Closed-loop Cortical Network Stimulation as treatment for refractory epilepsy originating from the primary motor cortex

Background In epilepsy patients, cortical electrical stimulation is therapeutically applied in the seizure onset zone (SOZ) to reduce seizures. However, in patients with epilepsy arising from the primary motor cortex (M1), stimulation can result in undesired muscle contractions or loss of motor control. We postulate that seizure frequency reduction can also be obtained by cortical network stimulation in a site outside M1 with a connection to the SOZ in M1. Methods Patients with electroclinical seizures suspected to arise from M1 were selected. SOZ was delineated during chronic intracranial EEG monitoring. Using Single Pulse Electrical Stimulation, the underlying effective corticocortical network was determined and a site for stimulation was selected that was connected to the SOZ. One subdural strip was implanted on top of the SOZ, and one on the stimulus location. A subcutaneous neurostimulator (Activa® PC+S, Medtronic), capable of recording and closed-loop stimulation, was connected to both strips. Seizure data was collected for three to five months and used to optimize a seizure detection algorithm. After this, closed-loop cortical network stimulation was applied during seven to nine months. Results In five subjects (two females, mean age 34 years, range: 21-51 years), a neurostimulation system was implanted. One subject was seizure free for 17 months post- implantation without applying any electrical stimulation. Two subjects were responders with a mean seizure frequency reduction of 73%. In two subjects, seizure frequency was reduced by on average 35%. Discussion In this clinical trial with five subjects suffering from refractory epilepsy arising in M1, seizure frequency was reduced with electrical stimulation in all subjects. This is a proof of concept showing that closed-loop cortical network stimulation can reduce seizure frequency as equal to direct SOZ stimulation in non-primary motor epilepsy. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04158531 ### Funding Statement Research reported in this publication was supported by EpilepsieNL under Award Number NEF17-07 (DvB) and NEF19-12 (DvB, SB). ### 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 REC2Stim (Rational Extra-eloquent Closed-loop Cortical Stimulation) study was approved by the ethics committee at the University Medical Center Utrecht and the national Dutch Health and Youth Care Inspectorate, in accordance with the Declaration of Helsinki (2013). This study was registered with [clinicaltrials.gov][1] ([NCT04158531][2]). 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 * Abbreviations: ARAT : action reach arm test CCEP : cortico-cortical evoked potentials DCP : data collection phase ECoG : electrocorticography FCD : focal cortical dysplasia LDA : linear discriminant algorithm M1 : primary motor cortex REC2Stim : rational extra-eloquent closed-loop cortical stimulation SEM : standard error of the mean SP : stimulation phase SPES : single pulse electrical stimulation SOZ : seizure onset zone USER test : Utrecht scale for evaluation of rehabilitation-participation [1]: http://clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04158531&atom=%2Fmedrxiv%2Fearly%2F2023%2F11%2F12%2F2023.11.11.23298410.atom