A Matter of Parameters: Tailored Transcranial Focused Ultrasound Enhances Cortico-Thalamo-Cortical Circuit Resonance

Transcranial focused ultrasound (tFUS) is an emerging neuromodulation tool, set apart from other stimulation techniques by its capacity for noninvasive, reversible neuromodulation with millimeter-scale precision. It can exert both excitatory and inhibitory effects by targeting specific cell types across different regions of the brain (Rabut et al., 2020). While the exact mechanism of action remains uncertain, ultrasound may interact with neural tissue through three biophysical processes: thermal effects, cavitation, and mechanical perturbations (Nandi et al., 2025). Although ultrasound absorption can generate local tissue heating; neuromodulation paradigms are designed to limit temperature elevation to avoid tissue damage and measured increases are typically minimal (Yoo et al., 2022). As a result, thermal effects are unlikely to explain the reversible neural modulation observed in most studies. Cavitation results from formation and movement of gas bubbles from endogenous dissolved gases or injected microbubbles. The most energetic form, inertial cavitation, involves rapid bubble growth and collapse that releases large amounts of energy and can damage tissue. Because inertial cavitation is intentionally avoided under neuromodulation conditions, it has not been linked to reversible neural excitation within commonly used parameter ranges (Yoo et al., 2022; Nandi et al., 2025). Therefore, mechanical interactions are considered the most plausible mechanism for reversible neuromodulation. These effects arise primarily through acoustic pressure-driven particle displacement and acoustic radiation force (ARF), which generate shear strains that deform cellular structures and perturb the neural membrane (Nandi et al., 2025). Such membrane deformations activate mechanosensitive channels; ion channels whose gating is controlled by mechanical forces. In the nervous system, several mechanosensitive channel families have been identified including PIEZO, TREK, and TRP channels (Yoo et al., 2022; Sorum et al., 2024). Activation of these channels alters ionic fluxes across the membrane, leading to calcium transients and ultimately modulation of neural activity. Ultrasound–neural interactions are … Correspondence should be addressed to Ugur Kilic at ugurkilic{at}arizona.edu.