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Electroencephalography and clinical Neurophysiology , 84 (1992) 172-179 © 1992 Elsevier Scientific Publishers Ireland, Ltd. 0168-5597/92/$05.00
EVOPOT 90696
Visual evoked potentials during spontaneously occurring spike-wave discharges in rats M. Inoue, E.L.J.M. Van Luijtelaar, J.M.H. Vossen and A.M.L. Coenen Department of Psychology, University of Nijmegen, 6500 HE Nijmegen (The Netherlands)
(Accepted for publication: 11 October 1991)
Summary Flash evoked visual potentials (VEPs) were recorded in freely moving WAG/Rij rats. These rats show spontaneously occurring spike-wave discharges in the EEG, interpreted as absence-like seizures. VEPs recorded during the presence of spike-wave discharges were compared with those obtained during normal states of vigilance as quiet wakefulness, slow-wave sleep and REM sleep. Almost similar VEPs were recorded during wakefulness and REM sleep, whereas during slow-wave sleep the second positive peak (P2) was considerably larger. In comparison with normal sleep-wake states, VEPs during spike-wavedischarges showed unique changes, such as a decrease in the N1 amplitude, an increase of the P4 amplitude and an enhanced afterdischarge. Other characteristics were similar to those seen during slow-wavesleep, such as an increase of the P2 amplitude and a diminished P2-N3-P3 complex. These findings indicate sensory alterations during a spike-wavedischarge. As expressed in the decrease of N1, afferent information cannot enter the thalamus during the rhythmic oscillatory mode. Such alterations may underlie the lowered responsiveness to external stimuli during spike-waveactivity. Key wards: Visual evoked potentials; Spike-wave discharges; Absence epilepsy; Sleep-wakefulnesscycle; (Rat)
In absence epilepsy the most conspicuous clinical manifestation is the decreased responsiveness to external stimuli. An impaired responsiveness related to spike-wave discharges as measured by several behavioral tests has been reported (Shimazono et al. 1953; Goldie and G r e e n 1961; Tizard and Margerison 1963; Mirsky and Van Buren 1965; G o o d e et al. 1970; Browne et al. 1974). In addition to these decrements in performance, decreased responsiveness varies with the time course of the spike-wave discharge (Mirsky and Van Buren 1965; Browne et al. 1974). It is possible that a sensory impairment underlies the decreased responsiveness or that the brain function changes during spike-wave discharges. Some investigators have studied flash evoked visual potentials (VEPs) to clarify the brain mechanisms underlying the decreased responsiveness to external stimuli in human absence epilepsy (Bergamini and Bergamasco 1967; Mirsky and Tecce 1968; Orren 1975; Mirsky 1989). VEPs have also been determined in animal models using drug-induced absence-like epilepsy (Mirsky et al. 1973; Burchiel et al. 1976; Pellegrini et al. 1986). All rats of an inbred strain, the W A G / R i j strain, show spontaneously occurring generalized spike-wave Correspondence to: Dr. A.M.L. Coenen, Department of Psychology, University of Nijmegen, P.O. Box 9104, 6500 HE Nijmegen (The Netherlands). Tel.: + 31.80.61.2544; Fax: +31.80.61.5938.
discharges in the cortical E E G with a spike frequency of 7 - 1 0 Hz, an amplitude of 100-450/xV, and a mean duration of 5 sec (range 1-30 sec; Fig. 1). These are accompanied by behavioral concomitants such as vibrissal twitching, accelerated breathing, head tilting and sometimes eye twitching. Both the E E G and the behavioral manifestations are reminiscent of human absence epilepsy (Van Luijtelaar and Coenen 1986, 1989; (Coenen and Van Luijtelaar 1987). The number of rats that are affected increases with age and an increment of the hourly number of spike-wave discharges was found during ontogeny. After 6 months of age, all individuals show spike-wave discharges occurring approximately 15 t i m e s / h (Coenen and Van Luijtelaar 1987). Pharmacological studies indicate that typical anti-absence drugs suppress spike-wave discharges, whereas these discharges are aggravated by atypical anti-absence drugs (Peeters et al. 1988). Therefore, the W A G / R i j strain of rat might be considered as an appropriate model for absence epilepsy. A proof of a sensory impairment during the occurrence of a spike-wave discharge might be regarded as supporting evidence for the view that such a discharge can be considered as a genuine epileptic p h e n o m e n o n (Semba et al. 1980; Kaplan 1985). In the present study, we recorded VEPs during spike-wave discharges in W A G / R i j rats and compared them with VEPs during normal states of vigilance as quiet wakefulness, slow-wave sleep and R E M sleep.
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VEPs D U R I N G SPIKE-WAVE DISCHARGES IN RATS
Fig. 1. Representative spike-wave discharges with (right) and without (left) photic stimuli in the E E G of a W A G / R i j rat. The upper trace is from the frontal cortex and the middle one from the visual cortex. The time at which photic stimuli are presented is shown in the bottom trace. In this figure, the first stimulus is presented in the beginning portion and the second one in the middle. Calibrations are 1 sec and 200/xV respectively. Positivity is upward deflected.
This comparison should reveal whether sensory impairments or changes of brain functioning occur during spike-wave discharges. Moreover, we distinguished 3 stages in the time course of a spike-wave discharge: the beginning, the middle and the end portions, to investigate whether impairments occur over the whole period of the spike-wave discharge.
Materials and methods Six W A G / R i j rats were used as subjects. The age of the animals ranged from 9 to 10 months. All rats were born and raised in our laboratory. They were housed individually and were maintained on a 12-12 LD cycle with white lights on from 21.00 to 9.00 h. Electrodes were permanently implanted under Hypnorm (0.1 ml/100 g) and Nembutal (1.5 mg/100 g) anesthesia. Two gilded screws were positioned on the dura: one on the frontal region (coordinates with skull surface flat and bregma 0-0: A 2.0, L 2.0) and a second one on the visual cortex (A -7.0, L 3.0) to conduct clear spikewave discharges and field potentials. The ground electrode was placed over the cerebellum. Two vinylcovered stainless steel electrodes were placed on the dorsal neck muscles for recording the EMG. One of the neck electrodes also served as a reference for monopolar EEG recording. Since recording of VEPs was carried out in quiet states of the animals, muscle artifacts were small and were completely eliminated by the averaging technique. All electrodes were led to a receptacle and the whole assembly was secured with two additional screws to the skull surface applied with dental acrylic cement. VEP records were made at least 2 weeks after the recovery period. The EMG and 2 E E G traces were registered through a polygraph (Mingograph 800, EIema-Sch6nander) with filters set at 0.5-700 Hz for the
EEG, and 27-700 Hz for the EMG. The output signals from the preamplifiers were recorded on a magnetic tape recorder (SE 7000) along with the trigger signals of the photic stimulation for later off-line analysis. Fifty VEPs were collected and averaged for each condition and digitized through A-D converters on an Apple II computer with a sampling rate of 1 msec for 1 sec epochs. Computer averaged evoked potentials were plotted on an X-Y recorder (Mosely 7035AM, Hewlett Packard). Animals were habituated to the experimental environment and to random photic stimulation on the day prior to the day of registration. The experiments were carried out from 9.00 to 17.00 h. During recording, the rat was placed in a plexiglass observation box (25 x 30 x 35 cm) and could move freely. The observation box was placed within a sound-attenuating shielded chamber with mirrors on the walls and the floor, to provide a roughly equal flash intensity in the chamber. Photic stimuli of 10/zsec duration were delivered with a Grass PS22 photostimulator, with the intensity set at a high level, point 8 (corresponding to 750,000 cd). The flash lamp was positioned just above a double window in the N1
N3
PI lOOxV a fterd ischarge P2 100~ec Fig. 2. A representative VEP of a W A G / R i j rat, obtained during quiet wakefulness. Positive and negative waves are indicated. The total excursion of the afterdischarge was measured from the peak of P4 to the end of the 1 sec lasting response. Negativity is upward deflected.
