The long-term goal of this project is to develop and test upper Iimb rehabilitation interventions that can improve bimanual motor function, or the ability to use both arms and hands together, for stroke survivors with moderate to severe impairment.

This study will utilize a novel method of non-invasive brain stimulation in conjunction with upper limb training given for 12 visits over a period of 6 weeks.

The study will include the following site visits:

• Eligibility Screening and Informed Consent Visit
• Baseline testing (4 visits total): 1 visit each for MRI, upper limb and bimanual motor function test, bimanual motor control, and neurophysiology related to control of the upper limbs
• Repeat baseline testing (4 visits total) of MRI, upper limb and bimanual motor function test, bimanual motor control, and neurophysiology related to control of the upper limbs
• 12 intervention visits during which patients will receive upper limb therapy in conjunction with non-invasive brain stimulation
• Repeat testing (4 visits total) of MRI, upper limb and bimanual motor function test, bimanual motor control, and neurophysiology related to control of the upper limbs
• A follow-up visit 1 month after the completion of interventions

In a pilot randomized controlled clinical trial, 18 stroke survivors more than 6 months after stroke onset, and have upper limb impairment will be enrolled. Participants will be randomized to receive a form of non-invasive brain stimulation called repetitive transcranial magnetic stimulation or rTMS or sham rTMS. Real or sham rTMS will be delivered over an area in the brain called the higher motor cortices within the stroke-unaffected hemisphere, cHMC for short. This area (cHMC) is important for using both arms and hands together, or bimanual motor function. Real or sham cHMC rTMS will be given prior to upper limb therapy twice a week for 6 weeks in the lab. The investigators will measure bimanual motor function and control twice at the beginning, once after the 6-week treatment and once at 1-month after treatment. The investigators will also test possible mechanisms related to the treatment using brain functional MRI and TMS twice at the beginning and once after 6-week treatment.

Inclusion Criteria:

• Age 18-90 yrs
• ≥6 months since first clinical stroke
• Impairment of the paretic hand, indicated by a score of <= 11 out of 14 on the hand section of UEFM
• Sufficient range of motion in the wrist and fingers for functional task practice: have at least 10 degrees active wrist extension, 10 degrees active thumb abduction/extension, and 10 degrees active extension in at least 2 additional digits
• Sufficient active shoulder and elbow movement to volitionally position the paretic hand in the workspace for table-top task practice

Exclusion Criteria:

• Brainstem or cerebellar stroke
• Bilateral strokes or multiple strokes affecting sensorimotor structures
• Cognitive impairment (Mini-Mental State Examination <24)
• Severe impairment of the paretic hand that limits functional task practice (UEFM hand score < 4 out of 14)
• Severe spasticity (Modified Ashworth Scale >3) or upper limb contracture
• Occupational therapy or upper limb Botox completed ≤ 2 months prior
• Contraindications to TMS or MRI (e.g. metal implant in head, seizure history, cardiac pacemaker)

Subjects will be told they will receive brain stimulation, but will be given no indication as to whether they will receive real or sham stimulation. Investigators analyzing functional outcome data, neurophysiology data and MRI data will receive coded data that conceals the identity of the subject. Therapists involved in training patients will not know which type of rTMS the participant receives.