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Induction of Human Motor Cortex Plasticity by Theta Burst Transcranial Ultrasound Stimulation

Ke Zeng, Ghazaleh Darmani, Anton Fomenko, Xue Xia, Stephanie Tran, Jean‐François Nankoo, Yazan Shamli Oghli, Yanqiu Wang, Andres M. Lozano, Robert Chen

Annals of Neurology 2022, 91, 238-252 · 10.1002/ana.26294

human healthyhealthyemg mepbehaviour

Abstract

Objective Transcranial ultrasound stimulation (TUS) is a promising noninvasive brain stimulation technique with advantages of high spatial precision and ability to target deep brain regions. This study aimed to develop a TUS protocol to effectively induce brain plasticity in human subjects. Methods An 80-second train of theta burst patterned TUS (tbTUS), regularly patterned TUS (rTUS) with the same sonication duration, and sham tbTUS was delivered to the motor cortex in healthy subjects. Transcranial magnetic stimulation (TMS) was used to examine changes in corticospinal excitability, intracortical inhibition and facilitation, and the site of plasticity induction. The effects of motor cortical tbTUS on a visuomotor task and the effects of occipital cortex tbTUS on motor cortical excitability were also tested. Results The tbTUS produced consistent increase in corticospinal excitability for at least 30 minutes, whereas rTUS and sham tbTUS produced no significant change. tbTUS decreased short-interval intracortical inhibition and increased intracortical facilitation. The effects of TMS in different current directions suggested that the site of the plastic changes was within the motor cortex. tbTUS to the occipital cortex did not change motor cortical excitability. Motor cortical tbTUS shortened movement time in a visuomotor task. Interpretation tbTUS is a novel and efficient paradigm to induce cortical plasticity in humans. It has the potential to be developed for neuromodulation treatment for neurological and psychiatric disorders, and to advance neuroscience research. ANN NEUROL 2022;91:238-252.

Abstract via europepmc.

Specieshuman
Subjects20 participants
Sessions per subjectnot reported
Randomisedyes
Blindingnot reported
Sham / controlinactive transducer
Auditory controlmasking sound
Readout timingoffline
Anaesthesianot applicable
Readoutsemg mep, behaviourTMS-elicited motor-evoked potentials (MEP amplitude, resting motor threshold, MEP recruitment curve, short-interval intracortical inhibition, intracortical facilitation); visuomotor tracking task (reaction time, movement time, accuracy)
Direction of effectexcitatorytbTUS to motor cortex increased MEP amplitude and recruitment-curve slope, decreased SICI and increased ICF for 30-60 minutes; rTUS, sham tbTUS, and tbTUS to occipital cortex produced no significant change in motor cortical excitability.
Adverse eventsnone observedNo subjects reported any adverse effects throughout the experiments, supporting the safety profile of the current pulsing schemes.

Exposures

Exposure 1: Motor cortex tbTUS and rTUS (Experiment 2)

Target: primary motor cortex — “left motor cortex (hotspot of right FDI muscle representation)
Device: Sonic Concepts · Sonic Concepts · H246

Pulse timing
Waveformtheta_burst, pulsed
Fundamental frequency (kHz)500✓✓
Pulse duration (ms)20, 0.32swept✓✓
Pulse repetition frequency (Hz)5, 1,000swept✓✓
Duty cycle (%)10, 32swept✓✓
Sonication duration (s)80, 0.5swept✓✓
Pressure and intensity, by domain
Free-field pressure (kPa)not reported
Free-field Isppa (W/cm²)2.26✓✓
Free-field Ispta (W/cm²)0.23, 0.72swept✓✓
In-situ estimatenot reported
In-situ pressure (kPa)not reported
In-situ Isppa (W/cm²)not reported
In-situ Ispta (W/cm²)not reported
Protocol, in the paper’s words

tbTUS: 80-second train of 20-ms ultrasound bursts (0.5 MHz) repeated every 200 ms (PRF 5 Hz, duty cycle 10%, 400 bursts). rTUS: 500-ms pulsed sonications with 0.32-ms tone bursts at 1,000 Hz PRF (32% duty cycle) delivered every 1.6 s for a total protocol time of 80 s (50 sonications). Both paradigms delivered 8 s of cumulative active ultrasound ('total sonication duration') within an 80 s protocol time; Gaussian white noise was played through earphones throughout to mask the auditory stimulus from the transducer.

