The aim of this study is to investigate the effects of intermittent theta burst stimulation primed with continous theta burst stimulation (cTBS), on top of a standard robot-assisted training (RAT) on improving the upper limb motor functions of stroke survivors and to explore potential sensorimotor neuroplasticity with electroencephalography (EEG).

Intermittent theta burst stimulation (iTBS) delivered to the affected primary motor cortex (M1) appears to enhance the brain response to rehabilitative intervention in patients with stroke. However, its clinical utility is highly affected by the response variability. New evidence has reported that preceding iTBS with a priming session of continuous theta burst stimulation (cTBS), may stabilize and even boost the facilitatory effect of iTBS on the stimulated M1, via metaplasticity. The aim of this study is to investigate the effects of iTBS primed with cTBS, on top of a standard robot-assisted training (RAT) on improving the upper limb motor functions of patients with chronic stroke and to explore potential sensorimotor neuroplasticity with electroencephalography (EEG). A three-arm randomized controlled trial (RCT) will be performed with an estimated total of 36 patients with subacute or chronic stroke. All participants will be randomly allocated to receive 10-session intervention of different TBS protocols (i.e., cTBS+iTBS, sham cTBS+iTBS and sham cTBS+sham iTBS), delivered for 3-5 sessions per week, lasting for 2-3 weeks. All participants will receive a 60-minute standard RAT after each stimulation session. Primary outcome will be Fugl-Meyer Assessment-Upper Extremity scores (FMA-UE). Secondary outcomes will be Action Research Arm Test (ARAT), kinematic outcomes generated during RAT as well as and EEG.

Inclusion Criteria:

• with a diagnosis of a unilateral ischemic or hemorrhagic stroke;
• with stroke onset more than 6 months;
• from 18 to 75 years old;
• with mild to moderate impairment of upper limb functions due to stroke, measured using the Hong Kong Version of the Functional Test for the Hemiplegic Upper Extremity (FTHUE-HK) from level 2 to level 7;
• be able to understand verbal instruction and follow one-step commands;
• be able to give informed consent to participate;

Exclusion Criteria:

• any contraindications to rTMS/TBS, such as unstable medical condition, history of epileptic seizures, metal implants in vivo (eg, pacemaker, artificial cochlear, and implant brain stimulator), and a history of receiving craniotomy;
• previous diagnosis of any neurological disease excluding stroke;
• presence of any sign of cognitive problems (Abbreviated mental test Hong Kong version < 6/10);
• patients with extreme spasticity in any hemiplegic upper limb joint (Modified Ashworth score > 2) or severe pain that hinder the upper limb motor training;
• with other notable impairment of the upper limb affected by stroke, eg, recent fracture, severe osteoarthritis, congenital upper limb deformity
• any sign of anxiety or depression, as assessed by the Hospital Anxiety and Depression Scale.
• concurrent participation in an upper limb rehabilitation program or a medicine trial.

The data will be shared for research purpose upon reasonable request.