Movement Disorders Vol. 6, No. 2, 1991, pp. 96104 0 1991 Movement Disorder Society
Review
Myoclonus in Papio papio Simon Brailowsky Department of Neurosciences, Institute of Cellular Physiology, U.N.A.M., Mexico
4 = generalized (i.e,, massive, bilateral, and synchronous) myoclonus continuing after the end of ILS (4). The photosensitive syndrome varies with age, gender, and geographical distribution: monkeys younger than 6 months are not photosensitive and those between 9 months and 4 years of age are more reactive to light than older animals. Females are more photosensitive than males. Lastly, the animals originating from the Casamance region are more often photosensitive (-60% of them) then baboons captured in other regions of Senegal, where this figure descends to 6 2 0 % (5). Besides a maturational factor, no anatomical or histological variations have yet been found to explain these differences in epileptic predisposition. Genetic factors might be involved.
The baboon Papio papio has been extensively used over the last 25 years for studying different aspects of brain pathology, but most of all, epilepsy. Indeed, since the original description by the Killams and Naquet (1) of the occurrence of a syndrome of natural photosensitivity in baboons originating from the Casamance region in Senegal, this animal has been extremely useful for the analysis of the pathophysiological mechanisms involved in generalized epilepsy from cortical origin and for the preclinical evaluation of potentially useful anticonvuisant drugs. Furthermore, since the fortuitous finding of a nonepileptic spontaneous myoclonus (2), this animal has become also a model for the study of myoclonic syndromes. In this paper, we will summarize the current knowledge on the three types of myoclonus found in Papio papio, of both epileptic and nonepileptic origin. We will define myoclonus as a brief and involuntary contraction of one or several muscle groups (3).
Electrographic Manifestations The electrographic manifestations of photosensitive epilepsy have been studied in detail. The principal sign of the EEG response to light is the appearance of paroxysmal discharges (spikes, polyspikes, and spike and waves) localized to the frontocentral regions of the cortex. These paroxysmal discharges (PD) are bilateral, symmetric, and synchronous over both hemispheres, although recent evidence obtained in baboons with section of the corpus callosum indicate that each hemisphere can independently generate PD during ILS (6). ‘The ILS-induced PD have a precise and constant temporal association with myoclonic activity. The surface-positive spike is followed by muscle activation: at 4 ms in the orbicularis oculi, 7 ms in the masseter, 8 ms in the biceps, and 24 ms for the paravertebral muscles (7) (Fig. 1). Recordings from cortical unit activity have shown that areas 4 and 6 display the highest activa-
MYOCLONUS TYPE A (EPILEPSY-RELATED) Clinical Manifestations In predisposed baboons, intermittent light stimulation (ILS) at -25 Hz induces clinical manifestations of generalized epilepsy-bilateral myoclonus that, in order of appearance and of photosensitivity, has been classified in four stages: stage 1 = myoclonus of the eyelids; 2 = myoclonus of eyelids, face and head muscles; 3 = generalization to the trunk and proximal limb muscles (at any of these stages, myoclonus will stop at the cessation of ILS); stage Address correspondence and reprint requests to Dr. S. Brailowsky at Depto. de Neurociencias, Instituto de Fisiologia Celular, U.N.A.M., Apdo. Postal 70-600, Mexico 04510 D.F., Mexico.
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FIG. 1. Electrographic manifestations of type A myoclonus in Papio pupio. In the upper channel, five superimposed EEG traces obtained from epidural screws implanted chronically in the fronto-rolandic cortex (FR) of a photosensitive baboon under light stimulation (flashes at 25 Hz) are shown. In the other two channels, a quantified EMG (number of units) of two different, contralateral, muscles is depicted. The EMG was obtained with bipolar needle electrodes. Note that the paroxysmal discharges precede the EMG activation.
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tion to ILS. Bursts of action potentials occur in these regions even before the PD appears in the EEG (8). These bursts are reversible upon the interruption of light stimulation. Detailed electrophysiological analysis has shown that the PDs are generated in the motor cortex (area 4), with the spike component originating from layer 111 and the wave that follows arising from the external granular layer (9). Subcortical involvement is always secondary to the cortical activation (10). Pharmacology Pharmacological studies performed either in naturally photosensitive baboons or in animals pretreated with allylglycine, an inhibitor of GABA synthesis (1 l), have shown that agents that facilitate GABAergic neurotransmission (barbiturates, benzodiazepines, progabide, GABA-transaminase inhibitors) have clear anticonvulsant effects (see review in ref. 12). Dopaminergic agents, such as apomorphine or ergot derivatives, and serotonin agonists (5-hydroxytryptophan, psilocybine or lysergic acid) have also a protective effect (13). More recently, an anticonvulsant action has been shown for the antagonists of the N-methyl-D-aspartate (NMDA) receptor (14). Lastly, drugs that interact with the cholinergic or the enkephalinergic system does not have a clear effect on photosensitivity. A recent study using localized, intracortical applications of GABA (15) demonstrated powerful anticonvulsant effects when the amino acid was in-
fused into the occipital or motor cortical areas, while prefrontal administration had no such effect. From this evidence, it was concluded that in the photosensitive epilepsy of the baboon, the visual cortex exerts a permissive role for the expression of photosensitivity, while the motor cortex has an executory function for the clinical signs of the syndrome.
MYOCLONUS TYPE B (EPILEPSY-UNRELATED) Clinical and Electrographic Manifestations This type of myoclonus can be observed both in photosensitive and in nonphotosensitive baboons. It was described for the first time in 1978 (16) in animals in which the cerebellar vermis had been ablated to explore a possible influence of the cerebellum in the photosensitive syndrome of the baboon, but it has also been found in intact monkeys (see below). The cerebellar lesion induced atonia and postural disturbances that lasted for 2-3 weeks. Myoclonus appeared from days to weeks after surgery and persisted for the whole survival time of the animal. The presence of this type of myoclonus did not modify that induced by ILS. Both types of myoclonus are easily distinguishable in photosensitive animals by their clinical and electrographic manifestations, by their sensitivity to pharmacological agents, and by their mode of onset (Fig. 2). Type B myoclonus involves mainly the neck,
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FIG. 2. Polygraphic recording of a naturally photosensitive baboon in which a vermal ablation was performed 3 months prior. In the upper half of the figure, the electrooculogram (EOG), the electroencephalogram from the regions shown in the brain diagram to the left, the electromyogram from both deltoids, and head movements recorded with an accelerometer are presented. Type B myoclonic activity either provoked by light somatosensory stimulation (marked with a P) or spontaneous (S) is apparent. Three different paper speeds are shown. In the bottom half of the figure, the electrographic response to intermittent light stimulation (ILS) appears as bursts of paroxysmal discharges, maximal at the fronto-rolandic territories, that coexist with type A generalized myoclonus ( + 3 from the scale described in the text) or with face muscles myoclonus (+ 2). For a full description see text.