Exposure 2: Occipital cortex tbTUS (Experiment 3, active control site)

Target: occipital lobe — “left occipital cortex (O1 position of the international 10-20 electrode EEG system)
Device: Sonic Concepts · Sonic Concepts · H246

Pulse timing
Waveformtheta burst
Fundamental frequency (kHz)500✓✓
Pulse duration (ms)20✓✓
Pulse repetition frequency (Hz)5✓✓
Duty cycle (%)10pulse duration × PRF gives 10%✓✓
Sonication duration (s)80✓✓
Pressure and intensity, by domain
Free-field pressure (kPa)not reported
Free-field Isppa (W/cm²)2.26✓✓
Free-field Ispta (W/cm²)0.23✓✓
In-situ estimatenot reported
In-situ pressure (kPa)not reported
In-situ Isppa (W/cm²)not reported
In-situ Ispta (W/cm²)not reported
Protocol, in the paper’s words

tbTUS (80-s train of 20-ms bursts repeated every 200 ms, PRF 5 Hz, 10% duty cycle, 8 s cumulative sonication within an 80 s protocol) delivered to left occipital cortex (O1) as an active control for site-non-specific/auditory effects; protocol otherwise identical to Experiment 2.

Flags from extraction

  • exposures[0].timing.pulse_duration_msList value 0.32 ms (rTUS tone-burst duration) is drawn from a separate sentence describing rTUS ('...PRF of 1,000Hz and duty cycle of 32%...'/Fig 2 legend 'tone-burst duration (TBD) of 0.32 milliseconds'); the quoted source_quote here covers the tbTUS value (20 ms).
  • exposures[0].timing.pulse_repetition_frequency_hzList value 1000 Hz (rTUS PRF) is drawn from the sentence describing the rTUS paradigm, reproduced in protocol_description; the quoted source_quote here covers the tbTUS value (5 Hz).
  • exposures[0].timing.duty_cycle_pctList value 32% (rTUS duty cycle) is drawn from the sentence describing the rTUS paradigm, reproduced in protocol_description; the quoted source_quote here covers the tbTUS value (10%).
  • exposures[0].timing.sonication_duration_sPaper explicitly defines 'total sonication duration' as the cumulative active (on-time) duration (8 s), distinct from the 80 s total protocol/train duration used to describe the repeating burst pattern; both figures are reported in the text (see protocol_description).
  • exposures[1].target.termsOccipital control target is defined only as the O1 EEG electrode position; not further localized to a specific visual subregion (e.g. V1), so classified generically as occipital_lobe.
  • n_sessions_per_subjectSession count (3) reflects Experiment 2 (tbTUS/rTUS/sham tbTUS on separate days, at least 1 week apart, in the 15-subject subset); other sub-experiments (occipital control, coil-orientation, visuomotor task) enrolled overlapping subsets of the 20 subjects with different numbers of visits.
  • blindingSham tbTUS was implemented by flipping the transducer so its inactive face contacted the scalp, but the paper does not explicitly state whether participants and/or assessors were blinded to condition.

Notes: Two exposures represent the two distinct target x frequency conditions in the paper (motor cortex at 500 kHz [tbTUS+rTUS], and occipital cortex at 500 kHz [tbTUS]); sham tbTUS is not modelled as a separate exposure per instructions (captured via sham_type='inactive_transducer'). Experiment 1 (free-water acoustic field mapping) and Experiments 4-5 (coil-orientation, visuomotor task) provide supporting/mechanistic data on the same two exposures rather than new conditions.