Transcranial ultrasound neuromodulation of a human white matter tract

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 statementWhite 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.