Project Summary Depression is the most common neuropsychiatric manifestation following stroke and current treatments are largely ineffective. Depression has both direct and indirect effects on response to rehabilitation treatment, thus subjects with post-stroke depression (PSD) are routinely excluded from rehabilitation trials and treatment options for these individuals are extremely limited. We propose to determine the efficacy of combining two known anti-depressant treatments shown to be effective in non-stroke depression, aerobic exercise (AEx) and repetitive transcranial magnetic stimulation (rTMS), on post-stroke depressive symptoms. Further, we will determine 1) the potential for AEx to enhance the effects of rTMS to treat depression; and 2) whether successful reduction in depressive symptoms is associated with improved recovery. This project is based on the scientific premise that depression negatively affects the potential to adapt in response to treatment such that rehabilitation may not produce the same changes that it does in non- depressed individuals. We hypothesize that effective treatment for PSD will result in a virtuous cycle whereby reducing depression enhances response to rehabilitation, thereby facilitating functional gains. That is, effectively treating depression will enable individuals to better recover from stroke. Furthermore, in addition to its beneficial effects on depression, AEx is known to improve post-stroke motor recovery, thus providing an attractive option for treating depression as well as an established vehicle to study the effects of PSD on response to rehabilitation. The experiments proposed as part of this project are designed to address critical questions related to: 1) the combined effects of AEx and rTMS (versus AEx or rTMS alone) on depressive symptoms; 2) the potential for PSD to limit response to rehabilitation; and 3) the relationship between baseline subject attributes and response to treatment.