Understanding the physiological impact of transcranial ultrasound in rodent brains may offer an important preclinical model for human scale magnetic resonance-guided focused ultrasound methods. However, precision tools for high-resolution transcranial ultrasound targeting and real-time in vivo tracking of its effects at the mouse brain scale are currently lacking. We report a versatile bidirectional hybrid fluorescence-ultrasound (FLUS) system incorporating a 0.35-mm precision spherical-phased

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... rray ultrasound emission with a fiberscope-based widefield fluorescence imaging. We show how the marriage between cortex-wide functional imaging and targeted ultrasound delivery can be used to transcranially map previously undocumented localized fluorescence events caused by reversible thermal processes and perform high-speed large-scale recording of neural activity induced by focused ultrasound. FLUS thus naturally harnesses the extensive toolbox of fluorescent tags and ultrasound's localized bioeffects toward visualizing and causally perturbing a plethora of normal and pathophysiological processes in the living murine brain. RESULTS Characterization of transcranial FUS delivery Simultaneous FUS and wide-field fluorescence imaging (Fig. 1A ) is accomplished by combining a wide-angle 512-element spherical ultrasound array with a fiberscopic insert (24) consisting of 100,000 single