Stroke is a leading cause of disability in the U.S. and many Veteran stroke survivors live with severe disability. Despite recent advances in rehabilitation treatments many stroke survivors have persistent physical and mental difficulties such as reduced physical and cognitive function and depression. Developing innovative treatments that address these problems is necessary to improve long-term outcomes for stroke survivors. Aerobic exercise (AEx) can improve physical and cognitive function, and reduce depression. Additionally, AEx may enhance physical rehabilitation by making the brain more receptive to, and consequently improving the response to an intervention. Therefore, combining AEx with physical rehabilitation has the potential to improve multiple aspects of stroke recovery. This study will examine the effect of combining AEx with physical rehabilitation on physical and mental function in stroke survivors. By gaining a better understanding of the effects of this combined intervention the investigators aim to advance the rehabilitative care of Veteran stroke survivors.

The purpose of this project is to examine the 'priming' effect of aerobic exercise (AEx) on a motor rehabilitation intervention for chronic stroke survivors. Aerobic exercise (AEx) promotes numerous functional, cognitive, and psychological benefits. For example, AEx has demonstrated positive effects on physical performance, cardiovascular health, global cognition, executive function and depressive symptoms in neurologically healthy individuals as well as survivors of stroke. Importantly, emerging evidence also supports the use of AEx as a priming tool to enhance motor outcomes following targeted rehabilitation. Potential mechanisms underlying the priming effects of AEx include increases in circulating brain-derived neurotrophic factor (BDNF) and corticomotor excitability (CME). The wide-ranging behavioral and physiological benefits of AEx ideally suit it to serve as an adjunctive primer to stroke rehabilitation programs. The investigators' conceptual framework involves priming with AEx prior to targeted motor rehabilitation to enhance the 'neuroplastic environment" and make the brain more amenable to adaptation, thereby enhancing response to rehabilitation. Specifically, the investigators propose to pair AEx with an upper extremity virtual reality rehabilitation game called Duck Duck Punch (DDP) as the platform for examining the adjunctive potential of AEx. To evaluate the priming effects of AEx, chronic stroke survivors will be randomly assigned to receive 8 weeks (3 sessions/week) of DDP preceded by either 15 minutes of AEx (AEx+DDP) or a stretching control (CON+DDP). This design will address the following specific aims:

Aim 1: Evaluate the priming effects of AEx on a motor rehabilitation intervention for chronic stroke survivors.

Aim 2: Quantify the effects of AEx priming on biomarkers of neuroplasticity.

By stimulating the neuroplastic environment the investigators aim to enhance the response to motor rehabilitation. However, additional stroke sequelae (eg. cognitive and psychological function) may influence the magnitude of change in motor function. Depression and impaired cognitive function can negatively influence stroke recovery outcomes, and are characterized by reduced neuroplastic potential and BDNF. Subsequently, subjects with depression or cognitive impairment are often excluded from rehabilitation trials. Thus, data that describes the relationship of multiple domains of stroke recovery as well as the neurobiological underpinnings of the response to rehabilitation will illuminate this gap in the literature and generate the formation of new hypotheses for future study.

Exploratory Aim: Examine the influence of cognitive and psychological function on motor response to AEx+DDP.

The primary goal of this proposal is to provide foundational support to develop AEx as an adjunctive primer to rehabilitation. The data generated will inform the development of additional AEx-based interventions for individuals following stroke as well as other neurological or neuropsychiatric conditions.

Inclusion Criteria:

• experienced unilateral stroke at least 6 months prior;
• voluntarily shoulder flexion of the affected arm 20 degrees with simultaneous elbow extension 10 degrees;
• moderate arm movement impairment (UE Fugl-Meyer Assessment > 21 but < 52 points;
• passive range of motion in paretic shoulder, elbow, wrist, thumb and fingers within 20 degrees of normal;
• 50-90 years of age;
• ability to communicate as per the therapists' judgement at baseline testing;
• ability to complete and pass an exercise tolerance test; 8) Box & Block test score of at least 3 blocks in 60 seconds with the affected arm.

Exclusion Criteria:

• lesion in brainstem/cerebellum as these may interfere with visual-perceptual/cognitive skills needed for motor re-learning;
• presence of other neurological disease that may impair motor learning skills;
• orthopedic condition or impaired corrected vision that alters reaching ability (e.g., prior rotator cuff tear without full recovery);
• paretic arm pain that interferes with reaching;
• unable to understand or follow 3-step directions;
• severe cognitive impairment (MoCA score 17);
• severe aphasia;
• inability to read English,
• history of congestive heart failure, unstable cardiac arrhythmias, hypertrophic cardiomyopathy, severe aortic stenosis, angina or dyspnea at rest or during ADL's;
• Severe hypertension with systolic >200 mmHg and diastolic >110 mmHg at rest;
• History of COPD or oxygen dependence;
• History of DVT or pulmonary embolism within 6 months;
• Uncontrolled diabetes with recent weight loss, diabetic coma, or frequent insulin reactions;
• UBACC score < 15; and for brain stimulation procedures only:
• electronic or metallic implants;
• history of seizures;
• women of child bearing potential.

The primary outcome measure will be assessed by a blinded rater to improve scientific rigor.