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Cobalt epilepsy in the squirrel monkey
Electroencephalography and Clinical Neurophysiology Elsevier Publishing Company, Amsterdam - Printed in The Netherlands
525
C O B A L T E P I L E P S Y IN T H E S Q U I R R E L M O N K E Y 1 R. J. GRIMM, J. G . FRAZEE, T. KAWASAKI AND M . SAVI6
Laboratory of Neurophysiology, Good Samaritan Hospital and Medical Center, Portland, Oregon 97210 (U. S.A.) (Accepted for publication: April 10, 1970)
Cobalt powder applied to the cortex of the mouse, rat, rabbit, cat and macaque produces an epileptogenic lesion of varying duration, longer in rodents, but shorter in the cat (Kopeloff 1960; Dow et al. 1962; Henjyoji and Dow 1965; Atsev et el. 1966; Dawson and Holmes 1966; Dimov 1966; Chusid and Kopeloff 1967; Mutani 1967). Clinical symptoms vary depending upon the size and site of the lesion. The principal findings reported here are that small amounts of cobalt powder on cerebral cortex in the squirrel monkey, Saimiri madeirae juruanus, induces an acute and generally short lived epileptogenesis of variable duration with rare spread of paroxysmal activity and no loss of consciousness. Also, by using gas anesthesia with a rapid recovery time, paroxysmal events may be detected within 30 min of cobalt placement. METHOD Eleven 0.5~0.6 kg monkeys were implanted under sterile technique with stainless-steel bone screws, E M G leads and depth stimulating electrodes, the latter for studies on the effect of cerebellar stimulation on cortical epileptogenesis (unpublished). The leads were soldered to a conventional head plug assembly affixed to the skull with dental acrylic. After 7-10 days of recovery, the monkeys were reanesthetized with halothane (Grimm et al. 1969). Measured small amounts of sterile metallic cobalt powder (1.2-3.5 mg) were soaked onto a moist 0.5×0.5 cm Gelfoam pledget and placed on the piaarachnoid surface of somatosensory cortex exposed by a small craniotomy. In one monkey, 20 mg of cobalt were injected via cannula into the hippocampal cortex. ECoG recording was begun within 15-20 rain after cobalt was applied and anesthesia was stopped. Monkeys were awake and moving within 45 rain, restrained in a small observation chamber by a flexible head plug connector to the input terminal of the polygraph. RESULTS All monkeys showed voltage flattening and irregularities of frequency in ECoG traces within 30-45 min of cobalt application. Paroxysmal sharp wave activity began as early as 25 min in one monkey, with an average latency 1 Supported by the U.S. Public Health Service, G r a n t NB02289.
to onset in all animals of 56 min. No correlation was found between cobalt tissue concentration and the latency of paroxysmal activity. In general, unilateral lesions were placed in the somatosensory cortex proximal to the central fissure (Fig. 1) to excite but not destroy motor cortex tissue. This procedure produces a model epilepsy preparation which develops motor and electrical signs of an acute focal epileptogenic process but which leaves no residual neurologic deficit. Once detectable, cobalt epileptogenesis in a cerebral focus passes steadily through several stages. Single paroxysmal sharp waves (80-150 msec), the cobalt primary (Co++P) response, arise during recovery from halothane when monkeys are drowsy but arousable. Initial responses are low amplitude, single sharp waves of simple wave form (Fig. 1, C; upper trace) and intermittent occurrence, e.g., 1 or 2/rain. After an initial appearance, the amplitude of the Co++P wave form and the frequency increase in the next 10-30 rain, and the discharge rate reaches 2-5 events/min. During this initial phase (stage I), either the occurrence of the Co++P or its evoked motor effect (beginning when sharp waves reach greater than 50 ~ of 0.4-1.0 mV maximal amplitude) in contralateral face, neck or limb nerves invariably generates ECoG arousal in the drowsing monkey. From the time of cobalt application to the build-up of the Co++P and appearance of concomitant motor jerks, approximately 90-120 rain pass. The beginning of the second phase (stage I I) is indicated by a specific change in wave form but not in frequency of the Co++P response. The Co++P changes by the addition of an oscillatory component (Fig. 1, C; middle trace), arising after the peak of the sharp wave deflection, which then increases in number of oscillations in succeeding discharges. We term this second phase characteristic the Co++P complex response. Such wave forms arise before sharp wave activity reaches a maximal amplitude and often before the appearance of motor jerks. They supplant simple Co÷+P responses, setting the stage for the most intense period of epileptogenesis, viz., 6-I 8 h after cobalt application. The third phase (stage III) of epileptogenesis begins approximately 3 h after cobalt application. It is characterized by two basic types of repetitive discharge of 1-7 sec duration: large amplitude Co++P responses with or without oscillatory components at 2/sec (Fig. 1, A), or
