Ultrasound neuromodulation in brain disorders: from mechanotransduction mechanisms to clinical translation.

Brain disorders impose a major global health burden, yet current pharmacological and neuromodulation therapies are often constrained by invasiveness, limited spatial precision, poor access to deep brain structures, or insufficient long-term efficacy. Non-invasive ultrasound neuromodulation has emerged as a promising approach combining high spatial resolution, deep tissue penetration, and reversible modulation. Its biological effects arise from multiscale mechanotransduction involving membrane deformation, mechanosensitive ion channels, intracellular calcium signaling, glial regulation, and neurovascular coupling. Together, these processes modulate neuronal excitability, synaptic plasticity, network connectivity, neuroinflammation, and cerebral perfusion. Preclinical studies support its therapeutic potential across neurological and psychiatric disorders, while early clinical studies indicate short-term tolerability and preliminary target engagement in Alzheimer's disease, Parkinson's disease, and depression. Emerging approaches, including individualized treatment planning, closed-loop stimulation, and sonogenetics, may further improve the precision and cellular specificity of ultrasound neuromodulation. This review summarizes the physical principles and cellular mechanisms of ultrasound neuromodulation, evaluates its therapeutic and clinical applications, and discusses key challenges and future directions, including personalized stimulation, closed-loop systems, sonogenetics, and disease-modifying strategies.