M. INOUE ET AL.
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Fig. 3. VEPs from one animal made during 1: quiet wakefulness (W), 2: slow-wave sleep (S), 3: REM sleep (REM), 4: spike-wave discharges following wakefulness (SWD-W), and 5: spike-wave discharges following slow-wave sleep (SWD-S). The time course of a spike-wave discharge was divided into (a) the beginning, (b) the middle, and (c) the end portion. VEPs obtained from each portion are shown. Negativity is upward deflected.
ceiling of the chamber, 100 cm above the animal to eliminate the click which accompanied the delivery of the flash. A second double window in the front wall of the chamber enabled observation of the animal's behavior. Photic stimuli were manually delivered at a random rate with a stimulus interval of more than 2 sec. The conditions during which the photic stimuli were presented was evaluated from the EEG of the frontal region together with the EMG and the behavior. Photic stimuli were presented during: (1) quiet wakefulness (W), (2) slow-wave sleep (S), (3) REM sleep (REM), (4) spike-wave discharges, during wakefulness (SWD-W), and (5) spike-wave discharges during sleep (SWD-S). Furthermore, the spike-wave discharges were divided into 3 periods: (a) the beginning of the spike-wave discharge from 0.5 to 1.5 see, (b) the middle portion which was the period between (a) and (c) at the mo-
ment of large amplitude spike-wave discharges, and (c) the end portion which was the last 1 sec of spike-wave activity. VEPs were obtained for each of these conditions. VEP components were designated as P1, N1, P2, N2, P3, N3 and P4 (Creel 1974; Fig. 2). For the reason that the P1 was relatively small and the N2 and the P3 were hardly detectable during S or spike-wave discharges, these components were only qualitatively considered and omitted from the quantitative analysis. Amplitudes of the VEPs were expressed as the difference between the peak of each component and baseline, whereby the baseline was defined as the point of onset of the P1 component. In order to quantify the degree of photically evoked afterdischarges, we used the type of method used by Shearer et al. (1976), which is described in detail by Fleming et al. (1973). These authors introduced the total excursion (TE). In the
TABLE I Mean amplitudes (/~V) and mean total excursions (cm) with S.D. of VEPs during the normal sleep-wake states (W: quiet wakefulness, SWS: slow-wave sleep, REM: REM sleep) and during various portions of the spike-wave discharge (SWD-W: spike-wave discharge following wakefulness and SWD-S: spike-wave discharge following slow-wave sleep). Components
W SWS REM SWD-W Beginning Middle End SWD-S Beginning Middle End
N1 (/.~V)
P2
- 162.50 + 8.69 - 160.48 + 17.31 - 164.80 + 17.50
81.03 + 11.81 140.55 + 30.50 92.08 + 12.73
- 125.80 + 36.20 - 112.80 + 27.85 - 135.73 + 22.04 - 129.88 4- 26.17 - 112.37 4-15.43 - 131.87 4-16.63
N3
P4
TE (cm)
- 83.58 -I-25.61 - 89.97 -I- 13.54 - 94.67 + 19.45
28.05 + 21.14 28.33 + 31.38 27.03 + 28.28
16.27 + 2.88 15.33 + 1.27 15.97 + 3.13
111.80 + 26.53 142.90 + 29.15 123.70 + 28.48
- 95.85 + 15.91 - 103.38 -I- 11.20 - 97.33 + 16.47
58.46 + 34.51 89.53 + 35.87 42.33 -t-27.84
20.12 + 4.23 21.17 + 3.24 16.33 -I-2.41
116.78 + 32.55 150.00 + 22.90 111.90 4- 29.36
- 93.98-1-19.52 - 94.78 + 11.84 - 96.70 + 27.28
61.13 + 33.25 86.23 + 25.13 58.93 + 29.67
20.33 + 5.16 21.13 + 6.20 16.90 + 3.30
VEPs
DURING SPIKE-WAVE DISCHARGES IN RATS
present study, TE was measured by tracing the pen inscription on each plot from the peak of the P4 component till the end of the 1 sec response with a map-reading wheel. Analysis of variance and Scheff6 post hoc tests were used for statistical verifications.
Results VEPs associated with each of the above mentioned conditions obtained in one animal are shown in Fig. 3. VEPs made during the normal states were similar to
(trY)
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those reported by other researchers (Creel 1974; Schwartzbaum 1975; Bigler 1977; Barnes and Dyer 1986). From a comparison of the VEPs with those of Van Hulzen and Coenen (1984) obtained in Wistar rats, it appeared that VEPs of WAG/Rij rats are comparable with those in this frequently used strain of rats, Table I contains the amplitude data of the various components of VEPs. A 1-way analysis of variance with conditions as factors showed significant differences between conditions in the N1 amplitude (F = 13.32, df 4, 25, P < 0.0001), the P2 amplitude (F = 11.90, df 4, 25,
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Fig. 4. Amplitude data of various VEP components, a: during the natural states of vigilance (W, S and REM) and during the middle portion of the spike-wave discharges (SWD-W, SWD-S). b: the changes during the time course of the spike-wave discharge (the beginning, the middle and the end). * P < 0.05; ** P < 0.01; *** P < 0.001.
