Seizures in Sleep and Sleep Transitions

Don Tucker, PhD, CEO and Chief Scientist of EGI, spoke on "Nocturnal Onset Generalized Seizures and Cortical Slow Oscillations of Sleep".

Recent studies have suggested that dEEG may provide insight into seizures that arise in sleep, or in the transitions between sleep and wakefulness. This research integrates observations on normal sleep mechanisms at the University of Wisconsin with observations on generalized seizures by scientists at GeoMedica and the University of Washington. The new hypothesis emerging from these observations is that some forms of human seizures may emerge from a disorder of the normal sleep mechanism of cortical slow oscillations.

Thalamic Control of the Cortex in Sleep and Seizures

In animal research, generalized spike-wave seizures have been shown to arise from disorders of the normal thalamocortical mechanisms that regulate sleep and consciousness. These mechanisms involve the widespread projections from the thalamus, at the core of each cerebral hemisphere, to the cortex of that hemisphere. Surrounding the thalamus is a thin sheet of neurons, the thalamic reticular nucleus, that has a point-to-point projection map to the major thalamic nuclei, and that appears to regulate the functioning of the thalamic neurons (that in turn regulate the general alertness of the cortex). The complexity of the circuit does not end there; the cortex, particularly the frontal pole, appears to play a major role in controlling the thalamocortical system through organized projections to the thalamic reticular nucleus.

Cortical Slow Oscillations in Normal Sleep

Insight into the cortical activity relevant to these thalamocortical relations has been provided by Giulio Tononi and his associates at the University of Wisconsin, who have pioneered the application of GeoMedica's 256-channel dEEG system in research on the neurophysiology of human sleep. In a recent report from the Tononi laboratory (Massimini et al., 2004), cortical slow oscillations (CSOs) were described in humans with similar features as seen in animal studies by Steriade and Amzica. These are oscillations at frequencies of less than 1 cycle per second, apparently reflecting a regulation of a "cortical down state" that is integral to the decreased function of the cortex in slow-wave sleep. With the improved accuracy of dEEG used for the sleep recordings, Masimini (et al., 2004) were able to determine that the cortical slow oscillations are typically detected at the medial pole of the frontal lobe (70% of the time, as in the figure above). The positions of conventional EEG electrodes (Afz, Cz, O1, O2, T7) are shown in relation to the 256-sensor positions at the right. 

Examining the origins of the CSOs in sleep, Massimini (et al., 2004) showed that the onset is typically at the frontal pole. In this figure, A shows the distribution of the onsets, with a larger circle indicating more frequent onsets. B shows the probabilities from the data in A interpolated to create an onset probability density map. C shows the average delays of the travelling CSOs, indicating the dominant direction of travel from the front to the back. Aligning the onset probabilites of the CSOs with the patient's MRI (D) shows the onset is at the frontal pole, at the junction of the dorsolateral with the orbital networks of the frontal lobe.

Frontal Discharges in Seizures

A remarkably similar localization of electrical activity, to the frontal pole, has recently been reported for the spike-wave discharges of so-called "generalized" seizures by Holmes at the University of Washington and Tucker and Brown at EGI (Holmes et al., 2004). In this dEEG topographic waveform plot, a one-second segment of the EEG is arrayed with each of the 256 channels in an approximate position looking down on the head, with the sides and bottom unwrapped to a flat projection, with the nose at the top of the page. The large amplitude spike-wave (or wave-spike) discharges of the seizure are seen to be maximal at the medial pole of the frontal lobe (in the middle of the forehead).

The slow wave/spike sequence shown in the previous topographic waveform plot is illustrated in this series of maps, with blue indicating negative potential and red indicating positive (with white at zero). The slow wave extends over the first 200 milliseconds (ms), with a similar anterior negativity over this interval. At 216 ms the anterior negative slow wave is interrupted by a sharp positive-going spike (illustrated from 220 to 234 ms), which appears to travel up the midline of the frontal lobe.

Analyzing each 4 ms sampling of this wave-spike transition in this seizure with GeoMedica's GeoSource software, Tucker, Holmes, Luu, & Brown (2007) found that the anterior negative slow wave reflects bilateral source activity in broad regions of anterior temporal and frontal lobes (illustrated by the 168 ms sample).  The positive spike showed a remarkable transition of activity first at the frontal pole (216 ms) then sweeping down into orbital frontal cortex (224 ms).  This sweep of highly synchronous electrical discharge was positive at the head surface (as in the previous figure at 224 ms) but was created by a surface-negative discharge on the ventral surface of the orbital frontal lobe (the negative dipole pointed down, and the positive dipole created the positive spike at the top of the head).

Observing Seizures Emerge from Cortical Slow Oscillations in Sleep

In patients recorded during long-term monitoring at the University of Washington Regional Epilepsy Center at Harborview Hospital, we have observed that generalized seizures, with the typical spike-wave pattern, may arise from the cortical slow oscillations that first appear to reflect normal sleep neurophysiology (Tucker, Holmes, in preparation).

This map shows the maximum negativity (blue) of a patient's apparently normal cortical slow oscillation, with a topography similar to that shown by Massimini et al. (2004).

Source estimation of this time point in the 256-channel data with the GeoSource software shows activation of the frontal pole of the left hemisphere, consistent with the surface distribution in the map 

Examining the time course of the progression from sleep waves to seizure onset with a conventional (bipolar Ten-Twenty) EEG chart display shows three cortical slow oscillations at left (the third of which is marked by the vertical line and was used for the figures above). In the middle of the chart page is a single discharge that occupies the same topography of the cortical slow oscillations, but with a spike-wave morphology that appears epileptiform. After about one second, this discharge is followed by the stereotyped large-amplitude discharges of a generalized seizure. 

Conclusion

These preliminary observations suggest that the neurophysiological mechanisms regulating the normal transitions between consciousness and sleep may be implicated in the loss of consciousness in absence epilepsy, and in the generalized seizures that arise in sleep and drowsiness.

Holmes, M. D., Brown, M., & Tucker, D. M. (2004). Are "generalized" seizures truly generalized? Evidence of localized mesial frontal and frontopolar discharges in absence. Epilepsia, 45(12), 1568-1579.

Massimini, M., Huber, R., Ferrarelli, F., Hill, S., & Tononi, G. (2004). The sleep slow oscillation as a traveling wave. J Neurosci, 24(31), 6862-6870.

Steriade, M. (2003). Neuronal substrates of sleep and epilepsy. New York: Cambridge University Press.

Steriade, M. & Amzica, F. (2003). Sleep oscillations developing into seizures in corticothalamic systems. Epilepsia, 44 Suppl 12, 9-20.

Tucker, D. M., Brown, M., Luu, P., & Holmes, M. D. (2007). Discharges in ventromedial frontal cortex during absence spells. Epilepsy and Behavior, 11, 546-557.

Tucker, D. M., & Holmes, M. D. (in preparation).  Emergence of spike-wave seizures from cortical slow oscillations in humans.