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Electroencephalographic characteristics and clinical symptoms of an avian genetic reflex epilepsy have been transferred from Fayoumi epileptic (Fepi) chickens to non-epileptic chickens by embryonic homotopic grafts of brain neuroepithelium. Transplanted tissues belonging to the prosencephalic vesicle transferred epileptic electrical features while tissues from the mesencephalic vesicle were responsible for seizure motor manifestations of the disease. Thus each of these tissues can express their own specificity when grafted separately in a normal host, but they co-operate to produce the complete epileptic phenotype when grafted together.

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

1. 1. The authors describe here the effects of intravenous administration of RP 60180, a novel kappa agonist, on conscious baboons of the species Papio papio , which spontaneously present photically induced epileptic responses. 2. 2. Animals (n = 2) were chronically implanted with epidural recording electrodes and tested whilst seated in a primate chair. The electrocorticogram (ECoG) and electrocardiogram (ECG) were recorded during a control period of at least 30 minutes before the injection of RP 60180 (1 to 4.5 mg/kg i.v.) and immediately afterwards. 3. 3. Qualitatively, up to the dose of 4.5 mg/kg i.v., RP 60180 did not modify ECoG backgroundin term of paroxysmal activity in comparison with that observed during the control period. It did not cause any manifest focal or generalized seizure discharges, nor did it consistently enhance or reduce photically induced myoclonic responses. 4. 4. From the dose of 1 mg/kg i.v., RP 60180 slowed ECG frequency. This effect, which lasted for about 30 minutes post-injection, was most often seen at the higher doses. 5. 5. In another set of experiments, one baboon received the kappa agonist U-50488 (a benzacetamide derivative of spiradoline) at 1 and 3 mg/kg i.v. U-50488, at 3 and to a lesser degree at 1 mg/kg i.v., induced paroxysmal bursts of slow wave ECoG activity and a slowing of the ECG. These effects lasted about 1 hour post-drug administration. During this period, we observed spontaneous vocalization, as if the animal were complaining, as well as shaking.

Summary: The homozygous Fayoumi strain of epileptic chickens (Fepi) is affected by generalized convulsions consistently induced by intermittent light stimulation (ILS) and by intense sound. Although interictal EEG recordings show continuous spikes and spike and wave activity, desynchronization and flattening (DF) of the EEG are observed during seizures. We have studied development of the epileptic phenotype in embryonic (E) and posthatching (P) Fepi. As compared with those of chicken embryos of a normal strain, no differences were observed in the EEG before embryonic day (E) 16. Clearly differentiated spikes and spike and waves appeared at E17 in Fepi. Metrazol-induced EEG seizures were observed at E16 in normal embryos and at E17 in Fepi. The Fepi showed some characteristics: Spontaneous EEG seizure-like discharges also appeared at E17 but decreased to-ward hatching; visual or acoustic hyperexcitability developed at E20 together with evoked responses in normal chickens; desynchronization of the EEG, typical of the epileptic seizure of the adult, could be induced by ILS at E20, but ILS- or sound-induced generalized motor seizures appeared at P1, a few hours after hatching. Results show that Fepi phenotype reaches full expression at P1, but the electric paroxysms are expressed earlier, paralleling synaptic maturation.

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.