Electroeneeph. clin. Neurophysiol., 1970, 29:525-528
R. J, GRIMM et al.
526
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Fig. 1 Records taken 8 h after a cobalt lesion. A : the upper four traces are from the lesioned hemisphere at the calibration gain indicated; paroxysmal events are clearly shown. The bottom two traces are from the control side. The gain for channels 1-7 and 1-8 is 300/~V or one-half of the calibration mark given. Artifact-like control records represent large amplitude waves in a sleeping monkey, condensed by a slow paper speed. B: a composite of overlapping line drawings indicating the site and approximate surface area of cobalt lesions in ten monkeys. F.C., central fissure; F.S., sylvian fissure. C: records of cobalt primary Co++P response (upper trace), cobalt primary complex (middle trace) and the beginning of a typical discharge train (bottom two traces).
discharge trains beginning with a Co++P complex in which the oscillatory component continues at 13-14 c/sec slowing terminally (not shown). Fig. 1, C (lower trace) shows a third type of discharge train consisting of repeating Co++P complexes of brief duration. During the 6-18 h period after cobalt is introduced, discharge trains are intermixed with Co++P complexes and, rarely, simple Co++P responses. It is also the phase in which either a voluntary effort to use the affected limb or rough external manipulation, loud hand claps or photic stimulation will evoke a Co++P complex and occasionally a discharge train. Between 18 and 24 h, stage IV begins ambiguously, identified by a decline in amplitude and force of jerks to roughly 1 0 ~ of maximal intensity, and ECoG traces show a corresponding reduction in amplitude; the frequency of paroxysmal events does not appear to change.
By 48 h, this final phase (stage IV) of epileptogenesis reveals a cessation of spontaneous jerks; by 72 h grossly detectable paroxysmal ECoG activity has disappeared in nine of eleven monkeys. Depending upon the lesion size, ECoG traces remain abnormal for a few weeks to several months. Fig. 2 illustrates records typical of control, acute and chronic records from a single monkey. Interestingly, in four of eleven monkeys small amplitude spontaneous jerks and associated ECoG sharp wave activity reappeared at the initial focus 10 days to 4 months later. This "secondary" response in the ipsilateral hemisphere typically waned over 5-10 days and disappeared. The origin of this phenomenon, also seen in the cat (Cereghino, unpublished thesis), remains unstudied. Histologic examination of lesion sites, the area injured, or initial cobalt concentration afford no ready clues. In one monkey, cobalt was injected into the left
Electroenceph. clin. Neurophysiol., 1970, 29:525-528
COBALT EPILEPSY IN THE SQUIRREL MONKEY
527
A 2-3 3-4 5-6 6-7
,,,,
~a
B 2-3 3-4 5-6 6-7
¢ 2-3 3-4
5-6 ~% 6-7
Fig. 2 Records from a cobalt experiment. A: control ECoG records before cobalt placement. The large amplitude periods indicate drowsiness. B: records taken 8 h after cobalt. Single paroxysmal events occasionally activate contralateral cortex. C: follow-up records at 48 h. Discharges have disappeared, but voltage and wave form irregularities remain. The inset drawing indicates electrode sites, area of cobalt application (dark zone, 0.25 cm2), and gross tissue damage (shaded area).
