Spinal cord ultrasound stimulation modulates corticospinal excitability in humans.

Low-intensity focused ultrasound offers deep tissue penetration and holds promise as a noninvasive tool for neuromodulating brain circuits. However, its effects on neural activity within the human spinal cord remain largely unexplored. To investigate the effects of spinal cord ultrasound stimulation (SCUS) on corticospinal excitability by varying acoustic parameters: spatial-peak pulse-average intensity (I_SPPA), duty cycle (DC), and pulse repetition frequency (PRF). Two experiments were conducted involving 62 healthy adult participants. In Experiment 1 (N = 36), participants were randomly assigned to either a low-intensity group (2.5 W/cm², N = 18) or a relatively high-intensity group (10 W/cm², N = 18) to examine parameter-dependent SCUS effects. SCUS was delivered as a 500 ms pulse train to the C8 spinal cord segment using two DCs (10 % and 30 %) and two PRFs (500 and 1000 Hz). Stimulation was applied concurrently with posterior-anterior (PA) oriented transcranial magnetic stimulation (TMS) over the left primary motor cortex (M1), and motor-evoked potentials (MEPs) were recorded from the right first dorsal interosseous (FDI) muscle. Active and sham SCUS trials were interleaved and compared. In Experiment 2 (N = 26), the specificity of SCUS effects was assessed in relation to TMS coil orientation and target muscle using the sonication parameter set of 10 W/cm² I_SPPA, 1000 Hz PRF, and 30 % DC. MEPs from the FDI were recorded using anterior-posterior (AP) and latero-medial (LM) coil orientations, while MEPs from the abductor digiti minimi (ADM) muscle were assessed using PA, AP, and LM orientations. MEPs were also recorded from the biceps brachii with PA orientation. Active and sham SCUS conditions were interleaved and compared. SCUS significantly suppressed MEP amplitudes compared to sham stimulation under relatively high-intensity (10 W/cm²), high-PRF (1000 Hz) conditions, regardless of DC. No significant effects were observed at lower intensity (2.5 W/cm²) or lower PRF (500 Hz). Follow-up experiments confirmed consistent inhibitory effects across multiple TMS coil orientations (PA, AP, LM) and in C8-innervated hand muscles (FDI and ADM), with no significant modulation observed in the more rostrally innervated biceps brachii muscle, supporting the specificity of C8-targeted SCUS. These findings demonstrate that SCUS can modulate corticospinal excitability in a parameter-specific manner, with suppression observed primarily under relatively high-intensity and high-PRF conditions. SCUS represents a promising noninvasive technique for targeted neuromodulation of spinal neural circuits in humans.