Stroke is the leading cause of disability in adults in the United States. Despite advances in hyperacute stroke care, advancements in stroke rehabilitation are lagging. We have previously shown that a non-invasive, cost-effective, easy to perform intervention, called ischemic conditioning (IC), can improve paretic leg strength, reduce muscle fatigue, and increase walking speed in chronic stroke survivors (>1 year post-stroke). The IC procedure makes the paretic leg transiently ischemic (5 minutes) using a cuff inflated to 225 mmHg, and repeats the occlusion 5 times with 5 minute periods of rest between cycles (45 total minutes). It is well accepted that the response to IC is complex and involves local, humoral and neural factors. The mechanism by which IC can confer motor benefit in stroke survivors is unknown. The aim of this study is to examine if IC can increase sympathetic nervous system (SNS) activity, which would promote an increased cardiovascular response to exercise and increased muscle strength. We hypothesize that plasma epinephrine and norepinephrine levels will increase more during a cold pressor test (a well-tolerated test to induce a sympathetic response) in chronic stroke survivors who undergo a single session of IC vs. IC-Sham. To accomplish the goals of this study, 15 chronic stroke survivors will each make two visits to the adult translational research unit at Medical College of Wisconsin (MCW) to have either IC or IC-Sham performed on their paretic leg in a counterbalanced order. Venous blood will be drawn before and after the IC or IC-Sham procedure and after a two-minute cold pressor test where the study participants submerge their hand into a bucket of ice water. This will cause an increased sympathetic response, which will be assessed by measuring blood pressure and the relative increase in the levels of circulating catecholamines (epinephrine and norepinephrine, assessed by high performance liquid chromatography).

Inclusion Criteria:

• Study participants must be between 18-85 years of age, able to give informed consent, >1 year post diagnosis of unilateral cortical or sub-cortical stroke, have residual lower limb paresis.

Exclusion Criteria:

• History of blood clots in the extremities or any condition in which compression of the thigh or transient ischemia is contraindicated (e.g. wounds in the leg), chronic pain syndrome, history of head trauma, comorbid neurological disorder, any uncontrolled hypertension (>160/100 mmHg), peripheral vascular disease, a myocardial infarction in the previous year, inability to follow 2 step commands, or history of multiple strokes.

The study PI will be blinded to the intervention until after all plasma samples have been analyzed.