shoulder and trunk muscles, with brief contractions lasting 30 ms on the average and followed occasionally by a longer (100-200 ms) tonic discharge. They are bilateral, symmetric and synchronous, appearing as an exaggerated startle response, corresponding to what Gastaut (17) named “secousses myocloniques” (myoclonic jerks). This activity is apparent during agitation periods and disappears completely when the animal is motionless or in the first stages of sleep. They can be elicited by tactile stimulation or passive movements only when the animal is in a state of full alertness or when the monkey resisted passive movements. At the EEG level, type B myoclonus is never preceded or accompanied by any sign of paroxysmal activity, and only a somatosensory evoked potential is observed 10-15 ms after the EMG discharge (trapezius) occurs (Fig. 3). To date, we have not found a structure, either in the cortex, the thalamus, the cerebellum, or the brainstem areas, where an electrical activity strictly related to the onset of the myoclonic activity is apparent. Pharmacological Studies In 1981, Valin et al. (18) described the occurrence of type B myoclonus in intact baboons, through a facilitatory action of benzodiazepines (BDZ) on this type of myoclonus. Testing the anticonvulsant ef-
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fects of diazepam and lorazepam on type A myoclonus, they observed that while these drugs blocked the ILS-induced clinical signs, they facilitated the occurrence of type B myoclonus. Interestingly, the temporal evolution of the drug effect was reversed: while type A myoclonus gradually disappeared, type B myoclonus emerged. When the anticonvulsant effect started to fade (-2 h after injection), both types of myoclonus could be found. In the original study performed in baboons with cerebellar lesions, Brailowsky et al. (16) also injected diazepam (1 mg/kg sc), which decreased photosensitivity and reduced type B myoclonus; however, the latter still could be elicited during the brief, active periods of the animal. In this study, the facilitatory effect of BDZ found by Valin et al. (18) was not observed. Several BDZ have shown this facilitatory effect on type B myoclonus: diazepam, clonazepam, lorazepam. Upon a second injection of the BDZ, a potentiation effect of the first injection was found, whereas administration of Ro 15-1788, a BDZ antagonist, blocked these effects (19). Pharmacological studies that focused on the GABAergic system have not shown a clear involvement of this neurotransmitter, while there is increasing evidence that the cholinergic system is implicated in the generation of type B myoclonus. Rektor et al. (20) found that atropine (1 mg/kg) potentiates the BDZ-induced type B myoclonus. The
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EEG (ER) EMG
j
unit 1
5-HTP has a moderate and transient inhibitory action on type B myoclonus only when administered at fairly high doses (15 mg/kg). This effect appears related more to a decreased arousal level-which has an inhibitory effect on this type of myoclonusthan to a specific action, as the myoclonus can still be elicited when stimulating the animal (7).Furthermore, the serotonin antagonist methysergide does not modify importantly either BDZ or atropineinduced type B myoclonus. MYOCLONUS TYPE C (SLEEP-RELATED) Clinical and Electrical Manifestations
unit 2
20
l0
I ! to I
I
o
M
r
100
n
IM unlt 3
FIG. 3. Electrographic manifestations of type B myoclonus in Pagio papio. In the upper channel, 7 superimposed EEG traces obtained from the frontorolandic cortex (FR) are shown. In the other traces, the summed activity of three different units from the trapezius muscle is depicted. Note that the EEG only shows a somatosensory evoked potential provoked by muscle activation, without any signs of paroxysmal activity preceding the EMG burst. Recordings obtained as indicated in Fig. I .
effect was suppressed by physostigmine, an anticholinesterase agent. More recently, Rektor et al. (21) found that atropine alone induced type B myoclonus for several hours. This effect, again, was reversed by physostigmine. The peripherally acting muscarinic antagonist methyl-quinuclidinyl benzylate had no effect on myoclonic activity. These authors suggested that the BDZ-induced facilitation of type B myoclonus resulted from a depression of the central cholinergic system, as atropine potentiated the BDZ effect and physostigmine antagonized it. Ro 15-1788 had no effect on the atropine-induced myoclonus. From these results, they concluded that type B myoclonus is related to an abnormality of the cholinergic system and that the BDZ effects could be explained by an indirect effect on cholinergic mechanisms. Studies on the serotoninergic system have shown that the serotonin precursor 5-HTP, a drug that has an antimyoclonic effect in humans, induces nonepileptic myoclonus in the rodent (22). In the baboon,
When Pupio pupio falls asleep, myoclonic activity can be seen. This activity appears as brief jerks that involve isolated muscle groups, organized either in trains or isolated, and resembles that described in humans during drowsiness and sleep. This type C myoclonus disappears during slow c wave sleep and reappears during rapid eye movement (REM) sleep stages. The baboon Pupio pupio has the particularity of the occurrence of spontaneous PD during sleep. Cepeda and Naquet (23) have studied their distribution and eventual association with myoclonic activity during the different sleep stages. They found that during stages I and I1 of slow wave sleep, the PD recorded in the frontocentral territories were associated with distal (tail) myoclonus, but without any association with eyelid activity. During stage 111, the myoclonus disappears but the PD persist, although they are less frequent. Lastly, during REM sleep, the myoclonic activity increases sharply while the PD are absent. Here, the myoclonus is different from that induced by light, because even if associated with PD, it spares the eyelid musculature which is the first to become activated by ILS in photosensitive animals. Another dissociation between PD and myoclonus has been reported by Naquet et al. (24) in baboons under hyperbaric conditions, since the animals showed myoclonus without any EEG discharges. However, when the pressure was increased, PD appeared associated with myoclonus and seizures. Summarizing, Pupio pupio can present different types of myoclonus, with distinctive clinical and electrographic characteristics (Table 1): (a) type A myoclonus, induced by ILS and related to photosensitive epilepsy-the generator of this activity is cortical, its activity appearing as PD in the fronto-
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TABLE 1. Myoclonus in Papio papio EEG
Neurotransmitters involved
Myoclonic jerks
+
GABA-BDZ; glu-asp
Anticonvulsants, NMDA antagonistsb
Action myoclonus
-
Ach-BDZ
Physostigmine
Varied
+-
CA-5-HT-Ach
Not known
Clinical Type “A” (“epileptic”) Type “B” (‘ ‘nonepileptic”) Type “C” (“physiologic”)
Pharmacology”
’Refers to drugs shown to diminish or block myoclonus. For a review of the pharmacology of photosensitive epilepsy of the baboon see ref. 13. NMDA antagonists: MK-801, ketamine, and aminophosphonoheptanoate(APH). GABA, y-aminobutyric acid; BDZ, benzodiazepines; glu, glutamate; asp, aspartate; Ach, acetylcholine; CA, catecholamines; 5-HT, 5-hydroxytryptamine.
