not in nerve terminals in rats of the three groups. The number of CAT-immunoreactive cell bodies was much greater in GABA-infused rats than in the control animals. GFAP immunolabelling showed an important number of astrocytes throughout the cortex of the GABA-infused hemisphere, whereas, astrocytic reaction was limited to the infusion site in controls. Immunocytochemical data concerning peptides revealed cortical neuronal elements labelled similarly in the three groups of rats. Noradrenergic, cholinergic and glial modifications observed mainly in GABA-infused rats can result from lesion and from a specific action of GABA in chronic infusion. These modifications may contribute to the epileptogenesis of GWS, as recently demonstrated by electrophysiological recordings that show a modulating action of NA on firing activity of neurons involved in the epileptic focus.

The epileptic homozygotes of the Fayoumi strain of chickens (Fepi) are affected by photogenic reflex epilepsy with complete penetrance. Here we demonstrate that they are equally affected by audiogenic reflex epilepsy induced by intense sound stimulation. All the Fepi display sound-induced seizures from hatching to adulthood consisting of initial ‘ictal arousal’ and running fits usually followed by generalized clonico-tonic convulsions. A running fit is the preconvulsive motor sympton specifically induced by auditory stimulation while neck myoclonus is the preconvulsive motor symptom specifically induced by photic stimulation. The EEG interictal spikes and spike and waves are suppressed and replaced by a desynchronized trace during the seizures of both kinds. Viable neural chimeras were obtained by graft of embryonic brain vesicles from Fepi donors into normal chick embryos. Transfer of the complete audiogenic and photogenic phenotypes was obtained in chimeras resulting from embryonic substitution of both the prosencephalon and mesencephalon. The substitution of the prosencephalon alone resulted in transfer of interictal paroxysmal EEG activity accompanied by the sound and light-induced desynchronization and ‘ictal arousal’ with no motor seizures. Chimeras with embryonic substitution of the mesencephalon alone displayed running fits and convulsions induced by sound stimulation but only neck myoclonus following light stimulation. The conclusions are reached that: (i) the Fepi is a model of audiogenic and photogenic reflex epilepsy; (ii) in both types, the seizure initiator and the convulsion generator are localized in the brainstem, although reinforcement from telencephalic visual structures is needed to trigger photogenic generalized convulsions.

Photogenic genetic epilepsy was studied in an avian model, using either the Fayoumi epileptic chicken (Fepi) or neural chimeras obtained by replacement of em bryonic brain vesicles in normal chickens with those of Fepi embryos. In these two kinds of animals motor seizures accompanied by electroencephalographic (EEG) desynchronization and flattening (DF) were evoked by intermittent light stimulation (ILS). In chimeras with on ly the prosencephalon grafted, motor seizures were less severe but DF remained. ILS-induced DF persisted un der paralysis by gallamine triethiodide (Flaxedil). Extra cellular recordings were made in the prosencephalon (wulst) and in the mesencephalon (optic tectum) of paralysed animals. Units recorded in the prosencephalon of Fepi and chimeras showed abnormal interictal burst ing activity, distinctly different from the non-epileptic Fayoumi heterozygotes (Fhtz) and normal chickens. The mesencephalic units of Fepi and chimeras having both prosencephalon and mesencephalon grafted showed two types of abnormal activities during ILS-induced DF, which were distinct from the non-epileptic chickens: type I neurons displaying early, high sensitivity to ILS fol lowed by a prolonged suppression of activity; type II neurons displaying an early and prolonged suppression of activity. The results are discussed with respect to the brain structures generating ictal and interictal EEG ac tivities and motor seizures.