hippocampal cortex producing a focal abnormality in 2.5 h which generated only repetitive 13 c/sec discharges. When the monkey was awake, the discharge train was accompanied by lip and tongue movements, occasionally followed by the monkey looking and sniffing at the ipsilateral hand. If drowsy, the onset of a hippocampal discharge produced no ECoG arousal. After 10 h, hippocampal discharges were associated with an arrest of ongoing activity. At onset, the monkey would turn its eyes left as if tracking a slow moving object during the duration of the discharge. By 24 h, 1-7 sec trains of small amplitude sharp waves limited to ipsilateral hemisphere occurred regularly at 3-4/rain. Such paroxysmal activity not evokable by external stimulation waned and disappeared by 72 h, leaving an ECoG abnormality. Unlike results in studies with the cat (Reimer et al. 1967), we did not observe generalization of activity or loss of consciousness with a hippocampal focus. All monkeys with acute cobalt lesions in the somatosensory cortex developed a similar order and pattern of paroxysmal activity. They differed only in the relative duration of each arbitrary phase of abnormal electrical
activity. For the majority of monkeys, paroxysmal discharges began within 1 h of cobalt placement and essentially ended by 48-72 h, leaving a residual ECoG asymmetry. The monkeys remain alert and healthy and move without difficulty, providing the lesion site remains eccentric to the motor cortex. We find that a small focal cobalt lesion in the somatosensory cortex proximal to the motor cortex will generate a large amplitude paroxysmal event with good signal-tonoise characteristics which can be easily counted electronically. Spread of paroxysmal activity is an unusual and irregular finding occurring only in the homologous zone of the contralateral cortex, never during a repetitive discharge and never generalizing or interrupting consciousness. SUMMARY Small amounts of cobalt powder will generate paroxysmal activity for 48-72 h in the unanesthetized squirrel monkey cortex. Using halothane anesthesia with a rapid recovery time, paroxysmal activity may begin Electroenceph. clin. Neurophysiol., 1970, 29: 525-528
R . J . GRIMM et al.
528
within 30 min of cobalt application. Discharges can be segregated by wave form, frequency and pattern into four clearly identifiable phases. Illustrations of these phases are given. As good signal-to-noise characteristics of paroxysmal events are obtainable, this model of focal epilepsy in squirrel monkeys is open for quantification techniques. RESUME EPILEPSIE AU COBALT CHEZ LE SINGE-ECUREUIL De petites quantit6s de poudre de cobalt peuvent provoquer une activit6 paroxystique pendant 48 h 72 h dans le cortex du singe-6cureuil non-anesth6si6. En utilisant une anesth6sie h l'halothane avec temps de r6cup6ration rapide, l'activit6 paroxystique peut d6buter dans les 30 min qui suivent l'application de cobalt. Les d~harges peuvent 6tre diff6renci6es suivant leur morphologie, leur fr6quence et leur pattern en 4 phases nettement identifiables dont des illustrations sont donn6es. Etant donn6e la bonne quatit6 des caract6ristiques signal-bruit des 6v6nements paroxystiques, ce module d'6pilepsie focale chez le singe-6cureuil permet l'application de techniques de quantification. REFERENCES ATS~V, E. M., ARUaWUNOV, V., DIMOV, S. D. and CHOVD~a~OV,D. Dynamics of electrical manifestations of brain activity in cats and rabbits with an experimental epileptogenic focus. In Z. SERViT(Ed.), Comparative
