Dose-Dependent Effects of Low-Intensity Focused Ultrasound on Human Deep White Matter Tracts

Background: Low-intensity focused ultrasound (LIFU) is emerging as a method for anatomically specific, noninvasive, and reversible neuromodulation of deep brain structures relevant to psychopathology. A key requirement for clinical translation is evidence of graded target engagement. We examined whether LIFU applied to deep white matter tracts produces dose-dependent functional connectivity changes in healthy adults. Methods: In this preregistered, double-blind, randomized study, 35 healthy adults underwent LIFU targeting (80 s, 10% duty cycle, estimated ISPPA 2.26 W/cm2, 0.5 MHz, in a {theta}-burst pattern) of individually modeled right thalamo-prefrontal white matter tracts under two dose conditions: one and three consecutive sonications. Dose-dependent changes in resting-state functional connectivity were examined during a 30-minute poststimulation period in 31 participants. Results: One sonication acutely increased right thalamic functional connectivity with the left thalamus (28 voxels; Z = 5.48, Cohen's d = 0.61), whereas three sonications decreased connectivity with the right dorsolateral prefrontal cortex (Z = -4.05, Cohen's d = -0.45). Poststimulation time-course analysis revealed a 3-LIFU-specific linear recovery trend in the left cerebellum (Z = 4.14, d = 0.48), reflecting initial suppression followed by progressive recovery across 30 minutes. Stronger thalamo-prefrontal structural connectivity was associated with condition-specific functional connectivity changes (left frontal pole; F = 14.73, {rho}2 = 0.41). Conclusions: These findings provide initial human evidence that LIFU is well tolerated and produces dose-dependent changes in functional connectivity associated with deep white matter tract stimulation, informing parameter selection for future circuit-based mechanistic and clinical studies.