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bioRxiv · 10.1101/2024.12.04.626580

Collapse of Interictal Suppressive Networks Permits Seizure Spread

Makhoul, G. S. P.·Doss, D. J.·Johnson, G. W.·Withers, C. P.·Cavender, A. C.·Hidalso Monroy Lerma, B.·Reda, A.·Bibro, C. E.·Liao, E.·Kang, H.·Dawant, B. M.·Reddy, S. B.·Crudele, A. N.·Constantinidis, C.·Roberson, S. W.·Bick, S. K.·Morgan, V. L.·Englot, D. J.
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Abstract

How do networks in the brain limit seizure activity? In the Interictal Suppression Hypothesis (ISH), we recently postulated that high inward connectivity to seizure onset zones (SOZs) from non-involved zones (NIZs) is a sign of broader network suppression at rest. 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 (SEEG) 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 seizures. After aligning all network connectivity matrices between seizures and patients, we calculated net connectivity changes from the SOZ, propagative zone (PZ), and NIZ. Across all seizure types, we observed two distinct phases as seizures initiated and evolved: a large rapid increase in directed communication towards the SOZ from NIZ followed by a collapse in network connectivity. During this first phase, SOZs could be distinguished from all other regions (One-Way ANOVA, p=8.32x10-19 - 2.22x10-7, lower range to upper range of p-values). In the second phase and post-ictal period, SOZ inward connectivity decreased yet remained distinct (One-Way ANOVA, p= 2.58x10-10-1.66x10-2). Furthermore, NIZs appeared to drive the increase in inward SOZ connectivity while global connectivity between NIZs concordantly decreased. Stratifying by seizure subtype, we found that consciousness-impairing seizures show loss of inward connectivity from the NIZ earlier than conscious 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 to the NIZ and the NIZs 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 respond to seizure onset and increase inhibitory signaling towards the SOZ, possibly in an attempt to thwart seizure activity. This inhibition appears to be insufficient to prevent seizure onset, and furthermore, loss of normal communication in the rest of the brain between NIZs may contribute to loss of consciousness during larger seizures. Dynamic connectivity patterns uncovered in this work may: i) allow more accurate delineation of surgical targets in focal epilepsy, ii) reveal why inward suppression of SOZs interictally may nonetheless be insufficient to prevent all seizures, and iii) provide insight into mechanisms of loss of consciousness during certain seizures.

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Makhoul, G. S. P., Doss, D. J., Johnson, G. W., Withers, C. P., Cavender, A. C., Hidalso Monroy Lerma, B., Reda, A., Bibro, C. E., Liao, E., Kang, H., Dawant, B. M., Reddy, S. B., Crudele, A. N., Constantinidis, C., Roberson, S. W., Bick, S. K., Morgan, V. L., Englot, D. J.. 2024-12-07. Collapse of Interictal Suppressive Networks Permits Seizure Spread. https://doi.org/10.1101/2024.12.04.626580

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