Collapse of interictal suppressive networks permits seizure spread

Abstract

How do brain networks limit seizure activity? In the Interictal Suppression Hypothesis, we recently postulated that high inward connectivity to seizure onset zones (SOZs) from non-involved zones (NIZs) is a sign of broader network suppression. If broad networks appear to be responsible for interictal SOZ suppression, what changes during seizure initiation, spread, and termination? For patients with drug-resistant epilepsy, intracranial monitoring offers a view into the electrographic networks which organize around and in response to the SOZ. In this manuscript, we investigate network dynamics in the peri-ictal periods to assess possible mechanisms of seizure suppression and the consequences of this suppression being overwhelmed. Peri-ictal network dynamics were derived from stereo electroencephalography recordings from 75 patients with drug-resistant epilepsy undergoing pre-surgical evaluation at Vanderbilt University Medical Center. We computed directed connectivity from 5-second windows in the periods between, immediately before, during, and after 668 seizures. We aligned connectivity matrices across seizures and patients, then calculated net connectivity changes from the SOZ, propagative zone, and NIZ. Across all seizure types, we observed two phases: a rapid increase in directed communication towards the SOZ followed by a collapse in network connectivity. During this first phase, SOZs could be distinguished from all other regions (One-Way ANOVA, P-value = 8.32x10-19-2.22x10-7). In the second phase and post-ictal period, SOZ inward connectivity decreased yet remained distinct (One-Way ANOVA, P-value = 2.58x10-10-1.66x10-2). NIZs appeared to drive increased SOZ connectivity while intra-NIZ connectivity concordantly decreased. Stratifying by seizure subtype, we found that consciousness-impairing seizures decrease inward connectivity from the NIZ earlier than consciousness-sparing seizures (one-way ANOVA, p<0.01 after false discovery correction). Tracking network reorganization against a surrogate for seizure involvement highlighted a possible antagonism between seizure propagation and the NIZ’s ability to maintain high connectivity to the SOZ. Finally, we found that inclusion of peri-ictal connectivity improved SOZ classification accuracy from previous models to a combined area under the curve of 93%. Overall, NIZs appear to actively increase inhibitory signaling towards the SOZ during seizure onset, possibly to thwart seizure activity. While inhibition appears insufficient to prevent seizure onset, the inability to restrict seizure propagation may contribute to loss of consciousness during larger seizures. Dynamic connectivity patterns uncovered in this work may: i) facilitate accurate delineation of surgical targets in focal epilepsy, ii) reveal why interictal suppression of SOZs may be insufficient to prevent all seizures, and iii) provide insight into mechanisms of loss of consciousness during certain seizures.