Sleep-Modulated Cross-Frequency Coupling Between δ Phase and β-γ Bistability: A System-Level Modulation of Epileptic Activity

ObjectiveWhile slow waves in {delta} (0.5-4 Hz) characterize NREM sleep, in patients with sleep-related epilepsy, seizures most frequently emerge during NREM stage 2, known to be promoted by {delta}-band instability. Meanwhile, the epileptogenic zone (EZ) shows localized bistability in {beta}-{gamma} band (15-200 Hz) neuronal oscillations--indicating a catastrophic shift toward seizure. We aim to clarify the mechanistic link between {delta}-band synchrony and {beta}-{gamma} band bistability in epilepsy. MethodsWe studied a cohort of fourteen patients with Sleep Hypermotor Epilepsy (22.3 {+/-} 10.8 years old; 7 males). 7-9-hour stereo-EEG sleep recordings were segmented into 10-minute of uninterrupted, interictal N2 and N3 epochs, and phase synchrony, phase-amplitude coupling (PAC), and bistability were assessed. Canonical correlation was examined to answer whether PAC links {delta}-phase to {beta}-{gamma} bistability. ResultsCompared to non-EZ, the EZ exhibited larger 15-200 Hz bistability along with stronger 2-8 Hz and 15-100 Hz synchrony throughout N2 and N3. Compared to N3, N2 showed stronger PAC between 2-30 Hz phases in the non-EZ and 5-150 Hz amplitudes in the EZ. Canonical correlations between {delta}-phase modulated PAC and both bistability and synchrony were identified during N2 (r = 0.86 and 0.82) and N3 (r = 0.84 and 0.80), with the strongest contributors being 2-4 Hz synchrony and bistability in 2-4 Hz and 15-200 Hz bands. Correlations between interictal spikes and canonical covariates of bistability and PAC (r2 = 0.62 for N2 and 0.56 for N3) validated their relevance to epileptogenicity. Significance{delta}-band synchrony and {beta}-{gamma} band bistability are not isolated epileptogenic mechanisms but likely act synergistically, playing a pivotal role in seizure generation through the coupling of {delta} phases and {beta}-{gamma} amplitudes across large networks, with significant contributions from non-epileptogenic tissues. Key pointsO_LIStrong {beta}-{gamma} bistability in neuronal oscillations localizes the EZ throughout N2 and N3 sleep. C_LIO_LIElevated {delta}-band phase synchrony characterizes the EZ and its functional neighbors throughout N2 and N3 sleep. C_LIO_LIa-band synchrony modulates local {beta}-{gamma} bistability through PAC, with significant contributions from non-EZ tissues. C_LI