Brain State-dependent Repetitive Transcranial Magnetic Stimulation for Motor Stroke Rehabilitation: A Proof of Concept Randomized Controlled Trial

Background: In healthy subjects, repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex (M1) demonstrated plasticity effects contingent on electroencephalography (EEG)-derived excitability states, defined by the phase of the ongoing sensorimotor mu-oscillation. The therapeutic potential of brain state-dependent rTMS in the rehabilitation of upper limb motor impairment post-stroke remains unexplored. Objective: Proof-of-concept trial to assess the efficacy of rTMS, synchronized to the sensorimotor mu-oscillation, in improving motor function and reducing upper-limb spasticity in stroke patients. Methods: We conducted a parallel group, randomized double-blind controlled trial in 30 chronic stroke patients. The experimental intervention group received EEG-triggered rTMS of the ipsilesional M1 (1,200 pulses; 0.33 Hz; 90% of the resting motor threshold (RMT)), while the control group received low-frequency rTMS of the contralesional motor cortex (1,200 pulses; 1 Hz, 115% RMT), i.e., an established treatment protocol. Both groups received 12 rTMS sessions (20 min, 3x per week, 4 weeks) followed by 50 min of physiotherapy. The primary outcome measure was the change in upper-extremity Fugl-Meyer assessment (FMA-UE) scores between baseline, immediately post-treatment and 3 months follow-up. Results: Both groups showed significant FMA-UE improvement and spasticity reduction (clinical and objective measures). There were no significant differences between the groups in any of the outcome measures. Conclusions: The application of brain state-dependent rTMS for rehabilitation in chronic stroke patients is feasible. This pilot study demonstrated that the brain oscillation-synchronized rTMS protocol produced beneficial effects on motor disability and spasticity that were comparable to those observed with an established therapeutic rTMS protocol. ### Competing Interest Statement CZ and BZ own shares in sync2brain GmbH (Tuebingen, Germany), a spin-off start-up company that commercializes the real-time EEG analysis technology used in this study to synchronize TMS stimulation with the phase of brain oscillations. ### Clinical Trial Clinical Trial ID: [NCT05005780][1] ### Funding Statement W.M was funded by the German Academic Exchange Program (DAAD) throughout the period of the project. D.B was supported by an intramural Junior Clinician Scientist grant while B.Z. and C.Z were funded by an EXIST Forschungstransfer grant from the German Federal Ministry for Economic Affairs and Energy. ### 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 of the University Hospital of Tuebingen gave ethical approval for this work Ethics approval No: 530/2019BO1 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 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05005780&atom=%2Fmedrxiv%2Fearly%2F2024%2F03%2F12%2F2024.03.10.24304040.atom