Therapeutic ultrasound for brain intervention: toward bioeffect-linked acoustic dose control

Central nervous system disorders remain challenging to treat because the blood–brain barrier restricts therapeutic delivery and deep brain structures are difficult to access. Therapeutic ultrasound offers non-invasive access to intracranial targets and can produce diverse biological effects by varying acoustic exposure and biological mediators. However, these applications have largely been developed and evaluated separately, and the field lacks a shared framework for comparing their biological effects, monitoring strategies and translational maturity. This Review organizes therapeutic brain ultrasound within a shared acoustic parameter space defined by frequency, pressure, pulse structure, skull transmission, biological mediators and tissue state. We examine thermal ablation, histotripsy, blood–brain barrier opening, sonodynamic therapy and neuromodulation, alongside emerging applications in liquid biopsy, glymphatic modulation, sonogenetics and acoustic brain–computer interfaces. Thermal ablation is clinically established for selected indications and uses temperature-based monitoring. Blood–brain barrier opening has demonstrated controllable permeability and enhanced drug delivery, although incremental clinical benefit remains to be established in randomized trials. Intracranial histotripsy remains preclinical. Sonodynamic therapy and neuromodulation have shown feasibility and biological or physiological target engagement, but clinical efficacy has not yet been established consistently across indications. To connect these diverse applications, we propose a bioeffect-linked acoustic dose-control framework that distinguishes three non-equivalent layers: patient-specific estimation of intracranial exposure, intraprocedural monitoring or delivered-dose surrogates, and post-treatment validation of intended biological effects and safety. The relevant readouts range from magnetic resonance thermometry and cavitation emissions to sensitizer-linked pharmacodynamics and electrophysiological responses. We outline modality-specific priorities for dose validation, controlled clinical evaluation and longitudinal safety assessment. A bioeffect-linked framework that connects measured or estimated acoustic exposure to modality-specific biological effects may improve reproducibility and guide the transition toward feedback-governed precision brain intervention.