Chantier qualité GA; Photosensitive reflex epilepsy is caused by the combination of an individual's enhanced sensitivity with relevant light stimuli, such as stroboscopic lights or video games. This is the most common reflex epilepsy in humans; it is characterized by the photoparoxysmal response, which is an abnormal electroencephalographic reaction, and seizures triggered by intermittent light stimulation. Here, by using genetic mapping, sequencing and functional analyses, we report that a mutation in the acceptor site of the second intron of SV2A (the gene encoding synaptic vesicle glycoprotein 2A) is causing photosensitive reflex epilepsy in a unique vertebrate model, the Fepi chicken strain, a spontaneous model where the neurological disorder is inherited as an autosomal recessive mutation. This mutation causes an aberrant splicing event and significantly reduces the level of SV2A mRNA in homozygous carriers. Levetiracetam, a second generation antiepileptic drug, is known to bind SV2A, and SV2A knock-out mice develop seizures soon after birth and usually die within three weeks. The Fepi chicken survives to adulthood and responds to levetiracetam, suggesting that the low-level expression of SV2A in these animals is sufficient to allow survival, but does not protect against seizures. Thus, the Fepi chicken model shows that the role of the SV2A pathway in the brain is conserved between birds and mammals, in spite of a large phylogenetic distance. The Fepi model appears particularly useful for further studies of physiopathology of reflex epilepsy, in comparison with induced models of epilepsy in rodents. Consequently, SV2A is a very attractive candidate gene for analysis in the context of both mono- and polygenic generalized epilepsies in humans.

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 cannula-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.

Pour la communauté française des neurosciences, l’institut Marey, petit pavillon du début du siècle détruit en 1978, n’a pas encore livré tous ses mystères. Depuis les années 1900 jusqu’à la création en 1947 d’un institut du CNRS, plusieurs générations de chercheurs s’y sont succédé. Parmi eux, trois acteurs pionniers, que le Comité pour l’histoire du CNRS a eu l’honneur de rencontrer le 21 janvier 2000. Denise Albe-Fessard, Pierre Buser et Robert Naquet se livrent ici en toute liberté de ton. Extraits. For the French neurosciences community, the history of the Marey Institute is still a mystery. On the 21st of January 2000, the Committee for the history of CNRS met three pioneers of French neurosciences, Denise Albe-Fessard, Pierre Buser and Robert Naquet.

Some predisposed Papio papio baboons may naturally present the different types of myoclonia such as myoclonia induced by movement (MIM) and myoclonia induced by intermittent light stimulation. Myoclonia induced by movement is symmetrical and synchronous; its appearance is facilitated by active movements of the animals or by proprioceptive stimulations such as those caused by pressure on the sternum or tension applied to a limb. Myoclonia induced by intermittent light stimulation is also symmetrical and synchronous; this myoclonia is always associated with electrocorticographic paroxysmal discharges. Pharmacological and electrophysiological data in animals and humans suggest that MIM has a brain stem origin. MIM is an important model to study Papio papio movement disorders and their relationship with epilepsy. The Papio papio movement-induced myoclonus may result from a natural abnormality of some muscarinic receptors on neurons situated in a cerebral region until now undetermined but most probably situated in the lower brain stem. It is known that the ability to develop epileptiform discharges in the absence of convulsant drugs results from the intrinsic organization of the neuronal network in some structures, such as the neocortex or hippocampus. In these models, the absence of paroxysmal discharges could result from neuronal networks of the structures, involving particularly the reticular formation, but different from cortical neuronal networks.

Publisher Summary It has been known since the 19th century that epilepsy in humans is frequently associated with lesions in different structures of the brain. For example, epilepsy-related hippocampal, cerebellar, and neocortical damage has been reported. Without ignoring the importance of the two latter regions, this chapter focuses on lesions of the hippocampus. Historically, two periods may be emphasized: the first from the 19th century to the end of the 1950s and the second from the 1970s to the present. It is only in the past 50 years that there has been important progress in documenting the presence of such lesions, in understanding the mechanisms involved in their origin, and in understanding their relationship to epileptic seizures, particularly, “status epilepticus.” Despite all this progress, one is surprised by the fact that the mechanisms proposed to be responsible for certain types of epileptic seizures—that is, those that appear later in life— cannot always be demonstrated with certainty. The subject is difficult because of the multiplicity of eliciting factors involved in humans and the difficulty of extrapolating findings from animal models.

