Thalamic epileptic spikes disrupt sleep spindles in patients with epileptic encephalopathy

Abstract

In severe epileptic encephalopathies, epileptic activity contributes to progressive cognitive dysfunction. Epileptic encephalopathies share the trait of spike-wave activation during non-REM sleep (EE-SWAS), a sleep stage dominated by sleep spindles, which are brain oscillations known to coordinate offline memory consolidation. Epileptic activity has been proposed to hijack the circuits driving these thalamocortical oscillations, thereby contributing to cognitive impairment. Using a unique dataset of simultaneous human thalamic and cortical recordings in subjects with and without EE-SWAS, we provide evidence for epileptic spike interference of thalamic sleep spindle production in patients with EE-SWAS. First, we show that epileptic spikes and sleep spindles are both predicted by slow oscillations during stage two sleep (N2), but at different phases of the slow oscillation. Next, we demonstrate that sleep-activated cortical epileptic spikes propagate to the thalamus (thalamic spike rate increases after a cortical spike, P ≈ 0). We then show that epileptic spikes in the thalamus increase the thalamic spindle refractory period (P ≈ 0). Finally, we show that in three patients with EE-SWAS, there is a downregulation of sleep spindles for 30 s after each thalamic spike (P < 0.01). These direct human thalamocortical observations support a proposed mechanism for epileptiform activity to impact cognitive function, wherein epileptic spikes inhibit thalamic sleep spindles in epileptic encephalopathy with spike and wave activation during sleep.

Keywords: EE-SWAS; cross-frequency relationships; interictal discharges; memory consolidation; non-rapid eye movement sleep.

Figure 1

Slow waves predict spikes and spindles at different phases. (A) Example simultaneous recordings of scalp EEG (purple traces), cortical stereoelectroencephalography (SEEG; orange trace) and thalamic SEEG (green trace) centred on slow oscillation down-state troughs (vertical dashed line). [A(i)] A cortical spike (orange trace) precedes the down-state. [A(ii)] A thalamic sleep spindle (green trace) follows the down-state. (B) Averaged cortical slow oscillations (SO) low-pass filtered below 30 Hz (purple) across all subjects. Slow waves initiate with a low-amplitude up-state ∼1.4 s before the down-state trough. The modulation coefficient (95% confidence interval) of cortical spike rate (orange) and thalamic spindle rate (green) is shown over the course of the slow oscillation. Spikes are positively modulated during the up-state to down-state transition. Sleep spindles are positively modulated during the up-state. Horizontal bars on the bottom axis indicate times during which the slow oscillation amplitude (purple), spindle rate modulation (green) and spike rate modulation (orange) are significant (P < 0.05). (C) Normalized cross-correlation histogram of events timed to down-state at 0 s reflecting the modulation of cortical spikes and thalamic spindle occurrences.

Figure 2

Slow oscillations with or without cortical spikes exhibit similar dynamics and impact on thalamic spindles. (A) Averaged unfiltered slow oscillations (SO) that did [orange; shaded area indicates 95% confidence intervals (CI)] or did not (green; shaded area indicates 95% CI) co-occur with a distant cortical spike. (B) Averaged unfiltered slow oscillations that co-occurred with a local scalp EEG spike (grey; shaded area indicates 95% CI) or with a distant cortical intracranial spike (orange; shaded area indicates 95% CI). (C) Thalamic spindle modulation (95% CI) for slow oscillations with (orange) and without (green) cortical spikes. Averaged slow oscillations are shown in purple. Spindles occur maximally during the slow oscillation up-state. (D) Same as C, but for thalamic spikes instead of cortical spikes. Thalamic spindles are significantly decreased on average for slow oscillations with thalamic spikes during the slow oscillation up-state between 0.125 and 0.75 s (see main text for details).

Figure 3

Cortical spikes drive thalamic spikes in subjects with spike and wave activation in sleep (SWAS). (A) Example epileptic spikes (left) from one subject in the cortex (Ctx) and thalamus (Thal) and (right) the averaged response time locked to cortical spikes. (B) Cross-correlation histograms of thalamic spikes relative to the time of cortical spikes for each subject. Zero indicates the moment of a cortical spike. (C) Model estimates of thalamic spike rate modulation attributable to the occurrence of a cortical spike (mean solid, confidence intervals shaded) for each patient group (see key). Significant increases [P < 0.05 when confidence intervals exclude one (black horizontal line)] in thalamic spike rate occur owing to a preceding (8–40 ms earlier) cortical spike.

Figure 4

Spikes inhibit spindles. (A) Spike rate and spindle rate across subjects and brain regions during stage two (N2) sleep are anti-correlated. (B) Example spike disruption of spindles in the thalamus. Before a spike (red arrow), spindles occur regularly; see upper trace for example spindles and lower image for spindle band peaks in the spectrogram. After a spike, spindles are not apparent in the trace (middle row) or spectrogram (bottom row). (C) Histograms of thalamic spindle refractory periods with (orange) and without (green) intervening thalamic spikes for subjects with epileptic encephalopathy. Insets show distributions for subjects with (yellow) and without (blue) spike-wave activation during sleep (SWAS). (D) The rate of thalamic spindles is reduced by thalamic spikes in subjects with epileptic encephalopathy-related SWAS (EE-SWAS). Estimates of spindle rate modulation parameters at each second (coloured dots) and grouped over 10 s intervals (violin plots with median and quartiles indicated). Thalamic spindle rates are downregulated when a preceding spike occurs between −35 and −5 s. Time 0 s (dashed vertical line) indicates the time of spindle occurrence. (E and F) Same as in C and D, except using scalp EEG-detected spindles. In F, scalp spindle rates are downregulated when a preceding spike occurs between −25 and −5 s. *P < 0.05.

Figure 5

Spindles consistently co-occur in the thalamus and the scalp EEG across all subject groups. (A) Averaged spindle response in individual subjects, time locked to maximum spindle amplitude in the thalamus, indicates consistent phase-locked spindle activity across the cortex and thalamus. (B) Modulation of scalp spindle rate at time 0 s across subjects in each group (green curves, mean solid, 95% confidence intervals shaded) by thalamic spindles. Background spectrograms of thalamic data time locked to scalp spindles. Warm (cool) colours include high (low) standardized power; see scale bar. Regions outlined in black indicate Bonferroni-corrected islands of significant changes in power. EE = epileptic encephalopathy; SWAS = spike-wave activation during sleep.

Figure 6

Proposed mechanistic circuit contributing to spindle deficit and cognitive dysfunction in epileptic encephalopathy associated with spike-wave activation during sleep (EE-SWAS). Our observations are consistent with this proposed mechanistic circuit.