Slow Oscillations Gate Interictal Spikes Across the Human Thalamocortical-Epileptogenic Network

Background: Slow oscillations (SOs; 0.5-1.5 Hz), a hallmark of non-rapid eye movement (NREM) sleep, are associated with a marked amplification of interictal epileptiform spike (IIS) activity in focal epilepsy. However, the network-level organization of this effect across the thalamocortical-epileptogenic system, and whether IIS-permissive SOs can be predicted from pre-onset brain states, remain unclear. Methods: We analyzed simultaneous scalp EEG and stereo-EEG (SEEG) recordings from 6 patients with drug-resistant focal epilepsy across 24 full-day recording days, sampling prefrontal cortex (PFC), thalamus, and seizure onset zone (SOZ). SO-IIS coupling was characterized across vigilance states using peri-event and phase-based analyses, with a gamma-based validation step to reduce contamination by IIS-related slow potentials. Pre-onset phase-amplitude coupling (PAC) was compared between IIS-permissive and non-permissive SOs. Results: SO-IIS coupling was observed across all regions, with the strongest and most temporally precise pre-trough IIS clustering in the SOZ (peak 4.4% in NREM), exceeding PFC (1.7%) and thalamic coupling. Thalamic coupling was preserved across wakefulness and NREM and was significant in 7/11 nuclei, with nucleus-specific phase preferences. SO morphological features, particularly up-slope and peak-to-peak amplitude at PFC contacts, predicted IIS occurrence in the SOZ. Pre-onset PAC differed significantly between permissive and non-permissive SOs across regions. Conclusions: SO-IIS coupling is a distributed, network-level phenomenon with region- and state-specific characteristics, and pre-onset PAC provides a predictive signature of IIS-permissive brain states. These findings support the feasibility of developing personalized, closed-loop neuromodulatory strategies targeting SO-gated IIS suppression in focal epilepsy. Keywords: Slow oscillations; Interictal epileptiform spikes; Focal epilepsy; Closed-loop neuromodulation; Phase-amplitude coupling