Feasibility of combination exercise and neuromodulation rehabilitation to improve post-stroke chronic pain

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There are over 7 million stroke survivors in the United States. In the Veteran population, stroke is the leading cause of neurological disability, and one of leading causes of hospitalization. Chronic pain after stroke can occur between 10-50% of stroke survivors. Post- stroke pain (PSP) can lead to further complications in a stroke survivor’s recovery. Exercise has been shown to improve pain symptoms of patients with PSP. the American Heart/Stroke Association recommended that exercise should be incorporated into the management of stroke survivors. Repetitive transcranial magnetic stimulation (rTMS) uses noninvasive cortical neurostimulation to improve neuropathic pain. A European commission to establish guidelines on therapeutic use of rTMS stated the evidence of rTMS of the contralateral primary motor cortex as definite analgesic effect with few safety issues (Level A recommendation). However, the effects of the treatment are transient, usually lasting a few hours to days[20]. While non- invasive, as a practical therapy for chronic PSP, more sustained efficacy of rTMS would be needed to be demonstrated. We hypothesize that pairing rTMS with exercise may develop a complementary effect to enhance the duration of symptomatic relief. This proposal is a single-site, randomized sham-controlled trial of rTMS and exercise in the treatment of Veterans with a diagnosis of chronic PSP who are at least 6-months from their cerebral stroke. The purpose of the pilot study is to evaluate the feasibility and safety of rTMS+exercise in Veterans diagnosed with chronic PSP. We will gather data to plan for a larger efficacy trial to assess sustained rTMS effects with exercise on pain outcomes. The long-term goal of the proposed work is to develop a non-pharmacologic intervention that also increases physical activity for patients suffering from chronic PSP. Following successful screening and baseline randomization, eligible patients will be treated with a regimen of rTMS vs sham rTMS for 1 week. Participants return for assessments at the end of week 1 and continue the assigned rTMS arm while adding supervised aerobic exercise 3 times weekly from week 2 to 9. Final assessment is at 3 months. Aim 1: Evaluate the feasibility of an efficacy study design comparing rTMS and exercise versus sham rTMS and exercise to reduce pain in patients with chronic PSP. Hypothesis 1: The pace of recruitment will be acceptable. We will recruit 36 patients, 32 of whom will complete the study within 3 months. Aim 2: Evaluate the safety of rTMS combined with aerobic exercise in patients with a history of ischemic stroke and chronic PSP. Hypothesis 2: Less than 10% of patients randomized to combined intervention of aerobic exercise plus rTMS will have adverse events and the observed rate will be comparable to patients randomized to aerobic exercise plus sham rTMS. Aim 3: To assess the correlation between neuronal connectivity of the motor cortex with pain and stroke outcomes following rTMS stimulation and aerobic exercise intervention in Veterans. Hypothesis 3: The measured strengthening of the structural and functional connectivity in the motor cortex following rTMS stimulation with the default mode network, limbic, and sensorimotor regions will be higher for the exercise plus rTMS compared with exercise plus sham rTMS (estimate only, without statistical testing).