Facilitation of epileptic activity during sleep is mediated by high amplitude slow waves

Abstract

Epileptic discharges in focal epilepsy are frequently activated during non-rapid eye movement sleep. Sleep slow waves are present during this stage and have been shown to include a deactivated ('down', hyperpolarized) and an activated state ('up', depolarized). The 'up' state enhances physiological rhythms, and we hypothesize that sleep slow waves and particularly the 'up' state are the specific components of non-rapid eye movement sleep that mediate the activation of epileptic activity. We investigated eight patients with pharmaco-resistant focal epilepsies who underwent combined scalp-intracerebral electroencephalography for diagnostic evaluation. We analysed 259 frontal electroencephalographic channels, and manually marked 442 epileptic spikes and 8487 high frequency oscillations during high amplitude widespread slow waves, and during matched control segments with low amplitude widespread slow waves, non-widespread slow waves or no slow waves selected during the same sleep stages (total duration of slow wave and control segments: 49 min each). During the slow waves, spikes and high frequency oscillations were more frequent than during control segments (79% of spikes during slow waves and 65% of high frequency oscillations, both P ∼ 0). The spike and high frequency oscillation density also increased for higher amplitude slow waves. We compared the density of spikes and high frequency oscillations between the 'up' and 'down' states. Spike and high frequency oscillation density was highest during the transition from the 'up' to the 'down' state. Interestingly, high frequency oscillations in channels with normal activity expressed a different peak at the transition from the 'down' to the 'up' state. These results show that the apparent activation of epileptic discharges by non-rapid eye movement sleep is not a state-dependent phenomenon but is predominantly associated with specific events, the high amplitude widespread slow waves that are frequent, but not continuous, during this state of sleep. Both epileptic spikes and high frequency oscillations do not predominate, like physiological activity, during the 'up' state but during the transition from the 'up' to the 'down' state of the slow wave, a period of high synchronization. Epileptic discharges appear therefore more associated with synchronization than with excitability. Furthermore, high frequency oscillations in channels devoid of epileptic activity peak differently during the slow wave cycle from those in channels with epileptic activity. This property may allow differentiating physiological from pathological high frequency oscillations, a problem that is unresolved until now.

Keywords: epilepsy; high frequency oscillations; intracerebral electroencephalography; sleep; slow wave.

© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.

Figures

Epileptic discharges are increased during non-REM sleep. By studying the sleep EEG in patients with focal epilepsies, Frauscher et al. show that the increase is specifically associated with high-amplitude slow waves. In contrast to physiological activity, it occurs at transitions from activation to deactivation states, a period of high synchronization.

Figure 1

Flow chart illustrating the principal steps of the study analysis.

Figure 2

Intracerebral correlates of scalp slow waves. (A) Superimposed individual scalp slow waves and their average. The averaging was done after aligning the peaks of the negative half-waves (shown as time zero; negative down). (B) Power in the delta band in scalp and intracerebral channels demonstrated the presence of intracerebral slow waves peaking at the same time as scalp slow waves (blue line). Similar results were found for channels with normal EEG activity (red line) and channels with interictal epileptic spikes (black line). The standard error of the channels' mean is depicted in broken lines for 16 scalp channels, 130 intracerebral channels with normal EEG activity, and 129 intracerebral channels with epileptic EEG activity. The grey bands indicate the time of the transitions from positive to negative (left) and negative to positive (right) half-waves, the grey level indicating the density of the 3964 individual transitions from positive to negative and negative to positive half-waves, darker when more transitions occur.

Figure 3

Density of spikes and HFOs as a function of the percentage of the highest amplitude slow waves analysed. The density is relative to the density found for the frontal widespread slow waves with the 25% highest amplitude. Error bars depict the standard error of the mean among the eight patients.

Figure 4

Gamma (blue line) and ripple band (red line) power for scalp channels (A) and for intracerebral channels with normal EEG activity (B). Broken lines indicate the standard error of the mean among the 16 scalp channels and the 130 intracerebral channels with normal EEG activity. Time zero corresponds to the peak of the negative half-waves, and their beginning and end are indicated by the grey bands, defined as in Fig. 2. As expected the ripple band in scalp channels is not very informative, because its amplitude is very low and hence confounded by the noise associated to the equipment (electrodes and amplifier). Of note, power in the gamma and ripple bands is higher after the negative half-wave, at the time of the cortical ‘up’ state.

Figure 5

Variation in time of the spike and HFO density. Time zero corresponds to the peak of the negative half-waves, and their beginning and end are indicated by the grey bands, as defined in Fig. 2. An increase in the spike rate is seen at the transition between the negative half-wave and the preceding positive half-wave (blue line). An increase in HFO density is seen at the transition between the negative half-wave and the preceding positive half-wave as well as during the negative half-wave and first part of the following positive half-wave (red line).

Figure 6

Representative examples for the coupling of epileptic spikes and HFOs across the slow wave cycle. Example of a slow wave and an epileptic spike (left), a slow wave and an HFO in a channel with epileptic activity (middle) and an HFO in a channel with normal EEG activity (right). The top row shows the slow wave in a scalp channel, the second row shows the same time period for an intracerebral channel with normal EEG activity, and the third row an intracerebral channel with epileptic EEG activity. The bottom row shows the HFO signal with a different time and amplitude scale, corresponding to the shaded periods in the intracerebral channels. All the channels are in the left frontal region [anterior cingulate gyrus (LCA1–2), orbitofrontal area (LOF1–2, LOF2–3), second frontal gyrus (LCA7–8), third frontal gyrus (LOF9–10)], each example corresponds to a different patient. The scalp slow wave on the right panel is of shorter duration than the scalp slow waves on the left or middle panel. *In this example a normal sleep slow wave and no epileptic spike is seen in a channel called ‘epileptic’ because it has spikes at other times. Note that the spike and the HFO in the intracerebral channel with epileptic activity (middle) occurs prior to the peak of the scalp negative half-wave, whereas the HFO in the channel with normal EEG activity (right) occurs after the peak of the scalp negative half-wave.

Figure 7

Variation in time of the HFO density. Time zero corresponds to the peak of the negative half-waves, and their beginning and end are indicated by the grey bands, as defined in Fig. 2. An increase in HFO density is observed at the transition between the negative half-wave and the preceding positive one in channels with epileptic EEG activity (red dotted line), but not in channels with normal EEG activity (blue solid line). In contrast, there is an increase in HFO density at the transition between the negative half-wave and the following positive one in channels with normal EEG activity.

Figure 8

Average ripple band power distributed over channels with normal EEG activity (blue line), and channels with interictal spikes (red line). (A) The pattern of the ripple band power in intracerebral channels with normal EEG activity is different from that in channels with epileptic EEG activity, due to the presence of HFOs. (B) The median, less influenced by outliers associated with individual HFOs, shows the same general pattern in channels with normal and epileptic EEG activity. Broken lines indicate the standard error of the mean in A and standard error of the median in B among the 130 intracerebral channels with normal EEG activity and the 129 intracerebral channels with epileptic EEG activity.