Rostain, J. C., M. C. Gardette-Chauffour, and R. Naquet. EEG and sleep disturbances during dives at 450 msw in helium-nitrogen-oxygen mixture. J. Appl. Physiol. 83(2): 575–582, 1997.—To study the effects of nitrogen addition to the breathing mixture on sleep disturbances at pressure, two dives were performed in which helium-nitrogen-oxygen mixture was used up to 450 m sea water (msw). In total, sleep of 12 professional divers was analyzed (i.e., 184 night records). Sleep was disrupted by compression and by stay at 450 msw: we observed an increase in awake periods and in sleep stages I and II and a decrease in stages III and IV and in rapid-eye-movement sleep periods. These changes, which were more intense at the beginning of the stay, began to decrease from the seventh day of the stay, but the return to control values was recorded only during the decompression at depths below 200 msw. These changes were equivalent to those recorded in other experiments with helium-oxygen mixture in the same range of depths and were independent of the intensity of changes recorded in electroencephalographic activities in awake subjects.

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.

In predisposed baboons (Papio papio), intermittent light stimulation (ILS) at 25 Hz may induce cortical spikes which symmetrically occupy both fronto-rolandic cortical areas and are accompanied by myoclonic jerks. When ILS is pursued, spikes are transformed into spike-waves or polyspike-waves and can have the capacity to either self-perpetuate after cessation of ILS in an “after-discharge” or followed by a generalized tonicclonic seizure. Electrographically, seizures start in the two frontorolandic areas simultaneously, and quickly diffuse to all brain structures except the rhinencephalon. Monocular as well as binocular ILS induces paroxysmal discharges (PDs) and seizures which, in both cases, occur bilaterally and symmetrically. In naturally photosensitive animals, PDs and seizures induced by ILS never start in the occipital areas.

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)

Central type benzodiazepine receptors were studied in vivo by positron emission tomography in brain areas of 2 different groups of the baboon Papio papio: non-photosensitive (group 1) and those with an allylglycine-induced decrease in GABA-mediated inhibition (group 2). Further, a naturally photosensitive Papio papio (+3 level of photosensitive response) was compared to both groups. Regional brain binding of the specific benzodiazepine receptor ligand, [11C]Ro 15-1788, was not significantly different between groups 1 and 2. In addition, the data from the naturally photosensitive Papio papio did not seem to differ markedly from groups 1 and 2 either. Pharmacological effects of increasing doses of beta-CCM (0.05-3 mg/kg i.v.) and regional benzodiazepine receptor occupancy by the drug were simultaneously studied using electroencephalographic activity recording and positron emission tomography. A positive correlation was observed between the degree of photosensitivity of the baboon and sensitivity to the action of beta-CCM, with increasing convulsant efficacy of beta-CCM in going from group 1 to the naturally photosensitive baboon, then to group 2. Dose-related displacement curves of [11C]Ro 15-1788 binding by beta-CCM revealed that reduction in brain GABA concentration did not modify the inhibitory potency of beta-CCM on [11C]Ro 15-1788 binding in cerebral cortex. This suggests a lack of detectable in vivo allosteric effects of GABA on beta-CCM binding during beta-CCM-induced seizures. Thus, a given dose of beta-CCM displayed increasing pharmacological potency in going from baboons with the lowest photosensitivity to those with the highest, whereas benzodiazepine receptor occupancy by beta-CCM was similar in the cerebral cortex of the different baboons. Conversely, a given level of convulsant activity of beta-CCM was related to a different benzodiazepine receptor occupancy by the drug, depending on the photosensitivity of Papio papio. A given dose of a drug may, thus, have a different pharmacological potency when occupying the same number of receptors, depending on the physiopathological state of the subject.

The photosensitive baboon Papio papio affords a primate model of light-induced epilepsy in which intermittent light stimulation (ILS) induces the appearance of paroxysmal discharges (PD) and bilateral myoclonus (Killam et al., 1967). The electrophysiological characteristics of this model have been described (Menini’s chapter, this book), and here we will concentrate on, first, reviewing the pharmacological studies in the baboon that have employed drugs related to the GABAergic system; second, on describing our recent data using GABA itself in localized, chronic infusion, and, third, describing a new epileptogenic syndrome discovered in these animals at the end of GABA infusions: a GABA withdrawal syndrome.