1. gamma-Aminobutyric acid (GABA) withdrawal syndrome (GWS) represents a particular model of focal epilepsy consecutive to the interruption of a chronic intracortical GABA infusion and is characterized by the appearance of focal epileptic electroencephalographic (EEG) discharges and localized clinical signs on withdrawal of GABA. Effects of Ca2+ channel blockers and N-methyl-D-aspartate (NMDA) antagonists were evaluated in living rats presenting a GWS after interruption of a 5-day GABA infusion into the somatomotor cortex and in neocortical slices obtained from such rats. Bursting properties and morphology of neurons were also analyzed in slices. 2. In living rats, the noncompetitive NMDA antagonist phencyclidine [1-(1-phenylcyclohexyl)piperidine] and the Ca2+ antagonist flunarizine [E-1 (bis(4fluorophenyl)methyl)-4(3phenyl2-propenyl)-piperazine] were administered systemically to two groups of rats. Rats in the first group (n = 12) were injected with the drug 30-60 min before discontinuation of the GABA infusion. In this case, phencyclidine (10 mg/kg ip) prevented the development of GWS (n = 5), whereas flunarizine (40 mg/kg ip) had no consistent effect on the GWS appearance and characteristics (n = 7). Rats in the second group (n = 12) were injected 60-90 min after GABA discontinuation, i.e., during a fully developed GWS. In that case, neither drug suppressed GWS. 3. Neuronal activities in the epileptic focus were studied in slices with conventional intracellular recording and stimulation techniques. From the 65 neurons recorded, 29 responded with EPSPs and paroxysmal depolarization shifts (PDSs) to white matter stimulation (synaptic bursting or SB cells). Nineteen other neurons presented, in addition to synaptically induced PDSs, bursts of action potentials (APs) induced by intracellular depolarizing current injection (intrinsic bursting or IB cells). The remaining 17 neurons presented no bursting properties to either synaptic stimulation or depolarizing current injection (nonbursting or NB cells). 4. The recorded neurons were located 0.7-1.2 mm distant from the lesion because of the penetration of the GABA infusion cannula. Intracellular injection of neurons (n = 4) with biocytin or Lucifer yellow revealed that both SB and IB neurons were large, spiny pyramidal neurons localized in layer V of the sensorimotor cortex. 5. Bath application of the selective antagonist of NMDA receptors DL-2amino-5phosphonovalerate or DL-2amino-7phosphonoheptanoate (10-50 microM) reversibly reduced the amplitude (by 25-50%) and the duration (by 20-25%) of PDSs in all cases (n = 17).(ABSTRACT TRUNCATED AT 400 WORDS)

Physiological sleep myoclonus (sleep onset myoclonus and myoclonus during paradoxical sleep) was recorded from the tails of 6 baboons (2 Papio hamadryas and 4 Papio papio) and its relationship with spontaneously occurring EEG paroxysmal discharges was studied. It was observed that during light slow wave sleep tail myoclonus (sleep onset myoclonus) was almost always associated with EEG paroxysmal discharges predominating in the fronto-rolandic cortex. During deep slow wave sleep the number of EEG paroxysmal discharges decreased and tail myoclonus disappeared. In contrast, during paradoxical sleep tail myoclonus became more frequent even in the absence of cortical paroxysmal discharges. Though at present we do not know whether sleep onset myoclonus is triggered or not by cortical paroxysmal discharges, we propose that sleep myoclonus (sleep onset myoclonus and myoclonus of paradoxical sleep) is independent of these discharges but that, at a given moment, the two phenomena may be coupled by a hypothetical subcortical pacemaker.

Repetitive limbic status epilepticus was produced in one baboon by intraamygdaloid microinjection of kainic acid. Brain metabolims was analysed by positron emission tomography (PET) after intravenous administration of 18fluorodexyglucose (18FDG). In a control examination the distribution of 18FDG was symmetric in homologous parts of the brain. In contrast, during the epileptic state a restricted zone, the fronto-temporal region, showed increased 18FDG incorporation. This region corresponded to the side of kainic acid injection and to the limbic epileptogenic focus as demonstrated by EEG recording. The use of the non-invasive PET technique is suggested as an adjunct to classical EEG and clinical observations for the location of an epileptic focus generating a status epilepticus.

The present study demonstrates that ethyl beta-carboline-3-carboxylate (beta-CCE), a benzodiazepine receptor antagonist, has hypnotic and sedative actions in cats. Moreover, at a dose that does not by itself affect sleep, beta-CCE reverses the action of diazepam on sleep organization. The hypnotic effect of subcutaneous administration of beta-CCE (5 mg/kg) lasts for 3-4 h. During this period, deep slow wave sleep (deep non-REM sleep) and paradoxical sleep (REM sleep) significantly increase, while wakefulness markedly decreases. These results, which are quite opposite to the effects of benzodiazepines on sleep organization in cats, support the notion that beta-CCE also acts as a benzodiazepine antagonist of sleep organization.

