Understanding the high-order network plasticity mechanisms of ultrasound neuromodulation

Transcranial ultrasound stimulation (TUS) is an emerging non-invasive neuromodulation technique, offering a potential alternative to pharmacological treatments for psychiatric and neurological disorders. While functional analysis has been instrumental in characterizing TUS effects, understanding the underlying mechanisms remains a challenge. Here, we developed a whole-brain model to represent functional changes as measured by fMRI, enabling us to investigate how TUS-induced effects propagate throughout the brain with increasing stimulus intensity. We implemented two mechanisms: one based on anatomical distance and another on broadcasting dynamics, to explore plasticity-driven changes in specific brain regions. Finally, we highlighted the role of higher-order functional interactions in localizing spatial effects of off-line TUS at two target areas--the right thalamus and inferior frontal cortex--revealing distinct patterns of functional reorganization. This work lays the foundation for mechanistic insights and predictive models of TUS, advancing its potential clinical applications. Significance StatementTranscranial ultrasound stimulation (TUS) offers a non-invasive approach to modulating brain activity, holding promise for treating psychiatric and neurological disorders. Despite its potential, the mechanisms underlying its effects remain poorly understood. By integrating human fMRI data with whole-brain computational models, we identified how high-order functional interactions localize and propagate TUS-induced effects from local to global brain scales. This work introduces two mechanisms--distance-based propagation and diffusion-like broadcasting--that predict functional plasticity changes, providing a foundation for understanding and optimizing the biological and cognitive outcomes of TUS. Our findings offer critical insights into the dynamics of neuromodulation, bridging experimental results and clinical applications.