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

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.

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.

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.

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.