A panoramic review of transcranial focused ultrasound neuromodulation: from basic research to clinical applications

Transcranial focused ultrasound (tFUS) is an emerging non-invasive brain stimulation technique that uses acoustic energy to achieve precise modulation of specific brain regions, showing significant potential in the treatment of neurological disorders. Building upon extensive foundational work in clinical safety and mechanistic understanding, this review examines temporal aspects of tFUS mechanisms and clinical applications, with particular attention to the distinction between immediate online effects and sustained offline aftereffects. We examine the mechanisms of action spanning molecular to network levels, regulatory effects on key brain functional systems (sensory, motor, cognitive, and emotional), and evidence for applications in neurological and psychiatric disorders, including neurodegenerative diseases, epilepsy, depression, and anxiety. Studies have demonstrated that tFUS can selectively regulate brain functions by influencing ion channels, synaptic transmission, neural oscillations, and brain networks at multiple levels, with effects showing distinct temporal profiles. Clinical trials provide evidence for potential efficacy and safety within established parameter guidelines. However, current understanding of temporal dynamics, long-term effects, and optimal parameter schemes requires further elucidation. The temporal mechanistic framework examined here may contribute to understanding therapeutic protocol optimization and sustained clinical benefits. Future research priorities include systematic parameter optimization, standardization of protocols across applications, and development of personalized approaches to address individual variability in treatment response.