Low-intensity focused ultrasound for neuromodulation: mechanisms, parameters, and emerging clinical applications—a critical review

Background Low-intensity focused ultrasound (LIFU) is a non-invasive neuromodulation technique that combines millimeter-scale spatial precision with access to cortical and deep targets — including the thalamus, basal ganglia, amygdala, and nucleus accumbens — that otherwise require invasive deep brain stimulation (DBS). Methods We conducted a narrative critical review of mechanistic, technical, and clinical LIFU literature from PubMed/MEDLINE, Europe PMC, Scopus, Web of Science and ClinicalTrials.gov (final search 30 June 2026), synthesizing in vitro , animal, human neurophysiological, neuroimaging, and early clinical evidence, with attention to the level of evidence, ITRUSST safety and reporting standards, and methodological confounds. Main findings Proposed biophysical mechanisms include acoustic radiation force, cavitation, and thermomechanical coupling at neuronal membranes, engaging mechanosensitive ion channels and reshaping excitatory–inhibitory (E/I) balance via glutamatergic and GABAergic pathways; the direction of modulation and the physical-to-cellular chain remain incompletely resolved. Theta-burst TUS (tbTUS) induces NMDA-associated LTP-like motor-cortical plasticity lasting 30–60 min. Human studies in movement disorders (Parkinson’s disease, essential tremor), treatment-resistant depression, anxiety, pain, Alzheimer’s disease, and stroke report physiological and early clinical effects. Importantly, the physiological readouts most often reported — motor-evoked potentials, local field potentials, functional connectivity, and neurotransmitter levels — index target engagement and acute neural effects but do not, by themselves, establish meaningful or sustained clinical benefit. Key challenges include parameter heterogeneity, auditory confounds, inconsistent reporting, skull variability, and a paucity of adequately powered randomized controlled trials. Conclusion LIFU is a promising but still largely investigational technology. ITRUSST consensus safety and reporting guidelines are beginning to standardize the field. Current clinical studies remain small, heterogeneous, and mostly short-term, supporting biological plausibility and target engagement rather than established therapeutic efficacy. This review emphasizes that controlled, adequately powered trials with long-term follow-up are needed before clinical adoption for any indication.