The primary aim of this project will be to determine the effects of the tRNS-augmented unilateral and bilateral MT, and their effects relative to the control interventions (sham tRNS with unilateral or bilateral MT) on restoring health outcomes including motor function, daily function, quality of life and self-efficacy, and motor control strategy as well as brain activities (electroencephalography, EEG) in stroke patients.

Developing effective rehabilitation interventions to maximize functional recovery remains to be a major challenge for stroke rehabilitation. Transcranial random noise stimulation (tRNS) has emerged as a promising brain neurotechnology to enhance neural plasticity to augment treatment effects of stroke neuorehabilitation therapies. Compared to traditional brain neurotechnology such as transcranial direct current stimulation (tDCS), tRNS does not have polarity constraints, thus providing more consistent modulatory effects, less response variability and less adverse effects, which make it a potentially ideal approach to combine with stroke rehabilitation therapies. Mirror therapy (MT) is effective at improving sensorimotor recovery in stroke patients. Because of its easiness for use in clinical settings, MT has been recommended by American Heart Association as a promising intervention for stroke patients. Combining tRNS with MT could be an appealing approach to further boost brain plasticity to maximize MT treatment benefits in the clinical settings. However, MT can be delivered using unilateral or bilateral approaches, which may induce differential treatment benefits. Identifying the optimal combination of MT with tRNS on recovering functions and brain mechanisms will be imperative for development of evidence-based precision brain neurotechnology-augmented stroke rehabilitation.

Therefore, this research project will (1) compare the effects of the tRNS-augmented unilateral and bilateral MT, and their effects relative to the control interventions (sham tRNS with unilateral or bilateral MT) comprehensively on motor function, daily function, quality of life and self-efficacy, motor control strategy and brain activities (electroencephalography, EEG) in stroke patients; (2) examine the retention effects and possible delayed response of tRNS-augmented unilateral and bilateral MT at 3-month and 6-month follow-up and (3) identify the predictors of the treatment success to determine good responders to the tRNS-augmented unilateral and bilateral MT to facilitate clinical translation of the intervention.

The investigator will conduct a randomized, sham controlled clinical trial with 128 stroke patients in this 5-year project. Patients will be randomly assigned to (1) tRNS-augmented unilateral MT, (2) tRNS-augmented bilateral MT, (3) sham tRNS with unilateral MT, and (4) sham tRNS with bilateral MT. Participants will receive 20 intervention sessions (90 minutes/day, 5 days/week, for 4 consecutive weeks). The outcome measures will include behavioral assessments to evaluate motor and daily function, quality of life and self-efficacy; kinematic assessments to evaluate motor control strategy; and EEG to assess brain activities (power). The behavioral measures will be performed at pre-test, interim-test, post-test, and 3-month and 6-month follow-up. The kinematic and EEG assessment will be administered at pre-test and post-test. In addition, the EEG assessment will be conducted during the intervention period to evaluate the dynamical changes of brain activities.

This research project will provide scientific evidence of the treatment effects of brain neurotechnology-augmented stroke rehabilitation therapy. Specifically, the findings will elucidate behavioral changes and possible biomechanical and brain mechanisms associated with the novel tRNS-augmented MT. In addition, the results will reveal the characteristics of good responders to the combined intervention. The overall results will contribute to formulation of precision hybrid brain neurotechnology with stroke rehabilitation therapies to maximize neural and functional recovery after stroke.

Inclusion Criteria:

1. ≥ 3 months onset from a first-ever unilateral stroke;
2. an initial FMA scores between 18 to 56, indicating moderate to mild upper extremity motor impairment (Thielman, Kaminski, & Gentile, 2008);
3. age between 35 to 85;
4. no excessive spasticity in any of the joints of the affected arm (shoulder, elbow, wrist and fingers);
5. ability to follow instructions and perform tasks (Mini Mental State Examination scores ≥24);
6. no participation in any neurorehabilitation experiments or drug clinical trials and
7. willing to provide written informed consent.

Exclusion Criteria:

1. contradiction to tRNS including a history of epilepsy, pregnant, having pacemakers and metallic implants in the neck and heads (Rossi, Hallett, Rossini, Pascual-Leone, & Safety of, 2009);
2. History of drug or alcohol abuse(Rossi et al., 2009);
3. concomitant neurological conditions such as dementia, Parkinson's disease, brain tumor, brain injury and other brain diseases (such as intracranial hypertension or cerebral edema);
4. Botulinum toxin injections 3 months before enrollment
5. have unstable cardiovascular status such as uncontrolled hypertension or New York Heart Association (NYHA) Class III/IV heart failure or are not suitable for receiving tRNS by the physician's assessments.