Stimulation of the Thalamus for Arousal Restoral in Temporal Lobe Epilepsy (START) Clinical Trial: Modulation of Natural Sleep and Focal Seizures

Abstract Thalamic stimulation has emerged as a promising neuromodulation target for treating disorders of consciousness. Impaired consciousness, a debilitating outcome in temporal lobe epilepsy (TLE) remains a central problem for patients whose seizures cannot be treated pharmacologically and cannot be stopped with conventional surgery or responsive hippocampal stimulation. Although prior studies suggest an essential role of the thalamic intralaminar central lateral (CL) nucleus in arousal and sleep, evidence for a direct effect of thalamic intralaminar stimulation on human arousal has been limited. To address these gaps, the START (stimulation of the thalamus for arousal restoral in TLE) clinical trial investigated the efficacy of bilateral CL thalamic stimulation to restore consciousness during human sleep and TLE seizures. Five patients with medically refractory mesial temporal lobe epilepsy were implanted with an investigational neurostimulator, the Medtronic Summit RC+STM. Optimal CL stimulation parameters were obtained through individualized titration in slow wave sleep, evaluated through analysis of patient movement from video recordings and electrophysiology from simultaneously recorded scalp and hippocampal electroencephalography (EEG). We found that bilateral CL stimulation led to robust arousal from sleep characterized by increased body movements and decreased low frequency power (2-15 Hz) in both cortical and hippocampal EEG during 5 minute epochs of stimulation compared to baseline slow wave sleep. We evaluated impaired consciousness during seizures using verbal and non-verbal behavioral tests administered automatically by smartwatch, and found significant behavioral impairment in three of five patients during seizures with hippocampal stimulation. Administering CL stimulation in patients with impaired consciousness during TLE seizures showed significant improvement in behavioral outcomes in two of three patients, with one patient reaching their baseline performance comparable to non-seizure times. Overall, we found that stimulation of the thalamic CL in TLE patients increased arousal during both sleep and seizures. These findings demonstrate the potential of CL as a therapeutic target for mitigating impaired consciousness in TLE and can serve as a foundation for additional studies to test generalizability of CL stimulation effects on other disorders of consciousness. Competing Interest Statement The authors have declared no competing interest. Clinical Trial NCT04897776 Funding Statement This work was supported by NIH/NINDS UG3/UH3 NS112826. 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: Ethics committee/IRB of Yale University School of Medicine, Mayo Clinic, and Dartmouth-Hitchcock medical center 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data generated in the present study will be made available from the corresponding author upon reasonable request.