Physiology & Behavior, Vol. 16, pp. 623--629. Pergamon Press and Brain Research Publ., 19'76. Printed in the U.S.A.

Electroencephalographic Correlates of the Audiogenic Seizure Response of Inbred Mice I STEPHEN C. MAXSON AND JOHN S. COWEN

Behavioral Genetics Laboratory, Department o f Biobehavioral Sciences The University o f Connecticut, Storrs, CT 06268 (Received 26 June 1975) MAXSON, S. C. AND J. S. COWEN. Electroencephalographic correlates of the audiogenic seizure response of inbred mice. PHYSIOL. BEHAV. 16(5) 623-629, 1976. - The cortical EEG of 5 inbred strains of mice susceptible to audiogenic seizures and of 3 inbred strains resistant to them as well as 3 accoustically primed inbred strains was recorded before, during, and after exposure to intense noise once a day for 4 consecutive days beginning at 29 or 30 days of age. None of the resistant mice had a convulsion and all of the susceptible mice had at least one convulsion. Before, during, and after the audiogenic seizure, there was no evidence of spike waves or paroxysmal activity in the trace from the bipolar cortical electrodes. Rather, there might be a slight amplification and acceleration of the trace at the stimulus onset with no further changes during wild circling activity, but with a diminution of the trace during clonic or clonic-tonic convulsions. This pattern was observed for all 5 genetically susceptible strains and for all 3 acoustically primed groups. However, during chemoconvulsive seizures with picrotoxin or thiosemicarbazide, these same mice as well as resistant mice show spike waves and paroxysmal activity of the cortex. It is suggested on the basis of these data that the neural mechanism for the expression of audiogenic seizures and chemoconvulsive seizures is different, that all audiogenic seizures have a common mechanism for expression but not for development of this phenotype, and that the audiogenic seizure is a type of brain stem epilepsy. Audiogenic seizures

Brainstem epilepsy

Cortical electroencephlography

SUSCEPTIBILITY to audiogenic seizures is one of the most intensively studied phenotypes in behavioral genetics [3, 12, 45, 6 4 ] , and successful genetic analysis of this reflex epilepsy is one step in understanding its ontogeny [ I 1, 13, 20, 25, 44, 60, 75]. The recent discovery o f acoustic priming, which is the induction o f susceptibility in resistant animals by exposure to an initial auditory stimulus, and the theories of its mechanism [31, 33, 58, 67] have also contributed to an unraveling of the developmental complexity of this phenotype. Most notable is the evidence that the development o f some susceptibilities, both genetic and acoustically induced, are due to disuse supersensitivity of the inferior colliculus [31,58]. Of equal importance is the suggestion that this is not the only route to susceptibility for acoustically primed mice [9,51], and that not all genetically susceptible mice have the same ontogeny as acoustically primed susceptible mice [19,50]. A neurological model or models, depending on the ontogenetic heterogenity of this phenomenon, for the expression of the audiogenic seizure response would further contribute to our understanding of this reflex epilepsy by directing these studies of genocopies and phenocopies to specific neural systems. Early studies of the EEG during audiogenic seizures suggested that, at least in some animals, it is a generalized epilepsy with paroxysmal activity of the cortex [6, 8, 28,

Inbred mice

47]. In agreement with this hypothesis are the findings that cortical ablation [39, 49, 72] and spreading depression of the cortex [7, 10, 38, 71] decrease susceptibility. However, the early EEG data have been disputed. Niaussat and Laget [54] showed in a Swiss albino stock of mice that during the audiogerLic seizure, there is no paroxysmal activity recorded from bipolar electrodes on the cortical surface, and in the same mice that during chemoconvulsions spike waves are present in the cortical electroencephalograms. On the basis of this finding, they suggested that audiogenic seizures have a neural mechanism different from that of the generalized grand mal convulsion and may be a unique type of reflex epilepsy. Because o f the diversity of ontogenetic pathways leading to this phenotype, their conclusion might apply only to this stock of susceptible animals. In order to assess the generality of their results, we recorded the cortical EEG of audiogenic seizures in 5 inbred strains of mice susceptible to audiogenic seizures and in 3 acoustically primed inbred strains. F o r each of the 8 routes to susceptibility, our observations were essentially the same as those of Niaussat and Lager [54], and on the basis of these findings, we propose that all audiogenic seizures are a type of subcortical epilepsy. This hypothesis is supported by and integrates other studies on neural mechanisms of the audiogenic seizure response and it is consistent with the diversity of ontogenetic pathways leading to audiogenic