and cellular pathophysiology of epilepsy. Excerpta Medica Found., New York, 1966: 221-234. CHUSID, J. D. and KOPELOFF, L. M. Epileptogenic effects of metal powder implants in motor cortex of monkeys. Int. J. Neuropsychiat., 1967, 3: 24-28. DAWSON, G. D. and HOLMES, O. Cobalt applied to the sensorimotor area of the cortex cerebri of the rat. J. Physiol. (Lond.), 1966, 185: 455-471. DIMOV, S. D. Changes in the cerebral bioelectric activity of rabbits following application of cobalt to the brain cortex. In Z. SERVIT (Ed.), Comparative and cellular pathophysiology of epilepsy. Excerpta Medica Found., New York, 1966: 235-242. Dow, R. S., FERNANDEz-GUARDIOLA,A. and MANNI, E. The production of cobalt experimental epilepsy in the rat. Electroenceph. clin. Neurophysiol., 1962, 14: 399-407. GRIMM,R. J., SAVIC, M., PETERSEN,P. F. and GRIFFITH, J. S. Halothane anesthesia for monkeys used in neurophysiologic studies. Lab. Prim. Newsl., 1969, 8: 7-15. HENJYOJI,E. Y. and Dow, R. S. Cobalt-induced seizures in the cat. Electroenceph. clin. Neurophysiol., 1965, 19: 152-161. KOPELOrF, L. M. Experimental epilepsy in the mouse. Proc. Soc. exp. Biol. (N. Y.), 1960, 104: 500-504. MUTANI, R. Cobalt experimental amygdaloid epilepsy in the cat. Epilepsia (.4mst.), 1967, 8: 73-92, 223-240. RErMER, G. R., GRIMM, R. J. and Dow, R. S. Effects of cerebellar stimulation in cobalt-induced epilepsy in the cat. Electroenceph. clin. Neurophysiol., 1967, 23: 456-462.
Reference: GRIMM,R. J., FRAZEE,J. G., KAWASAKI,T. and SAVIC,M. Cobalt epilepsy in the squirrel monkey. Electroenceph, clin. Neurophysiol., 1970, 29: 525-528.
525
C O B A L T E P I L E P S Y IN T H E S Q U I R R E L M O N K E Y 1 R. J. GRIMM, J. G . FRAZEE, T. KAWASAKI AND M . SAVI6
Laboratory of Neurophysiology, Good Samaritan Hospital and Medical Center, Portland, Oregon 97210 (U. S.A.) (Accepted for publication: April 10, 1970)
Cobalt powder applied to the cortex of the mouse, rat, rabbit, cat and macaque produces an epileptogenic lesion of varying duration, longer in rodents, but shorter in the cat (Kopeloff 1960; Dow et al. 1962; Henjyoji and Dow 1965; Atsev et el. 1966; Dawson and Holmes 1966; Dimov 1966; Chusid and Kopeloff 1967; Mutani 1967). Clinical symptoms vary depending upon the size and site of the lesion. The principal findings reported here are that small amounts of cobalt powder on cerebral cortex in the squirrel monkey, Saimiri madeirae juruanus, induces an acute and generally short lived epileptogenesis of variable duration with rare spread of paroxysmal activity and no loss of consciousness. Also, by using gas anesthesia with a rapid recovery time, paroxysmal events may be detected within 30 min of cobalt placement. METHOD Eleven 0.5~0.6 kg monkeys were implanted under sterile technique with stainless-steel bone screws, E M G leads and depth stimulating electrodes, the latter for studies on the effect of cerebellar stimulation on cortical epileptogenesis (unpublished). The leads were soldered to a conventional head plug assembly affixed to the skull with dental acrylic. After 7-10 days of recovery, the monkeys were reanesthetized with halothane (Grimm et al. 1969). Measured small amounts of sterile metallic cobalt powder (1.2-3.5 mg) were soaked onto a moist 0.5×0.5 cm Gelfoam pledget and placed on the piaarachnoid surface of somatosensory cortex exposed by a small craniotomy. In one monkey, 20 mg of cobalt were injected via cannula into the hippocampal cortex. ECoG recording was begun within 15-20 rain after cobalt was applied and anesthesia was stopped. Monkeys were awake and moving within 45 rain, restrained in a small observation chamber by a flexible head plug connector to the input terminal of the polygraph. RESULTS All monkeys showed voltage flattening and irregularities of frequency in ECoG traces within 30-45 min of cobalt application. Paroxysmal sharp wave activity began as early as 25 min in one monkey, with an average latency 1 Supported by the U.S. Public Health Service, G r a n t NB02289.
