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

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.

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 min 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.

ctbTUS induced inhibitory after-effects measured by MEP amplitude lasting up to 60 min (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).

ctbTUS induced inhibitory after-effects lasting up to 60 min 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.