rolandic areas that always precede the muscular activation; this myoclonus is reactive to several drugs, the most effective for its suppression being those that facilitate GABAergic neurotransmission; (b) type B myoclonus, facilitated by movement and independent from cortical epileptogenic processes-it is never associated with PD, either cortical or subcortical, nor with abnormal potentials when examined with averaging techniques; it occurs infrequently in normal animals, is facilitated with vermal lesions, atropine and benzodiazepines, and it might originate from the lower brain stem (see below); and (c) type C myoclonus, appearing during sleep in epileptic or nonepileptic animals-it can be associated, however, with frontorolandic PD depending on the sleep stage, although the relationship between the two is still obscure. PHYSIOPATHOLOGICAL CONSIDERATIONS In humans, the study of myoclonus has to consider its behavioral characteristics and the type of electrographic discharge eventually associated: the type of activity (irregular or rhythmic, fast or slow), its intensity (variable or constant), its spatial distribution (localized or generalized, uni- or bilateral, segmental or parcellar), its temporal distribution (intermittent or permanent, fixed or movable from one body segment to another), its appearance (spontaneous or provoked) and modifying factors (reactivity to sensory stimulation, to behavioral or levels of vigilance changes, reactivity to drugs), and its electrographic features, both at EMG and EEG levels (17). However, despite an attentive and detailed phenomenological description of the myoclonic activity, the paucity of information regarding its pathophysiology has conditioned to a certain extent some confusion in terminology and classifica-
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tion. Therefore, the myoclonus found in the baboon could be compared with several types of human syndromes, according to the author cited. The advantage, however, of having an animal model of different types of myoclonus is that hypothesis regarding the origin and mechanisms of the neuropathology involved can be tested. These hypotheses can be summarized as follows. (a) Type A myoclonus of the baboon is close to that of human photosensitive epilepsy. A cortical origin for this activity can be proposed as there is a close association between the myoclonic jerks and abnormal discharges in the EEG; the denomination “pyramidal” (25) or “cortical” (26,27) can then be applied. Such association between epilepsy and a myoclonic syndrome has been described in cases of myoclonic epilepsy and in the Unverricht-Lundborg and Ramsay-Hunt syndromes, but also in cases of metabolic (Le., uremia) or drug toxicity. In the baboon, the paroxysmal discharges that generate the myoclonic activity are located in the motor cortex, particularly in the deep layers of the cortex (9), where the pyramidal efferents originate (28). Epileptic foci in this area are associated with spinal activation, whereas foci in other cortical areas are not. The neurochemical mechanisms in type A myoclonus can involve several neurotransmitter systems, although the present evidence points to the GABAergic neurotransmission as critically irnplicated. Lloyd et al. (29) have shown an inverse correlation between GABA levels in CSF and photosensitivity, and Brailowsky et al. (16) showed that increasing GABA levels locally at the visual or motor cortices blocks the electroclinical response to ILS . (b) Type B myoclonus seems to be generated subcortically, as it occurs in the absence of any cortical
MYOCLONUS ZN PAPIO PAPIO electrical or epileptogenic phenomena. Discussing the pathophysiology involved in the postural and myoclonic dysfunctions induced by surgical lesions of cortical, thalamic and brainstem structures in monkeys, Denny-Brown (30) concluded that the critical area for the generation of myoclonus is localized in the lower brain stem, but under control of the cortex and the thalamus. A secondary regulatory influence will originate in the cerebellum and dorsal columns. Shimamura and Livingston (3 1) further suggested that the basic mechanism involve a spinobulbospinal reflex, one of the two propiospinal systems with a facilitatory action on spinal motor neurons. A small lesion in the lower part of the reticular formation, 2 mm lateral from the midline at the obex and in the direction of the pyramid, was capable of blocking the fast conducting part of this propiospinal circuit. Denny-Brown (30) confirmed these observations and further identified the critical structure of this spinobulbospinal reflex as the nucleus reticularis gigantocellularis . Regarding the role of the cerebellum in the pathophysiology of type B myoclonus in the baboon, verma1 ablations have a facilitatory effect (16) with no effects of such lesions on natural photosensitivity (2). In humans, a cerebellar syndrome often includes ataxia, tremor and intention myoclonus. From this evidence, it can be suggested that the cerebellum has an inhibitory action on myoclonus. The facilitatory effects of BDZ and atropine on type B myoclonus suggest that the baboon presents an inherited functional abnormality of the cholinergic system. A brainstem muscarinic dysfunction that renders Pupio pupio extremely sensitive to muscarinic blockade has been postulated (7). (c) Type C myoclonus has been defined as myoclonus occurring during sleep and having an inconstant relationship with cortical PD. In the baboon, it can appear in the absence of any cortical discharge. The probable origin of this activity would be the brain stem, associated or not to a state of cortical hyperexcitability . Both cortical and subcortical generators could become synchronized in stages I and I1 of slow wave sleep, being independent on the other sleep-waking states. This type of myoclonus, even if associated with PD, appears to be different from that involved in photosensitivity as it concerns more the distal musculature than the face muscles, the first to become activated by ILS. This myoclonus can be better related to sleep myoclonus, when not accompanied by PD, and to posthypoxic or de-