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P < 0.0001), and the P4 amplitude (F = 7.83, df 4, 25, P < 0.001). For this analysis, the VEPs from the middle portion of the spike-wave discharges were taken. Data from Table I are graphically presented in Fig. 4. VEPs obtained during normal sleep and wakefulness were characterized by identical large N1 amplitudes throughout all stages. During S, an increase of the P2 amplitude was seen, whereas the P2-N2-P3 complex was absent. During W and REM, the shape of the P2-N2-P3 complex was almost similar. Identical N3 and P4 amplitudes were measured during these normal stages. An afterdischarge was seen during W and REM and, to a rather small degree, during S. VEPs obtained during spike-wave discharges were compared with those of the normal states of vigilance. A Scheff6 post hoc test (P < 0.05) showed that the N1 amplitude during SWD-W and SWD-S was significantly smaller than the amplitude during the normal stages. The P2 amplitude during SWD-W, SWD-S and during S was significantly larger than during W and REM. The P2-N2-P3 complex was invisible during spike-wave discharges and during S. Although the amplitudes of N3 did not show a significant change during spike-wave discharges, the P4 component was larger during them than during the normal stages (Scheff6 P < 0.05). As seen in Fig. 3, there was an apparent afterdischarge during spike-wave discharges and this tended to be larger than that seen during W or REM. Indeed, the ANOVA for the TE value showed a significant condition effect (F = 3.72, df 4, 25, P < 0.05). However, a Scheff6 post hoc test (P < 0.05) did not show significant differences. The amplitude changes during the time course of the spike-wave discharges are depicted in Fig. 4. Repeated measurements of multiple analysis of variance corrected by the Greenhouse-Geisser technique, with time course and the level of vigilance prior to a spikewave discharge as factors, showed significant differ-
ences between the time course of the N1 amplitude (F = 7.60, df 2, 20, P < 0.01), the P2 amplitude (F = 16.98, df 2, 20, P < 0.001) and the P4 amplitude (F = 31.60, df 2, 20, P < 0.0001). All amplitude changes showed similar directions of the modulations in each portion of the spike-wave discharge, compared with those during W. These changes were most prominent in the middle part of the spike-wave discharge. The P2-N2-P3 complex was only detectable at the beginning and at the end, but not in the middle portion. The TE value also showed a significant time difference (F = 18.55, df 2, 20, P < 0.0001). The largest values were seen in the beginning and the middle portion of the spike-wave discharge. There were no significant differences in the amplitude of the various components and in the TE value between VEPs made during SWD-W and SWD-S. Table II shows the latency data of the VEP components. There were significant differences in the N1 (F = 4.60, df 4, 25, P < 0.01), the P2 (F = 8.65, df 4, 25, P < 0.001), and the N3 components (F = 5.00, df 4, 25, P < 0.01). A Scheff6 post hoc test (P < 0.05), however, indicated that significant differences between conditions were due to longer latencies during S for the P2 component and during REM for the N3. The latencies of the N1 and the P2 components during spike-wave discharges were intermediate between S and W, but did not differ significantly from those seen during W. The latency of the N3 component was only longer during REM. There were no significant changes of latency over the time course of the spike-wave discharge.
Discussion
In this experiment it was convincingly demonstrated that the architecture of VEPs determined during spike-wave discharges is different from those obtained
TABLE II Mean latencies (msec) with S.D. of VEPs during the normal sleep-wake states and during various portions of the spike-wave discharge. Components
W SWS REM SWD-W Beginning Middle End SWD-S Beginning Middle End
N1
P2
N3
P4
29.50 + 0.84 32.50+1.76 30.00 + 0.89
52.17 + 2.56 62.67+5.32 53.00 + 3.41
165.83 + 3.25 167.33+7.42 177.00___3.34
222.83 + 5.88 238.50+ 9.65 230.67 + 12.19
30.50+1.38 32.00+ 1.55 30.00+ 1.10
54.00+2.76 56.17+ 1.47 54.17+3.31
168.33+4.55 166.33-1-1.47 169.67+5.50
223.67+ 3.88 228.00+ 6.75 221.67+ 6.47
30.50+1.52 31.00+ 1.90 30.50+ 1.05
53.67+1.36 55.17+3.31 54.17+ 1.17
167.83+6.71 170.00+5.37 169.50+5.82
227.83+ 8.91 228.50+ 9.61 227.00+ 6.57
VEPs D U R I N G SPIKE-WAVE DISCHARGES IN RATS
during the natural sleep-wake states. Some waves (N1, P4 and TE) changed in a unique way, differing from all the natural states, whereas another (P2) took the shape belonging to slow-wave sleep. A stable large amplitude of the N1 component was found throughout the normal sleep-wake states. However, a decrease of N1 was found in VEPs during spike-wave discharges. This primary wave is considered to reflect the activity of the retino-geniculo-cortical pathway and, in general, the amplitude of this N1 wave depends on the intensity of the actual stimulus (Creel 1974). Therefore, the decrease of N1 during spike-wave discharges may reflect a suppression in the primary visual pathway. Although a dysfunction of the retina is possible, a more likely explanation can be found in a dysfunction of the lateral geniculate nucleus (LGN), probably together with the visual cortex. The thalamus plays a main role in rhythmic oscillations such as spindle activity; several lines of evidence suggest that the thalamus is involved in the generation of spike-wave discharges (Buzs~iki et al. 1988; Vergnes et al. 1990) and some authors assumed that spike-wave discharges are modified sleep spindles (Hal~sz 1984). It is suggested that the sensory input and the rhythmic oscillations interfere in the thalamus, which gives rise to a reduced visual input, expressed in a lowering of N1, and in a resetting of rhythmical activity, resulting in a shift of the rhythm (Creutzfeldt 1973). The latter is expressed by an enhancement of the P4 amplitude followed by a long-lasting afterdischarge during spikewave discharges, as found in this experiment. The afterdischarge is prominent in the beginning and t h e middle portions of a spike-wave discharge, but not at the end of the discharge. Therefore, it can be expected that the shift of rhythm does not occur and the rhythmic tendency is already terminated at the end portion of the spike-wave activity. The oscillatory mechanisms of afterdischarges are reviewed by Bigler (1977) and, according to this author, the generation of the afterdischarge of VEPs is dependent on the recurrent inhibitory and rebound excitatory systems at the level of the LGN. The enhancement of the afterdischarge during a spike-wave discharge is also explained by a facilitation of this system. The N3 and the P4 components are both considered to represent the first occurrence of the recurrent inhibitory-excitatory system. The P4 enhancement during spike-wave activity especially indicates the enhanced rebound excitability in this system. Furthermore, the photically evoked afterdischarge in itself has been proposed as a model for absence epilepsy (Shearer et al. 1976). This rhythmic oscillation, measured as total excursion (TE), is affected by convulsive and anticonvulsive drugs (Fleming et al. 1973; Shearer et al. 1974). The amplitude of the P2 component and the disappearance of the P2-N2-P3 complex of the VEP mea-
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sured during spike-wave discharges are phenomena similar to those found during slow-wave sleep. It is commonly found that the P2 in this state is larger as compared to wakefulness and REM sleep (Yoshida and Iwahama 1979; Sigiienza et al. 1984). These responses are thought to be geniculo-cortical and can be heavily modulated by the ascending reticular system and the diffuse thalamic projections or saccadic eye movements (Singer 1977). Their power is dependent on the activity of structures related with these systems (Creel 1974; Barnes and Dyer 1986). During the various sleep-wake states, differences exist in the control of the thalamic and cortical responses (Coenen and Vendrik 1972; Singer 1977). During slow-wave sleep, the late tonic responses to stimuli in the thalamus and the cortex are suppressed and the spontaneous activity in these structures is smaller. On the other hand, neurons tend to fire more synchronously (Singer 1977; Steriade and Llin~s 1988). Such suppressed and synchronized responses might be represented by disappearance of the P2-N2-P3 complex and the increased amplitude of the P2 component. The latency data indicate that the brain function during spike-wave discharges might be an intermediate state between wakefulness and slow-wave sleep, because the latencies for the components which changed significantly in amplitude were in between those found during quiet wakefulness and during slow-wave sleep. Such latency changes could be taken to reflect changes in conductance velocity and synaptic delays. However, even the mechanisms responsible for the changes in latency during the normal states of vigilance remain largely unknown. VEPs determined during spike-wave discharges following wakefulness and following slow-wave sleep have similar architectures. It seems that the modulation of the sensory processing during spike-wave discharges is not influenced by the prior state of vigilance. All changes in VEP components as consequences of a spike-wave discharge take place during the whole course of the discharge, and these changes are most pronounced in the middle of the discharge. This is in agreement with behavioral studies in patients (Browne et al. 1974; Mirsky and Van Buren 1965). In animal models of drug-induced absence epilepsy, VEPs have also been studied (Mirsky et al. 1973; Burchiel et al. 1976; Pellegrini et al. 1986). So far, however, these have not been in genetic animal models. In studies that compared states with and without spike-wave discharges in patients, conducted by Mirsky (1989), it was reported that the early phase of the VEP during a spike-wave discharge was degraded, which was interpreted as due to sensory disruption. Furthermore, there was a report that a late component (P300) in the interictal period in absence patients is reduced in comparison to normal individuals (Duncan 1988).
