Noninvasive Epileptogenic Signal Direction Determination by Effective Connectivity of Resting State Functional MRI - Independent of EEG

The goal of this study was to determine resting state fMRI effective connectivity (RSEC) capacity, agnostic of epileptogenic events, in distinguishing seizure onset zones (SOZ) from propagation zones (pZ). Consecutive patients (2.1-18.2 years old), with epilepsy and hypothalamic hamartoma, pre-operative rs-fMRI-directed surgery, post-operative imaging, and Engel class I outcomes were collected. Cross-spectral dynamic causal modelling (DCM) was used to estimate RSEC between the ablated rs-fMRI-SOZ to its region of highest connectivity outside the HH, defined as the propagation zone (pZ). RSEC between the SOZ and PZ was characterized as positive (excitatory), negative (inhibitory), or null. It was hypothesized that connectivity from the SOZ would be excitatory and connectivity from the pZ would be inhibitory. Sensitivity, accuracy, positive predictive value were determined for node-to-node connections. A Parametric Empirical Bayes (PEB) group analysis was performed to identify effects of Engel class outcome and age. RSEC strength was also evaluated for correlation with percent seizure frequency improvement, sex, and region of interest size. Of the SOZ’s RSEC, only 3.6% had no connection of significance to the pZ when patient models were individually reduced. Among remaining, 96% were in expected (excitatory signal found from SOZ→pZ and inhibitory signal found from pZ→SOZ) versus 3.6% reversed polarities. Both polarity signals were equivalently as expected, with one false signal direction out of 26 each (3.7% total). Sensitivity of 96%, accuracy of 93%, and positive predictive value of 96% in identifying and differentiating the SOZ and pZ. Groupwise PEB analysis confirmed SOZ→pZ EC was excitatory, and pZ→SOZ EC was inhibitory. Patients with better outcomes (Engel Ia vs. Ib) showed stronger inhibitory signal (pZ→SOZ). Age was negatively associated with absolute RSEC bidirectionally, but had no relationship with Directionality SOZ identification performance. This study demonstrates the accuracy of Directionality to identify the origin of excitatory and inhibitory signal between the surgically confirmed SOZ and the region of hypothesized propagation zone in children with DRE due to a HH. Thus, this method validation study in a homogenous DRE population may have potential in narrowing the SOZ-candidates for epileptogenicity in other DRE populations and utility in other neurological disorders. Highlights ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The IRB of Phoenix Childrens Hospital gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data made available under institutional IRB approval that supports the findings of this study are available in the supplementary material of this article. * BMA : Bayesian Model Averaging BMR : Bayesian Model Reduction BOLD : blood oxygen level dependent CAT12 : Computational Anatomy Toolbox version 12 DCM : dynamic causal modeling DRE : drug resistant epilepsy EEG : electroencephalography EEG-fMRI : simultaneous EEG and functional MRI GLM : general linear model HH : hypothalamic hamartoma ICA : independent component analysis iEEG : intracranial EEG IED : interictal epileptogenic discharges IED-BOLD : simultaneous EEG-fMRI detected interictal epileptogenic discharges corresponding to blood oxygen level dependent rs-fMRI signal changes LITT : laser interstitial thermal ablation therapy MEG : magnetoencephalography PCA : principal components analysis PEB : Parametric Empirical Bayes pZ : propagation zone ROI : region of interest rs-fMRI : resting state functional MRI RSFC : (static) resting state functional connectivity RSEC : resting state effective connectivity SL : SearchLight SOZ : seizure onset zone