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generative syndromes when correlated with PD, where the cerebral cortex may show various degrees of hyperexcitability. This will be the case in clinical syndromes such as Lance-Adams, RamsayHunt, Unverricht-Lundborg, Creutzfeldt-Jakob, Alzheimer’s disease, etc. (7,27,32). For both type B and type C myoclonus, a lower brainstem generating area can be proposed. The candidates would be the reticularis magnocellularis and reticularis gigantocellularis nuclei, adjacent structures with overlapping neuronal populations (33). During REM sleep, this area becomes activated to stimulate inhibitory interneurons in the spinal cord. Furthermore, these neurons are cholinoceptive (33). Thus, for type B myoclonus, where a facilitatory effect of atropine has been reported (20,21), a blockade of the brainstem excitatory drive to glycinergic spinal interneurons would be the basis for the appearance of myoclonic activity. In conclusion, the baboon Papio pupio offers a unique opportunity for the study of different types of myoclonic activity coexisting in the same animal. Much work remains to be done for a better understanding of the pathophysiological mechanisms involved, and modern techniques in the neurosciences will allow new approaches to be used in this animal model of human syndromes. REFERENCES 1 . Killam EK, Killam KF, Naquet R. An animal model of light sensitive epilepsy. Electroencephalogr Clin Neurophysiol 1967;22:497-513. 2 . Brailowsky S, Walter S, Larochelle L, Naquet R. Cervelet et Cpilepsie photosensible chez le Papio pupio: effets des lesions ctrtbelleuses sur la photosensibilitt?et les potentiels tvoquts visuels. Rev EEG Neurophysiol 1975;5:247-51. 3. Gastaut H. Dictionnnire de l’epilepsie. Geneva: OMS, 1973. 4. Meldrum BS, Balzamo E, Gadea M, Naquet R. Photic and drug induced epilepsy in the baboon (Papio pupio). The effect of isoniazid, thiosemicarbazide, pyridoxine and aminooxyacetic acid. Electroencephalogr Clin Neurophysiol 1970;29:333-47. 5. Balzamo E, Bert J, Mtnini C, Naquet R. Excessive light sensitivity in Papio papio: its variations with age, sex and geographic origin. Epilepsia 1974 ;16:269-76. 6. Fukuda H, Valin A , Bryere P, Riche D, Wada JA, Naquet R. Role of the forebrain commisure and hemispheric independence in photosensitive response of epileptic baboons. Electroencephnlogr Clin Neurophysiol 1988;69:363-70. 7. Menini C, Naquet R. Les myoclonies. Rev Neurol (Paris) 1986;142:3-28. 8. Mtnini C, Silva-Comte C, Stutzmann JM, Dimov S. Cortical unit discharges during photic intermittent stimulation in the Papio papio. Relationship with paroxysmal fronto-rolandic activity. Electroencephalogr Clin Neurophysiol 1981 ;52: 42-9. 9. Silva-Barrat C, Brailowsky S, Levesque G , Mtnini C. Epileptic discharges induced by intermittent light stimulation in
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photosensitive baboons: a current source density study. Epilepsy Res 1988;2:1-8. 10. Fischer-Williams M, Poncet M, Riche D, Naquet R. Light induced epilepsy in the baboon Papio papio: cortical and depth recordings. Electroencephalogr Clin Neurophysiol 1968;25:557-69. 11. Horton RW, Meldrum BS. Seizures induced by allylglycine, 3-mercaptopropionic acid and 4-deoxypyridoxin in mice and photosensitive baboons, and different modes of inhibition of cerebral glutamic acid decarboxylase. Br J Pharmacol 1973;49:52-63. 12. Brailowsky S, Menini C, Silva-Barrat C, Riche D, Naquet R. Anticonvulsant effects of intracortical chronic infusion of GABA in generalized epilepsy. In: Avoli M, Gloor P, Kostopoulos G, Naquet R, eds. Generalized epilepsy: neurobiological approaches. Boston: Birkhauser, 1990:126-136. 13. Meldrum BS, Brailowsky S, Naquet R. Approche pharmacologique de I’Cpilepsie photosensible du Papio papio. Actualite‘s Pharmacologiques 1978;8:81-99. 14. Meldrum BS, Croucher MJ, Badmann J, Collins JF. Antiepileptic action of excitatory aminoacid antagonists in the photosensitive baboon Papio pupio. Neurosci Lett 1983;39: 1014. 15. Brailowsky S, Silva-Barrat C, MCnini C, Riche D, Naquet R. Effects of localized, chronic GABA infusions into different cortical areas of the photosensitive baboon, Papio pupio. Electroencephulogr Clin Neurophysiol 1989;72:147-56. 16. Brailowsky S, Mtnini C, Naquet R. Myoclonus developing after vermisectomy in photosensitive Papio papio. Eleetroencephalogr Clin Neurophysiol 1978;45:82-9. 17. Gastaut H. SCmeiologie des myoclonus et nosologie analytique des syndromes myocloniques. Rev Neurol (Paris) 1968;119:1-30. 18. Valin A, Cepeda C, Rey E, Naquet R. Opposite effects of lorazepam on two kinds of myoclonus in the photosensitive Papio p a p i o . Electroencephalogr Clin Neurophysiol 1981$2: 647-5 1. 19. Valin A, Kaijima M, Brykre P, Naquet R. Differential effect of the benzodiazepine antagonist Ro15-1788 on two types of myoclonus in baboon Papio pupio. Neurosci Lett 1983;38: 79-84. 20. Rektor I, Brykre P, Valin A, Silva-Barrat C, Naquet R, MCnini C. Physostigmine antagonizes the benzodiazepine-
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induced myoclonus in the Papio papio baboon. Neurosci Lett 1984;52:91-6. 21. Rektor I, Brytre P, MCnini C. Stimulus-sensitive myoclonus of the baboon Papio pupio: pharmacological studies reveal interactions between benzodiazepines and the central cholinergic system. Exp Neurol 1986;91:13-22. 22. Klawans HL, Goetz C, Weiner WJ. 5-hydroxytryptophaninduced myoclonus in guinea pigs and the possible role of serotonin in infantile myoclonus. Neurology (Minneap) 1973;23 :123440. 23. Cepeda C, Naquet R. Physiologic sleep myoclonus in baboons. Electroencephalogr Clin Neurophysiol 1985;60: 158-62. 24. Naquet R, Lemaire C, Rostain JC. High pressure nervous syndrome: psychometric and clinico-electroencephalographic correlations. Phil Trans R SOCLond 1984;B304:95102. 25. Halliday AM. The electrophysiological study of myoclonus in man. Brain 1967;90:241-84. 26. Hallett M. Myoclonus: relation to epilepsy. Epilepsia 1985;26(suppl 1): 67-77. 27. Marsden CD, Hallett M, Fahn S. The nosology and pathophysiology of myoclonus. In: Marsden CD, Fahn S , eds. Movement disorders. London: Butterworth, 1982:196-248. 28. Elger CE, Speckmann EJ. Focal interictal epileptiform discharges (FIED) and its relation to spinal field potentials in the rat. Electroencephalogr Clin Neurophysiol 1980;48:44760. 29. Lloyd KG, Scatton B, Voltz C, Brykre P, Valin A, Naquet R. CSF aminoacid and monoamine metabolite levels of Papi0 papio: correlation with photosensitivity. Brain Res 1986;363:3904. 30. Denny-Brown D. Quelques aspects physiologiques des myoclonus. Rev Neurol (Paris) 1968;119:121-9. 31. Shimamura M, Livingston RB. Longitudinal conduction systems serving spinal and brainstem coordination. J Neurophysiol 1963;26:258-72. 32. Lance JW, Adams RD. The syndrome of intention or action myoclonus as a sequel to hypoxic encephalopathy. Brain 1963;86:11 1-36. 33. Chase MH, Morales FR. The antonia and myoclonia of active (REM) sleep. Annu Rev Psycho1 1990;41:557-84.