to onset in all animals of 56 min. No correlation was found between cobalt tissue concentration and the latency of paroxysmal activity. In general, unilateral lesions were placed in the somatosensory cortex proximal to the central fissure (Fig. 1) to excite but not destroy motor cortex tissue. This procedure produces a model epilepsy preparation which develops motor and electrical signs of an acute focal epileptogenic process but which leaves no residual neurologic deficit. Once detectable, cobalt epileptogenesis in a cerebral focus passes steadily through several stages. Single paroxysmal sharp waves (80-150 msec), the cobalt primary (Co++P) response, arise during recovery from halothane when monkeys are drowsy but arousable. Initial responses are low amplitude, single sharp waves of simple wave form (Fig. 1, C; upper trace) and intermittent occurrence, e.g., 1 or 2/rain. After an initial appearance, the amplitude of the Co++P wave form and the frequency increase in the next 10-30 rain, and the discharge rate reaches 2-5 events/min. During this initial phase (stage I), either the occurrence of the Co++P or its evoked motor effect (beginning when sharp waves reach greater than 50 ~ of 0.4-1.0 mV maximal amplitude) in contralateral face, neck or limb nerves invariably generates ECoG arousal in the drowsing monkey. From the time of cobalt application to the build-up of the Co++P and appearance of concomitant motor jerks, approximately 90-120 rain pass. The beginning of the second phase (stage I I) is indicated by a specific change in wave form but not in frequency of the Co++P response. The Co++P changes by the addition of an oscillatory component (Fig. 1, C; middle trace), arising after the peak of the sharp wave deflection, which then increases in number of oscillations in succeeding discharges. We term this second phase characteristic the Co++P complex response. Such wave forms arise before sharp wave activity reaches a maximal amplitude and often before the appearance of motor jerks. They supplant simple Co÷+P responses, setting the stage for the most intense period of epileptogenesis, viz., 6-I 8 h after cobalt application. The third phase (stage III) of epileptogenesis begins approximately 3 h after cobalt application. It is characterized by two basic types of repetitive discharge of 1-7 sec duration: large amplitude Co++P responses with or without oscillatory components at 2/sec (Fig. 1, A), or
Electroeneeph. clin. Neurophysiol., 1970, 29:525-528
R. J, GRIMM et al.
526
A
1-3 1"
3
7
4
8
4-5
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.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
600 J15 SEC
400 ~V
l
|1 SEC
Fig. 1 Records taken 8 h after a cobalt lesion. A : the upper four traces are from the lesioned hemisphere at the calibration gain indicated; paroxysmal events are clearly shown. The bottom two traces are from the control side. The gain for channels 1-7 and 1-8 is 300/~V or one-half of the calibration mark given. Artifact-like control records represent large amplitude waves in a sleeping monkey, condensed by a slow paper speed. B: a composite of overlapping line drawings indicating the site and approximate surface area of cobalt lesions in ten monkeys. F.C., central fissure; F.S., sylvian fissure. C: records of cobalt primary Co++P response (upper trace), cobalt primary complex (middle trace) and the beginning of a typical discharge train (bottom two traces).
discharge trains beginning with a Co++P complex in which the oscillatory component continues at 13-14 c/sec slowing terminally (not shown). Fig. 1, C (lower trace) shows a third type of discharge train consisting of repeating Co++P complexes of brief duration. During the 6-18 h period after cobalt is introduced, discharge trains are intermixed with Co++P complexes and, rarely, simple Co++P responses. It is also the phase in which either a voluntary effort to use the affected limb or rough external manipulation, loud hand claps or photic stimulation will evoke a Co++P complex and occasionally a discharge train. Between 18 and 24 h, stage IV begins ambiguously, identified by a decline in amplitude and force of jerks to roughly 1 0 ~ of maximal intensity, and ECoG traces show a corresponding reduction in amplitude; the frequency of paroxysmal events does not appear to change.