1This study was supported by a grant from The Grant Foundation, Inc. and NIH grant RR 00602-03. The technical assistance of Ms. Edith Abreu is gratefully acknowledged. 623

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MAXSON AND COWEN

seizure susceptibility. It also has implications for using audiogenic seizures as an animal model of epilepsies in man. METHOD

Animals Male and female mice of inbred strains differing in susceptibility to audiogenic seizures were used. These included C57BL/6Bg (seizure resistant), C57BL/6Bg-Gad-1a (seizure prone), DBA/1Bg-asr (seizure resistant), DBA/1Bg (seizure prone), DBA/2Bg (seizure prone), Rb/3/Bg (seizure resistant), Rb/1/Bg (seizure prone), and HAS/Bg (seizure prone). The C57BL/6Bg, DBA/1Bg, and DBA/2Bg are substrains of the C57BL/6J, DBA/1J, and DBA/2J. Mice of the parent strain were obtained from The Jackson Laboratory in the late 1940's by Dr. Benson Ginsburg of the University of Chicago. They have always been inbred by brother to sister matings and they have been separated from The Jackson Laboratory parental strains, without intercrossing to them, for more than the required 12 generations of brother to sister inbreeding [62]. The C57BL/6BgGad-1 a strain is coisogenic with the C57BL/6Bg strain. These differ in a single mutant gene that increases seizure susceptibility [23, 24, 50]. The mutation occurred spontaneously in the C57BL/6Bg strain. The DBA/1Bg-asr strain is coisogenic with the DBA/1Bg. These differ in a single mutant gene that suppresses seizure susceptibility. This mutant arose spontaneously in the DBA/1Bg strain [511. The Rb/1/Bg and Rb/3/Bg were derived from R. Busnel's high and low seizure lines of Fring's selected stocks [ 17]. The difference in susceptibility between these stocks is attributed to a single gene [44]. Since they were obtained by Dr. Benson Ginsburg, they have been inbred by brother to sister mating for 20 or more generations. The HAS/Bg strain is a separate derivation by Ginsburg [36] from the high seizure line of Frings [17]. These have also been inbred by brother to sister matings for twenty or more generations. For each strain, cortical EEG's were measured on 5 - 6 mice. The above seizure resistant strains may be made seizure prone at 20 to 35 days of age by exposing them at 19 days of age for 1 min to an initial auditory stimulus of 95 to 105 dB (re 2 × 10-4 dyne/cm 2 ) from an electric doorbell. Four to six mice of each resistant strain (C57BL/6Bg, DBA/1Bgasr, and Rb/3Bg)were thus acoustically primed at 19 days of age. The cortical EEG's of the mice were also measured. All mice were obtained from our specific-pathogen-free colony; these mice are free of Pseudomonas, Salmonella, and 13 common mouse viruses. The mice of this study were born, raised, and maintained in standard laboratory cages with filter bonnets. Acidified (pH 2.5); chlorinated ( 1 2 - 1 8 ppm) water was available ad lib as was pasteurized food (Charles River Mouse Chow). These mice were maintained on a 12 hour light cycle from 6 a.m. to 6 p.m.

Surgery Between 23 and 27 days of age, silver bead electrodes were chronically implanted on the surface of the cortex. The electrodes were assembled and implanted according to the procedure of Zornetzer [76]. In a pilot study, the two silver ball electrodes were placed on opposite hemispheres; however, in order to increase the signal amplitude, the two silver ball electrodes were placed on the same side of the brain throughout these experiments. For the silver bead

surface cortical electrodes, holes were drilled in the skull 1.0 mm lateral to the mid sagittal suture and either 1.5 mm or 7.0 mm anterior of Lambda. Chloral hydrate (40 mg/kg, IP) was used as the anesthetic. After surgery, the mice were housed individually. All mice survived the surgery, and up to the end of the testing period, only 3 mice sustained electrode disruptions.