Review
Myoclonus in Papio papio Simon Brailowsky Department of Neurosciences, Institute of Cellular Physiology, U.N.A.M., Mexico
4 = generalized (i.e,, massive, bilateral, and synchronous) myoclonus continuing after the end of ILS (4). The photosensitive syndrome varies with age, gender, and geographical distribution: monkeys younger than 6 months are not photosensitive and those between 9 months and 4 years of age are more reactive to light than older animals. Females are more photosensitive than males. Lastly, the animals originating from the Casamance region are more often photosensitive (-60% of them) then baboons captured in other regions of Senegal, where this figure descends to 6 2 0 % (5). Besides a maturational factor, no anatomical or histological variations have yet been found to explain these differences in epileptic predisposition. Genetic factors might be involved.
The baboon Papio papio has been extensively used over the last 25 years for studying different aspects of brain pathology, but most of all, epilepsy. Indeed, since the original description by the Killams and Naquet (1) of the occurrence of a syndrome of natural photosensitivity in baboons originating from the Casamance region in Senegal, this animal has been extremely useful for the analysis of the pathophysiological mechanisms involved in generalized epilepsy from cortical origin and for the preclinical evaluation of potentially useful anticonvuisant drugs. Furthermore, since the fortuitous finding of a nonepileptic spontaneous myoclonus (2), this animal has become also a model for the study of myoclonic syndromes. In this paper, we will summarize the current knowledge on the three types of myoclonus found in Papio papio, of both epileptic and nonepileptic origin. We will define myoclonus as a brief and involuntary contraction of one or several muscle groups (3).
Electrographic Manifestations The electrographic manifestations of photosensitive epilepsy have been studied in detail. The principal sign of the EEG response to light is the appearance of paroxysmal discharges (spikes, polyspikes, and spike and waves) localized to the frontocentral regions of the cortex. These paroxysmal discharges (PD) are bilateral, symmetric, and synchronous over both hemispheres, although recent evidence obtained in baboons with section of the corpus callosum indicate that each hemisphere can independently generate PD during ILS (6). ‘The ILS-induced PD have a precise and constant temporal association with myoclonic activity. The surface-positive spike is followed by muscle activation: at 4 ms in the orbicularis oculi, 7 ms in the masseter, 8 ms in the biceps, and 24 ms for the paravertebral muscles (7) (Fig. 1). Recordings from cortical unit activity have shown that areas 4 and 6 display the highest activa-
MYOCLONUS TYPE A (EPILEPSY-RELATED) Clinical Manifestations In predisposed baboons, intermittent light stimulation (ILS) at -25 Hz induces clinical manifestations of generalized epilepsy-bilateral myoclonus that, in order of appearance and of photosensitivity, has been classified in four stages: stage 1 = myoclonus of the eyelids; 2 = myoclonus of eyelids, face and head muscles; 3 = generalization to the trunk and proximal limb muscles (at any of these stages, myoclonus will stop at the cessation of ILS); stage Address correspondence and reprint requests to Dr. S. Brailowsky at Depto. de Neurociencias, Instituto de Fisiologia Celular, U.N.A.M., Apdo. Postal 70-600, Mexico 04510 D.F., Mexico.
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FIG. 1. Electrographic manifestations of type A myoclonus in Papio pupio. In the upper channel, five superimposed EEG traces obtained from epidural screws implanted chronically in the fronto-rolandic cortex (FR) of a photosensitive baboon under light stimulation (flashes at 25 Hz) are shown. In the other two channels, a quantified EMG (number of units) of two different, contralateral, muscles is depicted. The EMG was obtained with bipolar needle electrodes. Note that the paroxysmal discharges precede the EMG activation.
Lotissirnus dorsi R
tion to ILS. Bursts of action potentials occur in these regions even before the PD appears in the EEG (8). These bursts are reversible upon the interruption of light stimulation. Detailed electrophysiological analysis has shown that the PDs are generated in the motor cortex (area 4), with the spike component originating from layer 111 and the wave that follows arising from the external granular layer (9). Subcortical involvement is always secondary to the cortical activation (10). Pharmacology Pharmacological studies performed either in naturally photosensitive baboons or in animals pretreated with allylglycine, an inhibitor of GABA synthesis (1 l), have shown that agents that facilitate GABAergic neurotransmission (barbiturates, benzodiazepines, progabide, GABA-transaminase inhibitors) have clear anticonvulsant effects (see review in ref. 12). Dopaminergic agents, such as apomorphine or ergot derivatives, and serotonin agonists (5-hydroxytryptophan, psilocybine or lysergic acid) have also a protective effect (13). More recently, an anticonvulsant action has been shown for the antagonists of the N-methyl-D-aspartate (NMDA) receptor (14). Lastly, drugs that interact with the cholinergic or the enkephalinergic system does not have a clear effect on photosensitivity. A recent study using localized, intracortical applications of GABA (15) demonstrated powerful anticonvulsant effects when the amino acid was in-
fused into the occipital or motor cortical areas, while prefrontal administration had no such effect. From this evidence, it was concluded that in the photosensitive epilepsy of the baboon, the visual cortex exerts a permissive role for the expression of photosensitivity, while the motor cortex has an executory function for the clinical signs of the syndrome.