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.

The effects of Ro 5-4864, a 1,4-benzodiazepine with a high affinity for the peripheral-type benzodiazepine (Bz) binding site, were investigated in the baboon (Papio papio), which is genetically predisposed to epilepsy. A proconvulsant effect of low doses (1-3 mg/kg, i.v.) of Ro 5-4864 was observed by studying its effect on the photic responses induced by intermittent light stimulation in non-photosensitive baboons. Higher doses of Ro 5-4864 (10 mg/kg, i.v.) were overtly convulsant. The Bzs clonazepam and diazepam blocked these convulsant actions of Ro 5-4864 whereas neither Ro 15-1788, an antagonist of central Bz binding sites, nor PK 11 195, an antagonist of peripheral Bz binding sites, had any effect. It thus appeared that the convulsant effect of Ro 5-4864 was not mediated by Bz binding sites of either the central or the peripheral type. It is possible that Ro 5-4864 exerts its convulsant action at the picrotoxin site of the central Bz receptor - gamma-aminobutyric acid receptor-chloride ionophore complex.

The effect of monocular intermittent light stimulation (ILS) of either hemivisual field (HVF) of the full visual field (FVF) was examined in Papio papio with or without forebrain bisection. ILS of the HVF or the FVF in non-bisected baboons produced bisymmetrical and bisynchronous spike and wave which was followed by a self-sustained seizure without EEG evidence of hemispheric independence. ILS of the FVF in bisected baboons also produced bilateral spike and wave and self-sustained seizures of a similar nature. With ILS of the HVF in bisected baboons, EEG seizures lateralized largely to the contralateral hemisphere and when the ILS of the HVF was switched to the other eye similarly lateralized spike and wave and a self-sustained seizure were produced in the other hemisphere. These findings suggest that (a) the forebrain commissure, most probably the corpus callosum (and possibly the hippocampal commissure), plays a major but not unique role in the bisynchronization and generalization of the ILS-induced spike and wave and the self-sustained seizures, and (b) each hemisphere possesses independent cerebral excitability to the ILS.

The action of lorazepam was studied in photosensitive baboons. Animals were either naturally very photosensitive or rendered photosensitive by a previous injection of allylglycine. Intravenous administration of varying doses, from 0.05 to 0.5 mg/kg, of lorazepam blocked the myoclonus induced by intermittent light stimulation in all the animals. However, in the naturally photosensitive baboon the injection of lorazepam favoured the appearance of spontaneous myoclonus with no important EEG modification. This myoclonus is different from that induced by intermittent light stimulation, which is always preceded by spike-wave cortical discharges. Lorazepam-induced myoclonus appears during the period when the animal is not photosensitive and its origin is probably in the medulla or in the brain stem.

Two vermisectomized photosensitive baboons exhibited two different types of myoclonus, one induced by intermittent light stimulation (ILS) and the other occuring "spontaneously". The characteristics of these two types of myoclonus are described from a clinical and from an ECoG point of view. Myoclonus induced by ILS (ML) started at the eyelids and secondarily invaded the face and body; it was always preceded by frontorolandic spike-waves or polyspike-waves. The "spontaneous" myoclonus which followed vermisectomy (MV) was "massive", but involved firstly the trunk and secondarily the face and limbs; no ECoG paraoxysm accompanied this myoclonus, but we observed a parietal evoked potential of small amplitude, 10--15 msec after its onset. If MLs can be considered as consequences of the fronto-rolandic paroxysmal discharges, MVs seem to originate in the brain stem but appear similar to action myoclonus. This experimental situation showing two types of myoclonus resembles human hereditary degenerative syndromes (dyssynergic cerebellar myoclonus, progressive myoclonic epilepsy), without being exactly comparable. The conditions in which MVs were seen and their modifications during sleep and by different drugs are described. The relationships between MVs and MLs and myoclonic epilepsy are discussed.

