Deep transcranial ultrasound stimulation using personalized acoustic metamaterials improves treatment-resistant depression in humans.

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. 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. 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. 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. 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.