BackgroundThe benefits of virtual reality (VR)-based rehabilitation were reported in patients after stroke, but there is insufficient evidence about how VR promotes brain activation in the central nervous system. Hence, we designed this study to explore the effects of VR-based intervention on upper extremity motor function and associated brain activation in stroke patients.Methods/designIn this single-center, randomized, parallel-group clinical trial with a blinded assessment of outcomes, a total of 78 stroke patients will be assigned randomly to either the VR group or the control group. All stroke patients who have upper extremity motor deficits will be tested with functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and clinical evaluation. Clinical assessment and fMRI will be performed three times on each subject. The primary outcome is the change in performance on the Fugl-Meyer Assessment Upper Extremity Scale (FMA-UE). Secondary outcomes are functional independence measure (FIM), Barthel Index (BI), grip strength, and changes in the blood oxygenation level-dependent (BOLD) effect in the ipsilesional and contralesional primary motor cortex (M1) on the left and right hemispheres assessed with resting-state fMRI (rs-fMRI), task-state fMRI (ts-fMRI), and changes in EEG at the baseline and weeks 4 and 8.DiscussionThis study aims to provide high-quality evidence for the relationship between upper extremity motor function and brain activation in stroke. In addition, this is the first multimodal neuroimaging study that explores the evidence for neuroplasticity and associated upper motor function recovery after VR in stroke patients.Clinical trial registrationChinese Clinical Trial Registry, identifier: ChiCTR2200063425.