Mechanisms of theta burst transcranial ultrasound induced plasticity in the human motor cortex
Yazan Shamli Oghli, Talyta Grippe, Tarun Arora, Tasnuva Hoque, Ghazaleh Darmani, Robert Chen
Brain Stimulation 2023, 16, 1135-1143 · 10.1016/j.brs.2023.07.056
Abstract
Background Transcranial ultrasound stimulation (TUS) is a novel non-invasive brain stimulation technique with high depth penetrance and spatial resolution. Theta-burst TUS (tbTUS) is a plasticity-inducing protocol which increases motor cortical excitability for up to 30 min following 80s of sonication. While this protocol may have therapeutic potential for the treatment of psychiatric and neurological disorders, the mechanisms of action of TUS remain unclear. Objective We conducted the first pharmacological study to examine the mechanisms of TUS in human primary motor cortex. By administering brain-active drugs with known mechanisms of action, we aimed to elucidate the mechanisms of tbTUS. Methods Fourteen healthy subjects participated in a within-subjects randomized, double-blind, cross-over study with five visits. At each visit, one of four study drugs (carbamazepine - Na + channel blocker, nimodipine - L-type Ca 2+ channel blocker, lorazepam - positive allosteric modulator of gamma-aminobutyric acid (GABA) type A receptor, dextromethorphan - N-methyl-d-aspartate receptor antagonist) or placebo was administered in random order, followed by tbTUS. Results The plasticity effects of tbTUS on motor cortex excitability measured by motor-evoked potential amplitudes elicited by transcranial magnetic stimulation were reduced by all study drugs compared to placebo. Conclusion tbTUS may induce NMDA-dependent synaptic plasticity since the effects are blocked by increased GABA A receptor activities and voltage-gated Na + and Ca 2+ channels blockers. These results are consistent with the hypotheses that tbTUS induced long-term potentiation-like mechanisms and that TUS involves activation of mechanosensitive Na + and Ca 2+ channels. Alternatively, non-specific pharmacologically induced changes in excitatory/inhibitory balance might have interfered with the effects of tbTUS.
Abstract via europepmc.
Exposures
Exposure 1: theta-burst TUS (tbTUS) to left M1
Target: primary motor cortex — “left M1 (FDI hotspot)”
Device: Sonic Concepts · Sonic Concepts Inc. · custom 2-channel annular array transducer ✓
| Waveform | theta 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 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 11.73 | ✓✓✓ |
| Free-field Ispta (W/cm²) | 1.17 | ✓✓✓ |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | 2.93 | ✓✓✓ |
| In-situ Ispta (W/cm²) | 0.29 | ✓✓✓ |
As with Zeng et al. [7], an 80s sonication with tone burst duration of 20 ms, 5Hz PRF, 10% duty cycle and 20W intensity was delivered. Sonication depth was set to 30 mm to approximate the scalp-to-cortex distance of the M1. One tbTUS delivery occurred per visit, after a 2.5 h drug/placebo wait period, at each of five study visits.
Flags from extraction
n_subjects— 16 subjects enrolled; 2 dropped out after visit 1 and are excluded from most analyses (14 analysed for most drugs, 13 for LRZ/DXT). n_subjects reported here is the enrolled total.exposures[0].timing.pulse_duration_ms— Paper calls this a 'tone burst duration' of 20 ms within an 80 s train; consistent with duty cycle (10%) / PRF (5 Hz) = 20 ms, so no arithmetic conflict, but confirming burst-rule resolution here for transparency.sham_type— Study tested drug x tbTUS only; no sham/control tbTUS condition was included (explicitly noted as a limitation).