Sustained reduction of essential tremor with low-power non-thermal transcranial focused ultrasound stimulations in humans
Thomas Bancel, Benoît Béranger, Maxime Daniel, Mélanie Didier, Mathieu Santin, Itay Rachmilevitch, Yeruham Shapira, Mickael Tanter, Eric Bardinet, Sara Fernandez Vidal, David Attali, Cécile Galléa, Alexandre Dizeux, Marie Vidailhet, Stéphane Lehéricy, David Grabli, Nadya Pyatigorskaya, Carine Karachi, Elodie Hainque, Jean-François Aubry
Brain Stimulation 2024, 17, 636-647 · 10.1016/j.brs.2024.05.003
Abstract
Background Transcranial ultrasound stimulation (TUS) is a non-invasive brain stimulation technique; when skull aberrations are compensated for, this technique allows, with millimetric accuracy, circumvention of the invasive surgical procedure associated with deep brain stimulation (DBS) and the limited spatial specificity of transcranial magnetic stimulation. Objective /hypothesis: We hypothesize that MR-guided low-power TUS can induce a sustained decrease of tremor power in patients suffering from medically refractive essential tremor. Methods The dominant hand only was targeted, and two anatomical sites were sonicated in this exploratory study: the ventral intermediate nucleus of the thalamus (VIM) and the dentato-rubro-thalamic tract (DRT). Patients (N = 9) were equipped with MR-compatible accelerometers attached to their hands to monitor their tremor in real-time during TUS. Results VIM neurostimulations followed by a low-duty cycle (5 %) DRT stimulation induced a substantial decrease in the tremor power in four patients, with a minimum of 89.9 % reduction when compared with the baseline power a few minutes after the DRT stimulation. The only patient stimulated in the VIM only and with a low duty cycle (5 %) also experienced a sustained reduction of the tremor (up to 93.4 %). Four patients (N = 4) did not respond. The temperature at target was 37.2 ± 1.4 °C compared to 36.8 ± 1.4 °C for a 3 cm away control point. Conclusions MR-guided low power TUS can induce a substantial and sustained decrease of tremor power. Follow-up studies need to be conducted to reproduce the effect and better to understand the variability of the response amongst patients. MR thermometry during neurostimulations showed no significant thermal rise, supporting a mechanical effect.
Abstract via europepmc.
Exposures
Exposure 1: VIM neuromodulation
Target: ventral intermediate nucleus — “ventral intermediate nucleus of the thalamus (VIM)”
Device: Insightec · Insightec · Exablate Neuro ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 650 | ✓✓✓ |
| Pulse duration (ms) | 30, 2swept | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 10, 167, 25swept | ✓✓✓ |
| Duty cycle (%) | 30, 33.4, 5swept | ✓✓✓ |
| Sonication duration (s) | 5swept | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reportedsingle value | |
| In-situ pressure (kPa) | 800 | ✓✓✓⚑ |
| In-situ Isppa (W/cm²) | 19.8 | ✓✓✓ |
| In-situ Ispta (W/cm²) | 0.4, 2.6, 2.8swept | ✓✓✓ |
Four sonication patterns (modes 1-4) were tested; all lasted 35 s (three 5 s bursts followed by a 10 s off period), except Mode 4 (9-point 1.5x1.5 mm grid, total 54 s, 1 s pulse trains repeated every 9 s). Modes 1 and 2 achieved a high duty cycle (one-third) via a long-duration/low-PRF or short-duration/high-PRF burst respectively; Modes 3 and 4 used a low duty cycle (5%). For VIM, patients typically received modes 1, 2 and 3 in sequence; each pulse lasted less than 30 ms.
Exposure 2: DRT neuromodulation
Target: dentatorubrothalamic tract — “dentato-rubro-thalamic tract (DRT)”
Device: Insightec · Insightec · Exablate Neuro ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 650 | ✓✓✓ |
| Pulse duration (ms) | 2swept | ✓✓✓ |
| Pulse repetition frequency (Hz) | 25swept | ✓✓✓ |
| Duty cycle (%) | 5swept | ✓✓✓ |
| Sonication duration (s) | 5, 1swept | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reportedsingle value | |
| In-situ pressure (kPa) | 800 | ✓✓✓⚑ |
| In-situ Isppa (W/cm²) | 19.8 | ✓✓✓ |
| In-situ Ispta (W/cm²) | 0.4, 0.1swept | ✓✓✓ |
DRT was stimulated using the low duty cycle (5%) mode 3 (35 s total: three 5 s bursts + 10 s off) and, in some patients, mode 4 (a 9-point 1.5x1.5 mm grid around the target, 1 s pulse trains per point, total 54 s). Patients typically moved from VIM stimulation (modes 1-3) to DRT stimulation with mode 3, then mode 4 to cover a larger zone.
Flags from extraction
exposures[0].in_situ.pressure_kpa— Table 3 reports per-sonication pressure (~0.17-0.99 MPa) and ISPTA (~0.02-2.8 W/cm2) values that vary across patients and sonication modes; only the main-text representative value (~0.8 MPa / 19.8 W/cm2 ISPPA) used for the standard high-power sonications is captured here.exposures[1].in_situ.pressure_kpa— Table 3 reports per-sonication pressure (~0.79-0.99 MPa) and ISPTA (~0.1-0.7 W/cm2) values for DRT sonications that vary across patients; only the main-text representative value is captured here.exposures[0].in_situ.method— The paper states the pressure was 'adjusted to produce' a target value inside the brain via the Insightec system but does not explicitly state whether this in-situ value is from simulation, derating, or measurement in the main text.n_sessions_per_subject— Not explicitly stated as a number; all sonications occurred in a single visit immediately before thalamotomy, but the paper does not give an explicit session count.exposures[0].timing.pulse_duration_ms— Values taken from Table 1 (sonication modes 1-3), which is a large flattened HTML table; quoted as the full table due to markdown flattening of the original multi-row table.