MYOCLONUS TYPE B (EPILEPSY-UNRELATED) Clinical and Electrographic Manifestations This type of myoclonus can be observed both in photosensitive and in nonphotosensitive baboons. It was described for the first time in 1978 (16) in animals in which the cerebellar vermis had been ablated to explore a possible influence of the cerebellum in the photosensitive syndrome of the baboon, but it has also been found in intact monkeys (see below). The cerebellar lesion induced atonia and postural disturbances that lasted for 2-3 weeks. Myoclonus appeared from days to weeks after surgery and persisted for the whole survival time of the animal. The presence of this type of myoclonus did not modify that induced by ILS. Both types of myoclonus are easily distinguishable in photosensitive animals by their clinical and electrographic manifestations, by their sensitivity to pharmacological agents, and by their mode of onset (Fig. 2). Type B myoclonus involves mainly the neck,
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FIG. 2. Polygraphic recording of a naturally photosensitive baboon in which a vermal ablation was performed 3 months prior. In the upper half of the figure, the electrooculogram (EOG), the electroencephalogram from the regions shown in the brain diagram to the left, the electromyogram from both deltoids, and head movements recorded with an accelerometer are presented. Type B myoclonic activity either provoked by light somatosensory stimulation (marked with a P) or spontaneous (S) is apparent. Three different paper speeds are shown. In the bottom half of the figure, the electrographic response to intermittent light stimulation (ILS) appears as bursts of paroxysmal discharges, maximal at the fronto-rolandic territories, that coexist with type A generalized myoclonus ( + 3 from the scale described in the text) or with face muscles myoclonus (+ 2). For a full description see text.
shoulder and trunk muscles, with brief contractions lasting 30 ms on the average and followed occasionally by a longer (100-200 ms) tonic discharge. They are bilateral, symmetric and synchronous, appearing as an exaggerated startle response, corresponding to what Gastaut (17) named “secousses myocloniques” (myoclonic jerks). This activity is apparent during agitation periods and disappears completely when the animal is motionless or in the first stages of sleep. They can be elicited by tactile stimulation or passive movements only when the animal is in a state of full alertness or when the monkey resisted passive movements. At the EEG level, type B myoclonus is never preceded or accompanied by any sign of paroxysmal activity, and only a somatosensory evoked potential is observed 10-15 ms after the EMG discharge (trapezius) occurs (Fig. 3). To date, we have not found a structure, either in the cortex, the thalamus, the cerebellum, or the brainstem areas, where an electrical activity strictly related to the onset of the myoclonic activity is apparent. Pharmacological Studies In 1981, Valin et al. (18) described the occurrence of type B myoclonus in intact baboons, through a facilitatory action of benzodiazepines (BDZ) on this type of myoclonus. Testing the anticonvulsant ef-
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fects of diazepam and lorazepam on type A myoclonus, they observed that while these drugs blocked the ILS-induced clinical signs, they facilitated the occurrence of type B myoclonus. Interestingly, the temporal evolution of the drug effect was reversed: while type A myoclonus gradually disappeared, type B myoclonus emerged. When the anticonvulsant effect started to fade (-2 h after injection), both types of myoclonus could be found. In the original study performed in baboons with cerebellar lesions, Brailowsky et al. (16) also injected diazepam (1 mg/kg sc), which decreased photosensitivity and reduced type B myoclonus; however, the latter still could be elicited during the brief, active periods of the animal. In this study, the facilitatory effect of BDZ found by Valin et al. (18) was not observed. Several BDZ have shown this facilitatory effect on type B myoclonus: diazepam, clonazepam, lorazepam. Upon a second injection of the BDZ, a potentiation effect of the first injection was found, whereas administration of Ro 15-1788, a BDZ antagonist, blocked these effects (19). Pharmacological studies that focused on the GABAergic system have not shown a clear involvement of this neurotransmitter, while there is increasing evidence that the cholinergic system is implicated in the generation of type B myoclonus. Rektor et al. (20) found that atropine (1 mg/kg) potentiates the BDZ-induced type B myoclonus. The
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MYOCLONUS IN PAPIO PAPIO
EEG (ER) EMG
j
unit 1
5-HTP has a moderate and transient inhibitory action on type B myoclonus only when administered at fairly high doses (15 mg/kg). This effect appears related more to a decreased arousal level-which has an inhibitory effect on this type of myoclonusthan to a specific action, as the myoclonus can still be elicited when stimulating the animal (7).Furthermore, the serotonin antagonist methysergide does not modify importantly either BDZ or atropineinduced type B myoclonus. MYOCLONUS TYPE C (SLEEP-RELATED) Clinical and Electrical Manifestations
unit 2
20
l0
I ! to I
I
o
M
r
100
n
IM unlt 3
FIG. 3. Electrographic manifestations of type B myoclonus in Pagio papio. In the upper channel, 7 superimposed EEG traces obtained from the frontorolandic cortex (FR) are shown. In the other traces, the summed activity of three different units from the trapezius muscle is depicted. Note that the EEG only shows a somatosensory evoked potential provoked by muscle activation, without any signs of paroxysmal activity preceding the EMG burst. Recordings obtained as indicated in Fig. I .
