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

Tsuchiyagaito, A.; Misaki, M.; Ren, X.; Clark, D.; Taren, A.; Chen, C.; Ironside, M.; Villarreal, M. F.; Kuplicki, R.; Mathew, S.; Paulus, M. P.; Philips, N.; Guinjoan, S. M.

doi:10.64898/2026.09.02.748985

bioRxiv · 10.64898/2026.09.02.748985

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

Tsuchiyagaito, A.·Misaki, M.·Ren, X.·Clark, D.·Taren, A.·Chen, C.·Ironside, M.·Villarreal, M. F.·Kuplicki, R.·Mathew, S.·Paulus, M. P.·Philips, N.·Guinjoan, S. M.

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Abstract

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.

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Tsuchiyagaito, A., Misaki, M., Ren, X., Clark, D., Taren, A., Chen, C., Ironside, M., Villarreal, M. F., Kuplicki, R., Mathew, S., Paulus, M. P., Philips, N., Guinjoan, S. M.. 2026-09-08. Dose-Dependent Effects of Low-Intensity Focused Ultrasound on Human Deep White Matter Tracts. https://doi.org/10.64898/2026.09.02.748985

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