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Paroxysmal discharges during paradoxical sleep anticipating the occurrence of focal motor seizures in cats
EXPERIMENTAL
NEUROLOGY
84,225-230
(1984)
RESEARCH
NOTE
Paroxysmal Discharges during Paradoxical Sleep Anticipating the Occurrence of Focal Motor Seizures in Cats CARLOS CEPEDA AND MARCOS VELASCO’ Division of Neurophysiology, Scientific Research Department, National Medical Center, I.M.S.S., P.O. Box 73-032, Mexico City, Mexico 03020 Received February 22, 1983; revision received November 10. 1983 Sleep recordings were made some days before the occurrence of focal motor seizures in cats injected with alumina cream in the motor cortex. The wakefulness EEG was completely normal. Slow-wave sleep showed spike-spindles and occasional isolated spikes. During paradoxical sleep, abortive seizures appeared. They were only electrographic and never produced arousal of the animals. The precipitating role of phasic paradoxical sleep on focal motor seizures is proposed.
Several lines of evidence suggest an intimate relationship between the development of seizures and changes in distribution, duration, and patterns of sleep. The demonstration by Cohen and Dement (3) of a significant decrease in paradoxical sleep (PxS) duration after generalized seizures induced either with pentetrazol or with electroshock, was a first step supporting the view that PxS and epileptic activity have important connections. In a recent study (2) we demonstrated that convulsions per se do not alter PxS because in a model of limbic seizures (without clinical convulsions) induced by kainic acid in the amygdala of the baboon, PxS and deep slow-wave sleep (SWS) were practically abolished throughout the duration of limbic status epilepticus. Furthermore, with the kindling model some authors (8) demonstrated an early disruption of the sleep-waking cycle before the occurrence of generalized Abbreviations: PxS-paradoxical sleep, SWS-slow-wave sleep, MUA-multiple-unit activity. ’ We are deeply indebted to Mr. Francisco Estrada-Villanueva and Mr. Humberto Range1 for expert technical assistance. 225 00144886/84
$3.00
Copyright 8 1984 by Academic Press. Inc. All rights of reproduction in any form mewed.
226
CEPEDA AND VELASCO
seizures. In consequence, it Seems that sleep alterations may precede and, probably, contribute to the development of seizures. The alumina cream model of focal motor seizures (10) represents a good instrument for the study of the evolution of epileptic activity. The slow and progressive development of the cortical focus, which follows a latent, a convulsive, and a remission stage, permits a precise analysis of EEG and sleep alterations before, during, and after the convulsive period. In the literature only a quantitative alteration of sleep as a possible prodrome of seizures has been described. Here we describe the existence of qualitative EEG changes during PxS anticipating or accompanying the advent of focal motor seizures. Eight male cats weighing 3.5 to 5.0 kg received a single microinjection of alumina cream (0.04 ml) in the right motor cortex according to a procedure described elsewhere (10). In a second operation carried out during the preconvulsive stage, between the 20th and 25th day after alumina cream injection, the same cats were implanted with bipolar electrodes which permitted the record of the EEG and multiple-unit activity (MUA) of mesencephalic and pontine reticular structures. In addition, the EEG of both motor cortices, ocular movements, and the EMG from neck muscles were recorded. After a short