Electroencephalography Bipolar recordings were made with a Princeton Alfied Research (Model 113) preamplifier and the writer unit of a Grass (Model 78) polygraph. Frequencies above 30 Hz and below 3 Hz were attenuated by filters. The preamplifier was set for a gain of 2K (100 uV/2.5 mm), and the chart recorder was set for a paper speed of either 15 mm/sec or 3 mm/sec. Teflon-coated multistranded silver wire (Medwire Corp., No. AG740T) and a mercury slip ring (4 channeled nonencapsulated, LVE-BRS, No. 51476) provided low noise hook-up to the preamplifier. Each mouse was tested for susceptibility to audiogenic seizures once a day for 4 consecutive days beginning at Day 29 or 30 of age, which was the third to seventh day post surgery. At this age the seizure risk is maximal for the susceptible C57BL/6Bg-Gad-1 a, DBA/1Bg, DBA/2Bg, Rb/1/Bg, and HAS/Bg strains and for the acoustically primed (19 days) C57BL/6Bg, DBA/1Bg-asr, and Rb/3/Bg strains; whereas it is minimal (essentially zero) for the resistant C57BL/6Bg, DBA/Blg-asr, and Rb/3/Bg strains. The mouse was connected to the recording apparatus and placed in a large glass beaker. There was an adaptation period of 5 to 25 min. prior to the sound stimulation. Cortical EEG recordings were taken for 5 to 10 min prior and posterior to, as well as during, the presentation of the intense noise (95 to 109 dB; re 2 × 10-* dyne/cm ~) of a hand rung serving bell. Because of the possibility of electrical interference, a hand rung bell was used rather than the customary doorbell. The mouse was exposed to the sound stimulus for a minute or until the occurrence of a clonic-tonic convulsion. Stimulus onset, seizure events [18], and stimulus offset were also recorded on the chart paper. Any mouse having a clonic-tonic convulsion with loss of respiration was given artificial resuscitation. The cortical EEG of each mouse was taken during spontaneous seizures produced by chemoconvulsants, either picrotoxin (4 mg/kg, IP) or thiosemicarbazide (50 mg/kg, IP). The recordings for spontaneous seizures were made on the day following the last test for audiogenic seizures. Thus, recording began 5 rain after injection of the chemoconvulsant and continued through several spontaneous convulsions. Most animals died as a consequence of the spontaneous chemoconvulsions. RESULTS None of the seizure resistant mice (C57BL/6Bg, DBA/1Bg-asr, and Rb/3/Bg strains) had a convulsion on any of the 4 exposures to the sound stimulus, and every one of the s e i z u r e susceptible mice (C57BL/6Bg-Gad-1 a, DBA/1Bg, DBA/2Bg, Rb/1/Bg, HAS/Bg, primed C57BL/6Bg, primed DBA/1Bg-asr, primed Rb/3/Bg) had at least one convulsion over the four exposures to the intense noise. All mice responded to either picrotoxin or thiosemicarbazide with repeated, spontaneous convulsions. With a minor exception, which is noted below, the cortical EEG before and after the sound stimulus was the

EEG CORRELATES OF AUDIOGENIC SEIZURES

625

same for all groups and for both resistant and susceptible mice (Figs. 1 and 2). It was identical to the normal cortical EEG traces of the waking state in mice and other rodents [54]. However, unlike the other strains, both the DBA/1Bg (seizure prone) and DBA/1Bg-asr (seizure resistant)mice also showed spontaneous and intermittent spike waves. Usually, there were 4 to 6 spikes over a 2 to 3 sec interval. These occurred before and/or during and/or after the sound stimulation. The cortical EEG during the sound stimulus for the seizure resistant mice was the same for all 3 strains. It was unchanged by onset or offset of the sound stimulus, but in the some records there might be a slight amplification and acceleration during the sound stimulus (Fig. 1).

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FIG. 2. Cortical electroencephalogram of a C57BL/6/Gad-1 a (seizure susceptible) mouse. Arrows indicate onset and offset of auditory stimulus. Phases of seizure are indicated as follows: (1) wild circling activity; (2) clonic convulsion; (3) clonic-tonic convulsion; (4) recovery. Chart recorder set for 15 mm/sec.