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VEPs during natural states in the present experiment seem to be similar to the VEPs obtained from Wistar rats in our laboratory (Van Hulzen and Coenen 1984), as mentioned earlier. However, the VEP is not a direct expression of a cognitive process. It would be fruitful to investigate cognitive processes going together with P300 during ictal and interictal states of the WAG/Rij rats in a further study. In conclusion, V E P s during spike-wave discharges differ in 3 unique features from those made during the natural states of vigilance. Firstly, they show a decrease of N1, secondly, an increase of the P4 component and, thirdly, a more powerful afterdischarge. Another feature of the VEP during spike-wave discharges, the increase of the P2 amplitude, corresponds with slowwave sleep. The latencies of the N1 and the P2 component lie between those of quiet wakefulness and slowwave sleep. These findings suggest that a functional alteration occurs in the sensory pathway and that the sensory input is diminished during a spike-wave discharge. Finally, the fact that such suppressive sensory processing during spike-wave discharges exists gives additional evidence for the validity of W A G / R i j rats as a model of absence epilepsy. We thank Dr. Z.J.M. Van Hulzen for his help and advice.
References Barnes, M.I. and Dyer, R. Superior colliculus lesions and flash evoked potentials from rat cortex. Brain Res. Bull., 1986, 16: 225-230. Bergamini, L. and Bergamasco, B. Cortical Evoked Potentials in Man. Thomas, Springfield, IL, 1967: 49-52. Bigler, E.D. Neurophysiology, neuropharmacoiogy and behavioral relationships of visual system evoked after-discharges: a review. Biobehav. Rev., 1977, 1: 95-112. Browne, T.R., Penry, R.J., Porter, R.J. and Dreifuss, F.E. Responsiveness before, during and after spike-wave paroxysms. Neurology, 1974, 24: 659-665. Burehiel, K.J., Myers, R.R. and Bickford, R.G. Visual and auditory evoked responses during penicillin-induced generalized spike and wave activity in cats. Epilepsia, 1976, 17: 293-311. Buzsfiki, G., Bickford, R.G. Ponomareff, G., Thai, L.J., Mandel, R. and Gage, F.H. Nucleus basalis and thalamic control of neocortical activity in the freely moving rat. J. Neurosci., 1988, 8: 40074026. Coenen, A.M.L. and Van Luijtelaar, E.L.J.M. The WAG/Rij rat model for absence epilepsy: age and sex factors. Epilepsy Res., 1987, 1: 97-301. Coenen, A.M.L. and Vendrik, A.J.H. Determination of the transfer ratio of cat's geniculate neurons through quasi-intracellular recordings and the relation with the level of alertness. Exp. Brain Res., 1972, 14: 227-242. Creel, D. Intensity of flash illumination and the visually evoked potential of rats, guinea pigs and cats. Vision Res., 1974, 14: 725-729. Creutzfeldt, O. The neuronal generation of the EEG. In: A. Rrmond (Ed.), Handbook of Eiectroencephalography and Clinical Neurophysiology, Vol. 2c. Elsevier, Amsterdam, 1973: 90-118.
Duncan, C.C. Application of event-related brainpotentials to the analysis of interictal attention in petit mal epilepsy. In: M.S. Myslobodsky and A.F. Mirsky (Eds.), Elements of Petit Mal Epilepsy. Peter Lang, New York, 1988: 341-364. Fleming, D.E., Rhodes, L.E., Wilson, C.E. and Shearer, D.E. Differential effects of convulsive drugs on photically evoked after-discharge parameters. Psychopharmacologia, 1973, 29: 77-84. Goldie, L. and Green, J.M. Spike and wave discharges and alterations of conscious awareness. Nature, 1961, 191: 200-201. Goode, D.J., Penry, J.K. and Dreifuss, F.E. Effects of paroxysmal spike-wave on continuous visual-motor performance. Epilepsia, 1970, 11: 241-254. Haifisz, P. Sleep, arousal and electroclinical manifestations of generalized epilepsy with spike-wave pattern. In: R. Degen and E. Niedermeyer (Eds.), Epilepsy, Sleep and Sleep Deprivation. Elsevier, Amsterdam, 1984: 97-106. Kaplan, B.N. The epileptic nature of rodent electrocortical polyspiking is still unproven. Exp. Neurol., 1985, 88: 425-430. Mirsky, A.F. Information processing in petit real epilepsy. In: B.P. Hermann and M. Seidenberg (Eds.), Childhood Epilepsies: Neurophysiological, Psychological and Intervention Aspects. Wiley, New York, 1989: 51-70. Mirsky, A.F. and Tecce, J.J. The analysis of visual evoked potentials during spike-wave EEG activity. Epilepsia, 1968, 9: 211-220. Mirsky, A.F. and Van Buren, J.M. On the nature of the "absence" in centrencephalic epilepsy: a study of some behavioral, electroencephalographic and autonomic factors. Electroenceph. clin. Neurophysiol., 1965, 18: 334-348. Mirsky, A.F., Bloch-Rojas, S., Tecce, J.J., Lessell, D. and Marcus, E. Visual evoked potentials during experimentally induced spikewave activity in monkeys. Electroenceph. clin. Neurophysiol., 1973, 35: 25-37. Orren, M.M. Evoked potential studies in petit mal epilepsy: visual information processing in relation to spike-wave discharges. In: W.A. Cobb and H. Van Duijn (Eds.), Contemporary Clinical Neurophysiology (EEG Suppl. 