Relative variations of the cerebral and extracerebral blood volume (CBV) were measured continuously by a novel atraumatic method in baboons to explore the relationship between changes in the systemic circulation and in the cerebral (and extracerebral) vascular responses, before, during and after generalized seizures induced by photic stimulation. Major bursts of generalized spikes and waves are accompanied by an increase of the mean arterial pressure and of the cerebral blood volume and a decrease of the nasal blood volume. During the seizure discharge a substantial increase in CBV occurs, associated with a dramatic increase in arterial pressure. However, the greatest increase in CBV occurs after the peak mean arterial pressure. The results show that the CBV does not passively follow the blood pressure and demonstrate the dramatic responsiveness of the nasal region to seizure discharge.

The effects of intracerebroventricular (i.c.v.) or systemic injections of Met- or Leu-enkephalin, beta-endorphin, FK 33.824 (D-Ala2, MePhe4, Met(O5)-ol-enkephalin) and of morphine and naloxone have been studied in baboons, Papio papio, which spontaneously show photically induced epileptic responses. Animals were chronically implanted with epidural or deep recording electrodes and a cannula in one lateral ventricle, and tested whilst seated in a primate chair. In some animals the natural syndrome was enhanced by the prior administration of DL-allylglycine, 100--200 mg/kg, i.v. Met- or Leu-enkephalin, 1--10 mg, i.c.v., did not lead to any manifest focal or generalized seizure discharges. Nor did it lead to any consistent enhancement or reduction of photically induced myoclonic responses (as tested 5--10 min after injection). beta-Endorphin, 0.1--0.5 mg, i.c.v., did not enhance or impair photically induced myoclonic responses. FK 33.824, 0.1--0.5 mg, i.c.v., depressed respiration and slowed EEG background rhythms for 9--15 h. This was associated with a loss of myoclonic responses to photic stimulation. These effects were reversed for 20--40 min following the injection of naloxone, 1 mg/kg i.m. A depression of respiration and a slowing of EEG rhythms was seen beginning 5--20 min after FK 33.824, 2 or 4 mg/kg, i.v. The higher dose also abolished photically induced myoclonic responses. Naloxone, 1 mg/kg, definitively reversed these effects. Morphine, 5--10 mg i.c.v., tended to increase the latency to onset of generalized myoclonus during photic stimulation. Myoclonic responses were delayed or diminished after morphine, 5 mg/kg, i.m. Naloxone, 1--2 mg/kg i.m., reversed this effect. Naloxone, 0.2--5.0 mg/kg i.m., alone, did not significantly modify photically induced myoclonus, either in animals of low or high initial responsiveness, or in those pretreated with allylglycine.

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.

Recording electrodes were implanted stereotaxically in limbic and thalamic structures and the mesencephalic reticular formation in twelve cats. The animals were submitted to daily stimulation of the left amygdaloid nucleus following the technique for the kindling procedure, always combined with 5 h 30 min post-stimulation monitoring. After about 18 days, generalized convulsive activity was established. The following results concerning the quantitative evolution of spontaneously occurring interictal spikes were obtained. Amygdaloid nuclei, the hippocampus and the thalamic nucleus ventralis lateralis (VL) demonstrated an increase of discharge activity during the kindling procedure, following by a significant decrease after convulsions had been elecited. Thalamic nucleus centrum medianum (CM) was the only recording site investigated where the amount of interictal discharge increased and remained at a high level even after generalized convulsions had been established. Fourier analysis of slow oscillations in discharge generation yielded two main types of significant periodicity. A 165 min oscillation could be detected in all structures tested except reticular formation, which developed a 110 min cycle shared only with the thalamic CM. Significant correlations in spike activity were obtained from various structures. Stimulated amygdala seemed to have alternating relations with thalamic CM and VL, whereas simultaneous oscillations excisted between MRF and CM. The occurrence of high voltage spikes in both contralateral and ipsilateral amygdalae was shown to be significantly correlated.

Studies of sleep organization of 8 subjects were performed during 4 dives between 500 and 610 msw (51 and 62 bar) in a helium-oxygen mixture. The results of the 156 sleep records showed that sleep was disrupted from 30 bar: awake periods and stages I and II increased, stages III and IV and REM periods decreased. These disturbances, which were more intense with fast compression and recovered during decompression, can be considered as further symptoms of the high pressure nervous syndrome (HPNS).

