Combined continuous theta burst transcranial ultrasound and magnetic stimulation for induction of cortical plasticity

BACKGROUND: Magnetic continuous theta burst stimulation (cTBS) is known to suppress human motor cortical excitability. Whether transcranial ultrasound stimulation (TUS) delivered in a continuous theta burst pattern (ctbTUS) produces similar inhibitory effects and whether co-applying ctbTUS with cTBS enhances these effects remains unclear. METHODS: Four stimulation conditions: ctbTUS + sham cTBS (ctbTUS), sham ctbTUS + cTBS (cTBS), sham ctbTUS + sham cTBS (sham), and ctbTUS + cTBS (cosTBS) were applied. Fifteen participants underwent neurophysiological testing with motor-evoked potentials (MEPs) recorded at 0, 10, 20, and 60 minutes post-stimulation, normalized to pre-intervention baselines. Additionally, 18 participants underwent resting-state functional MRI (rsfMRI) to assess functional connectivity (FC) between the hand representation of the motor cortex (M1) and other brain regions. Simulated skull density, transducer-skull space, and online-inhibition characteristics were evaluated as modulatory factors. RESULTS: ctbTUS induced inhibitory after-effects measured by MEP amplitude lasting up to 60 minutes (p=0.001). However, cosTBS reduced this inhibition, although immediate MEP suppression remained (p=0.024). rsfMRI revealed reduced FC between M1 and bilateral pre/post-central gyri and increased cerebellar FC after ctbTUS, but such after-stimulation patterns were absent after cosTBS. Higher pseudo-computed-tomography-derived skull density was associated with more negative ΔFC (or FC suppression, β = -0.844, p = 0.004). Participants with online inhibition showed greater offline MEP suppression (p=0.004). CONCLUSIONS: ctbTUS induced inhibitory after-effects lasting up to 60 minutes but cosTBS decreased this suppression, likely via calcium-dependent plasticity or homeostatic plasticity effects. Skull density, and individual sensitivity to TUS are critical factors influencing TUS efficacy.