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.

Papio papio may show two different kinds of myoclonus. A first type corresponds to myoclonus induced by photic stimulation (25 Hz). This type is always preceded by paroxysmal discharges. Another type of myoclonus may be induced, or at least facilitated, by some benzodiazepines, especially lorazepam and, to a lesser extent, diazepam. This type is neither preceded nor accompanied by paroxysmal discharges. A single injection of lorazepam (1 mg/kg i.v.) blocks the first type of myoclonus but favors the appearance of the second. However, these effects do not follow the same evolution; while myoclonus induced by photic stimulation disappears immediately after the injection, benzodiazepine-induced myoclonus appears only 10-15 min. Furthermore, whereas the former reappears after 150-210 min, the latter may persist for a longer time (up to 1 h). A preliminary pharmacologic study of benzodiazepine-induced myoclonus indicates that drugs increasing brain GABA level block this type of myoclonus. The possible reticular origin of benzodiazepine-induced myoclonus is suggested.

The authors emphasize the interest of combining classical electrophysiological methods and neuroanatomical degeneration techniques in the anatomofunctional study of ipsilateral associative cortical connections. Such studies ought to comprise three stages; the first in the animal in chronic experimentation, which permits longitudinal study of the topographical distribution of the nonspecific evoked potentials; the second essential stage consists of making a precise map of the preterminal anterograde degenerations in relation to their density after ipsilateral lesion of the specific cortex; the third stage permits analysis of the evoked potentials obtained from the same stereotaxic planes as those used for neuroanatomy or those obtained in areas inaccessible to chronic experimentation, but which also show degenerations. The convergence of evoked potentials and degenerated fibers in the same territory helps to establish significant correlations and postulation of the projection pathways. An example of practical application is furnished by the use of this experimental procedure in the photosensitive baboon (Papio papio). Convergence of anterograde degenerations and visual evoked potentials in the cortex of the gyri and especially in the sulci is discussed.

Forebrain-bisected cats underwent kindling at primary and secondary amygdala sites. The behavioral effect of amygdala kindling was then examined according to the extent of the surgical lesion in the forebrain commissures. Bisection of the corpus callosum with or without lesion of the hippocampal commissure modified both kindling and kindled symmetrical generalized seizure into a lateralized and asymmetrical form. Lesion of the hippocampal commissure was correlated with the loss of the expected positive transfer effect at the secondary amygdala site. These results suggest that whereas the corpus callosum plays a major role in patterning convulsive generalization and generalized convulsion, the hippocampal commissure is involved in mediation of the transhemispheric positive transfer effect. Evidence of a callosal inhibitory influence on amygdala kindling was not obtained.

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.

Excessive sensitivity (levels 3 and 4) in a population of 1,122 Papio papio was related with age, sex, and geographical origin. (1) Age. There was no clinical response to intermittent light stimulation under the age of 5 months. These was no difference between animals 6 months to 2 years (J1) and those aged 2 to 4 years (J2). Adult females were less often light sensitive (levels 3 and 4 = 32.9%) than immature females (52.4%). Adult males could usually not be tested, but were probably less often sensitive than immature males. (2) Sex. Immature females (J1 + J2) were more often light sensitive (52.4%) than immature males (38.1%). (3) Geographical origin. No animals from East Senegal (Sansande Region) were very light sensitive. Animals from Casamance were more often light sensitive (56.2%) than those from the Niokolo-Koba National Park (N.K.N.P.) (20%). Of two samples taken at one spot between these two regions, one group resembled the population from Casamance and the second resembled that from the N.K.N.P. This observation raises several questions about the respective roles of genetic, ecological, and ethological factors.