34). Elsevier, Amsterdam, 1975: 251-257. Peeters, B.W.M.M., Spooren, W.P.J.M., Van Luijtelaar, E.L.J.M. and Coenen, A.M.L. The WAG/Rij rat model for absence epilepsy: anticonvulsant drug evaluation. Neurosci. Res. Commun., 1988, 2: 93-97. Pellegrini, A., Zanotti, L., Ermani, M., Chemello, R. and Testa, G. Laminar field potentials and unit activity in the cortex during visual evoked potentials in feline generalized penicillin epilepsy. Exp. Neurol., 1986, 94: 455-468. Schwartzbaum, J.S. Interrelationship among multiunit activity of the midbrain reticular formation and lateral geniculate nucleus, thalamocortical arousal, and behavior in rats. J. Comp. Physiol. Psychol., 1975, 89: 131-157. Semba, K., Szechtman, H. and Komisaruk, B.R. Synchrony among rhythmicity of petit real epilepsy: spontaneous spike and wave discharges in neuronal bursts in intact awake rats. Brain Res., 1980, 195: 281-298. Shearer, D.E., Fleming, D.E., Bigler, E.D. and Wilson, C.E. Suppression of photically evoked after-discharge bursting following administration of anticonvulsants in waking rats. Pharmacol. Biochem. Behav., 1974, 2: 839-842. Shearer, D.E., Fleming, D.E. and Bigler, E.D. The photically evoked afterdischarge: a model for the study of drugs useful in the treatment of petit real epilepsy. Epilepsia, 1976, 17: 429-435. Shimazono, Y., Hirai, T., Okuma, T., Fukuda, T. and Yamamasu, E. Disturbance of consciousness in petit mal epilepsy. Epilepsia, 1953, 2: 49-55. Sigiienza, J.A., De Andres, I., Ibarz, J.M. and Reinoso-Suarez, F. Cortical visual evoked potentials during the sleep wakefulness cycle of the freely moving cat. Characterization and statistical
VEPs DURING SPIKE-WAVE DISCHARGES IN RATS comparisons. Electroenceph. clin. Neurophysiol., 1984, 59: 165171. Singer, W. Control of thalamic transmission by corticofugal and ascending reticular pathways in the visual system. Physiol. Rev., 1977, 57: 386-420. Steriade, M. and Llin~is, R.R. The functional states of the thalamus and the associated neuronal interplay. Physiol. Rev., 1988, 68: 649-742. Tizard, B. and Margerison, J.H. Psychological functions during wave-spike discharge. Br. J. Soc. Clin. Psychol., 1963, 3: 6-15. Van Hulzen, Z.J.M. and Coenen, A.M.L. Photically evoked potentials in the visual cortex following paradoxical sleep deprivation in rats. Physiol. Behav., 1984, 32: 557-563. Van Luijtelaar, E.L.J.M. and Coenen. A.M.L. Two types of electrical
179 paroxysms in an inbred strain of rats. Neurosci. Lett., 1986, 70: 393-397. Van Luijtelaar, E.L.J.M. and Coenen. A.M.L. The W A G / R i j model for generalized absence seizures. In: E.B. Manelis, J.N. Loeber and F.E. Dreifuss (Eds.), Advances in Epileptology, Vol. 17. Raven Press, New York, 1989: 78-83. Vergnes, M., Marescaux, C. and Depaulis, A. Mapping of spontaneous spike and wave discharges in Wistar rats with genetic generalized non-convulsive epilepsy, Brain Res., 1990, 523: 87-91. Yoshida, K. and lwahama, S. Interrelationship among hippocampal theta activity, visual evoked response and rapid eye movement during paradoxical sleep in rats. Jpn. Physiol. Res., 1979, 21: 122-131.
Electroencephalography and clinical Neurophysiology , 84 (1992) 172-179 © 1992 Elsevier Scientific Publishers Ireland, Ltd. 0168-5597/92/$05.00
EVOPOT 90696
Visual evoked potentials during spontaneously occurring spike-wave discharges in rats M. Inoue, E.L.J.M. Van Luijtelaar, J.M.H. Vossen and A.M.L. Coenen Department of Psychology, University of Nijmegen, 6500 HE Nijmegen (The Netherlands)
(Accepted for publication: 11 October 1991)
Summary Flash evoked visual potentials (VEPs) were recorded in freely moving WAG/Rij rats. These rats show spontaneously occurring spike-wave discharges in the EEG, interpreted as absence-like seizures. VEPs recorded during the presence of spike-wave discharges were compared with those obtained during normal states of vigilance as quiet wakefulness, slow-wave sleep and REM sleep. Almost similar VEPs were recorded during wakefulness and REM sleep, whereas during slow-wave sleep the second positive peak (P2) was considerably larger. In comparison with normal sleep-wake states, VEPs during spike-wavedischarges showed unique changes, such as a decrease in the N1 amplitude, an increase of the P4 amplitude and an enhanced afterdischarge. Other characteristics were similar to those seen during slow-wavesleep, such as an increase of the P2 amplitude and a diminished P2-N3-P3 complex. These findings indicate sensory alterations during a spike-wavedischarge. As expressed in the decrease of N1, afferent information cannot enter the thalamus during the rhythmic oscillatory mode. Such alterations may underlie the lowered responsiveness to external stimuli during spike-waveactivity. Key wards: Visual evoked potentials; Spike-wave discharges; Absence epilepsy; Sleep-wakefulnesscycle; (Rat)
In absence epilepsy the most conspicuous clinical manifestation is the decreased responsiveness to external stimuli. An impaired responsiveness related to spike-wave discharges as measured by several behavioral tests has been reported (Shimazono et al. 1953; Goldie and G r e e n 1961; Tizard and Margerison 1963; Mirsky and Van Buren 1965; G o o d e et al. 1970; Browne et al. 1974). In addition to these decrements in performance, decreased responsiveness varies with the time course of the spike-wave discharge (Mirsky and Van Buren 1965; Browne et al. 1974). It is possible that a sensory impairment underlies the decreased responsiveness or that the brain function changes during spike-wave discharges. Some investigators have studied flash evoked visual potentials (VEPs) to clarify the brain mechanisms underlying the decreased responsiveness to external stimuli in human absence epilepsy (Bergamini and Bergamasco 1967; Mirsky and Tecce 1968; Orren 1975; Mirsky 1989). VEPs have also been determined in animal models using drug-induced absence-like epilepsy (Mirsky et al. 1973; Burchiel et al. 1976; Pellegrini et al. 1986). All rats of an inbred strain, the W A G / R i j strain, show spontaneously occurring generalized spike-wave Correspondence to: Dr. A.M.L. Coenen, Department of Psychology, University of Nijmegen, P.O. Box 9104, 6500 HE Nijmegen (The Netherlands). Tel.: + 31.80.61.2544; Fax: +31.80.61.5938.
