Parameter-Effect Mappings of Cortical and Subcortical Low-Intensity Focused Ultrasound Neuromodulation in Humans: A Comparative Review

Transcranial low-intensity focused ultrasound (LIFU) has emerged as a promising technology for non-invasive, spatiotemporally precise modulation of human brain activity, offering access to deep structures beyond the reach of electromagnetic methods. Yet, its parameter-effect relationships remain poorly understood, particularly across different anatomical targets. Here, we systematically synthesize human LIFU studies to compare how acoustic parameters—especially pulse repetition frequency (PRF) and duty cycle (DC)—shape neuronal and behavioral neuromodulatory outcomes in cortical versus subcortical regions. Cortical stimulation shows a nonlinear parameter landscape, with facilitation emerging in low-PRF/low-DC and high-PRF/high-DC regimes, and suppression predominating in the intermediate PRF-DC combinations. By contrast, subcortical stimulation exhibits a more monotonic trend along the DC axis: suppression dominates at lower DC across a wide PRF range, while facilitation is largely confined to higher DC regimes. These divergent landscapes delineate clearer parameter boundaries between cortical and subcortical targets. We interpret these target-dependent differences through cellular, cytoarchitectural, network-level, and acoustic mechanisms. Together, these findings sketch emerging principles for a mechanistically grounded parameter framework for human LIFU neuromodulation