Mechanisms of open and hidden placebo in stroke recovery: targeting neuroplasticity insights of the placebo effect - study protocol for a controlled, parallel, randomised clinical trial.

introductionStroke stands as one of the worldwide leading causes of disability, highlighting the need to develop new therapies. Although placebo effects in motor recovery have been reported to produce clinically meaningful improvements, the neural substrates underlying these effects, particularly across different modalities such as open-label and hidden placebo, remain unclear. This study aims to characterise the neurophysiological signatures of hidden and open placebo during motor-cortex stimulation in chronic stroke survivors and its correlation to motor recovery. METHODS AND ANALYSIS: This single-centre, parallel-group, controlled, randomised clinical trial will enrol 56 adults (≥6 months post-stroke) with upper-limb hemiparesis. Participants are block-randomised (2:2:2:1) to (i) open-label placebo tablets, (ii) hidden sham repetitive transcranial magnetic stimulation (rTMS), (iii) no intervention or (iv) active low-frequency (1 Hz) rTMS over the contra lesional primary motor cortex. The primary endpoint is change in frontal alpha asymmetry (FAA) on high-density electroencephalogram from baseline to 2 weeks. Secondary endpoints include β-band premotor-to-M1 coherence and Fugl-Meyer Upper Extremity scores. Exploratory outcomes include additional motor performance measures (Jebsen-Taylor Hand Function Test and Nine-Hole Peg Test), corticospinal excitability (single-pulse and paired-pulse TMS) and patient-reported measures (mood, expectancy and behavioural activation-inhibition), all assessed from baseline to 2 weeks. Analyses will follow an intention-to-treat framework with multivariable regression adjusting for age, sex, stroke severity, lesion location and time since stroke. ETHICS AND DISSEMINATION: The study was conducted in accordance with the Declaration of Helsinki and approved by the Mass General Brigham Institutional Review Board (protocol #2023P000884). All participants will be required to provide informed consent before enrolling in the study. An open-label phase will be offered to participants allocated to any of the groups that received no active intervention (sham rTMS stimulation, open-label placebo or no-intervention groups). This phase will consist of a task-specific, upper-limb, home-based rehabilitation programme. The results of this study will be shared in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: NCT05832567.