discharges in the cortical E E G with a spike frequency of 7 - 1 0 Hz, an amplitude of 100-450/xV, and a mean duration of 5 sec (range 1-30 sec; Fig. 1). These are accompanied by behavioral concomitants such as vibrissal twitching, accelerated breathing, head tilting and sometimes eye twitching. Both the E E G and the behavioral manifestations are reminiscent of human absence epilepsy (Van Luijtelaar and Coenen 1986, 1989; (Coenen and Van Luijtelaar 1987). The number of rats that are affected increases with age and an increment of the hourly number of spike-wave discharges was found during ontogeny. After 6 months of age, all individuals show spike-wave discharges occurring approximately 15 t i m e s / h (Coenen and Van Luijtelaar 1987). Pharmacological studies indicate that typical anti-absence drugs suppress spike-wave discharges, whereas these discharges are aggravated by atypical anti-absence drugs (Peeters et al. 1988). Therefore, the W A G / R i j strain of rat might be considered as an appropriate model for absence epilepsy. A proof of a sensory impairment during the occurrence of a spike-wave discharge might be regarded as supporting evidence for the view that such a discharge can be considered as a genuine epileptic p h e n o m e n o n (Semba et al. 1980; Kaplan 1985). In the present study, we recorded VEPs during spike-wave discharges in W A G / R i j rats and compared them with VEPs during normal states of vigilance as quiet wakefulness, slow-wave sleep and R E M sleep.
173
VEPs D U R I N G SPIKE-WAVE DISCHARGES IN RATS
Fig. 1. Representative spike-wave discharges with (right) and without (left) photic stimuli in the E E G of a W A G / R i j rat. The upper trace is from the frontal cortex and the middle one from the visual cortex. The time at which photic stimuli are presented is shown in the bottom trace. In this figure, the first stimulus is presented in the beginning portion and the second one in the middle. Calibrations are 1 sec and 200/xV respectively. Positivity is upward deflected.
This comparison should reveal whether sensory impairments or changes of brain functioning occur during spike-wave discharges. Moreover, we distinguished 3 stages in the time course of a spike-wave discharge: the beginning, the middle and the end portions, to investigate whether impairments occur over the whole period of the spike-wave discharge.
Materials and methods Six W A G / R i j rats were used as subjects. The age of the animals ranged from 9 to 10 months. All rats were born and raised in our laboratory. They were housed individually and were maintained on a 12-12 LD cycle with white lights on from 21.00 to 9.00 h. Electrodes were permanently implanted under Hypnorm (0.1 ml/100 g) and Nembutal (1.5 mg/100 g) anesthesia. Two gilded screws were positioned on the dura: one on the frontal region (coordinates with skull surface flat and bregma 0-0: A 2.0, L 2.0) and a second one on the visual cortex (A -7.0, L 3.0) to conduct clear spikewave discharges and field potentials. The ground electrode was placed over the cerebellum. Two vinylcovered stainless steel electrodes were placed on the dorsal neck muscles for recording the EMG. One of the neck electrodes also served as a reference for monopolar EEG recording. Since recording of VEPs was carried out in quiet states of the animals, muscle artifacts were small and were completely eliminated by the averaging technique. All electrodes were led to a receptacle and the whole assembly was secured with two additional screws to the skull surface applied with dental acrylic cement. VEP records were made at least 2 weeks after the recovery period. The EMG and 2 E E G traces were registered through a polygraph (Mingograph 800, EIema-Sch6nander) with filters set at 0.5-700 Hz for the
EEG, and 27-700 Hz for the EMG. The output signals from the preamplifiers were recorded on a magnetic tape recorder (SE 7000) along with the trigger signals of the photic stimulation for later off-line analysis. Fifty VEPs were collected and averaged for each condition and digitized through A-D converters on an Apple II computer with a sampling rate of 1 msec for 1 sec epochs. Computer averaged evoked potentials were plotted on an X-Y recorder (Mosely 7035AM, Hewlett Packard). Animals were habituated to the experimental environment and to random photic stimulation on the day prior to the day of registration. The experiments were carried out from 9.00 to 17.00 h. During recording, the rat was placed in a plexiglass observation box (25 x 30 x 35 cm) and could move freely. The observation box was placed within a sound-attenuating shielded chamber with mirrors on the walls and the floor, to provide a roughly equal flash intensity in the chamber. Photic stimuli of 10/zsec duration were delivered with a Grass PS22 photostimulator, with the intensity set at a high level, point 8 (corresponding to 750,000 cd). The flash lamp was positioned just above a double window in the N1
N3
PI lOOxV a fterd ischarge P2 100~ec Fig. 2. A representative VEP of a W A G / R i j rat, obtained during quiet wakefulness. Positive and negative waves are indicated. The total excursion of the afterdischarge was measured from the peak of P4 to the end of the 1 sec lasting response. Negativity is upward deflected.
M. INOUE ET AL.
174
hfl
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"/
V V-V
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IO0~,V
4
c
.
~
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....
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Fig. 3. VEPs from one animal made during 1: quiet wakefulness (W), 2: slow-wave sleep (S), 3: REM sleep (REM), 4: spike-wave discharges following wakefulness (SWD-W), and 5: spike-wave discharges following slow-wave sleep (SWD-S). The time course of a spike-wave discharge was divided into (a) the beginning, (b) the middle, and (c) the end portion. VEPs obtained from each portion are shown. Negativity is upward deflected.
