Focused Ultrasound Neuromodulation: Biophysical Mechanisms, Neural Effects, and Clinical Translation

Low-intensity transcranial ultrasound stimulation (TUS) has emerged as a promising noninvasive neuromodulation technology capable of targeting both cortical and deep brain structures with millimeter-scale spatial precision. Recent advances in ultrasound hardware, acoustic modeling, neuronavigation, and multimodal imaging have accelerated the field from proof-of-concept demonstrations toward mechanistic investigation and early clinical translation. In parallel, growing evidence from animal and human studies has begun to clarify how ultrasound influences neural activity across cellular, circuit, and systems levels. In this review, we synthesize recent progress in understanding the biophysical mechanisms, neurophysiological effects, and network-level consequences of TUS. We discuss insights from optical imaging, electrophysiology, EEG source imaging, and functional MRI, highlighting how these complementary approaches reveal cell-type-specific responses, bidirectional modulation of neural circuits, and distributed changes in functional connectivity beyond the sonicated target. We further examine evidence that functional imaging is evolving from a simple measure of regional activation to a multidimensional biomarker of target engagement, circuit modulation, and treatment response. Despite these advances, important challenges remain. We conclude that TUS is approaching a translational inflection point in which rigorous mechanistic studies, standardized methodologies, and imaging-based biomarkers can establish ultrasound as both a powerful causal neuroscience tool and a clinically viable neuromodulation therapy for disorders involving dysfunctional brain circuits.