effect was suppressed by physostigmine, an anticholinesterase agent. More recently, Rektor et al. (21) found that atropine alone induced type B myoclonus for several hours. This effect, again, was reversed by physostigmine. The peripherally acting muscarinic antagonist methyl-quinuclidinyl benzylate had no effect on myoclonic activity. These authors suggested that the BDZ-induced facilitation of type B myoclonus resulted from a depression of the central cholinergic system, as atropine potentiated the BDZ effect and physostigmine antagonized it. Ro 15-1788 had no effect on the atropine-induced myoclonus. From these results, they concluded that type B myoclonus is related to an abnormality of the cholinergic system and that the BDZ effects could be explained by an indirect effect on cholinergic mechanisms. Studies on the serotoninergic system have shown that the serotonin precursor 5-HTP, a drug that has an antimyoclonic effect in humans, induces nonepileptic myoclonus in the rodent (22). In the baboon,
When Pupio pupio falls asleep, myoclonic activity can be seen. This activity appears as brief jerks that involve isolated muscle groups, organized either in trains or isolated, and resembles that described in humans during drowsiness and sleep. This type C myoclonus disappears during slow c wave sleep and reappears during rapid eye movement (REM) sleep stages. The baboon Pupio pupio has the particularity of the occurrence of spontaneous PD during sleep. Cepeda and Naquet (23) have studied their distribution and eventual association with myoclonic activity during the different sleep stages. They found that during stages I and I1 of slow wave sleep, the PD recorded in the frontocentral territories were associated with distal (tail) myoclonus, but without any association with eyelid activity. During stage 111, the myoclonus disappears but the PD persist, although they are less frequent. Lastly, during REM sleep, the myoclonic activity increases sharply while the PD are absent. Here, the myoclonus is different from that induced by light, because even if associated with PD, it spares the eyelid musculature which is the first to become activated by ILS in photosensitive animals. Another dissociation between PD and myoclonus has been reported by Naquet et al. (24) in baboons under hyperbaric conditions, since the animals showed myoclonus without any EEG discharges. However, when the pressure was increased, PD appeared associated with myoclonus and seizures. Summarizing, Pupio pupio can present different types of myoclonus, with distinctive clinical and electrographic characteristics (Table 1): (a) type A myoclonus, induced by ILS and related to photosensitive epilepsy-the generator of this activity is cortical, its activity appearing as PD in the fronto-
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S. BRAILO WSK Y
TABLE 1. Myoclonus in Papio papio EEG
Neurotransmitters involved
Myoclonic jerks
+
GABA-BDZ; glu-asp
Anticonvulsants, NMDA antagonistsb
Action myoclonus
-
Ach-BDZ
Physostigmine
Varied
+-
CA-5-HT-Ach
Not known
Clinical Type “A” (“epileptic”) Type “B” (‘ ‘nonepileptic”) Type “C” (“physiologic”)
Pharmacology”
’Refers to drugs shown to diminish or block myoclonus. For a review of the pharmacology of photosensitive epilepsy of the baboon see ref. 13. NMDA antagonists: MK-801, ketamine, and aminophosphonoheptanoate(APH). GABA, y-aminobutyric acid; BDZ, benzodiazepines; glu, glutamate; asp, aspartate; Ach, acetylcholine; CA, catecholamines; 5-HT, 5-hydroxytryptamine.
rolandic areas that always precede the muscular activation; this myoclonus is reactive to several drugs, the most effective for its suppression being those that facilitate GABAergic neurotransmission; (b) type B myoclonus, facilitated by movement and independent from cortical epileptogenic processes-it is never associated with PD, either cortical or subcortical, nor with abnormal potentials when examined with averaging techniques; it occurs infrequently in normal animals, is facilitated with vermal lesions, atropine and benzodiazepines, and it might originate from the lower brain stem (see below); and (c) type C myoclonus, appearing during sleep in epileptic or nonepileptic animals-it can be associated, however, with frontorolandic PD depending on the sleep stage, although the relationship between the two is still obscure. PHYSIOPATHOLOGICAL CONSIDERATIONS In humans, the study of myoclonus has to consider its behavioral characteristics and the type of electrographic discharge eventually associated: the type of activity (irregular or rhythmic, fast or slow), its intensity (variable or constant), its spatial distribution (localized or generalized, uni- or bilateral, segmental or parcellar), its temporal distribution (intermittent or permanent, fixed or movable from one body segment to another), its appearance (spontaneous or provoked) and modifying factors (reactivity to sensory stimulation, to behavioral or levels of vigilance changes, reactivity to drugs), and its electrographic features, both at EMG and EEG levels (17). However, despite an attentive and detailed phenomenological description of the myoclonic activity, the paucity of information regarding its pathophysiology has conditioned to a certain extent some confusion in terminology and classifica-
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tion. Therefore, the myoclonus found in the baboon could be compared with several types of human syndromes, according to the author cited. The advantage, however, of having an animal model of different types of myoclonus is that hypothesis regarding the origin and mechanisms of the neuropathology involved can be tested. These hypotheses can be summarized as follows. (a) Type A myoclonus of the baboon is close to that of human photosensitive epilepsy. A cortical origin for this activity can be proposed as there is a close association between the myoclonic jerks and abnormal discharges in the EEG; the denomination “pyramidal” (25) or “cortical” (26,27) can then be applied. Such association between epilepsy and a myoclonic syndrome has been described in cases of myoclonic epilepsy and in the Unverricht-Lundborg and Ramsay-Hunt syndromes, but also in cases of metabolic (Le., uremia) or drug toxicity. In the baboon, the paroxysmal discharges that generate the myoclonic activity are located in the motor cortex, particularly in the deep layers of the cortex (9), where the pyramidal efferents originate (28). Epileptic foci in this area are associated with spinal activation, whereas foci in other cortical areas are not. The neurochemical mechanisms in type A myoclonus can involve several neurotransmitter systems, although the present evidence points to the GABAergic neurotransmission as critically irnplicated. Lloyd et al. (29) have shown an inverse correlation between GABA levels in CSF and photosensitivity, and Brailowsky et al. (16) showed that increasing GABA levels locally at the visual or motor cortices blocks the electroclinical response to ILS . (b) Type B myoclonus seems to be generated subcortically, as it occurs in the absence of any cortical