ceiling of the chamber, 100 cm above the animal to eliminate the click which accompanied the delivery of the flash. A second double window in the front wall of the chamber enabled observation of the animal's behavior. Photic stimuli were manually delivered at a random rate with a stimulus interval of more than 2 sec. The conditions during which the photic stimuli were presented was evaluated from the EEG of the frontal region together with the EMG and the behavior. Photic stimuli were presented during: (1) quiet wakefulness (W), (2) slow-wave sleep (S), (3) REM sleep (REM), (4) spike-wave discharges, during wakefulness (SWD-W), and (5) spike-wave discharges during sleep (SWD-S). Furthermore, the spike-wave discharges were divided into 3 periods: (a) the beginning of the spike-wave discharge from 0.5 to 1.5 see, (b) the middle portion which was the period between (a) and (c) at the mo-
ment of large amplitude spike-wave discharges, and (c) the end portion which was the last 1 sec of spike-wave activity. VEPs were obtained for each of these conditions. VEP components were designated as P1, N1, P2, N2, P3, N3 and P4 (Creel 1974; Fig. 2). For the reason that the P1 was relatively small and the N2 and the P3 were hardly detectable during S or spike-wave discharges, these components were only qualitatively considered and omitted from the quantitative analysis. Amplitudes of the VEPs were expressed as the difference between the peak of each component and baseline, whereby the baseline was defined as the point of onset of the P1 component. In order to quantify the degree of photically evoked afterdischarges, we used the type of method used by Shearer et al. (1976), which is described in detail by Fleming et al. (1973). These authors introduced the total excursion (TE). In the
TABLE I Mean amplitudes (/~V) and mean total excursions (cm) with S.D. of VEPs during the normal sleep-wake states (W: quiet wakefulness, SWS: slow-wave sleep, REM: REM sleep) and during various portions of the spike-wave discharge (SWD-W: spike-wave discharge following wakefulness and SWD-S: spike-wave discharge following slow-wave sleep). Components
W SWS REM SWD-W Beginning Middle End SWD-S Beginning Middle End
N1 (/.~V)
P2
- 162.50 + 8.69 - 160.48 + 17.31 - 164.80 + 17.50
81.03 + 11.81 140.55 + 30.50 92.08 + 12.73
- 125.80 + 36.20 - 112.80 + 27.85 - 135.73 + 22.04 - 129.88 4- 26.17 - 112.37 4-15.43 - 131.87 4-16.63
N3
P4
TE (cm)
- 83.58 -I-25.61 - 89.97 -I- 13.54 - 94.67 + 19.45
28.05 + 21.14 28.33 + 31.38 27.03 + 28.28
16.27 + 2.88 15.33 + 1.27 15.97 + 3.13
111.80 + 26.53 142.90 + 29.15 123.70 + 28.48
- 95.85 + 15.91 - 103.38 -I- 11.20 - 97.33 + 16.47
58.46 + 34.51 89.53 + 35.87 42.33 -t-27.84
20.12 + 4.23 21.17 + 3.24 16.33 -I-2.41
116.78 + 32.55 150.00 + 22.90 111.90 4- 29.36
- 93.98-1-19.52 - 94.78 + 11.84 - 96.70 + 27.28
61.13 + 33.25 86.23 + 25.13 58.93 + 29.67
20.33 + 5.16 21.13 + 6.20 16.90 + 3.30
VEPs
DURING SPIKE-WAVE DISCHARGES IN RATS
present study, TE was measured by tracing the pen inscription on each plot from the peak of the P4 component till the end of the 1 sec response with a map-reading wheel. Analysis of variance and Scheff6 post hoc tests were used for statistical verifications.
Results VEPs associated with each of the above mentioned conditions obtained in one animal are shown in Fig. 3. VEPs made during the normal states were similar to
(trY)
175
those reported by other researchers (Creel 1974; Schwartzbaum 1975; Bigler 1977; Barnes and Dyer 1986). From a comparison of the VEPs with those of Van Hulzen and Coenen (1984) obtained in Wistar rats, it appeared that VEPs of WAG/Rij rats are comparable with those in this frequently used strain of rats, Table I contains the amplitude data of the various components of VEPs. A 1-way analysis of variance with conditions as factors showed significant differences between conditions in the N1 amplitude (F = 13.32, df 4, 25, P < 0.0001), the P2 amplitude (F = 11.90, df 4, 25,
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W
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a
o
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Fig. 4. Amplitude data of various VEP components, a: during the natural states of vigilance (W, S and REM) and during the middle portion of the spike-wave discharges (SWD-W, SWD-S). b: the changes during the time course of the spike-wave discharge (the beginning, the middle and the end). * P < 0.05; ** P < 0.01; *** P < 0.001.
176
M. INOUE ET AL.
P < 0.0001), and the P4 amplitude (F = 7.83, df 4, 25, P < 0.001). For this analysis, the VEPs from the middle portion of the spike-wave discharges were taken. Data from Table I are graphically presented in Fig. 4. VEPs obtained during normal sleep and wakefulness were characterized by identical large N1 amplitudes throughout all stages. During S, an increase of the P2 amplitude was seen, whereas the P2-N2-P3 complex was absent. During W and REM, the shape of the P2-N2-P3 complex was almost similar. Identical N3 and P4 amplitudes were measured during these normal stages. An afterdischarge was seen during W and REM and, to a rather small degree, during S. VEPs obtained during spike-wave discharges were compared with those of the normal states of vigilance. A Scheff6 post hoc test (P < 0.05) showed that the N1 amplitude during SWD-W and SWD-S was significantly smaller than the amplitude during the normal stages. The P2 amplitude during SWD-W, SWD-S and during S was significantly larger than during W and REM. The P2-N2-P3 complex was invisible during spike-wave discharges and during S. Although the amplitudes of N3 did not show a significant change during spike-wave discharges, the P4 component was larger during them than during the normal stages (Scheff6 P < 0.05). As seen in Fig. 3, there was an apparent afterdischarge during spike-wave discharges and this tended to be larger than that seen during W or REM. Indeed, the ANOVA for the TE value showed a significant condition effect (F = 3.72, df 4, 25, P < 0.05). However, a Scheff6 post hoc test (P < 0.05) did not show significant differences. The amplitude changes during the time course of the spike-wave discharges are depicted in Fig. 4. Repeated measurements of multiple analysis of variance corrected by the Greenhouse-Geisser technique, with time course and the level of vigilance prior to a spikewave discharge as factors, showed significant differ-
ences between the time course of the N1 amplitude (F = 7.60, df 2, 20, P < 0.01), the P2 amplitude (F = 16.98, df 2, 20, P < 0.001) and the P4 amplitude (F = 31.60, df 2, 20, P < 0.0001). All amplitude changes showed similar directions of the modulations in each portion of the spike-wave discharge, compared with those during W. These changes were most prominent in the middle part of the spike-wave discharge. The P2-N2-P3 complex was only detectable at the beginning and at the end, but not in the middle portion. The TE value also showed a significant time difference (F = 18.55, df 2, 20, P < 0.0001). The largest values were seen in the beginning and the middle portion of the spike-wave discharge. There were no significant differences in the amplitude of the various components and in the TE value between VEPs made during SWD-W and SWD-S. Table II shows the latency data of the VEP components. There were significant differences in the N1 (F = 4.60, df 4, 25, P < 0.01), the P2 (F = 8.65, df 4, 25, P < 0.001), and the N3 components (F = 5.00, df 4, 25, P < 0.01). A Scheff6 post hoc test (P < 0.05), however, indicated that significant differences between conditions were due to longer latencies during S for the P2 component and during REM for the N3. The latencies of the N1 and the P2 components during spike-wave discharges were intermediate between S and W, but did not differ significantly from those seen during W. The latency of the N3 component was only longer during REM. There were no significant changes of latency over the time course of the spike-wave discharge.