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FIG. 1. Cortical electroencephalogram of C57BL/6 (seizure resistant) mouse. Arrows indicate onset and offset of auditory stimulus. Chart recorder set for 15 mm/sec. Similarly, the cortical EEG during the audiogenic seizure was the same for all of the seizure susceptible mice. Again, there might be a slight amplification and acceleration of the trace after the onset of the sound stimulus. This is similar to the observation in the seizure resistant mice. During the wild circling activity, there was little or no change in the trace, and during the clonic phase of the convulsion, there might be a slight reduction in the amplitude of the trace. There was no evidence at any time of high amplitude spikes or paroxysmal activity in the cortical EEG. If the convulsion continued to a clonic-tonic phase, there was a virtual disappearance of all graphic elements of the trace which was then essentially flat. After the clonic or clonic-tonic convulsion, there was a gradual return of the record to normal activity. This pattern of electrical activity during the sound stimulus and audiogenic seizure can be seen in Fig. 2. In Fig. 2, the latency to wild circling activity is 9 sec and the duration of the clonic-tonic seizure is about 10 sec. As can be seen in Fig. 3, the cortical EEG pattern for the spontaneous convulsion after injection of picrotoxin was different. There were many, repeated spike waves of high amplitude and frequent paroxysmal activity. Similar c o r t i c a l EEG patterns were obtained with thio-

FIG. 3. Cortical electroencephalogram of a C57BL/6/Gad-1 a (seizure susceptible) mouse after picrotoxin (4 mg/kg, IP). Arrows indicate behavioral convulsions. Chart recorder set for 3 mm/sec.

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FIG. 4. Cortical electroencephalogram of a C57BL/6/Gad-1 a (seizure susceptible) mouse after thiosemicarbazide (50 mg/kg, IP). Arrows indicate behavioral convulsions. Chart recorder set for 15 mm/sec. semicarbazide (Fig. 4). Also, this cortical EEG pattern for chemoconvulsive seizures is seen in all mice, both audiogenie seizure susceptible and resistant, used in this study. Bipolar recordings across the hemispheres as in the pilot study and within a hemisphere as in these experiments showed similar patterns.

626

MAXSON AND COWEN DISCUSSION

The finding that in the same animal epileptiform activity can be recorded from the cortex during chemoconvulsions, but not during audiogenic seizures, suggests that these observations are not artifacts of the recording and/or animals and that the neural mechanism for the expression of audiogenic seizures might be different from that of most other reflex and/or spontaneous epilepsies. Furthermore, this replication of similar findings by Niaussat and Laget [54] in a Swiss albino stock and its extension to 5 inbred strains of genetically susceptible and three of acoustically primed mice indicates very strongly that in mice there is a common neural mechanism for the audiogenic seizure response. Also, because there is an absence of epileptiform activity in the cortical EEG of audiogenic seizures in rats [42], in the surface EEG of audiogenic seizures of rabbits [53], and in the cortical EEG of cats [68], this mechanism may apply not only to seizures in all mice, but also to those in other susceptible species. It is also very likely that susceptibilities induced by deficiencies of vitamin B6 [29] or of magnesium [43] and by withdrawal of alcohol [16] or by withdrawal of barbiturates [22] would involve the same neural system for the audiogenic seizure response. There already exists experimental models for generalized convulsions without epileptiform activity of the cortex and with arousal of the cortex. These are the brain stem seizures. Electrical stimulation of the mesencephalic reticular formation of rabbits and of cats elicits hypersynchronous activity in the midbrain, arousal activity in the cortex, and behavioral convulsions [2, 41, 56]. Similarly, systemic injections of strychnine produce m o t o r convulsions, major paroxysmal activity in the spinal cord, lower brain stem, cerebellum, and subthalamus, as well as faint seizure activity in the thalamus, but none at all in the cerebrum [35,48]. Again, in the cortex arousal is seen. These experimental models and the results of this study suggest that the physiopathology of the audiogenic seizure response may involve paroxysmal activity confined to the subcortex, especially the brain stem. This hypothesis is further supported by evidence that the afferent, mediating and modulating neural systems implicated in audiogenic seizures can or do influence the activity of the midbrain reticular formation. Massive lesions of the inferior colliculus in mice [32,70], rats [37,69], and cats [69] markedly attenuate or completely block the audiogenic seizure response in susceptible animals; whereas lesions in the auditory cortex in susceptible rats [72] as well as spreading depression of the cortex in susceptible rats [7, 10, 38] and in susceptible mice [71 ] either increase latencies or decrease severity, but do not completely abolish the audiogenic seizure response. Similarly, lesions of the medial geniculate body in rats reduce the severity of, but do not eliminate, audiogenic seizure responses [40]. These findings imply that collicular-fugal pathways to mesencephalic structures are the necessary afferent link for the elaboration of the audiogenic seizure response and that the primary thalamo-cortical pathway of the auditory system has only a modulatory role. Kesner [37] suggested that either collaterals from the auditory pathway to midbrain reticular formation [59] or connections from inferior colliculus to interlaminar thalamic nuclei (indirectly [ 52] or directly [ 55 ] ) or pathways from inferior colliculus to superior colliculus [52] mediate the role of the auditory tectum. The findings [37] that

