Discovering Neurophysiological Characteristics of Pathological High-Frequency Oscillations in Epilepsy with an Explainable Deep Generative Model

Interictal high-frequency oscillation (HFO) is a promising biomarker of the epileptogenic zone (EZ). However, objective definitions to distinguish between pathological and physiological HFOs have remained elusive, impeding HFOs’ clinical applications. We employed self-supervised deep generative variational autoencoders to learn such discriminative HFO features directly from their morphologies in a data-driven manner. We studied a large retrospective cohort of 185 patients who underwent intracranial monitoring and analyzed 686,410 candidate HFO events collected from 18,265 brain contacts across diverse brain regions. The model automatically clustered HFOs into distinct morphological groups in the latent space. One cluster consisted of putative morphologically defined pathological HFOs (mpHFOs): HFOs in that cluster were observed to be associated with spikes and exhibited high signal intensity both in the HFO band (>80 Hz) at detection and in the sub-HFO band (10-80 Hz) surrounding the detection and were primarily localized in the seizure onset zone (SOZ). Moreover, resection of brain regions based on a higher prevalence of interictal mpHFOs better predicted postoperative seizure outcomes than current clinical standards based on SOZ removal. Our self-supervised, explainable, deep generative model distills pathological HFOs and thus potentially helps delineate the EZ purely from interictal intracranial EEG data. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The authors have no conflict of interest to disclose. HN is supported by the National Institute of Neurological Disorders and Stroke (NINDS) (K23NS128318), the Sudha Neelakantan & Venky Harinarayan Charitable Fund, the Elsie and Isaac Fogelman Endowment, and the UCLA Children's Discovery and Innovation Institute (CDI) Junior Faculty Career Development Grant (#CDI-SEED-010124). AD is supported by the Uehara Memorial Foundation and the SENSHIN Medical Research Foundation. EA is supported by the National Institute of Health (R01NS064033). RS serves on scientific advisory boards and speakers bureaus and has received honoraria and funding for travel from Eisai, Greenwich Biosciences, UCB Pharma, Sunovion, Supernus, Lundbeck Pharma, Liva Nova, and West Therapeutics (advisory only); receives royalties from the publication of Pellock's Pediatric Neurology (Demos Publishing, 2016) and Epilepsy: Mechanisms, Models, and Translational Perspectives (CRC Press, 2011). RS is also supported by the Sudha Neelakantan & Venky Harinarayan Charitable Fund. RJS is supported by the NINDS R01NS106957, R01NS033310, and R01NS127524. JEJ is supported by NINDS U54NS100064 and R01NS033310. RJS and JEJ are supported by the Christina Louise George Trust. The research described was also supported by NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001881. ### 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 institutional review board (IRB) at UCLA and Wayne State University gave ethical approval for the study protocol. We obtained written informed consent from patients or the guardians of pediatric patients. 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the corresponding authors.