recuperation period (2 to 3 days), the animals were recorded 12 h every day until the commencement of motor seizures. Sleep stages were visually scored and grossly divided into three stages: wakefulness, SWS, and PxS according to standard criteria. In five animals (approximately 60% of the population studied) we observed the appearance of some surprizing EEG abnormalities during PxS. They generally preceded, by 1 or 2 days, the occurrence of focal motor seizures. However, in one case both occurred the same day. The pattern of such abnormalities was not constant in every case, but in general, it mimicked electroencephalographic tonic-clonic discharges (Fig. 1). Those seizures, tentatively called “abortive,” commenced with a very short period of highfrequency discharges followed by some high-amplitude spikes as is observed during the clonic phase of fully developed seizures. Abortive seizures during PxS did not induce arousal of the animal, nor have we observed clinical jerking or any other type of clinical manifestation. It is important to note that electrical discharges were not propagated to the subcortical structures recorded. The most constant feature of abortive seizures was their short duration. Instead of the 40 to 60 s of normal focal motor seizures, abortive seizures lasted only 8 to 10 s on average. On the other hand, it must be recalled that abortive seizures occurred only during PxS. The wakefulness record was completely normal and SWS could be qualified as normal except for the occasional occurrence of isolated spikes or, more frequently, by spikespindles. The integration of MUA made it possible to disclose important
PAROXYSMAL PAROXYSMAL
DISCHARGES EEG
ACTIVITY
DURING
DURING
221
SLEEP
PxS
RAS 1
HIPP
EMG I
EOG ---rINTEGRATED
MULTIPLE
UNIT
ACTIVITY
MRF
EMG
FIG. 1. Abortive seizure recorded during paradoxical sleep(FM) 2 days before the occurrence of fully developed tonic-clonic seizures. Note the absence of clinical uwrelates. Integrated multiple unit activity (MUA) shows, by contrast, a precise correlation with paroxysmal EEG activity. In this case reticular MUA recorded from mesencephalic and pontine structures preceded the ap pearance of paroxysmal discharges. RAS, LAS-right, left anterior sigmoid gyrus. The alumina cream lesion was placed in the RAS. PRF, MRF-pontine, mesencephalic reticular formation.
correlations between encephalographic discharges and neuronal reticular activation. Figure 2 shows the average increments in MUA of mesencephalic and pontine reticular formations. It was observed that MUA of the pontine structure increased significantly concomitant with the onset of cortical discharges. The fact that, in general, paroxysmal discharges were preceded by MUA increments implies that these were not the consequence of EEG seizures but, on the contrary, that the latter were probably triggered by the former. Several investigators [cf. (4)] make a distinction between tonic and phasic PxS. Ocular movements, muscular jerks, and significant increments in MUA
CEPEDA AND VELASCO
228
PRF *
INCREASE
A
IO
t UNIlS/sec 1
DECREASE -20
Ii3
i6
14
12
IO
6
6
4
2
I
I
I
I
1
2
4
6
6
+lOsec
6
+Iosec
ONSET OF PAROXYSMAL
DISCHARQES
MRF 30 20 INCREASE
A
IO
t UNITS/set
D
1
IO
DECREASE
1 16
I6
14
I2
IO
6
6
4
2
0
ONSET OF PAROXYSMAL
2
4
6
DISCNARBES
FIG. 2. Average increments (seven abortive seizures from five cats) in the MUAs of pontine and mesencephalic reticular formations 20 s before and 10 s after the onset of abortive seizures. Observe the significant increment (P < 0.05) in MUAs of the PRF concomitant with the onset of paroxysmal discharges.
