Abstract
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 array ultrasound emission with a fiberscope-based wide-field 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.
Highlights
Transcranial ultrasound of both high and low intensities is increasingly used to treat and study the brain with high spatial and temporal specificity [1]
Several methods have been developed in the context of magnetic resonance–guided focused ultrasound (MRgFUS) therapy to characterize the effects of high ultrasonic intensity in brain tissue [2] and monitor the occurrence of thermal lesions [3]
To achieve accurate in situ targeting despite strong skull-induced aberrations, we further introduce a fluorescence-b ased analog of MRgFUS harnessing the dependence of fluorescent protein brightness on temperature [23]
Summary
Transcranial ultrasound of both high and low intensities is increasingly used to treat and study the brain with high spatial and temporal specificity [1]. Multiple methods have been deployed, e.g., to examine mouse brain responses to an ultrasonic stimulus including electrode recordings [8], muscle electromyography [9], laser speckle [10], optical intrinsic signal [11], and wide-field fluorescence imaging [12, 13]. These studies used unfocused or weakly focused beams measuring multiple millimeters across, which target very large cortical, subcortical, and peripheral sections of the mouse central nervous system, not faithfully resembling the human MRgFUS case [1, 14]. The spatial specificity has been improved using higher ultrasound frequencies [16], but no concurrent functional readout was available to monitor neural activities in the mouse brain
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