Transcranial ultrasound neuromodulation of a human white matter tract
Dylan Curtin, Juhi Walinjkar, Elsa F. Fouragnan, Joshua J. Hendrikse, James P. Coxon
2025 · 10.1101/2025.11.10.687582
Abstract
Non-invasive methods to causally modulate human white matter tracts have proved elusive. In vitro and in vivo studies indicate that myelinated axons are sensitive to mechanical perturbations from ultrasound, providing a mechanistic rationale for targeting white matter tracts with ultrasound neuromodulation. Here, we demonstrate that transcranial ultrasound stimulation (TUS) targeted at the human corticospinal tract induces site-specific changes in motor neurophysiology. In a within-subject study, 15 healthy adults received 5 Hz repetitive TUS targeted at the left corticospinal tract at the level of the superior internal capsule. The homologous tract in the opposite hemisphere and the ipsilateral motor cortex were targeted as comparison conditions to confirm site specificity. Left corticospinal tract TUS increased corticomotor excitability and intracortical facilitation, whereas left motor cortex TUS reduced intracortical inhibition. Supporting analysis using diffusion tractography indicated that the magnitude of these changes depended jointly on ultrasound pressure and white matter microstructure (fractional anisotropy). These findings provide causal evidence that ultrasound can modulate white matter neurophysiology and establish TUS as a tool for non-invasive neuromodulation of white matter tracts in health and disorders of white matter. Significance statement White matter pathways are central to brain function and disease, yet causal tools to modulate these tracts in humans are lacking. We show that neuronavigated, low-intensity transcranial ultrasound targeted to the corticospinal white matter tract induces site-specific changes in motor neurophysiology. Supporting analyses using diffusion MRI tractography indicated that individual responses depended jointly on ultrasound pressure and local tissue properties, supporting an anatomy-informed, precision approach. These findings establish tract-targeted ultrasound as a non-invasive way to modulate human white matter neurophysiology, opening new opportunities for mechanistic tests of brain circuits and for developing circuit-guided interventions in neurological and psychiatric disorders.
Abstract via europepmc.
Exposures
Exposure 1: Left corticospinal tract (PLIC)
Target: corticospinal tract, internal capsule — “left corticospinal tract at the level of the superior internal capsule”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · NeuroFUS TPO with CTX-500-101 four-element annular transducer ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 20 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 5 | ✓✓✓ |
| Duty cycle (%) | 10pulse duration × PRF gives 10% | ✓✓✓ |
| Sonication duration (s) | 80 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 20 | ✓✓✓ |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | simulationmean or range across subjects | |
| In-situ pressure (kPa) | 490 | ✓✓✓⚑ |
| In-situ Isppa (W/cm²) | 8.08 | ✓✓✓ |
| In-situ Ispta (W/cm²) | not reported |
5 Hz repetitive TUS, 20 ms pulses every 200 ms (400 pulses), 80 s, once per session; TMS measures at baseline and 5, 20, 35 and 50 min after sonication.
Exposure 2: Left M1 hand area
Target: primary motor cortex — “left M1 hand area”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · NeuroFUS TPO with CTX-500-101 four-element annular transducer ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 20 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 5 | ✓✓✓ |
| Duty cycle (%) | 10pulse duration × PRF gives 10% | ✓✓✓ |
| Sonication duration (s) | 80 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 20 | ✓✓✓ |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | simulationmean or range across subjects | |
| In-situ pressure (kPa) | 410 | ✓✓✓ |
| In-situ Isppa (W/cm²) | 5.55 | ✓✓✓ |
| In-situ Ispta (W/cm²) | not reported |
5 Hz repetitive TUS, 20 ms pulses every 200 ms (400 pulses), 80 s, once per session; TMS measures at baseline and 5, 20, 35 and 50 min after sonication.
Exposure 3: Right corticospinal tract (PLIC)
Target: corticospinal tract, internal capsule — “contralateral (right) CST”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · NeuroFUS TPO with CTX-500-101 four-element annular transducer ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 20 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 5 | ✓✓✓ |
| Duty cycle (%) | 10pulse duration × PRF gives 10% | ✓✓✓ |
| Sonication duration (s) | 80 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 20 | ✓✓✓ |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | simulationmean or range across subjects | |
| In-situ pressure (kPa) | 520 | ✓✓✓ |
| In-situ Isppa (W/cm²) | 9.08 | ✓✓✓ |
| In-situ Ispta (W/cm²) | not reported |
5 Hz repetitive TUS, 20 ms pulses every 200 ms (400 pulses), 80 s, once per session; TMS measures at baseline and 5, 20, 35 and 50 min after sonication.
Flags from extraction
n_subjects— 18 recruited, 15 analysed; right CST session attended by only 10 of the 15; one non-analysed participant completed one TUS-TMS session.n_sessions_per_subject— Up to three TUS sessions (left CST, left M1, right CST); not stated as a single number and the right CST session was done by 10 participants.randomised— Left CST and left M1 order pseudo-randomised and counterbalanced; right CST always last.sham_type— No sham; active comparison sites (contralateral CST, ipsilateral M1) used.exposures[0].in_situ.pressure_kpa— Table 1 mean values from per-participant k-Wave simulation (pseudo-CT skull, not validated); SD in quote. Same for all in_situ values.exposures[0].timing.waveform— Called 5 Hz repetitive TUS, not theta burst.