characterize phasic PxS. Taking into account this difference, our results indicate that abortive seizures are associated with the phasic periods of PxS activation. On the other hand, the observation that abortive seizures occurred only during PxS may be correlated with the fact that some cerebral structures have a higher rate of discharge during PxS than during waking (5, 6, 12). In our case, we found that MUA of the pontine reticular formation was low
PAROXYSMAL
DISCHARGES
DURING
SLEEP
229
during wakefulness (43.0 -t 4.9 X f SE units/mm), decreased slightly during SWS (41.2 f 9.0), and increased greatly during PxS (90.2 + 17.2). How can we explain the appearance of paroxysmal activity during PxS? The activating role of sleep on paroxysmal activity is well known. Depending on the type of seizures, site of the focus, etc., SWS and PxS may have differential activating effects. Several works (9, 11) have shown that SWS facilitates whereas PxS inhibits the occurrence of isolated spikes in different models of epilepsy (kindling and alumina cream). Furthermore, in the natural model of photosensitive epilepsy in Pupio pupiu baboons, a similar dilferential effect (1) was demonstrated. By contrast, Passouant noted the facilitatory role of PxS on particular forms of focal seizures (7). With the alumina cream model we showed (11) the facihtatory effect of SWS on type B discharges (isolated spikes) and the inhibitory effect of PxS on that same type of discharge. It is possible, on the contrary, that type C seizures (tonic-clonic discharges) are facilitated by the phasic periods of PxS. In alumina cream-treated cats it is very frequently observed that the first tonic-clonic seizure occurs during a PxS period. We suggest that both types of sleep have facilitatory effects on epileptic discharges. However, depending on the type of discharges, the effects may be different and sometimes opposite. In conclusion, abortive seizures during PxS may be the cortical expression of a high degree of reticular activation, as demonstrated by the increments in multiple unit activities. For some time we have observed that focal motor and limbic seizures are actually precipitated by phasic PxS (unpublished data). It is possible that the high bombardment of the cerebral cortex by reticular influences during PxS induces a specific and local reaction (abortive seizure) in a cortex which has become hyperexcitable by the topical application of aluminium. REFERENCES 1. BERT, J., V. PEGRAM, J. M. RHODES, E. BALZAMO, AND R. NAQUET. 1970. A comparative sleep study of two cercopithecinae. Electroenceph. Clin. Neurophysiol. 28: 32-40. 2. CEPEDA, C., T. TANAKA, D. RICHE, AND R. NAQUET. 1982. Limbic status epilepticus: behaviour and sleep alterations after intm-amygdaloid kninic acid microinjections in Papio papio baboons. Electroenceph. Clin. Neurophysiol. 54: 603-6 13. 3. COHEN, H. B., AND W. C. DEMENT. 1966. Sleep: suppression of rapid eye movement phase in the cat after electroconvulsive shock. Science 154: 396-398. 4. DRUCKER-COLIN, R. R., J. G. BERNAL-PEDRAZA, F. J. DIAz-MITOMA, AND J. ZAMORAQUEZADA. 1977. Qscillutory changes in multiple unit activity during rapid eye movement sleep. Exp. Neural. 57: 331-341. 5. EVARTS, E. V. 1964. Temporal patterns of discharge of pyramidal truct neurons during sleep and weking in the monkey. J. Neurophysiol. 27: 152-171. 6. KANAMORI, N., K. SAKAI, AND M. JOUVET. 1980. Neuronal activity specific to paradoxical
230
CEPEDA
AND
VELASCO
sleep in the ventromedial medtdlary reticular formation of unrestrained cats. Brain Res. 189: 251-255.
7. PASSOUANT, P. 1977. Influence des &us de vigilance sur les epilepsies. Pages 57-65 in W. P. KOELLA AND P. LEVIN, Eds., Sleep 1976. Karger, Basel, Switzerland. 8. SHOUSE,M. N., AND M. B. STERMAN. I98 1. Sleep and kindling: effectsof generalized seizure induction. Exp. Neural. 71: 563-580. 9. TANAKA, T., H. LANGE, AND R. NAQUET. 1976. Sleep, suhcortical stimulation and kindling in the cat. Pages 117-135 in J. WADA, Ed., Kindling. Raven Press, New York. 10. VELASCO, M., F. VELASCO, F. ESTRADA-VILLANUEVA, AND A. OLVERA. 1973. Alumina cream-induced focal motor epilepsy in cats. Part I. Lesion size and temporal course. Epilepsia 14: 3- 14. 11. VELASCO,M., F. VELASCO, C. CEPEDA,X. ALMANZA, AND F. ESTRADA-VILLANLJEVA. 1977. Alumina cream-induced focal motor epilepsy in cats. I. Wakefulness-sleep modulation of cortical paroxysmal EEG spikes. Electroenceph. Clin. Neurophysiol. 43: 59-66. 12. VERTES, R. P. 1977. Selective firing of rat pontine gigantocellular neurons during movement and REM sleep. Brain Res. 128: 146-152.