By 48 h, this final phase (stage IV) of epileptogenesis reveals a cessation of spontaneous jerks; by 72 h grossly detectable paroxysmal ECoG activity has disappeared in nine of eleven monkeys. Depending upon the lesion size, ECoG traces remain abnormal for a few weeks to several months. Fig. 2 illustrates records typical of control, acute and chronic records from a single monkey. Interestingly, in four of eleven monkeys small amplitude spontaneous jerks and associated ECoG sharp wave activity reappeared at the initial focus 10 days to 4 months later. This "secondary" response in the ipsilateral hemisphere typically waned over 5-10 days and disappeared. The origin of this phenomenon, also seen in the cat (Cereghino, unpublished thesis), remains unstudied. Histologic examination of lesion sites, the area injured, or initial cobalt concentration afford no ready clues. In one monkey, cobalt was injected into the left
Electroenceph. clin. Neurophysiol., 1970, 29:525-528
COBALT EPILEPSY IN THE SQUIRREL MONKEY
527
A 2-3 3-4 5-6 6-7
,,,,
~a
B 2-3 3-4 5-6 6-7
¢ 2-3 3-4
5-6 ~% 6-7
Fig. 2 Records from a cobalt experiment. A: control ECoG records before cobalt placement. The large amplitude periods indicate drowsiness. B: records taken 8 h after cobalt. Single paroxysmal events occasionally activate contralateral cortex. C: follow-up records at 48 h. Discharges have disappeared, but voltage and wave form irregularities remain. The inset drawing indicates electrode sites, area of cobalt application (dark zone, 0.25 cm2), and gross tissue damage (shaded area).
hippocampal cortex producing a focal abnormality in 2.5 h which generated only repetitive 13 c/sec discharges. When the monkey was awake, the discharge train was accompanied by lip and tongue movements, occasionally followed by the monkey looking and sniffing at the ipsilateral hand. If drowsy, the onset of a hippocampal discharge produced no ECoG arousal. After 10 h, hippocampal discharges were associated with an arrest of ongoing activity. At onset, the monkey would turn its eyes left as if tracking a slow moving object during the duration of the discharge. By 24 h, 1-7 sec trains of small amplitude sharp waves limited to ipsilateral hemisphere occurred regularly at 3-4/rain. Such paroxysmal activity not evokable by external stimulation waned and disappeared by 72 h, leaving an ECoG abnormality. Unlike results in studies with the cat (Reimer et al. 1967), we did not observe generalization of activity or loss of consciousness with a hippocampal focus. All monkeys with acute cobalt lesions in the somatosensory cortex developed a similar order and pattern of paroxysmal activity. They differed only in the relative duration of each arbitrary phase of abnormal electrical
activity. For the majority of monkeys, paroxysmal discharges began within 1 h of cobalt placement and essentially ended by 48-72 h, leaving a residual ECoG asymmetry. The monkeys remain alert and healthy and move without difficulty, providing the lesion site remains eccentric to the motor cortex. We find that a small focal cobalt lesion in the somatosensory cortex proximal to the motor cortex will generate a large amplitude paroxysmal event with good signal-tonoise characteristics which can be easily counted electronically. Spread of paroxysmal activity is an unusual and irregular finding occurring only in the homologous zone of the contralateral cortex, never during a repetitive discharge and never generalizing or interrupting consciousness. SUMMARY Small amounts of cobalt powder will generate paroxysmal activity for 48-72 h in the unanesthetized squirrel monkey cortex. Using halothane anesthesia with a rapid recovery time, paroxysmal activity may begin Electroenceph. clin. Neurophysiol., 1970, 29: 525-528
R . J . GRIMM et al.
