Contents lists available at ScienceDirect Epilepsy Research journal homepage: www.elsevier.com/locate/epilepsyres Effective connectivity analysis of iEEG and accurate localization of the epileptogenic focus at the onset of operculo-insular seizures Elie Bou Assi a, ⁎ , Sandy Rihana b , Dang K. Nguyen c,1 , Mohamad Sawan a,1 a Polystim Neurotech Lab, Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, QC, Canada b Biomedical Engineering Department, Holy Spirit University of Kaslik (USEK), Jounieh, Lebanon c University of MontrealHospital Center (CHUM), University of Montreal, Montreal, QC, Canada ARTICLEINFO Keywords: Insular epilepsy Effective connectivity Intracranial electroencephalography Autoregressive modeling Spectrum weighted adaptive directed transfer function ABSTRACT Recognition of insular epilepsy may sometimes be challenging due to the rapid speed at which insular seizures can spread throughout the cortex via extensive connections to surrounding cortices. The spectrum weighted adaptive directed transfer function, a multivariate causality-based effective connectivity measure, was applied to intracranial electroencephalography recordings to identify generators of seizure activity. A non-parametric test based on surrogate data testing was used to validate statistical significance of causal relations. Outflow and inflow of seizure activity were extracted from the computed transfer matrix. Recorded data of 21 seizures from seven patients were analyzed including five who were rendered seizure-free after operculo-insular resection. Effective connectivity analysis of 7 s following electrical onset confirmed an operculo-insular seizure origin in 5 patients with a good post-operative seizure outcome, and for whom the resected region was sampled by in- tracranial electroencephalography contacts. Different or additional seizure foci were identified in 2 patients with a bad post-operative seizure outcome. Findings highlight the feasibility of accurate operculo-insular seizure foci localization based on quantitative approaches. 1. Introduction Epilepsy is a chronic condition characterized by recurrent seizures (or ‘ictus’) resulting from abnormal and excessive neuronal discharges. When antiepileptic drugs fail to control seizures, surgical resection of the epileptic focus is recommended if it can be delineated by a set of tests which often include qualitative visual interpretation of in- tracranial electroencephalography (iEEG) recordings of seizures. Several authors have recently applied quantitative effective con- nectivity analyses on such recordings to characterize the complex epi- leptic network of the different brain areas involved in the generation, propagation, and modulation of seizures. By exploiting temporal pre- cedence among a set of signals to reveal information transfers from ‘driver’ to ‘secondary’ nodes of the network, effective connectivity analyses may help understand seizure semiology and optimize deli- neation of the area to be resected for seizure cure (Jia et al., 2014; van Mierlo et al., 2013). Until now, such methods have mainly been used to analyze temporal or frontal lobe seizures (Klamer et al., 2015; Martinez-Vargas et al., 2017; van Mierlo et al., 2013; Wilke et al., 2010). While little attention has been given to insular seizures (Hagiwara et al., 2017), effective connectivity measures could possibly help explain the diversity in their ictal symptoms and facilitate their identification knowing how complex their ictal intracranial EEG pat- terns can be (often with the involvement of several distinct structures in as much that visual identification of the area of seizure onset is diffi- cult) (Levy et al., 2017). Highly connected to surrounding frontal, temporal and parietal lobes (Ghaziri et al., 2017), the insula is a multimodal area involved in the processing of several sensory stimuli (viscerosensory, somatosen- sory, auditory, gustatory, and olfactory) and cognitive processes (at- tention, social cognition, and decision-making) (Uddin et al., 2017). Such structural and functional connectivity considerations may explain why insular seizures are diverse in terms of EEG patterns but also in clinical presentation such as early viscerosensory auras (common in temporal lobe seizures), somatosensory auras (as in parietal lobe sei- zures) and hypermotor symptoms (resembling frontal lobe seizures) (Obaid et al., 2017). Such mimicry has most likely misled some clin- icians into thinking that their patients, suffering from insular epilepsy, https://doi.org/10.1016/j.eplepsyres.2019.02.006 Received 28 July 2018; Received in revised form 23 December 2018; Accepted 21 February 2019 ⁎ Corresponding author at: Polystim Neurotech Lab (polystim.org), Institute of Biomedical Engineering, Polytechnique Montreal (polymtl.ca), 2900, boul. Édouard- Montpetit, Université de Montréal Campus, 2500, Chemin de Polytechnique, Room M5306, Lassonde Building, Montréal, QC, H3T 1J4, Canada. E-mail address: elie.bou-assi@polymtl.ca (E. Bou Assi). 1 Equally contributing PIs. Epilepsy Research 152 (2019) 42–51 Available online 11 March 2019 0920-1211/ © 2019 Elsevier B.V. All rights reserved. T