Precision meets plasticity: engineering and neurobiological frontiers of low-intensity focused ultrasound neuromodulation.

Low-intensity focused ultrasound (LIFU) is emerging as a promising non-invasive tool for neuromodulation, with the potential to reach deep brain structures implicated in psychiatric and neurodegenerative disorders. Despite its rapid development, the translation of LIFU into reliable clinical applications remains limited by incomplete understanding of its mechanisms, variability in outcomes, and technical constraints. This review integrates neurobiological and engineering perspectives to clarify how LIFU interacts with neural and glial systems and how physical factors shape its efficacy. Evidence shows that LIFU can bidirectionally modulate neuronal excitability and network connectivity, influence synaptic plasticity, and alter neurovascular and glial dynamics in a highly parameter- and context-dependent manner. Moreover, LIFU may transiently affect blood-brain barrier permeability and inflammatory signaling, offering opportunities for therapeutic delivery but also raising safety concerns. Engineering considerations (including skull-induced aberrations, imperfect beam focusing, and variability in transducer design) further complicate reproducibility across individuals and studies. These limitations contribute to the heterogeneous results observed in clinical trials targeting depression, addiction, and cognitive impairment. Bridging these challenges requires standardization of acoustic exposure metrics, advanced computational modeling of patient-specific skull properties, and systematic investigation of biological markers associated with ultrasound response. By integrating biophysical optimization with individualized neurobiological profiling, LIFU could evolve from an exploratory technique to a precision neuromodulation tool capable of safely and effectively addressing circuit dysfunctions underlying major brain disorders.