Thalamocortical network neuromodulation for epilepsy

Objectives Despite the growing interest in network-guided neuromodulation for epilepsy, uncertainty about the safety and long-term efficacy of thalamocortical stimulation persist. Our evaluation focused on the use of a 4-lead open-loop implantable pulse generator (IPG) for thalamocortical network neuromodulation. Methods We retrospectively reviewed seven subjects with diverse seizure networks (SNs)-poorly localized, regional, or multifocal-undergoing thalamocortical neuromodulation. Employing a 4-lead system, electrodes targeted both thalamic and cortical SN nodes. We assessed seizure severity, life satisfaction, and sleep quality on a 10-point scale, and seizure frequency via telephone interviews and chart review. Six subjects underwent open-loop stimulation trials during intracranial EEG (iEEG) to confirm SN engagement and optimize settings, targeting the suppression of interictal epileptiform discharges (IEDs) and seizures. Outcomes were assessed by Wilcoxon sign-rank test, 0.05 significance level. Results After a median of 17 months post-implantation (range 13-60), subjects had a median disabling seizure reduction of 93% (range 50-100%, p=0.0156), with 100% responder rate (≥ 50% reduction in seizure frequency). The median improvement in seizure severity was 3.5 out of 10 points (p=0.0312), life satisfaction 4.5 points (p= 0.0312), and quality of sleep 3 points (p=0.062). No perioperative complications occurred. Rare transient seizure exacerbations and stimulation-related sensory/motor side effects resolved with parameter adjustments. One subject required surgical revision due to delayed infection. Six subjects had permanent electrode placement refined by iEEG trial stimulation; five subjects had >90% reduction in seizure frequency during iEEG stimulation. Significance Thalamocortical network neuromodulation using a 4-lead open-loop system is safe, and is associated with significant improvements in seizure control and patient quality of life. Trial stimulation during iEEG shows promise for enhancing SN engagement and parameter optimization, but requires further study. Prospective controlled trials are needed to establish the validity of thalamocortical network neuromodulation for epilepsy. ### Competing Interest Statement G.A.W., B.N.L., J.J.V.V., M.S., and B.H.B. declare intellectual property licensed to Cadence Neuroscience (BNL waived contractual rights). B.N.L. declares intellectual property licensed to Seer Medical (contractual rights waived). G.A.W. licensed intellectual property and serves on the scientific advisor board of NeuroOne, Inc. B.N.L., G.A.W, N.M.G. are investigators for the Medtronic Deep Brain Stimulation Therapy for Epilepsy Post-Approval Study. B.N.L is an investigator for the Neuroelectrics tDCS for Patients with Epilepsy Study. J.J.V.V., G.A.W., B.N.L., N.M.G. are investigators for the NeuroPace RNS NAUTILUS study. K.L. is Chief Executive Officer and co-founder, and D.S. is Chief Scientific Officer and co-founder of Cadence Neuroscience. N.M.G has consulted for NeuroOne, Inc. (funds to Mayo Clinic). B.N.L has consulted for Epiminder, Medtronic, Neuropace, and Philips Neuro (all funds to Mayo Clinic). The remaining authors declare no competing interests. ### Funding Statement This study did not receive any funding. ### 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: Ethical approval of this work was granted by the Mayo Clinic Institutional Review Board. 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 authors