Immediate excitatory effect of transcranial ultrasound intensity on the human primary motor cortex: a double-blind, sham-controlled and crossover study.

OBJECTIVE: To systematically characterize the intensity-dependent effects of low-intensity transcranial ultrasound stimulation (TUS) on excitability in the human primary motor cortex (M1) and to identify an effective intensity threshold for inducing immediate excitatory changes. METHODS: In a randomized, double-blind, sham-controlled crossover design, twenty-five healthy right-handed adults (mean age, 24.0 ± 3.3 years) received 20 min of 500 kHz TUS to their M1 hotspot. Five sessions were conducted, each employing a different spatial peak pulse average intensity (ISPPA: 3, 6, 9, or 12 W/cm2 or sham stimulation in the free-field). Corticospinal and intracortical excitability were assessed immediately before and after sonication using single and paired-pulse transcranial magnetic stimulation (TMS) protocols to measure motor-evoked potential (MEP) amplitudes, short and long-interval intracortical inhibition (SICI/LICI), intracortical facilitation (ICF), and cortical silent period (cSP). RESULTS: A clear intensity-dependent effect was observed. Only sonication at 12 W/cm2 significantly increased MEP amplitudes (p = 0.036), indicating enhanced corticospinal excitability. TUS also significantly shortened the cSP duration at intensities of 6 (p = 0.039), 9 (p = 0.036), and 12 (p = 0.003) W/cm2compared with pre-TUS. Notably, these changes occurred without any significant modulation of intracortical measures (SICI, LICI, and ICF) across all conditions. The observed excitatory effect was not correlated with baseline MEP amplitude or gender. CONCLUSION: Our findings demonstrate that TUS modulates human M1 excitability in a selective and intensity-dependent manner, identifying an ISPPA of 12 W/cm2 as a critical threshold for driving corticospinal potentiation. This provides a rational basis for parameter selection in future TUS protocols and advances its development as a precision tool for therapeutic applications in neurological disorders. CLINICAL TRIAL REGISTRATION: Identifier, ChiCTR2600125507.