Unstable Slow Oscillations Couple with Epileptogenic Fast-Rhythm Bistability in Sleep-Related Epilepsy: An SEEG Study

Objective While slow waves in δ (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 δ-band instability. Meanwhile, the epileptogenic zone (EZ) shows localized bistability in β–γ band (15–200 Hz) neuronal oscillations—indicating a catastrophic shift toward seizure. We aim to clarify the mechanistic link between δ-band synchrony and β–γ band bistability in epilepsy.

We 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 δ-phase to β–γ bistability.

Compared 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 δ-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 δ-band synchrony and β–γ band bistability are not isolated epileptogenic mechanisms but likely act synergistically, playing a pivotal role in seizure generation through the coupling of δ phases and β–γ amplitudes across large networks, with significant contributions from non-epileptogenic tissues. Key points Strong β–γ bistability in neuronal oscillations localizes the EZ throughout N2 and N3 sleep. Elevated δ-band phase synchrony characterizes the EZ and its functional neighbors throughout N2 and N3 sleep. ä-band synchrony modulates local β–γ bistability through PAC, with significant contributions from non-EZ tissues. Competing Interest Statement F.C. serves as Key Opinion Leader for Dixi Medical, manufacturer of SEEG electrodes. Footnotes ↵† These authors jointly supervised this work. Manuscript substantially revised and sections reorganized; Methods clarified; Figures reorganized for clarity; Additional supplementary figures and tables added; One author added; Minor textual and reference updates throughout. Data availability Raw data and patient information cannot be shared due to Italian governing laws and Ethical Committee restrictions. Interim results, as well as final processed data that support the findings of this study, are available from the corresponding authors upon reasonable request. Abbreviations - CCA - canonical correlation analysis - EZ - epileptogenic zone - FCD - focal cortical dysplasia - PAC - phase-amplitude coupling - RDP - relative δ power, an assessment of δ amplitude instability