Investigation of Metaplasticity Associated with Transcranial Focused Ultrasound Neuromodulation in Humans
Mandy Yi Rong Ding, Tarun Arora, Can Sarica, Andrew Z. Yang, Negar Nasrkhani, Talyta Grippe, Jean-François Nankoo, Stephanie Tran, Nardin Samuel, Xue Xia, Andres M. Lozano, Robert Chen
The Journal of Neuroscience 2024, 44, e2438232024 · 10.1523/jneurosci.2438-23.2024
Abstract
Low-intensity transcranial focused ultrasound stimulation (TUS) is a novel technique for noninvasive brain stimulation (NIBS). TUS delivered in a theta (5 Hz) burst pattern (tbTUS) induces plasticity in the human primary motor cortex (M1) for 30-60 min, showing promise for therapeutic development. Metaplasticity refers to activity-dependent changes in neural functions governing synaptic plasticity; depotentiation is the reversal of long-term potentiation (LTP) by a subsequent protocol with no effect alone. Metaplasticity can enhance plasticity induction and clinical efficacy of NIBS protocols. In our study, we compared four NIBS protocol combinations to investigate metaplasticity on tbTUS in humans of either sex. We delivered four interventions: (1) sham continuous theta burst stimulation with 150 pulses (cTBS150) followed by real tbTUS (tbTUS only), (2) real cTBS150 followed by sham tbTUS (cTBS only), (3) real cTBS150 followed by real tbTUS (metaplasticity), and (4) real tbTUS followed by real cTBS150 (depotentiation). We measured motor-evoked potential amplitude, short-interval intracortical inhibition, long-interval intracortical inhibition, intracortical facilitation (ICF), and short-interval intracortical facilitation before and up to 90 min after plasticity intervention. Plasticity effects lasted at least 60 min longer when tbTUS was primed with cTBS150 compared with tbTUS alone. Plasticity was abolished when cTBS150 was delivered after tbTUS. cTBS150 alone had no significant effect. No changes in M1 intracortical circuits were observed. Plasticity induction by tbTUS can be modified in manners consistent with homeostatic metaplasticity and depotentiation. This substantiates evidence that tbTUS induces LTP-like processes and suggests that metaplasticity can be harnessed in the therapeutic development of TUS.
Abstract via europepmc.
Exposures
Exposure 1: tbTUS to left M1 (hand motor hotspot)
Target: primary motor cortex — “left primary motor cortex (M1) hand motor hotspot (FDI representation)”
Device: Sonic Concepts · Sonic Concepts · H246 (custom two-element annular array) ✓
| 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) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | simulationsingle value | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | 1.69 | ✓✓✓ |
| In-situ Ispta (W/cm²) | 0.17 | ✓✓✓ |
The tbTUS paradigm consisted of an 80 s train of pulses with a pulse repetition frequency (PFR) of 5 Hz, pulse duration of 20 ms delivered every 200 ms (5 Hz), and duty cycle of 10%, for a total number of 400 pulses. Sham tbTUS delivered the same theta burst pattern, but the transducer was flipped so that the active face of the transducer was directed away from the head.
Flags from extraction
blinding— Paper states experimenters were not blinded (limitation), while participants received sham via flipped transducer; classified as single-blind.adverse_events— No systematic adverse-event assessment reported; only subjective post-session questioning about sensations described.