Image-guided low-intensity focused ultrasound neuromodulation: acoustic targeting optimization and functional validation in a reward circuit model.

OBJECTIVE: To develop and validate an ultrasound-guided low-intensity focused ultrasound (USg-LIFU) platform for subject-specific deep-brain neuromodulation and test whether ventral tegmental area (VTA) targeting modulates alcohol-related behaviour in a mouse model of alcohol use disorder. METHODS: USg-LIFU uses ultrasound tomography (UT)-assisted acoustic velocity mapping and subject-specific finite element method (FEM) simulations to incorporate reconstructed acoustic-property information into FEM-based focal prediction and guide mechanical alignment of the predicted focal zone toward the target. Targeting accuracy is verified ex vivo using high-intensity focused ultrasound (HIFU) to create thermal lesions in mouse brain tissue. In vivo neuromodulatory effects were tested in cHAP mice () that underwent six USg-LIFU sessions targeting the VTA over 14 days and compared with sham controls (). Daily measures were recorded to assess alcohol and water intake, and blood alcohol concentration (BAC) was assessed before, during, and after treatment. RESULTS: Simulations showed that changes in brain acoustic velocity shifted focal position and altered pressure distribution, underscoring the need for subject-specific correction. Ex vivo studies demonstrated that the optimized focus converged on the predefined intracranial target, with visible thermal damage at the intended location after sonication. In vivo, most LIFU-treated mice showed reduced ethanol intake and increased water consumption after treatment initiation, whereas sham animals maintained or strengthened alcohol preference. Across the treatment period, mean alcohol intake decreased by approximately in the treated group, consistent with reductions in BAC measurements. CONCLUSION: USg-LIFU achieved accurate subject-specific targeting and produced measurable modulation of alcohol-related behaviour, supporting its potential as an accessible platform for non-invasive deep-brain neuromodulation.