Dynamic excitation/inhibition balance preceding seizure onset and its link to functional and structural brain architecture

BACKGROUND: Altered excitation/inhibition (E/I) balance is a key mechanism in epilepsy, but its dynamic changes before seizure onset remain unclear. The interictal suppression hypothesis suggests that inhibitory input isolates epileptic regions, yet little is known about E/I dynamics in the pre-ictal phase. METHODS: We analyzed high-density EEG recordings from patients with drug-resistant focal epilepsy, each with at least one recorded seizure. Cortical activity was reconstructed using source modeling, and time-resolved changes in the aperiodic exponent-a non-invasive marker of E/I balance-were computed. Directed functional connectivity was assessed via spectral Granger causality. These metrics were correlated with cortical thickness and neurotransmitter receptor density maps. RESULTS: The aperiodic exponent increased progressively in the minutes preceding seizures, reflecting a global shift toward cortical inhibition, with no significant differences between epileptic and non-epileptic regions. Delta and theta power also increased preictally. Epileptic regions showed significantly more outward than inward connectivity, and more outward connectivity than non-epileptic areas. In non-epileptic regions, higher inhibition was associated with greater outward connectivity. Cortical thickness positively correlated with inhibition only in non-epileptic areas. Lower muscarinic receptor density was associated with stronger inhibitory shifts. CONCLUSIONS: Seizure onset is preceded by a widespread shift toward inhibition, possibly representing a compensatory mechanism that fails as ictal thresholds are crossed. This shift is linked to altered connectivity and disrupted structure-function coupling in epileptic regions. The dynamic aperiodic exponent emerges as a promising biomarker for seizure prediction and a potential target for neuromodulation strategies.