lesions of the interlaminar nuclei of the thalamus had slight but insignificant effects on susceptibility and the findings [69] that lesions of the superior coUiculus have no effect on susceptibility strongly support the first of Kesner's suggestions. Interestingly, the wild circling activity and the clonic or clonic-tonic convulsions may be mediated by different coUicular-fugal pathways. In cats [69], total lesions of the inferior colliculus abolish both wild circling activity and convulsions; whereas lesions sparing the ventral aspects of the inferior colliculus block only the wild circling activity. In these studies of the auditory pathway, 3 species and 3 or more routes to susceptibility have been used. Consequently, it is very likely that the pathway from the inferior colliculus to midbrain reticular formation is essential in the elaboration of all audiogenic seizures and is common to the neural systems mediating all audiogenic seizure responses. Bur6s [7] suggests that the mediating link between the afferent input and final common pathway of the seizure is the midbrain reticular formation. He bases this hypothesis on the findings that susceptibilities to audiogenic seizures are correlated with the maturation of the reticular formation rather than the auditory cortex, that hypothermia (28 ° C) blocks both susceptibility to audiogenic seizures and cortical arousal, and that restraint suppresses susceptibility to audiogenic seizures. In addition, there is the evidence cited above that the thalamo-cortical pathway does not have an essential role, whereas the collicular-reticular pathway does. In further support of this hypothesis are also the findings reported by Krushinskii [42] that the epileptiform activity appears to originate in the midbrain of susceptible rats, and of Kesner [37] that large lesions of the midbrain reticular formation abolish the. convulsions of audiogenic seizures in susceptible rats. These same lesions did not abolish the wild circling activity, but they did increase their latency and increase the duration of the first wild circling activity. Kesner [37] suggested that the wild circling activity may be under the influence of the bulbar reticular formation, whereas the convulsions may be mediated by the midbrain. Perhaps wild circling activity is produced by input from the dorsal aspect of the inferior colliculus to the bulbar reticular formation, whereas the convulsion is elicited by impulses from the ventral aspects of the inferior colliculus to the midbrain reticular formation. This hypothesis implies that although both wild circling activity and convulsions are elicited by auditory stimulation, different neural pathways are involved in their expression, and that although correlations between magnitude of electroshock and severity of convulsions suggests a quantitative continuum [27], the different phases of both electroshock and audiogenic seizures are, in fact, qualitatively different and neurologically distinct. In either case, the paroxysmal activity in the bulbar reticular formation and/or midbrain reticular formation would excessively stimulate the spinal cord and result in overt audiogenic seizure response [27, 65, 66]. Thus, the necessary elements for an audiogenic seizure response are input from the inferior colliculus to reticular formation and consequent initiation of a subcortical seizure. In addition, modulating effects from other sensory s~stems and from forebrain structures are known. Neither the visual [26,63 ] nor the vestibular system [ 15 ] appear to have any influence on susceptibility whereas there is considerable evidence that the somato-motor system has a major effect on susceptibility either directly by input to the