528
within 30 min of cobalt application. Discharges can be segregated by wave form, frequency and pattern into four clearly identifiable phases. Illustrations of these phases are given. As good signal-to-noise characteristics of paroxysmal events are obtainable, this model of focal epilepsy in squirrel monkeys is open for quantification techniques. RESUME EPILEPSIE AU COBALT CHEZ LE SINGE-ECUREUIL De petites quantit6s de poudre de cobalt peuvent provoquer une activit6 paroxystique pendant 48 h 72 h dans le cortex du singe-6cureuil non-anesth6si6. En utilisant une anesth6sie h l'halothane avec temps de r6cup6ration rapide, l'activit6 paroxystique peut d6buter dans les 30 min qui suivent l'application de cobalt. Les d~harges peuvent 6tre diff6renci6es suivant leur morphologie, leur fr6quence et leur pattern en 4 phases nettement identifiables dont des illustrations sont donn6es. Etant donn6e la bonne quatit6 des caract6ristiques signal-bruit des 6v6nements paroxystiques, ce module d'6pilepsie focale chez le singe-6cureuil permet l'application de techniques de quantification. REFERENCES ATS~V, E. M., ARUaWUNOV, V., DIMOV, S. D. and CHOVD~a~OV,D. Dynamics of electrical manifestations of brain activity in cats and rabbits with an experimental epileptogenic focus. In Z. SERViT(Ed.), Comparative
and cellular pathophysiology of epilepsy. Excerpta Medica Found., New York, 1966: 221-234. CHUSID, J. D. and KOPELOFF, L. M. Epileptogenic effects of metal powder implants in motor cortex of monkeys. Int. J. Neuropsychiat., 1967, 3: 24-28. DAWSON, G. D. and HOLMES, O. Cobalt applied to the sensorimotor area of the cortex cerebri of the rat. J. Physiol. (Lond.), 1966, 185: 455-471. DIMOV, S. D. Changes in the cerebral bioelectric activity of rabbits following application of cobalt to the brain cortex. In Z. SERVIT (Ed.), Comparative and cellular pathophysiology of epilepsy. Excerpta Medica Found., New York, 1966: 235-242. Dow, R. S., FERNANDEz-GUARDIOLA,A. and MANNI, E. The production of cobalt experimental epilepsy in the rat. Electroenceph. clin. Neurophysiol., 1962, 14: 399-407. GRIMM,R. J., SAVIC, M., PETERSEN,P. F. and GRIFFITH, J. S. Halothane anesthesia for monkeys used in neurophysiologic studies. Lab. Prim. Newsl., 1969, 8: 7-15. HENJYOJI,E. Y. and Dow, R. S. Cobalt-induced seizures in the cat. Electroenceph. clin. Neurophysiol., 1965, 19: 152-161. KOPELOrF, L. M. Experimental epilepsy in the mouse. Proc. Soc. exp. Biol. (N. Y.), 1960, 104: 500-504. MUTANI, R. Cobalt experimental amygdaloid epilepsy in the cat. Epilepsia (.4mst.), 1967, 8: 73-92, 223-240. RErMER, G. R., GRIMM, R. J. and Dow, R. S. Effects of cerebellar stimulation in cobalt-induced epilepsy in the cat. Electroenceph. clin. Neurophysiol., 1967, 23: 456-462.
Reference: GRIMM,R. J., FRAZEE,J. G., KAWASAKI,T. and SAVIC,M. Cobalt epilepsy in the squirrel monkey. Electroenceph, clin. Neurophysiol., 1970, 29: 525-528.