Ultrasound Modulation of Brain Function

Transcranial ultrasound/ultrasonic stimulation (TUS) is a neuromodulation technique with spatial resolution unmatched by other non-invasive approaches, positioning it as a promising tool for modulating brain function and treating neurological and psychiatric disorders. Despite growing interest, the biophysical mechanisms underlying TUS-evoked neural activity remain unresolved. This review critically evaluates evidence for three proposed mechanisms: temperature rise, intramembrane cavitation, and mechanical force. Mechanically mediated activation of mechanosensitive ion channels, primarily via acoustic radiation force, has the strongest and most consistent evidence; intramembrane cavitation lacks direct support; and temperature rise contributes under some parameter regimes without appearing to be a universal mechanism. Beyond direct biophysical mechanisms, this review addresses the auditory confound, that is, the capacity of TUS to evoke neural activity indirectly through cochlear activation rather than focal mechanical action. Across the majority of animal and human studies, it cannot be determined whether TUS-evoked activity reflects direct pressure-mediated neuromodulation or indirect auditory activation. Studies employing gold-standard controls-auditory masking, active control sites, and deafening-provide the clearest evidence for spatially selective, non-auditory effects, though such controls remain inconsistently applied. Resolving the relative contribution of direct and auditory-mediated mechanisms will be essential to establishing TUS as a spatially precise neuromodulation tool.