Wala Mahmoud ¹ David Baur ² Brigitte Zrenner ³ Arianna Brancaccio ⁴ Paolo Belardinelli ⁴ Ander Ramos-Murguialday ⁵ Christoph Zrenner ³ Ulf Ziemann ^6*

• ¹ Institute for Clinical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany
• ² Department of Neurology, University Hospital Tübingen, University of Tübingen, Tübingen, Baden-Württemberg, Germany
• ³ Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
• ⁴ Centre for Mind and Brain Sciences, University of Trento, Rovereto, Trentino-Alto Adige, Italy
• ⁵ Tecnalia Research & Innovation, San Sebastian, Spain
• ⁶ Neurology, University of Tübingen, Tübingen, Germany

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 μoscillation. 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 µoscillation, in improving motor impairment and reducing upper-limb spasticity in stroke patients.We conducted a parallel group, randomized double-blind controlled trial in 30 chronic stroke patients (clinical trial registration number: NCT05005780). The experimental intervention group received EEG-triggered rTMS of the ipsilesional M1 (1,200 pulses; 0.33 Hz; 100% 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 improvement in the primary outcome measure (FMA-UE) and the secondary outcome measures. This included the reduction in spasticity, measured objectively using the hand-held dynamometer, and enhanced motor function as measured by the Wolf Motor Function Test (WMFT). There were no significant differences between the groups in any of the outcome measures.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 impairment, motor function and spasticity that were comparable to those observed with an established therapeutic rTMS protocol.