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.

We have analyzed the influence of several physical parameters in photosensitive epilepsy in two baboons ( Papio papio ), one very photosensitive and the other only slightly photosensitive. In order to describe average reactivity of the animals to intermittent light stimulation we chose 3 indices: I = mean intensity of the paroxysmal discharges, L = mean latency of these discharges, E = ratio of the number of effective stimulations to total number of stimulations. Comparing stimulations of different wavelengths, the most effective in revealing photosensitivity were the colours blue-green and dark green (487 and 538 nm); the least effective were green (544 nm) and red (676 nm). The paroxysmal discharges triggered by intermittent light stimulation were more intense, more frequent and of shorter latency when the distance between the light source and the animal was decreased, or when the surface area of the source was increased. With white light, increasing the pupil diameter increased the intensity of paroxysmal discharges in both animals, but to a greater extent in the more photosensitive animal. Closing the eyes also increased the response intensity but only when the pupils were dilated with homatropine. The effects of eye closure and pupillary dilatation, using coloured light stimulation, were not constant and seemed to depend upon the degree of photosensitivity of the baboon under study. These effects and the validity of the selected indices are discussed; the indices I and E are linked by a simple relation which we were able to evaluate, whereas L generally varies in the opposite direction to the other two indices.

Resume Une etude experimentale des effets “cliniques”, electrographiques et anatomo-pathologiques des embolies gazeuses carotidiennes a ete entreprise chez le chat. Les resultats portent sur 18 animaux qui ont ete suivis de 1 jour a 36 jours apres l'embolie. L'evolution electrographique est caracterisee, avant tout, dans les premieres heures qui suivent l'embolie par des remaniements morphologiques incessants, qui font suite a une periode de silence electrique initial. Cette periode de silence, qui est de breve duree, est plus ou moins generalisee a l'ensemble de l'hemisphere lese, mais predomine dans le territoire postero-interne. La recuperation debute toujours par le territoire antero-externe de l'hemisphere et en quelques heures une activite voisine de la normale s'etablit. Cette recuperation peut etre definitive, mais dans la moitie des cas, vers la 6eme h, s'individualise une periode caracterisee avant tout par l'existence de pointes periodiques pouvant etre generalisees a l'un ou aux deux hemispheres, mais predominant toujours au niveau du gyrus marginalis. Cette periode d'activite paroxystique disparait en general entre la 24eme et la 36eme h pour laisser place a un trace normal, ou persiste parfois une depression relative de l'electrogenese dans le territoire postero-interne. Du point de vue anatomo-pathologique, l'embolie gazeuse provoque une lesion histologique retrouvee seulement au niveau du neocortex et presque exclusivement au niveau du gyrus marginalis. Cette lesion evolue en trois stades: stade de spongiose, stade de reaction gliale, stade de fonte kystique. Des correlations sont etablies: d'une part entre l'evolution electro-clinique et les lesions histologiques (le stade des phenomenes electrographiques paroxystiques correspond notamment au stade de spongiose corticale), d'autre part entre ce type d'ischemie cerebrale corticale localisee et d'autres manifestations ischemiques rencontrees en pathologie experimentale et humaine.

Resume Differentes interventions chirurgicales portant sur les nerfs faciaux et la musculature perioculaire ont ete realisees chez des Papio papio plus ou moins photosensibles. La resection du nerf facial fait apparaitre dans les mois qui suivent, un spasme facial predominant au niveau de la musculature peribuccale. La resection de la musculature perioculaire provoque, dans les semaines qui suivent l'intervention, des modifications des potentiels evoques visuels dans le territoire fronto-rolandique ou ils revetent un caractere paroxystique. L'etude de leur cycle d'excitabilite fait apparaitre une facilitation importante de leurs composantes tardives. Le degre de photosensibilite est peu modifie par ces deux types d'intervention, mais le declenchement des myoclonies chez des animaux anterieurement photosensibles a ete plus aise qu'auparavant. Les relations entre les decharges paroxystiques provoquees par la stimulation lumineuse intermittente a differentes frequences au niveau fronto-rolandique et les myoclonies faciales qui leur sont associees sont etudiees en detail. Les rapports entre spasme facial et photosensibilite d'une part, et resection de la musculature perioculaire et modifications des PEV fronto-rolandiques d'autre part, sont discutes ainsi que leur mode d'apparition.