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.

The feasibility of studying myocardium muscarinic receptors, non invasively, in a “live” being can be demonstrated using positron emission tomography (PET) and a ligand labelled by carbon 11, an externally detectable short lived radionuclide. Criteria necessary for in vitro characterization of muscarinic receptors by a specific ligand were verified in vivo by this method. This demonstration was carried out after injecting in a baboon, high specific activity 11 C-MQNB (the methiodide salt of quinuclidinyl benzylate) a muscarinic antagonist drug, and displacing the radioactive ligand by increasing amounts of atropine. Displacement was proportionnal to the dose of atropine and a correlation was observed between displacement and pharmacological activity (increase of heart rate). Stereospecificity of the binding was also demonstrated by using two stereoisomers of benzetimide : dexetimide and levetimide.

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.

Summary The effects of the intravenous injection of Δ9 -tetrahydrocannabinol (0.01 to 5 mg/kg body weight) on the EEG, behavior, and photically induced epilepsy, have been studied in 11 adolescent baboons (Papio papio) with marked photosensitive epilepsy. Tameness, anorexia, and akinesia were evident for 4 hr or more after 0.5 to 5 mg/kg. The EEG showed prolonged bursts of symmetrical, rhythmic spikes and waves at about 3/sec associated with no motor signs other than fixation of gaze. There was no consistent enhancement or diminution in the EEG or myoclonic response to intermittent photic stimulation after drug administration. Resume Les effets de l'injection intraveineuse de Δ9-tetrahydrocannabinol (0.01 a 5 mg/kg de poids) ont eteetudies sur l'EEG, le comportement, et l'epilepsie induite par la stimulation lumineuse intermittente chez 11 babouins adolescents, du type Papio papio, choisis pour leur haut degre de photosensibilite. Docilite, anorexie, et akinesie etaient evidentes au moins pendant les 4 heures qui suivaient une injection de 0.5 a 5 mg/kg de la drogue. L'EEG montrait la survenuede longues bouffees de pointes ondes rythmiques, symetriques a 3 C/S; celles-ci n'etaient accompagnees d'aucun signe clinique en dehors d'un regard fixe de l'animal. L'injection de drogue n'a provoque aucune augmentation ou diminution notable des reponses electro-cliniques induites par la stimulation lumineuse intermittente. Resumen Se han estudiado las modificaciones del comportamiento del EEG y de la epilepsia foto-inducida producidas por la inyeccion intravenosa de Δ9-tetrahidro-canabinol (0.01 a 5 mg/kg de peso) en 11 zambos adolescentes Papio papio con intensa epilepsia fotosensible. Se observaron evidentes signos de docilidad, anorexia y akinesia durante mas de 4 horas despues de la inyeccion. El EEG mostro brotes simetricos y prolongados de punta-onda ritmica de 3/seg sin que se detectaran signos motores a excepcion de la mirada fija. No se observo un aumento o disminucion de las respuestas mioclonicas o en el EEG a la foto-estimulacion intermitente despues de la inyeccion. Zusammenfassung Untersuchung uber die Wirkungen intravenoser Injektionen von Δ9-Tetrahydrocannabinol (0.01 bis 5 mg pro kg Korpergewicht) auf EEG, Verhalten und Fotoepilepsie bei 11 ausgewachsenen Papio papio Pavianen mit deutlicher foto-sensibler Epilepsie. Nach Injektionen von 0.5 bis 5 mg pro kg Korpergewicht zeigten die Tiere fur 4 oder mehr Stunden Zahmheit, Anorexie und Akinesie. Im EEG traten langdauernde Ausbriuche symmetrischer, rhythmischer 3/sek spikes and waves auf, die ausser einem starren Blick von keinen motorischen Symptomen begleitet waren. Die intermittierende Fotostimulation zeigte nach Injektion keine entsprechende Ver-Starkung oder Verminderung der EEG-Befunde oder eines Fotomyoklonus.

