PROJECT SUMMARY/ABSTRACT Stroke is a disease of epidemiological proportions in the industrialized world and is a leading cause of long- term disability. Half of all stroke patients suffer long-term motor deficits severe enough to be disabling despite contemporary rehabilitative efforts, which underscores the need for novel, neurorestorative therapies to enhance post-stroke motor recovery. We have previously proposed dentate nucleus deep brain stimulation (DN-DBS) as a therapy to facilitate motor recovery for patients with chronic upper extremity hemiparesis due to ischemic stroke. Our working hypothesis is that low-frequency DN-DBS augments excitatory dentatothalamocortical output, thereby enhancing cerebral cortical excitability, facilitating functional reorganization in perilesional cortical areas and further supporting motor recovery. Using a rodent model of ischemia, we have demonstrated that chronic stimulation can facilitate motor recovery and that the improvements are accompanied by sustained increments in excitability, reorganization of motor representation, and increased expression of markers of long-term potentiation and synaptogenesis in perilesional regions of the cerebral cortex. The experiments proposed in the present study will help to ensure successful human translation of this promising novel treatment while also systematically examining its mechanistic underpinnings. Specifically, the proposed experiments are designed to determine: a) how the anatomical extent and distribution of the ischemic core influences both treatment efficacy and carry-over of benefits; b) how movement-related, synchronized oscillatory activity across deep cerebellar nuclei and neocortex changes post-stroke and as a result of DN-DBS treatment and whether that activity could serve as a control signal in a paired-associative (closed-loop) treatment paradigm; c) whether age at the time of infarct negatively impacts therapeutic efficacy; and d) the anatomical and functional mechanisms underlying DN- DBS-enhanced motor rehabilitation. These studies will be performed by an investigative team with multiple long-standing collaborations aimed towards the development of DN-DBS technologies for the treatment of motor impairments following stroke.