Dose-Dependent Effects of Low-Intensity Focused Ultrasound on Human Deep White Matter Tracts
Aki Tsuchiyagaito, Masaya Misaki, Xi Ren, Danielle Clark, Adrienne Taren, Chieh V. Chen, Maria Ironside, Mirta F. Villarreal, Rayus Kuplicki, Sanjay Mathew, Martin Paulus, Noah S. Philip, Salvador M. Guinjoan
2026 · 10.64898/2026.09.02.748985
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/cm 2 , 0.5 MHz, in a θ-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, ηp² = 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.
Abstract via europepmc.
Exposures
Exposure 1: 1-LIFU and 3-LIFU to right thalamo-prefrontal white matter tracts
Target: white matter — “individually modeled right thalamo-prefrontal white matter tracts”
Device: not reported
| Waveform | theta burst | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 20 | ✓✓✓ |
| Pulse repetition frequency (Hz) | not reported | ⚑ |
| Duty cycle (%) | 10 | ✓✓✓ |
| Sonication duration (s) | 80 | ✓✓✓⚑ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 9.06 | ✓✓✓ |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reportedsingle value | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | 2.26 | ✓✓✓ |
| In-situ Ispta (W/cm²) | not reported |
Theta-burst pattern of 400 20-ms pulses delivered every 180 ms, 10% duty cycle, 80 s total. 1-LIFU = one epoch; 3-LIFU = three consecutive epochs separated by two 30-s intervals.
Flags from extraction
n_subjects— 35 enrolled; 31 participants and 80 sessions analysed; enrolled number givenexposures[0].timing.pulse_repetition_frequency_hz— Text says 400 20-ms pulses every 180 ms with 10% duty cycle and 80 s; no PRF stated and the arithmetic does not close, so not recordedexposures[0].in_situ.method— Tissue-level estimate of 2.26 W/cm2 given without saying how it was obtainedexposures[0].device— No transducer or system named in the main textexposures[0].timing.sonication_duration_s— One 80 s sonication per epoch; 1-LIFU = one epoch, 3-LIFU = three epochs separated by 30 ssham_type— No sham; comparison is one versus three sonications plus a no-LIFU baseline visit