Title: Elucidating Network-Level Mechanisms of Seizure Termination in Drug-Resistant Epilepsy across Spontaneous, Induced, and Cognitively Modulated Seizures to Enable Targeted Neuromodulation

Epilepsy affects over 50 million people worldwide, and medically refractory epilepsy (MRE) accounts for approximately 30% of these cases. Many individuals with MRE are not candidates for resective surgery, leaving neuromodulation as their only remaining therapeutic option. Yet current neuromodulation approaches remain suboptimal, in part because stimulation targets are selected based on the seizure onset zone (SOZ)—a region well suited to guide resective surgery but not necessarily the most effective target for neuromodulation. This project aims to unravel the network mechanisms underlying intrinsic seizure termination in the brain, leveraging these mechanisms to design more effective, mechanistically grounded targets for neurostimulation. We hypothesize that a conserved seizure termination state actively restores network stability, and that cognitively interrupted seizures succeed by directly engaging this same intrinsic mechanism. Drawing on a unique dataset spanning native, induced, and cognitively interrupted seizures, we estimate dynamic network models from intracranial EEG to define brain states that capture distinct network configurations across seizure onset, progression, and termination, thereby identifying the brain regions that drive termination as principled targets for neurostimulation. This work stands to fundamentally reshape how neuromodulation targets are selected in MRE.