NEUROLOGY
84,225-230
(1984)
RESEARCH
NOTE
Paroxysmal Discharges during Paradoxical Sleep Anticipating the Occurrence of Focal Motor Seizures in Cats CARLOS CEPEDA AND MARCOS VELASCO’ Division of Neurophysiology, Scientific Research Department, National Medical Center, I.M.S.S., P.O. Box 73-032, Mexico City, Mexico 03020 Received February 22, 1983; revision received November 10. 1983 Sleep recordings were made some days before the occurrence of focal motor seizures in cats injected with alumina cream in the motor cortex. The wakefulness EEG was completely normal. Slow-wave sleep showed spike-spindles and occasional isolated spikes. During paradoxical sleep, abortive seizures appeared. They were only electrographic and never produced arousal of the animals. The precipitating role of phasic paradoxical sleep on focal motor seizures is proposed.
Several lines of evidence suggest an intimate relationship between the development of seizures and changes in distribution, duration, and patterns of sleep. The demonstration by Cohen and Dement (3) of a significant decrease in paradoxical sleep (PxS) duration after generalized seizures induced either with pentetrazol or with electroshock, was a first step supporting the view that PxS and epileptic activity have important connections. In a recent study (2) we demonstrated that convulsions per se do not alter PxS because in a model of limbic seizures (without clinical convulsions) induced by kainic acid in the amygdala of the baboon, PxS and deep slow-wave sleep (SWS) were practically abolished throughout the duration of limbic status epilepticus. Furthermore, with the kindling model some authors (8) demonstrated an early disruption of the sleep-waking cycle before the occurrence of generalized Abbreviations: PxS-paradoxical sleep, SWS-slow-wave sleep, MUA-multiple-unit activity. ’ We are deeply indebted to Mr. Francisco Estrada-Villanueva and Mr. Humberto Range1 for expert technical assistance. 225 00144886/84
$3.00
Copyright 8 1984 by Academic Press. Inc. All rights of reproduction in any form mewed.
226
CEPEDA AND VELASCO
seizures. In consequence, it Seems that sleep alterations may precede and, probably, contribute to the development of seizures. The alumina cream model of focal motor seizures (10) represents a good instrument for the study of the evolution of epileptic activity. The slow and progressive development of the cortical focus, which follows a latent, a convulsive, and a remission stage, permits a precise analysis of EEG and sleep alterations before, during, and after the convulsive period. In the literature only a quantitative alteration of sleep as a possible prodrome of seizures has been described. Here we describe the existence of qualitative EEG changes during PxS anticipating or accompanying the advent of focal motor seizures. Eight male cats weighing 3.5 to 5.0 kg received a single microinjection of alumina cream (0.04 ml) in the right motor cortex according to a procedure described elsewhere (10). In a second operation carried out during the preconvulsive stage, between the 20th and 25th day after alumina cream injection, the same cats were implanted with bipolar electrodes which permitted the record of the EEG and multiple-unit activity (MUA) of mesencephalic and pontine reticular structures. In addition, the EEG of both motor cortices, ocular movements, and the EMG from neck muscles were recorded. After a short recuperation period (2 to 3 days), the animals were recorded 12 h every day until the