Limbic status epilepticus was produced with single microinjections of kainic acid in the amygdala of baboons ( Papio papio ). Long-term studies of the behavioral, electrographic and sleep alterations were performed. During status epilepticus the animals did not display aggressive behaviour. Feeding behaviour was diminished. Sleep was also deeply disturbed. Wakefulness was greatly increased, light slow wave sleep was diminished and deep slow wave sleep and paradoxical sleep were abolished. Sleep alterations persisted throughout the duration of status epilepticus (48–72 h). A modulation of paroxysmal discharges was observed depending on the degree of epileptogenicity of the limbic focus. Increased wakefulness cannot be attributed to convulsions since limbic status epilepticus in baboons is not accompanied by positive motor signs. It is proposed that increased wakefulness, of a particular type as revealed by the alterations of different accompanying behaviours, during this type of status epilepticus, depends on an internal arousing mechanism.

Certain benzodiazepines (BZs) like lorazepam, diazepam or clonazepam induce myoclonus jerks in photosensitive and non-photosensitive baboons, Papio papio , which are not accompanied by EEG paroxysmal discharges (type B). The effect of the selective BZ antagonist Ro 15-1788 was evaluated in this myoclonus. Ro 15-1788 completely blocked type B myoclonus without decreasing the level of vigilance in the two types of baboons, and reversed the antiepileptic action of the BZs in photosensitive ones, permitting the reappearance of myoclonus following EEG paroxysmal discharges (type A). l -5-hydroxytryptophan and progabide also blocked type B myoclonus, but the blockade was only transiently effective and was always accompanied by slight drowsiness.

The data gathered in 30 years’ study in man and in several animal species, but especially in the Papio papio baboon, tend to show that the cortex plays a decisive part in the seizure and interval discharges induced by intermittent light stimulation in photic epilepsy. two regions of the cortex predominate: the frontorolandic and occipital regions. The cortical cortex can, indeed, transmit or control the visual input to the frontorolandic region and can cause intermittent discharges in certain specific conditions in baboons and in certain human patients. The corticocortical pathway conveys the visual impulses to the frontorolandic cortex and is certainly modulated by deep structures like the reticular systems and the thalamus. At present no more can be said since further research is needed.

An anatomical atlas has been constructed of the brain of the baboon (Papio papio) in the orbito-meatal plane (OM-plane) which is frequently used in experimental positron emission tomography (PET) investigations. The atlas comprises 12 photographic reproductions of histological brain sections separated by 2.5 mm intervals, and covers telencephalic to pontine brain stem levels. The anatomical atlas was used in analysis of some PET scan images obtained after administration of either a benzodiazepine (BZ) antagonist, (11C)-Ro 15-1788, or a dopamine D2 receptor antagonist, (76Br)-bromospiperone. Since PET camera detects radiation emitted from a slice of tissue of 15 mm thickness, each PET image corresponds to the tissue represented on six levels of the anatomical atlas. In optimal conditions, the PET image shows a pattern of receptor labelling reminiscent of anatomical structures in the atlas. Sometimes, however, the superimposition of different labelled structures yields a PET image which lacks any apparent resemblance with individual anatomical structures. In these cases, the analysis of the PET scan must rely on the anatomical atlas, as well as available data on the distribution of specific binding sites.

