Low-Intensity Ultrasound Brain Stimulation Safely Reduces Depression Symptoms

A new study confirmed the safety and effectiveness of low-intensity transcranial ultrasound stimulation (TUS) for depression.1

“Our findings revealed that TUS stimulation targeting the BA46 area of left dlPFC exhibited a noteworthy therapeutic impact, ameliorating symptoms of depression and anxiety in patients while also significantly affecting sleep patterns,” wrote investigator Xin Cai, from Shenzhen Samii Medical Center in China, and colleagues.1

Two noninvasive transcranial stimulation methods show promise for depression: the US Food & Drug Administration (FDA)-approved transcranial magnetic stimulation (TMS) for treatment-resistant cases, and transcranial direct current stimulation (tDCS), which is under study for symptom improvement.2,3,4 However, both have limitations in spatial precision and depth, restricting their ability to target deep brain regions. Thus, a third approach has gained attention: TUS.

TUS offers greater resolution and depth, enabling precise neuromodulation with minimal off-target effects.1 Ultrasound may modulate neurotransmitter release, neuronal excitability, or glial function, potentially explaining observed changes in brain activity.

Pilot studies support TUS’s potential for depression. In one case, a patient with treatment-resistant, non-psychotic depression achieved symptom remission within 24 hours after repeated stimulation of three anterior cingulate targets, sustained for ≥6 weeks.5

Investigators conducted a single-blind, randomized, sham-controlled trial to assess the efficacy and safety of TUS in reducing depressive symptoms, while also addressing the challenge of precise targeting.1 To overcome limitations of conventional MRI-based guidance, the study validated a dual-navigation approach combining real-time optical tracking with MR acoustic radiation force imaging. The team targeted a subregion of the left dlPFC, a region strongly linked to depression, where broader methods such as TMS and tDCS may inadvertently stimulate adjacent areas and produce mixed therapeutic effects. The sham arm received the identical treatment as the active arm, but without energy output.

The trial included 36 patients with depression (24 TUS, 12 sham). Participants completed psychiatric evaluations and functional MRI scanning. Baseline characteristics were similar across arms; the TUS arm had a mean age of 38.46 years (range, 19 to 57 years), 10 males and 14 females, and mean baseline scores of 17.42 ± 5.19 for HAM-D 24, 13.79 ± 6.49 for HAM-A 14, and 11.38 ± 3.17 for PSQI.

After 10 days of TUS, patients showed significant improvements in depression, anxiety, and sleep quality, with effects lasting up to 4 weeks. Mean HAM-D-24 scores in the TUS arm declined from 17.42 ± 5.19 at baseline to 11.67 ± 4.83 at the fifth visit (P <.01), 10.50 ± 5.28 at the end of treatment (P <.001), 9.29 ± 4.83 at 2 weeks post-treatment (P <.001), and 8.96 ± 5.20 at 4 weeks post-treatment (P <.001). By the end of the trial, 70.8% of participants on TUS achieved clinically meaningful reductions, and 41.5% reached response-level criteria.

HAM-A-14 and PSQI scores showed similar improvements. Both HAM-A 14 and PSQI scores reduced from baseline to the fifth visit (P =.048 for PSQI), end of treatment (P =.026 and P =.01), at 2 weeks post-treatment (P =.0006 and P =.015), and 4 weeks post-treatment (P <.001 and P <.001), respectively.

Sham participants showed only minor improvements in HAM-D-24, HAM-A 14, and PSQI scores until receiving TUS.

Functional connectivity analyses revealed TUS-associated changes in regions involved in emotion processing, including subgenual anterior cingulate cortex, ventral posterior cingulate cortex, and precuneus. All connectivity changes correlated with symptom improvement.

Safety was favorable, with only 3 adverse events occurring in the TUS Group: 2 transient headaches and one increased mental excitability.

“The absence of serious adverse events (SAEs) and device-related dropouts contrasts sharply with TMS trials reporting 28–45 % incidence of headaches and 5% risk of seizures,” investigators wrote. “This safety advantage likely stems from the subthreshold energy delivery of TUS, which avoids the indiscriminate neuronal depolarization caused by electromagnetic induction.”

The team noted that increased mental excitability in one participant may indicate that TUS enhances cognitive flexibility, in contrast to TMS, which can contribute to cognitive fatigue.

“We anticipate that the outstanding safety and precise targeting demonstrated in this study will encourage the broader application of TUS therapy within deep nuclei for addressing depression and other psychiatric disorders,” investigators wrote.

References

1. Cai X, Sun W, Zheng X, et al. Safety and efficacy of low intensity transcranial ultrasound stimulation for depression: A single-blind randomized controlled clinical study. J Affect Disord. 2026;394(Pt B):120666. doi:10.1016/j.jad.2025.120666

2. Payesko J. BrainsWay's Next Generation Stimulator For Treatment of MDD Cleared by FDA. HCPLive. Published on May 9, 2018. Accessed January 6, 2026. https://www.hcplive.com/view/brainsways-next-generation-stimulator-for-treatment-of-mdd-cleared-by-fda

3. Derman C. FDA Clears BrainsWay’s TMS Device for Adolescents with MDD Aged 15 to 21 Years. HCPLive. Published on November 19, 2025. Accessed January 6, 2026. https://www.hcplive.com/view/fda-clears-brainsway-tms-device-adolescents-mdd-aged-15-to-21-years

4. Kuntz L. Transcranial Direct Current Stimulation for Major Depressive Disorder: A Look at Starstim. Published on March 8, 2024. Accessed January 6, 2026. https://www.psychiatrictimes.com/view/transcranial-direct-current-stimulation-for-major-depressive-disorder-a-look-at-starstim

5. Riis TS, Feldman DA, Vonesh LC, et al. Durable effects of deep brain ultrasonic neuromodulation on major depression: a case report. J Med Case Rep. 2023;17(1):449. Published 2023 Oct 28. doi:10.1186/s13256-023-04194-4