MYOCLONUS ZN PAPIO PAPIO electrical or epileptogenic phenomena. Discussing the pathophysiology involved in the postural and myoclonic dysfunctions induced by surgical lesions of cortical, thalamic and brainstem structures in monkeys, Denny-Brown (30) concluded that the critical area for the generation of myoclonus is localized in the lower brain stem, but under control of the cortex and the thalamus. A secondary regulatory influence will originate in the cerebellum and dorsal columns. Shimamura and Livingston (3 1) further suggested that the basic mechanism involve a spinobulbospinal reflex, one of the two propiospinal systems with a facilitatory action on spinal motor neurons. A small lesion in the lower part of the reticular formation, 2 mm lateral from the midline at the obex and in the direction of the pyramid, was capable of blocking the fast conducting part of this propiospinal circuit. Denny-Brown (30) confirmed these observations and further identified the critical structure of this spinobulbospinal reflex as the nucleus reticularis gigantocellularis . Regarding the role of the cerebellum in the pathophysiology of type B myoclonus in the baboon, verma1 ablations have a facilitatory effect (16) with no effects of such lesions on natural photosensitivity (2). In humans, a cerebellar syndrome often includes ataxia, tremor and intention myoclonus. From this evidence, it can be suggested that the cerebellum has an inhibitory action on myoclonus. The facilitatory effects of BDZ and atropine on type B myoclonus suggest that the baboon presents an inherited functional abnormality of the cholinergic system. A brainstem muscarinic dysfunction that renders Pupio pupio extremely sensitive to muscarinic blockade has been postulated (7). (c) Type C myoclonus has been defined as myoclonus occurring during sleep and having an inconstant relationship with cortical PD. In the baboon, it can appear in the absence of any cortical discharge. The probable origin of this activity would be the brain stem, associated or not to a state of cortical hyperexcitability . Both cortical and subcortical generators could become synchronized in stages I and I1 of slow wave sleep, being independent on the other sleep-waking states. This type of myoclonus, even if associated with PD, appears to be different from that involved in photosensitivity as it concerns more the distal musculature than the face muscles, the first to become activated by ILS. This myoclonus can be better related to sleep myoclonus, when not accompanied by PD, and to posthypoxic or de-
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generative syndromes when correlated with PD, where the cerebral cortex may show various degrees of hyperexcitability. This will be the case in clinical syndromes such as Lance-Adams, RamsayHunt, Unverricht-Lundborg, Creutzfeldt-Jakob, Alzheimer’s disease, etc. (7,27,32). For both type B and type C myoclonus, a lower brainstem generating area can be proposed. The candidates would be the reticularis magnocellularis and reticularis gigantocellularis nuclei, adjacent structures with overlapping neuronal populations (33). During REM sleep, this area becomes activated to stimulate inhibitory interneurons in the spinal cord. Furthermore, these neurons are cholinoceptive (33). Thus, for type B myoclonus, where a facilitatory effect of atropine has been reported (20,21), a blockade of the brainstem excitatory drive to glycinergic spinal interneurons would be the basis for the appearance of myoclonic activity. In conclusion, the baboon Papio pupio offers a unique opportunity for the study of different types of myoclonic activity coexisting in the same animal. Much work remains to be done for a better understanding of the pathophysiological mechanisms involved, and modern techniques in the neurosciences will allow new approaches to be used in this animal model of human syndromes. REFERENCES 1 . Killam EK, Killam KF, Naquet R. An animal model of light sensitive epilepsy. Electroencephalogr Clin Neurophysiol 1967;22:497-513. 2 . Brailowsky S, Walter S, Larochelle L, Naquet R. Cervelet et Cpilepsie photosensible chez le Papio pupio: effets des lesions ctrtbelleuses sur la photosensibilitt?et les potentiels tvoquts visuels. Rev EEG Neurophysiol 1975;5:247-51. 3. Gastaut H. Dictionnnire de l’epilepsie. Geneva: OMS, 1973. 4. Meldrum BS, Balzamo E, Gadea M, Naquet R. Photic and drug induced epilepsy in the baboon (Papio pupio). The effect of isoniazid, thiosemicarbazide, pyridoxine and aminooxyacetic acid. Electroencephalogr Clin Neurophysiol 1970;29:333-47. 5. Balzamo E, Bert J, Mtnini C, Naquet R. Excessive light sensitivity in Papio papio: its variations with age, sex and geographic origin. Epilepsia 1974 ;16:269-76. 6. Fukuda H, Valin A , Bryere P, Riche D, Wada JA, Naquet R. Role of the forebrain commisure and hemispheric independence in photosensitive response of epileptic baboons. Electroencephnlogr Clin Neurophysiol 1988;69:363-70. 7. Menini C, Naquet R. Les myoclonies. Rev Neurol (Paris) 1986;142:3-28. 8. Mtnini C, Silva-Comte C, Stutzmann JM, Dimov S. Cortical unit discharges during photic intermittent stimulation in the Papio papio. Relationship with paroxysmal fronto-rolandic activity. Electroencephalogr Clin Neurophysiol 1981 ;52: 42-9. 9. Silva-Barrat C, Brailowsky S, Levesque G , Mtnini C. Epileptic discharges induced by intermittent light stimulation in
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photosensitive baboons: a current source density study. Epilepsy Res 1988;2:1-8. 10. Fischer-Williams M, Poncet M, Riche D, Naquet R. Light induced epilepsy in the baboon Papio papio: cortical and depth recordings. Electroencephalogr Clin Neurophysiol 1968;25:557-69. 11. Horton RW, Meldrum BS. Seizures induced by allylglycine, 3-mercaptopropionic acid and 4-deoxypyridoxin in mice and photosensitive baboons, and different modes of inhibition of cerebral glutamic acid decarboxylase. Br J Pharmacol 1973;49:52-63. 12. Brailowsky S, Menini C, Silva-Barrat C, Riche D, Naquet R. Anticonvulsant effects of intracortical chronic infusion of GABA in generalized epilepsy. In: Avoli M, Gloor P, Kostopoulos G, Naquet R, eds. Generalized epilepsy: neurobiological approaches. Boston: Birkhauser, 1990:126-136. 13. Meldrum BS, Brailowsky S, Naquet R. Approche pharmacologique de I’Cpilepsie photosensible du Papio papio. Actualite‘s Pharmacologiques 1978;8:81-99. 14. Meldrum BS, Croucher MJ, Badmann J, Collins JF. Antiepileptic action of excitatory aminoacid antagonists in the photosensitive baboon Papio pupio. Neurosci Lett 1983;39: 1014. 15. Brailowsky S, Silva-Barrat C, MCnini C, Riche D, Naquet R. Effects of localized, chronic GABA infusions into different cortical areas of the photosensitive baboon, Papio pupio. Electroencephulogr Clin Neurophysiol 1989;72:147-56. 16. Brailowsky S, Mtnini C, Naquet R. Myoclonus developing after vermisectomy in photosensitive Papio papio. Eleetroencephalogr Clin Neurophysiol 1978;45:82-9. 17. Gastaut H. SCmeiologie des myoclonus et nosologie analytique des syndromes myocloniques. Rev Neurol (Paris) 1968;119:1-30. 18. Valin A, Cepeda C, Rey E, Naquet R. Opposite effects of lorazepam on two kinds of myoclonus in the photosensitive Papio p a p i o . Electroencephalogr Clin Neurophysiol 1981$2: 647-5 1. 19. Valin A, Kaijima M, Brykre P, Naquet R. Differential effect of the benzodiazepine antagonist Ro15-1788 on two types of myoclonus in baboon Papio pupio. Neurosci Lett 1983;38: 79-84. 20. Rektor I, Brykre P, Valin A, Silva-Barrat C, Naquet R, MCnini C. Physostigmine antagonizes the benzodiazepine-
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