The effects of the intravenous or intracerebroventricular injection of the stereoisomers, and the racemic mixture, of allyglycine (2-amino-pent-4-enoic acid) have been studied in baboons, Papio papio , with photosensitive epilepsy. Enhancement of the natural syndrome of photosensitive epilepsy is seen 1–12 h (maximally at 3–8 h) after l -allylglycine, 100 mg/kg, intravenously, or d,l -allyglycine, 200 mg/kg intravenously. Such enhancement is seen with a slower onset, and to a lesser, and more variable, extent after d -allylglycine, 500–750 mg/kg, intravenously. Brief focal or generalised seizures occured (in the absence of intermittent photic stimulation) after l -allylglycine, 150–200 mg/kg, intravenously. This effect is similar to that previously observed after d,l -allylglycine, 300–400 mg/kg. d -Allylglycine, 780 mg/kg, intravenously produced episodes of vertical nystagmus with increased extensor motor tone, but no ‘spontaneous’ seizures. Intracerebroventricuar injection of l -allylglycine, d -allylglycine or d,l -allylglycine, 100 mg in 1 ml saline, did not modify the natural syndrome of photosensitive epilepsy. d -allylglycine, or d,l -allylglycine, 100 mg intracerebroventricularly, after 1–2 h gave rise to a syndrome with vomiting, sustained vertical nystagmus, and intermittent extensor spasms. The results are interpreted in terms of regional differences in the metabolism of the two isomers to active compounds that can inhibit glutamic acid decarboxylase. d -Allylglycine is active only at the brain stem and cerebellum because d -amino acid oxidase is largely confined to these brain areas.

beta-Carboline-3-carboxylic acid ethyl ester (beta-CCE) was tested on two models of epilepsy in the baboon: kainic acid-induced limbic status epilepticus and photosensitive epilepsy. Beta-CCE, at very low doses ranging from 8 to 100 microgram/kg (i.v.), induced a reactivation of the limbic focus and photomyoclonic and generalized seizures in photosensitive and non-photosensitive baboons. The proconvulsant effect of beta-CCE may be associated with its binding to a particular subclass of benzodiazepine receptors.

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.

An in vivo characterization of specific central type benzodiazepine (BZD) binding sites, labelled with [11C]Ro 15-1788 was performed, using positron emission tomography. After i.v. injection of 10 mCi [11C]Ro 15-1788 (corresponding to 1 nmol/kg), sequential quantitative tomographic slices of the brain were obtained during 80 min. In some experiments various doses of different cold drugs (BZD agonist or antagonist) were injected i.v. subsequently in order to explore the specificity of the binding of the radioligand in brain structures. The main criteria usually utilized in vitro to demonstrate a specific binding to receptors, such as regional distribution, stereospecificity and saturability of the binding and pharmacological effect linked to the receptor's occupancy, were demonstrated in the brain of a living baboon.

Several putative neurotransmitter amino acids and monoamime metabolites were measured in the cerebrospinal fluid of spontaneously photosensitive baboons (Papio papio) at different periods witvarying degrees of photosensitivity in the same animals. At maximum photosensitivity the inhibitory amino acids γ-aminobutyric acid and taurine were lower, and those of asparagine (metabolite of the excitatory amino acid aspartate) were higher, than when the animals were not photosensitive. Thus a decreased inhibition and perhaps increased excitation correlates witthe level of photosensitivity.

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.

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.

1. 1. Light-induced epilepsy in the young baboon, Papio papio, was studied with chronically implanted depth electrodes in nineteen animals, and the findings were correlated with cortical recordings. 2. 2. Spontaneous bifrontal discharges (mainly spike and wave) occurred in these animals, which tended to block with eye-opening and altering. The discharges were maximal during spontaneous drowsiness. 3. 3. With photic stimulation at 20–25/sec these discharges spread first over the anterior cortical superficial and deep areas, then to the internal capsule, pons and brain-stem, and finally became widespread in all recorded deep structures, excluding the rhinencephalon. The discharges were accompanied by clonic movements, first of the eyelids, then successively of the face, head, upper and lower limbs and generalized, without apparent disturbance of consciousness. A relative independence of the anterior and posterior parts of the cortex was noted, with paroxysmal discharges anteriorly and a concurrent driving response to photic stimulation posteriorly. 4. 4. The above electro-clinical phenomena might stop with cessation of the photic stimulation or might develop into self-sustained tonico-clonic generalized epilepsy, with loss of consciousness. The seizure started always in the fronto-Rolandic areas and continued with generalized synchronous bursts of poly-spikes and slow waves. Except for the independent rhinecephalic activity, all the seizure discharges, however widespread, were closely linked with those in the fronto-Rolandic cortex, where they remained maximal throughout. 5. 5. This form of epilepsy in a primate may be analogous to reflex, light-triggered epilepsy in man but the topography of light-induced paroxysmal electrical activity observed in the baboon differs from the usually seen in man.