Deep transcranial ultrasound stimulation using personalized acoustic metamaterials improves treatment-resistant depression in humans
David Attali, Thomas Tiennot, Thomas J. Manuel, Maxime Daniel, Alexandre Houdouin, Philippe Annic, Alexandre Dizeux, Alexandre Haroche, Ghita Dadi, Adèle Henensal, Mylène Moyal, Alice Le Berre, Cécile Paolillo, Sylvain Charron, Clément Debacker, Maliesse Lui, Sabrina Lekcir, Rosella Mancusi, Thierry Gallarda, Tarek Sharshar, Khaoussou Sylla, Catherine Oppenheim, Arnaud Cachia, Mickael Tanter, Jean-Francois Aubry, Marion Plaze
Brain Stimulation 2025, 18, 1004-1014 · 10.1016/j.brs.2025.04.018
Abstract
Background Neuromodulation of deep brain regions has shown promise for treatment-resistant depression (TRD). However, it currently requires neurosurgical electrode implantation, posing significant risks and limiting widespread use while TRD affects around 100 million people worldwide. Low-intensity transcranial ultrasound stimulation (TUS) could allow precise and non-invasive deep neuromodulation, provided that the challenge of the defocusing effects of the skull is tackled. Objective/hypothesis Here, we present the development of a portable and neuronavigated TUS prototype based on the use of patient-specific metamaterials (metalens) that correct for skull-induced aberrations. We then present the first application of metalens-based Transcranial Ultrasound Stimulation (mTUS) in TRD. The primary objective was to assess the safety and efficacy of mTUS targeting on individual level specific white matter tracts of the subcallosal cingulate involved in TRD. Methods The safety and precision of this device was addressed through a series of numerical simulations and experimental measurements on ex vivo human skulls. Five participants with TRD were included in this open-label study (ClinicalTrials.gov identifier: NCT06085950) and underwent an intensive 5-day course of mTUS with a total of 25 sessions of 5 min each. Results No serious adverse events occurred during the study. By day 5 of treatment, depression severity was reduced by an average of 60.9 % (range: [30 %-83.9 %]), and four out of five patients qualified as responders, with two of them in remission. Conclusions This study provides first-in-human evidence of the potential of mTUS as a precise, safe and effective non-invasive neuromodulation technique for neuropsychiatric disorders involving deep brain regions, offering a safer and more accessible alternative to invasive approaches.
Abstract via europepmc.
Exposures
Exposure 1: mTUS to left subcallosal cingulate (SCC)
Target: subgenual anterior cingulate cortex — “left subcallosal cingulate (SCC), at the crossing of the forceps minor, cingulum bundle and uncinate fasciculus”
Device: IGT / Imasonic · Imasonic (transducer); Image Guided Therapy (driving electronics) · Serial Number 13474-1002 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 4.5 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 14 | ✓✓✓ |
| Duty cycle (%) | 5pulse duration × PRF gives 6.3%, which disagrees with the stated value | ✓✓✓⚑ |
| Sonication duration (s) | 5 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | deratingmean or range across subjects | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | 0.184 | ✓✓✓⚑ |
The electronics were programmed to deliver ramped pulses with a 5% duty cycle (pulse duration of 4.5 ms including ramp duration of 0.75 ms, pulse repetition interval of 71 ms, pulse repetition frequency of 14 Hz), repeated in a pulse train (pulse train duration of 5 s, pulse train repetition interval of 15 s, pulse train repetition frequency of 0.07 Hz, pulse train duty cycle of 33%), resulting in an overall duty cycle of 1.8%. The 5-s pattern was repeated 20 times for a total treatment time of 5 min. Pulsed ultrasound was applied for 5 min, 5 times per day for 5 days with a minimum delay of 1 h between two sessions.
Flags from extraction
exposures[0].in_situ.ispta_w_cm2— Paper reports derated ISPTA both without correction (91.7 mW/cm2 mean) and with the personalized metalens (184.4 mW/cm2 mean) in the same sentence; the metalens value (as actually used clinically) is recorded here.exposures[0].timing.duty_cycle_pct— Stated pulse duty cycle is 5%, but pulse duration (4.5 ms) x PRF (14 Hz) = 6.3%, a minor discrepancy possibly reflecting rounding of the ramp duration; recorded as stated (5%).randomised— Open-label single-arm pilot trial; no randomisation to treatment arms was performed.