Cortical stimulation reveals effective disconnection of the epileptogenic network at seizure onset

Seizure onset, the transition from interictal to ictal network states, remains poorly understood despite decades of research. To date, most analyses of seizure onset rely on descriptors of passively recorded network variables such as spectral features or functional connectivity. However, direct causal analysis of brain network dynamics across the ictal transition have yet to be systematically studied. We therefore sought to characterize the ictal transition using active network probing via corticocortical evoked potentials (CCEPs) generated by direct cortical stimulation.

We analyzed a unique dataset of pediatric and adult epilepsy patients in whom electroclinical seizures were triggered by low-frequency (<2 Hz) direct cortical stimulation. CCEP amplitudes were quantified preceding, during, and following seizure onset, comparing responses within versus outside the spontaneous seizure onset zone (SOZ) across anatomic locations and seizure onset patterns.

Seizure onset was characterized by a rapid, dramatic reduction of CCEP amplitudes within the SOZ. CCEPs were relatively preserved at sites outside the SOZ, indicating preferential loss of incoming, rather than outgoing, responses to the SOZ, a phenomenon we term "effective disconnection." This effect was independent of SOZ anatomic location but was preferentially associated with a low-voltage fast activity seizure onset pattern on exploratory analysis. In a subset of patients, CCEPs returned during seizure evolution after the fast activity phase, at times with reversal of response polarity.

These findings provide a novel characterization of the ictal transition based on the sensitivity of the seizure-generating network to external perturbation and provide a framework for causal network interrogation during seizure onset and early evolution. The described pattern of effective disconnection indicates preferential loss of incoming connectivity to the SOZ at seizure onset. We propose an integrative, hypothesis-generating model linking local inhibitory dynamics and network connectivity at seizure onset and demonstrate the utility of peri-ictal cortical stimulation as a tool for interrogating epilepsy networks.