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627

midbrain reticular formation or indirectly via the somatomotor cortex. Physical restraint of movement which may reduce sensory input or change the pattern of input attenuates the severity of the seizure response [46,73]; however, small lesions of the nucleus cuneatus and gracilis only increase the latency between the wild circling activity and the convulsion [4]. Removal of the vibrassae, which presumably decreases the sensory input, may also reduce the latency to the seizure response [57]. Furthermore, structures of the central motor system influence susceptibility to audiogenic seizures. Thus, lesions of the somato-motor cortex [39, 49, 72] and the anterior cerebellum [5] antagonize susceptibility either by decreasing the frequency of convulsion and/or by increasing the latency of one or more phases of the seizure. Lesions of the septal nuclei [37], amygdala [37], and prefrontal cortex [72] also decrease the incidence of convulsions; whereas lesions of the dorsal hippocampus [39,49], but not of the ventral hippocampus [37,40] increase the incidence of convulsions. Lesions of the caudate nucleus also increase seizure susceptibility [37]. The contradictory report of Beach and Weaver [1], indicating an increase in susceptibility after cortical lesions, can be explained by the encroachment of these ablations on the dorsal hippocampus and corpus striatum. All of the systems that have modd a t i n g effects on susceptibility to audiogenic seizure have direct or indirect inputs to the midbrain reticular formation. Thus, they could act to alter the excitability of the midbrain reticular formation and thereby alter the susceptibility to audiogenic seizures. This unified model for the expression of the audiogenic seizure response allows considerable room for diversity in the developmental route to susceptibility. Genetic substitutions, acoustic priming, and other treatments may induce susceptibility by effects on the afferent and/or mediating and/or modulating systems. Thus, exposure of resistant mice to an intense noise may produce susceptibility by disuse supersensitivity of the inferior colliculus [31, 58, 74]. The supersensitized inferior colliculus would then respond to an intense noise with a greater input to the midbrain reticular formation. This mechanism of acoustic priming may be a phenocopy for some genetic susceptibilities. For example, Swiss mice of the line Rb have damaged hair ceils in the cochlea which could result in a disuse supersensitivity in their auditory system [ 14], and C57BL/6cc (albino) have, at 16 to 19 days of age, a greater threshold for auditory stimuli which could also result in a disuse supersensitivity of the auditory system [30]. How-

ever, this is not the only route to susceptibility. Maxson et al. [511 as well as Chen and Fuller [9] have suggested that there may be more than one mechanism of acoustic priming. Also, Maxson and Sze [50] and Fuller [19] have suggested that the developmental mechanisms of some genetic susceptibilities are not the same as those for acoustic priming by disuse supersensitivity. For example, genetic variation of the hippocampus has been implicated in the susceptibilities of DBA/1 mice [23,24], and genetic variation in the biogenic amines have been implicated in the susceptibilities of the DBA/2 strain [61]. Here the susceptibilities appear to be the result of genetic effects acting on the modulating systems. Thus, the development of susceptibility to audiogenic seizures may be due to genetic, sensory, and other effects on the auditory system or midbrain reticular formation or somatomotor system or limbic forebrain. These findings and this hypothesis not only have implications for understanding the neural and developmental mechanisms of the audiogenic seizure response, but also for using it as an experimental model of generalized epilepsies in man. Recently, several investigators have suggested that it could be used as an animal model of susceptibility produced by depressant withdrawal [16,22]. Although behaviorally the audiogenic seizures would appear to be a good model for generalized epilepsy, electrophysiologically their usefulness as a model appears to be limited [34]. Because the seizure is confined to the subcortex and because there is no paroxysmal activity recorded in the cortex, audiogenic seizures do not resemble, at least in the EEG, the reflex or spontaneous or drug withdrawal epilepsies of man. However, this may not make it entirely irrelevant to our understanding of the human epilepsies. Gastaut and Fisher-Williams [21 ] proposed that generalized grand mal seizures originate with paroxysmal activity in the thalamic reticular formation which is transmitted by the diffuse cortical pathways to the cortex, and that the consequent seizure in the cortex leads to its functional inactivation with a release of the bulbar reticular formation from the neocortical inhibition and with a consequent production of hyperexcitability in the brain stem. In this theory, the grand mal seizure consists of two related but separable components: a thalamo-cortical one with a loss of consciousness and a brain stem one with peripheral convulsions. The audiogenic seizure may be, as is proposed in this paper, the analog of the latter component, and as such may provide a natural model for its study.

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Electroencephalographic correlates of the audiogenic seizure response of inbred mice.

Physiology & Behavior, Vol. 16, pp. 623--629. Pergamon Press and Brain Research Publ., 19'76. Printed in the U.S.A. Electroencephalographic Correlate...
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