PROJECT SUMMARY / ABSTRACT The Organizing Concept of the parent Phase II COBRE in Stroke Recovery is that better understanding of the experience-dependent nature of neural plasticity allows us to investigate and exploit inherent neural recovery processes, develop and translate novel mechanism-based interventional strategies, and ultimately improve the function and quality of life of individuals recovering from stroke. And Overall Specific Aim 2 focuses on strengthening innovative scientific cores that support/advance stroke recovery research – such as the Brain Stimulation Core. Transcranial focused ultrasound (tFUS) offers unprecedented spatial resolution and depth of focus versus other methods of non-invasive brain stimulation - such as transcranial magnetic stimulation (TMS), transcranial electrical stimulation (tES), or deep brain stimulation (DBS) - and has been shown to be a safe and effective method of delivering precise ultrasonic energy to the brain without causing tissue damage or lasting neurological effects. The existing technology used by COBRE investigators has significant limitations. In direct alignment with the Organizing Concept and Overall Specific Aim above, we propose to acquire the first-in-class, state-of-the art transcranial focused ultrasound (tFUS) targeting, navigation, and sonication platform for administration of noninvasive deep brain stimulation (the NeuroFUS Pro Neuronavigated tFUS System). This platform will serve a pioneering suite of equipment designed to advance novel interventions for post stroke motor recovery, cognitive impairment, depression, and pain using the emerging new technology of ultrasound. This proprietary cutting-edge system incorporates technology that 1) allows for the advancement of focused ultrasound interventions in a stroke population, 2) enables precision administration with sub-centimeter spatial resolution of individual brain targets relevant to stroke recovery, 3) variable penetration depths ranging from 20- 80mm allowing for whole brain targets for cortical or subcortical sonication, 4) optimize sonication parameters and compare the calculated exposure and dose parameters based on individual skull and brain anatomy, and 5) administer tFUS using individual MRI targeting to conduct mechanistic and behavioral experiments that can rapidly advance this area of research. Taken together, this advanced focused ultrasound platform promises to make a large leap in the area of post-stroke rehabilitation by enabling access to previously inaccessible stroke- related brain areas. It will allow us to create new potential treatments for stroke recovery and allow us to further strengthen our research program through additional NIH funding opportunities. Such opportunities are a cornerstone of our COBRE sustainability plan to continue to thrive after Phase III.