commencement of motor seizures. Sleep stages were visually scored and grossly divided into three stages: wakefulness, SWS, and PxS according to standard criteria. In five animals (approximately 60% of the population studied) we observed the appearance of some surprizing EEG abnormalities during PxS. They generally preceded, by 1 or 2 days, the occurrence of focal motor seizures. However, in one case both occurred the same day. The pattern of such abnormalities was not constant in every case, but in general, it mimicked electroencephalographic tonic-clonic discharges (Fig. 1). Those seizures, tentatively called “abortive,” commenced with a very short period of highfrequency discharges followed by some high-amplitude spikes as is observed during the clonic phase of fully developed seizures. Abortive seizures during PxS did not induce arousal of the animal, nor have we observed clinical jerking or any other type of clinical manifestation. It is important to note that electrical discharges were not propagated to the subcortical structures recorded. The most constant feature of abortive seizures was their short duration. Instead of the 40 to 60 s of normal focal motor seizures, abortive seizures lasted only 8 to 10 s on average. On the other hand, it must be recalled that abortive seizures occurred only during PxS. The wakefulness record was completely normal and SWS could be qualified as normal except for the occasional occurrence of isolated spikes or, more frequently, by spikespindles. The integration of MUA made it possible to disclose important
PAROXYSMAL PAROXYSMAL
DISCHARGES EEG
ACTIVITY
DURING
DURING
221
SLEEP
PxS
RAS 1
HIPP
EMG I
EOG ---rINTEGRATED
MULTIPLE
UNIT
ACTIVITY
MRF
EMG
FIG. 1. Abortive seizure recorded during paradoxical sleep(FM) 2 days before the occurrence of fully developed tonic-clonic seizures. Note the absence of clinical uwrelates. Integrated multiple unit activity (MUA) shows, by contrast, a precise correlation with paroxysmal EEG activity. In this case reticular MUA recorded from mesencephalic and pontine structures preceded the ap pearance of paroxysmal discharges. RAS, LAS-right, left anterior sigmoid gyrus. The alumina cream lesion was placed in the RAS. PRF, MRF-pontine, mesencephalic reticular formation.
correlations between encephalographic discharges and neuronal reticular activation. Figure 2 shows the average increments in MUA of mesencephalic and pontine reticular formations. It was observed that MUA of the pontine structure increased significantly concomitant with the onset of cortical discharges. The fact that, in general, paroxysmal discharges were preceded by MUA increments implies that these were not the consequence of EEG seizures but, on the contrary, that the latter were probably triggered by the former. Several investigators [cf. (4)] make a distinction between tonic and phasic PxS. Ocular movements, muscular jerks, and significant increments in MUA
CEPEDA AND VELASCO
228
PRF *
INCREASE
A
IO
t UNIlS/sec 1
DECREASE -20
Ii3
i6
14
12
IO
6
6
4
2
I
I
I
I
1
2
4
6
6
+lOsec
6
+Iosec
ONSET OF PAROXYSMAL
DISCHARQES
MRF 30 20 INCREASE
A
IO
t UNITS/set
D
1
IO
DECREASE
1 16
I6
14
I2
IO
6
6
4
2
0
ONSET OF PAROXYSMAL
2
4
6
DISCNARBES
FIG. 2. Average increments (seven abortive seizures from five cats) in the MUAs of pontine and mesencephalic reticular formations 20 s before and 10 s after the onset of abortive seizures. Observe the significant increment (P < 0.05) in MUAs of the PRF concomitant with the onset of paroxysmal discharges.
