Project Summary/Abstract Representational plasticity in the cerebral cortex is a dramatic example of the brain’s accommodative response to injury or training. An emerging approach for rehabilitating, and potentially enhancing, sensation involves the use of noninvasive, transcranially-directed focused ultrasound (FUS) to directly affect neural function. Compared with other noninvasive neuromodulation techniques applicable to humans, FUS offers the possibility of modulating neural activity with superior spatial resolution even for targets deep within the brain. Despite the allure of FUS as a modulation approach, many aspects of the technology relevant to translational capability are unclear, and conflicting results have been reported for even macroscopic effects. In order to fully leverage the use of FUS for rehabilitative or augmentative purposes in humans, the impact on behavior must be well characterized and robust. Characterizing the transformation of targeted stimulation to behavioral changes therefore requires a combination of new experimental approaches for (1) monitoring the direct neural effects of targeted stimulation in the brain, and (2) monitoring quantitative behavioral readouts in the same animal. By leveraging novel optical tools and behavioral experimental approaches, the proposed research will address key knowledge gaps that currently limit development and refinement of FUS neuromodulation for use in humans. Because the Aims collectively connect neural mechanisms with behavior, this work would represent a significant step toward the potentially transformative prospect of customized sensory modulation for therapeutic or augmentative applications.