Substrates for Post-Stroke Arm Rehabilitation

Strokes commonly damage motor pathways in the brain which leads to "hemiparesis", the collective term given to the syndrome of motor dysfunction after stroke. Upper extremity hemiparesis is comprised of both loss of abilities (negative signs- weakness and loss of dexterity or fractionated motor control) and intrusion of abnormal movements (positive signs- spasticity, abnormal resting postures, and synergies).

Recent work from our group and others shows that components of motor hemiparesis are dissociable: they can be separated and each map onto different and specific brain pathways. In this proposal, we focus on one specific component of post-stroke hemiparesis: proximal upper extremity motor control. Proximal upper extremity motor control can be measured as the ability to individuate and coordinate shoulder and elbow movements. We ask (i) where does proximal upper extremity motor control localize in the post-stroke brain? (ii) can we improve motor control with a specific form of targeted, high-dose, high-intensity therapy? And (iii) does therapy lead to corresponding changes in anatomy and physiology of brain pathways? Our central hypothesis is that intensive, targeted training improves proximal upper extremity motor control and induces corresponding anatomical and physiological changes of the corticospinal tract. To test this hypothesis, we will conduct three specific aims: (1) Determine baseline relationships between the corticospinal tract and proximal upper extremity motor control, (2) Define changes in proximal upper extremity motor control induced by targeted rehabilitation training, and (3) Define changes in corticospinal tract anatomy and physiology induced by targeted rehabilitation training. We leverage a clinical trial design of N = 50 patients with moderate-severe hemiparesis randomized to two groups: Arm Basis Training (a protocolized form of occupational therapy targeting motor control) versus usual care. Before and after six weeks of therapy, all patients will undergo kinematic assessment of motor control, diffusion magnetic resonance imaging to assess corticospinal tract axon density, and transcranial magnetic stimulation to assess corticospinal excitability. Dr. Lin, an acute care neurologist with neurorehabilitation and neuroscience training and the Director of the MGH Neurorecovery Clinic, will lead the project and bring together a world-class team of investigators and consultants, supported by the rich and multidisciplinary environment at Massachusetts General Hospital, Harvard Medical School, and collaborating institutions. This project is a mechanistic and hypothesis-driven investigation of the neuroanatomic and neurophysiologic signatures of a specific component of hemiparesis, proximal upper extremity motor control, and its response to targeted rehabilitation. The unique integration of kinematics, neuroanatomy, and neurophysiology in patients after stroke will transform stroke rehabilitation with a precision approach that targets brain structure and function.

Inclusion criteria

• first time unilateral ischemic or hemorrhagic stroke occurring within the 3-6 months
• upper extremity motor impairment as measured by the Upper Extremity Fugl-Meyer Assessment (UE-FMA) Score <= 44
• ability to participate in a 6-week intensive upper extremity intervention in English as determined by a licensed occupational therapist.

Exclusion criteria

• bilateral stroke
• unstable medical status affecting functional status
• pre-stroke upper extremity injury or conditions that limited use
• visual or auditory impairment limiting ability to participate in study procedures
• significant aphasia (NIHSS sub-item 9 > 1) or cognitive (NIHSS 1a or 1b or

1c > 1) deficits

• known or expected inability to maintain follow-up through the study intervention and post- assessment
• contraindications to MRI
• contraindications to TMS
• known history of uncontrolled seizure disorder.