A new approach to treat severe depression using focused ultrasound

Depressive episodes are the most common mental disorders worldwide. One in five people will suffer from depression during their lifetime, with suicidal risk causing several thousand deaths each year in France. A new study published in the journal Brain Stimulation and conducted by researchers of Institut Physics for Medicine Paris (Inserm, ESPCI Paris-PSL, CNRS) and GHU Paris (Inserm/University of Paris Cité) reveals promising results with a five-day treatment using low-intensity focused ultrasound to modulate the activity of deep brain regions involved in depression.

In 2021, Santé Publique France revealed that 12.5% of individuals aged 18 to 85 had experienced a major depressive episode during the previous year [1]. Despite advances in the pharmacological treatment of depression, the therapeutic effects of antidepressants may take several weeks or remain insufficiant in one third of patients [2].

Therefore, it is crucial to develop new therapeutic approaches with faster effects. One strategy for treating drug-resistant depression is the stimulation of deep brain regions, such as the subcallosal cingulate region. So far, this was only possible through the implantation of intracerebral electrodes, an invasive procedure associated with significant neurosurgical risks, limiting its accessibility to a small number of patients.

A new study involving researchers from Institute Physics for Medicine Paris (Inserm, ESPCI Paris-PSL, CNRS) and physicians from GHU Paris (Inserm/University of Paris Cité), published in the journal Brain Stimulation, shows promising results from a five-day treatment using low-intensity focused ultrasound. This innovative technology allows the modulation of the activity of deep brain regions involved in depression, but in a non-invasive manner. Ultrasound waves have the property of propagating through human tissues and stimulating targeted brain areas remotely through mechanical action, triggering the opening of mechanosensitive channels. However, the irregular thickness of the skull, which distorts the ultrasound waves and limits the ability to focus them precisely on the targeted area, had prevented the development of this technology for several decades. At GHU Paris Sainte-Anne, psychiatrists and researchers Marion Plaze and David Attali, in Dr. Thierry Gallarda’s service, participated in the development and implementation of an innovative portable device that uses acoustic lenses to concentrate ultrasound waves with unprecedented precision. These lenses compensate for the distortions caused by the skull, allowing for more accurate targeting. The lens technology was developed at the Physics Institute for Medicine (Inserm, ESPCI Paris-PSL, CNRS) by researchers and engineers Jean-Francois Aubry (CNRS), Thomas Tiennot (ESPCI), and Mickael Tanter (Inserm), who are co-authors of the study. The researchers were able to model the skull’s effect on the ultrasound waves and determine the optimal shape for these acoustic lenses, which are uniquely fabricated and personalized for each patient. They patented the technology and co-founded the startup SonoMind with Jeremy Bercoff (president) and Philippe Chapuis (technical director) to accelerate the clinical transfer of this technology.

The precision of the transcranial ultrasound stimulation represents a major technological breakthrough in the fields of personalized medicine and neuroscience. For the first time, it becomes possible to stimulate deep brain structures, such as the subcallosal cingulate region, in a targeted, precise, and non-invasive manner using a portable device.

The clinical trial involved five consecutive days of ultrasound treatment targeting this brain region. The protocol was carried out on five patients with severe, medication-resistant depression to test the safety of this new approach. The results are promising, with no serious adverse events and excellent tolerance: patients reported no discomfort or pain during the sessions. Depression severity scores progressively decreased over the treatment days. “Although the results are encouraging, they should be interpreted with caution, as this is a first safety study with a limited number of patients and without a placebo group,” says the research team.

Additional studies are necessary and already planned, involving larger patient cohorts. If rapid and significant therapeutic effects are confirmed, along with the safety profile of the technique and the persistence of effects over time, transcranial ultrasound stimulation could be expanded to other applications in the coming years, particularly in psychiatry, addiction disorders, and neurology.

These studies are building on of 25 years of research on focusing ultrasound through the skull, 15 years on modulating brain activity with ultrasound, and 7 years of collaboration between researchers at the Physics Institute for Medicine (CNRS/ESPCI Paris-PSL/Inserm) and psychiatrists-researchers at GHU Paris and the Paris Institute of Psychiatry and Neurosciences (Inserm/University of Paris Cité).

Link to full-text publication

Attali D* & Tiennot T* et al., Deep transcranial ultrasound stimulation using personalized acoustic metamaterials improves treatment-resistant depression in humans, Brain Stimulation, April 2025 https://doi.org/10.1016/j.brs.2025.04.018

Contacts

jean-francois.aubry[at]espci.fr

Notes

1. Prévalence des épisodes dépressifs en France chez les 18-85 ans : résultats du Baromètre santé 2021
2. Rush et al, American Journal of Psychiatry, 2006

Acknowledgements

The research has received continuous support from Inserm, CNRS, and ESPCI Paris-PSL, GHU Paris, and the University of Paris Cité, as well as financial support from the Bettencourt Schueller Foundation, the National Research Agency, and innovative funding from Inserm (Neurotechnology Impulse Program and Ultrasound Research Technology Accelerator). The clinical trial also received financial support from the Focused Ultrasound Foundation (Charlottesville, VA, USA).