Transcranial low-intensity pulsed ultrasound in neurological disorders: mechanisms, therapeutic applications, and translational challenges.

Transcranial low-intensity pulsed ultrasound (LIPUS) is an emerging non-invasive modality with high spatial precision, substantial tissue penetrability, and favorable biosafety. Acting predominantly through mechanical rather than thermal bioeffects, LIPUS modulates mechanosensitive ion channels, intracellular calcium signaling, synaptic transmission, glial activation, neurovascular coupling, and, in selected settings, blood-brain barrier permeability. These features support its growing application in neurological disorders. In this review, we summarize the mechanistic basis of transcranial LIPUS and discuss its therapeutic applications in Alzheimer's disease, Parkinson's disease, epilepsy, ischemic stroke, and major depressive disorder. Across these conditions, LIPUS has been associated with neuroprotection, enhanced synaptic plasticity, suppression of pathological neural activity, attenuation of neuroinflammation, promotion of vascular remodeling, and facilitation of targeted delivery through reversible blood-brain barrier opening. We further highlight the major barriers to clinical translation, including heterogeneity of stimulation parameters, incomplete mechanistic understanding, limited comparability across studies, and insufficient large-scale clinical validation. Current evidence supports transcranial LIPUS as a promising ultrasound-based platform for neuromodulation and brain repair, while emphasizing the need for standardized protocols and rigorous translational studies.