Sleep-Modulated Cross-Frequency Coupling Between δ Phase and β-γ Bistability: A System-Level Modulation of Epileptic Activity
ObjectiveTo investigate the mechanistic link between large-scale {delta}-band (0.5-4 Hz) synchrony during sleep and local bistability of the {beta}-{gamma} band (15-200 Hz), a biomarker of the epileptogenic zone.

Methods7-9-hour stereo-EEG sleep recordings were obtained from 14 subjects (22.3 {+/-} 10.8 years old; 7 males) with sleep-related hypermotor epilepsy. These recordings were segmented into 10-minute epochs of uninterrupted interictal N2 and N3 stages of NREM sleep. We assessed phase synchrony, phase-amplitude coupling (PAC), and {beta}-{gamma} band (15-200 Hz) bistability. Canonical correlation analysis was used to explore whether PAC links {delta}-synchrony to {beta}-{gamma} band bistability.

ResultsCompared to non-epileptogenic regions (nEZ), the epileptogenic zone (EZ) exhibited stronger 15-200 Hz bistability and greater 2-8 Hz and 15-100 Hz phase synchrony. Compared to N3, N2 showed stronger PAC between 2-30 Hz phases in nEZ and 5-150 Hz amplitudes in EZ. Canonical correlations between direction-specific {delta}-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.

Interpretation{delta}-band synchrony and {beta}-{gamma} band bistability play a pivotal role in epileptogenic mechanisms, likely through the coupling of {delta} phases and {beta}-{gamma} amplitudes across large-scale networks--with a significant contribution from the nEZ tissues.