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

Kai-Hsiang Stanley Chen, Yih-Chih Jacinta Kuo, Wei-Chih Yang, Jean-François Nankoo, Yan-Siou Dong, Hsin-Yun Chang, Hao-Li Liu, Yao-Chia Shih, Gin-Shin Chen, Robert Chen

NeuroImage 2026, 338, 122067 · 10.1016/j.neuroimage.2026.122067

human healthyhealthyemg mepfmri

Abstract

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 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. Results 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). Conclusions 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.

Abstract via europepmc.

Specieshuman

Subjects15, 18swept participants

Sessions per subject4

Randomisedyes

Blindingsingle

Sham / controlinactive transducer

Auditory controlnone

Readout timingoffline

Anaesthesianot applicable

Readoutsemg mep, fmri — Motor evoked potentials (MEP) from right first dorsal interosseous muscle; resting-state fMRI functional connectivity of the left M1 hand representation

Direction of effectinhibitoryctbTUS alone produced significant MEP suppression lasting up to 60 min and reduced left M1-hand-based functional connectivity with bilateral pre-/post-central gyri (with increased cerebellar connectivity); co-delivering ctbTUS with cTBS (cosTBS) produced only an immediate (0 min) MEP suppression and abolished the sustained inhibitory after-effect and the FC changes.

Adverse eventsnone observedAll participants who completed the stimulation or rsfMRI studies did not report any adverse effects, and none reported hearing sounds or tactile sensation other than those produced by the TMS coil.

Exposures

Exposure 1: Continuous theta burst TUS (ctbTUS) to left M1 hand representation

Target: primary motor cortex — “hand representation of the primary motor cortex (M1), FDI motor hotspot”
Device: Sonic Concepts · Sonic Concepts Inc, Bothell, Washington · H246 ✓

Pulse timing
Waveform	theta burst
Fundamental frequency (kHz)	500	✓✓✓
Pulse duration (ms)	40	✓✓✓
Pulse repetition frequency (Hz)	5	✓✓✓
Duty cycle (%)	20pulse duration × PRF gives 20%	✓✓✓
Sonication duration (s)	40	✓✓✓

Pressure and intensity, by domain
Free-field pressure (kPa)	612	✓✓✓
Free-field Isppa (W/cm²)	not reported	⚑
Free-field Ispta (W/cm²)	not reported
In-situ estimate	deratingsingle value
In-situ pressure (kPa)	183.6	✓✓✓
In-situ Isppa (W/cm²)	0.84	✓✓✓
In-situ Ispta (W/cm²)	0.17	✓✓✓
Isppa, domain unspecified (W/cm²)	20	✓✓✓

Protocol, in the paper’s words

The parameters of ctbTUS were 5 Hz pulse repetition frequency, 40 ms burst duration equal to 20% duty cycle and 40 s sonication duration. For the sham ctbTUS, the power output was set to 0 W. Four conditions (ctbTUS, cTBS, cosTBS, sham) were tested in random order, counterbalanced among participants, with each paradigm at least one week apart; MEPs were recorded at baseline and 0, 10, 20 and 60 min after each stimulation paradigm. A separate online-inhibition responder test used a different TUS protocol (1000 Hz pulse repetition frequency, 30% duty cycle, 500 ms sonication duration, with a single TMS test pulse delivered at 490 ms) to classify participants as with (OI+) or without (OI-) online inhibition.

Flags from extraction

n_subjects — Neurophysiological (n=15) and rsfMRI (n=18) cohorts overlapped by 6 participants; the paper never states a combined unique total, so group sizes are listed rather than summed.
exposures[0].free_field.isppa_w_cm2 — The '20 W/cm2' value is described as 'shown on the TPO panel' (amplifier output setting) rather than an explicitly labelled measured free-field Isppa; recorded as stated.
exposures[0].timing.protocol_description — A second TUS protocol (1000 Hz PRF, 30% duty cycle, 500 ms sonication) was used only for an online-inhibition responder test, not for the main ctbTUS after-effect measurements; its parameters are given in protocol_description rather than the numeric timing fields to avoid conflating two different stimulation protocols on the same target/frequency.