Discussion
In this experiment it was convincingly demonstrated that the architecture of VEPs determined during spike-wave discharges is different from those obtained
TABLE II Mean latencies (msec) with S.D. of VEPs during the normal sleep-wake states and during various portions of the spike-wave discharge. Components
W SWS REM SWD-W Beginning Middle End SWD-S Beginning Middle End
N1
P2
N3
P4
29.50 + 0.84 32.50+1.76 30.00 + 0.89
52.17 + 2.56 62.67+5.32 53.00 + 3.41
165.83 + 3.25 167.33+7.42 177.00___3.34
222.83 + 5.88 238.50+ 9.65 230.67 + 12.19
30.50+1.38 32.00+ 1.55 30.00+ 1.10
54.00+2.76 56.17+ 1.47 54.17+3.31
168.33+4.55 166.33-1-1.47 169.67+5.50
223.67+ 3.88 228.00+ 6.75 221.67+ 6.47
30.50+1.52 31.00+ 1.90 30.50+ 1.05
53.67+1.36 55.17+3.31 54.17+ 1.17
167.83+6.71 170.00+5.37 169.50+5.82
227.83+ 8.91 228.50+ 9.61 227.00+ 6.57
VEPs D U R I N G SPIKE-WAVE DISCHARGES IN RATS
during the natural sleep-wake states. Some waves (N1, P4 and TE) changed in a unique way, differing from all the natural states, whereas another (P2) took the shape belonging to slow-wave sleep. A stable large amplitude of the N1 component was found throughout the normal sleep-wake states. However, a decrease of N1 was found in VEPs during spike-wave discharges. This primary wave is considered to reflect the activity of the retino-geniculo-cortical pathway and, in general, the amplitude of this N1 wave depends on the intensity of the actual stimulus (Creel 1974). Therefore, the decrease of N1 during spike-wave discharges may reflect a suppression in the primary visual pathway. Although a dysfunction of the retina is possible, a more likely explanation can be found in a dysfunction of the lateral geniculate nucleus (LGN), probably together with the visual cortex. The thalamus plays a main role in rhythmic oscillations such as spindle activity; several lines of evidence suggest that the thalamus is involved in the generation of spike-wave discharges (Buzs~iki et al. 1988; Vergnes et al. 1990) and some authors assumed that spike-wave discharges are modified sleep spindles (Hal~sz 1984). It is suggested that the sensory input and the rhythmic oscillations interfere in the thalamus, which gives rise to a reduced visual input, expressed in a lowering of N1, and in a resetting of rhythmical activity, resulting in a shift of the rhythm (Creutzfeldt 1973). The latter is expressed by an enhancement of the P4 amplitude followed by a long-lasting afterdischarge during spikewave discharges, as found in this experiment. The afterdischarge is prominent in the beginning and t h e middle portions of a spike-wave discharge, but not at the end of the discharge. Therefore, it can be expected that the shift of rhythm does not occur and the rhythmic tendency is already terminated at the end portion of the spike-wave activity. The oscillatory mechanisms of afterdischarges are reviewed by Bigler (1977) and, according to this author, the generation of the afterdischarge of VEPs is dependent on the recurrent inhibitory and rebound excitatory systems at the level of the LGN. The enhancement of the afterdischarge during a spike-wave discharge is also explained by a facilitation of this system. The N3 and the P4 components are both considered to represent the first occurrence of the recurrent inhibitory-excitatory system. The P4 enhancement during spike-wave activity especially indicates the enhanced rebound excitability in this system. Furthermore, the photically evoked afterdischarge in itself has been proposed as a model for absence epilepsy (Shearer et al. 1976). This rhythmic oscillation, measured as total excursion (TE), is affected by convulsive and anticonvulsive drugs (Fleming et al. 1973; Shearer et al. 1974). The amplitude of the P2 component and the disappearance of the P2-N2-P3 complex of the VEP mea-
177
sured during spike-wave discharges are phenomena similar to those found during slow-wave sleep. It is commonly found that the P2 in this state is larger as compared to wakefulness and REM sleep (Yoshida and Iwahama 1979; Sigiienza et al. 1984). These responses are thought to be geniculo-cortical and can be heavily modulated by the ascending reticular system and the diffuse thalamic projections or saccadic eye movements (Singer 1977). Their power is dependent on the activity of structures related with these systems (Creel 1974; Barnes and Dyer 1986). During the various sleep-wake states, differences exist in the control of the thalamic and cortical responses (Coenen and Vendrik 1972; Singer 1977). During slow-wave sleep, the late tonic responses to stimuli in the thalamus and the cortex are suppressed and the spontaneous activity in these structures is smaller. On the other hand, neurons tend to fire more synchronously (Singer 1977; Steriade and Llin~s 1988). Such suppressed and synchronized responses might be represented by disappearance of the P2-N2-P3 complex and the increased amplitude of the P2 component. The latency data indicate that the brain function during spike-wave discharges might be an intermediate state between wakefulness and slow-wave sleep, because the latencies for the components which changed significantly in amplitude were in between those found during quiet wakefulness and during slow-wave sleep. Such latency changes could be taken to reflect changes in conductance velocity and synaptic delays. However, even the mechanisms responsible for the changes in latency during the normal states of vigilance remain largely unknown. VEPs determined during spike-wave discharges following wakefulness and following slow-wave sleep have similar architectures. It seems that the modulation of the sensory processing during spike-wave discharges is not influenced by the prior state of vigilance. All changes in VEP components as consequences of a spike-wave discharge take place during the whole course of the discharge, and these changes are most pronounced in the middle of the discharge. This is in agreement with behavioral studies in patients (Browne et al. 1974; Mirsky and Van Buren 1965). In animal models of drug-induced absence epilepsy, VEPs have also been studied (Mirsky et al. 1973; Burchiel et al. 1976; Pellegrini et al. 1986). So far, however, these have not been in genetic animal models. In studies that compared states with and without spike-wave discharges in patients, conducted by Mirsky (1989), it was reported that the early phase of the VEP during a spike-wave discharge was degraded, which was interpreted as due to sensory disruption. Furthermore, there was a report that a late component (P300) in the interictal period in absence patients is reduced in comparison to normal individuals (Duncan 1988).
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VEPs during natural states in the present experiment seem to be similar to the VEPs obtained from Wistar rats in our laboratory (Van Hulzen and Coenen 1984), as mentioned earlier. However, the VEP is not a direct expression of a cognitive process. It would be fruitful to investigate cognitive processes going together with P300 during ictal and interictal states of the WAG/Rij rats in a further study. In conclusion, V E P s during spike-wave discharges differ in 3 unique features from those made during the natural states of vigilance. Firstly, they show a decrease of N1, secondly, an increase of the P4 component and, thirdly, a more powerful afterdischarge. Another feature of the VEP during spike-wave discharges, the increase of the P2 amplitude, corresponds with slowwave sleep. The latencies of the N1 and the P2 component lie between those of quiet wakefulness and slowwave sleep. These findings suggest that a functional alteration occurs in the sensory pathway and that the sensory input is diminished during a spike-wave discharge. Finally, the fact that such suppressive sensory processing during spike-wave discharges exists gives additional evidence for the validity of W A G / R i j rats as a model of absence epilepsy. We thank Dr. Z.J.M. Van Hulzen for his help and advice.
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