Temporal Lobe Epilepsy is dominated by Region Specific Interictal Cortical Inhibition

Epilepsy is typically characterized by excessive neuronal excitability, manifesting as seizures and interictal epileptiform discharges (IEDs) in the EEG. However, the dynamics of excitation and inhibition (E/I balance) remain poorly understood. Here, we leverage the aperiodic exponent of the EEG power spectrum—a marker indicative of synaptic inhibition—to investigate shifts in E/I balance during antiseizure medication (ASM) tapering in patients with mesial temporal lobe epilepsy (TLE). We analyzed EEG data from 28 TLE patients and 25 controls with non-epileptic episodes (NEE) undergoing presurgical video EEG monitoring. Unexpectedly, TLE patients showed a localized increase in the aperiodic exponent in the ipsilesional temporal lobe during ASM tapering, absent in controls. This inhibition increase correlated with seizure latency and predicted seizure occurrence. Intracranial recordings from 10 TLE patients revealed higher aperiodic exponents in the lateral temporal cortex compared to the hippocampus, suggesting stronger inhibition in the lateral cortex. Notably, hippocampal IEDs triggered transient inhibitory responses in the lateral cortex, accompanied by increased high-frequency activity and disrupted hippocampus-to-lateral connectivity. These findings suggest that TLE likely involves complex inhibitory mechanisms beyond the epileptic focus in the interictal period, with neocortical inhibition potentially containing epileptic activity, and offers a new tool to map epileptic brain regions.