Closed-loop neurostimulation for epilepsy leads to improved outcomes when stimulation episodes are delivered during periods with less epileptiform activity

In patients with drug-resistant epilepsy, electrical stimulation of the brain in response to epileptiform activity can make seizures less frequent and debilitating. When effective, this therapy, known as closed-loop responsive neurostimulation (RNS), produces long-lasting changes in brain dynamics that correlate with clinical outcomes. Since periods with frequent epileptiform activity are less conducive to neuroplasticity, we hypothesize that stimulation timing, specifically stimulation during brain states with less epileptiform activity, is critical in driving long-term changes that restore healthy brain networks. To test this, we quantified stimulation episodes during low- and high-risk epochs—that is, stimulation during periods with a low or high risk of generating seizures and less or more epileptiform activity—in a cohort of 40 patients treated with RNS. Patients were categorized into three groups: super responders (>90% reduction, n=10), intermediate responders (≥ 50% reduction and ≤ 90% reduction), n=19, and poor responders (<50% reduction, n=11). As hypothesized, in this retrospective study, seizure reduction (median 64.6% reduction at last follow-up) was correlated with more frequent stimulation during low-risk periods compared with high-risk periods. Additionally, stimulation events were more likely to be phase-locked to prolonged episodes of abnormal activity for intermediate and poor responders when compared to super responders, consistent with the hypothesis that improved outcomes are driven by stimulation during low-risk states. These results suggest that stimulation during low-risk periods may more readily induce plasticity that, in turn, facilitates network changes leading to long-term seizure reduction. One Sentence Summary Increased stimulation during periods of reduced seizure risk corresponds with improved therapy in responsive neurostimulation for epilepsy. ### Competing Interest Statement JDR has served as a consultant for Medtronic, NeuroPace, and Corlieve Therapeutics. CRB has served as a consultant for NeuraModix and Abbott and holds intellectual property related to neuromodulation therapy. All other authors declare that they have no competing interests. ### Funding Statement National Institutes of Health, National Institute for Neurological Disorders and Stroke F32NS114322 (DNA), National Institutes of Health, National Institute for Neurological Disorders and Stroke K23NS114178 (JDR) ### 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 of the University of Utah 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 All de-identified data are available upon request to the corresponding author.