Baboons (Papio papio) with photosensitive have been chronically prepared with guide cannulae and deep electrodes to study the effects of focal injections of opioids. In the hippocampus, amygdala and thalamus (centre median) 50--100 micrograms morphine, 20--100 micrograms Met-enkephalin or 2--10 micrograms FK 33,824 do not induce local or general electrographic or motor signs of epilepsy. The acute epileptogenic effect of morphine and enkephalins observed in rats is not a general phenomenon whereas the anticonvulsant action of opioids acting on mu-receptors is seen in rodents and primates.

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.

Bromine-76 labeled bromospiperone has been prepared with a very high specific activity (>1 Ci/ μ mole). In-vivo studies in rat corroborated by PET studies in baboon have shown that the regional concentration of this radioligand parallels the morphologic distribution of dopamine receptors and that its binding in the striatum is saturable and displaceable. Tomographic images show a clear delineation of the striatal region 2.5 hours after administration of the radioligand.

The effect of intermittent light stimulation (ILS) on the distribution of thiamine derivatives in three brain areas (occipital, motor, and premotor) was compared in photosensitive and nonphotosensitive baboons. ILS induces paroxysmal discharges in the motor and premotor areas of photosensitive animals only. In baboons submitted to ILS, thiamine triphosphate (TTP) decreases in both photosensitive and nonphotosensitive animals; thiamine monophosphate (TMP) increases in photosensitive animals, which present ILS-induced paroxysmal discharges, whereas it is unaffected in nonphotosensitive animals. The variations are the most significant in the occipital (visual) cortex. A consumption of TTP may result from electrical activity induced by light stimulation in the occipital area. No correlation between ILS-induced paroxysmal activity and a decrease in TTP contents was found. However, photosensitive animals are affected differently from nonphotosensitive animals, as their content of TMP in the cerebral cortex increases on stimulation. However, as long as the exact role of thiamine compounds in relation to membrane excitability in the nervous system remains unknown, it is impossible to conclude whether the differences observed in the metabolism of thiamine compounds are the cause or the consequence of the photosensitivity in the baboon Papio papio.

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.

Twenty-four professional divers were put through a series of electroencephalographic (EEG) and psychometric tests at the surface and at 180 m after a fast compression (15 min) in an attempt to determine their susceptibility to high-pressure nervous syndrome (HPNS). The subjects were classified according to the EEG changes between the surface and 180 m: group 0, less than 10% increase in theta-band activity in the anterior region of the scalp; group 1, between 10 and 100% increase in theta-activity; group 2, theta-activity increase above 100%. Eight subjects were selected to make a dive to 450 m to verify the quality of our classification (3 from group 0, 3 from group 1, 2 from group 2). The results showed that, for the psychometric tests, the large individual variability between the surface and 180 m does not allow us to prejudge the behavior of each subject at 450 m, but the classification established from absolute values is stable from the surface to 450 m. For the EEG activities, intensity of the modifications at 450 m can be predicted at group level by a 180-m dive, performed with fast compression and similar breathing mixtures.

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.

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.

Cortical and subcortical multiunitary activities (MUA) and EEG were simultaneously recorded in baboons rendered photosensitive by a subconvulsant dose of DL-allylglycine. Intermittent light stimulation (ILS) trains induce in those 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 superioris, pulvinar) show a significant MUA increase which is not related to the PD spike or wave but is correlated to the flashes. The first structure showing bursts of MUA that frequently precede the PD appearance is the FR cortex. When PDs appear, the bursts are related to the spikes of PDs and are followed by an inhibition during the slow wave. The pontine and mesencephalic reticular formations and the facial nuclei are activated in bursts after the FR PDs have reached a certain amplitude. The thalamic nuclei ventralis lateralis, centrum medianum and lateralis posterior are activated only later, when the FR PDs have 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 unparalyzed animals.