Acoustic parameter-effect relationships in transcranial focused ultrasound neuromodulation: a narrative review

Background and Objective: Transcranial focused ultrasound (tFUS) is an emerging non-invasive neuromodulation technique capable of targeting both superficial and deep brain regions with millimeter-scale spatial precision. Its neuromodulatory effects are strongly influenced by acoustic parameters, including center frequency, acoustic pressure or intensity, pulse repetition frequency (PRF), duty cycle (DC), pulse duration (PD), and sonication duration (SD). However, an integrated framework explaining how variations in these parameters give rise to specific bioeffects, engage candidate mechanisms, lead to downstream neuromodulatory responses, and ultimately affect translational feasibility is still lacking.

Methods: PubMed, Web of Science, and Google Scholar were searched for English-language studies published from database inception through 1 May 2026 using combinations of terms related to included "transcranial focused ultrasound", "neuromodulation", and "acoustic parameters". Reference lists of key studies and recent reviews were also screened, resulting in the inclusion of 113 eligible studies.

Key Content and Findings: This review first summarizes the principal acoustic parameters used in tFUS and explains how their interactions shape ultrasound-induced bioeffects. Evidence linking acoustic parameters to candidate mechanisms, including mechanosensitive ion-channel gating, thermosensitive channel activation, and membrane-capacitance changes, is then evaluated. Parameter-effect relationships are organized across cellular, synaptic, functional, and circuit levels in preclinical and mechanistic studies. Potential factors underlying apparently conflicting findings, including brain state, oscillatory phase, and circuit architecture, are also discussed. Major barriers to clinical translation, including species differences, patient-specific dosing, and methodological standardization, are highlighted together with potential strategies for acoustic parameter optimization.

Conclusions: The effects of tFUS cannot be attributed to any single acoustic parameter or considered purely excitatory or inhibitory. Instead, they emerge from interactions among acoustic parameters, the biological and physiological state of the brain, and the level at which neuromodulatory outcomes are assessed. This complexity highlights the importance of systematic and context-specific optimization of acoustic parameters for safe, reproducible, and effective applications of tFUS neuromodulation.