Rehabilitation is one of the few options to improve function and reduce disability after stroke, but rehabilitation training cannot typically restore pe-stroke function. Thus, there is an urgent need to find an effective agent that, when paired with rehabilitation training, will facilitate the neurobiological processes of learning, and will substantially improve human stroke outcomes. Ischemic conditioning is one such promising agent. Ischemic conditioning is an endogenous phenomenon in which exposing a target organ or another, remote organ or tissue to one or more brief episodes of sub-lethal ischemia results in protection of the target organ against ischemia. A clinically-feasible method is remote limb ischemic conditioning (RLIC), where episodes of ischemia and reperfusion are induced with a blood pressure cuff. In humans, the cardioprotective effects of RLIC have been demonstrated repeatedly, while neuroprotective effects are just beginning to be evaluated. Here, we propose that the multifactorial, epigenetic mechanisms of RLIC might extend beyond cardio- and neuroprotection and into plasticity, learning, and recovery. Based on robust preliminary data, our central hypothesis is that the multifactorial mechanisms of RLIC can be harnessed as a neurorecovery agent to enhance stroke rehabilitation and outcomes. The current proposal is designed to gather the critical information needed to move this promising intervention down the translational pathway. In this Phase I project, we will deliver RLIC via cycles of inflation and deflation of a blood pressure cuff to the upper arm. We will compare RLIC + training vs. sham conditioning + training, in 200 neurologically- intact adults, in various experimental manipulations. Aim 1 will determine which types of rehabilitation training are facilitated by RLIC. Aim 2 will optimize the RLIC protocol by evaluating the necessary cuff-pressures to induce RLIC, the dose-response properties and retention effects of RLIC, and explore potential serum markers of RLIC. Aim 3 will identify key characteristics of responders to RLIC by studying middle-aged and older adults with and without specific co-morbidities and medications that have been identified in the preclinical literature and/or are common post stroke. Finally, Aim 4 will explore the feasibility of using RLIC + training in 15 people within the first few weeks after stroke. Outcomes from this project will provide the necessary data to maximize the design of a Phase II randomized, controlled trial in persons with stroke. A major advantage of RLIC over other potential central nervous system priming options is its simple technology, low cost, and clinical feasibility. While our initial translational target is stroke, the potential benefits of RIC extend far beyond stroke to other neuro- and geriatric (e.g. balance and falls) rehabilitation populations.