characterize phasic PxS. Taking into account this difference, our results indicate that abortive seizures are associated with the phasic periods of PxS activation. On the other hand, the observation that abortive seizures occurred only during PxS may be correlated with the fact that some cerebral structures have a higher rate of discharge during PxS than during waking (5, 6, 12). In our case, we found that MUA of the pontine reticular formation was low
PAROXYSMAL
DISCHARGES
DURING
SLEEP
229
during wakefulness (43.0 -t 4.9 X f SE units/mm), decreased slightly during SWS (41.2 f 9.0), and increased greatly during PxS (90.2 + 17.2). How can we explain the appearance of paroxysmal activity during PxS? The activating role of sleep on paroxysmal activity is well known. Depending on the type of seizures, site of the focus, etc., SWS and PxS may have differential activating effects. Several works (9, 11) have shown that SWS facilitates whereas PxS inhibits the occurrence of isolated spikes in different models of epilepsy (kindling and alumina cream). Furthermore, in the natural model of photosensitive epilepsy in Pupio pupiu baboons, a similar dilferential effect (1) was demonstrated. By contrast, Passouant noted the facilitatory role of PxS on particular forms of focal seizures (7). With the alumina cream model we showed (11) the facihtatory effect of SWS on type B discharges (isolated spikes) and the inhibitory effect of PxS on that same type of discharge. It is possible, on the contrary, that type C seizures (tonic-clonic discharges) are facilitated by the phasic periods of PxS. In alumina cream-treated cats it is very frequently observed that the first tonic-clonic seizure occurs during a PxS period. We suggest that both types of sleep have facilitatory effects on epileptic discharges. However, depending on the type of discharges, the effects may be different and sometimes opposite. In conclusion, abortive seizures during PxS may be the cortical expression of a high degree of reticular activation, as demonstrated by the increments in multiple unit activities. For some time we have observed that focal motor and limbic seizures are actually precipitated by phasic PxS (unpublished data). It is possible that the high bombardment of the cerebral cortex by reticular influences during PxS induces a specific and local reaction (abortive seizure) in a cortex which has become hyperexcitable by the topical application of aluminium. REFERENCES 1. BERT, J., V. PEGRAM, J. M. RHODES, E. BALZAMO, AND R. NAQUET. 1970. A comparative sleep study of two cercopithecinae. Electroenceph. Clin. Neurophysiol. 28: 32-40. 2. CEPEDA, C., T. TANAKA, D. RICHE, AND R. NAQUET. 1982. Limbic status epilepticus: behaviour and sleep alterations after intm-amygdaloid kninic acid microinjections in Papio papio baboons. Electroenceph. Clin. Neurophysiol. 54: 603-6 13. 3. COHEN, H. B., AND W. C. DEMENT. 1966. Sleep: suppression of rapid eye movement phase in the cat after electroconvulsive shock. Science 154: 396-398. 4. DRUCKER-COLIN, R. R., J. G. BERNAL-PEDRAZA, F. J. DIAz-MITOMA, AND J. ZAMORAQUEZADA. 1977. Qscillutory changes in multiple unit activity during rapid eye movement sleep. Exp. Neural. 57: 331-341. 5. EVARTS, E. V. 1964. Temporal patterns of discharge of pyramidal truct neurons during sleep and weking in the monkey. J. Neurophysiol. 27: 152-171. 6. KANAMORI, N., K. SAKAI, AND M. JOUVET. 1980. Neuronal activity specific to paradoxical
230
CEPEDA
AND
VELASCO
sleep in the ventromedial medtdlary reticular formation of unrestrained cats. Brain Res. 189: 251-255.
7. PASSOUANT, P. 1977. Influence des &us de vigilance sur les epilepsies. Pages 57-65 in W. P. KOELLA AND P. LEVIN, Eds., Sleep 1976. Karger, Basel, Switzerland. 8. SHOUSE,M. N., AND M. B. STERMAN. I98 1. Sleep and kindling: effectsof generalized seizure induction. Exp. Neural. 71: 563-580. 9. TANAKA, T., H. LANGE, AND R. NAQUET. 1976. Sleep, suhcortical stimulation and kindling in the cat. Pages 117-135 in J. WADA, Ed., Kindling. Raven Press, New York. 10. VELASCO, M., F. VELASCO, F. ESTRADA-VILLANUEVA, AND A. OLVERA. 1973. Alumina cream-induced focal motor epilepsy in cats. Part I. Lesion size and temporal course. Epilepsia 14: 3- 14. 11. VELASCO,M., F. VELASCO, C. CEPEDA,X. ALMANZA, AND F. ESTRADA-VILLANLJEVA. 1977. Alumina cream-induced focal motor epilepsy in cats. I. Wakefulness-sleep modulation of cortical paroxysmal EEG spikes. Electroenceph. Clin. Neurophysiol. 43: 59-66. 12. VERTES, R. P. 1977. Selective firing of rat pontine gigantocellular neurons during movement and REM sleep. Brain Res. 128: 146-152.