A new study published in the journal Molecular Psychiatry provides initial evidence for a non-invasive brain stimulation technique aimed at reducing symptoms of depression, anxiety, and trauma-related disorders. Researchers found that targeting the amygdala using focused ultrasound led to measurable changes in brain activity and symptom relief across multiple psychiatric diagnoses. The approach was found to be safe, well tolerated, and potentially effective, but the authors stress that more rigorous trials are needed before it can be considered a viable treatment.
Mood and anxiety disorders are often linked to overactivity in the amygdala. While some treatments like medication and talk therapy may help regulate this region, non-invasive brain stimulation options like transcranial magnetic stimulation have limited ability to reach deeper brain areas. Focused ultrasound, by contrast, can target these deeper areas directly and precisely. However, until now, very little was known about whether this technique could safely and effectively reduce symptoms in people with mental health conditions.
“A primary motivation for us is to improve treatment outcomes for individuals with mood, anxiety, and trauma-related disorders,” said Gregory A. Fonzo, assistant professor of psychiatry and behavioral sciences and co-director of the Charmaine and Gordon McGill Center for Psychedelic Research and Therapy at the University of Texas at Austin’s Dell Medical School.
“Although we have effective treatments, not everyone will derive a substantial benefit from existing approaches. Thus, it is particularly important to design and test out novel approaches that might perform better for some individuals.”
“I have a strong interest in brain-based treatments, or treatments that work directly on the brain to promote a therapeutic benefit. The ability for focused ultrasound to directly modulate the function of deep, subcortical brain regions is an exciting advance in the neurotechnology space, and we were excited to explore its potential in improving symptoms in individuals with mood, anxiety, and trauma-related disorders.”
The study was conducted in two phases. First, the researchers used magnetic resonance imaging to guide brief, single sessions of focused ultrasound to the left amygdala while participants were inside the scanner. This phase included 29 adults with diagnosed mood, anxiety, or trauma-related disorders and 23 healthy participants as a comparison group. Each participant received both a real and a sham (placebo) version of the ultrasound in a double-blind design. This phase was designed to test whether the stimulation could alter brain activity during and immediately after treatment, as measured by changes in blood oxygenation.
In the second phase, the same patients with mental health conditions underwent a three-week course of focused ultrasound treatments. They returned to the lab every weekday for 15 total sessions. These repeated sessions were not blinded and were intended to assess safety, treatment feasibility, and any changes in symptoms or brain function over time. Patients completed symptom questionnaires before and after treatment and underwent another MRI scan to assess how their brains responded to emotional stimuli after the intervention.
The first phase of the study showed that active ultrasound stimulation reduced activity in the left amygdala more than sham stimulation. This was observed in both patients and healthy participants, suggesting that the technology was capable of directly modulating this brain region.
About two-thirds of the participants showed some level of reduced amygdala activity. The researchers also found that individuals with higher levels of emotional distress tended to show stronger reductions in amygdala activity, hinting that people with more severe symptoms may benefit most from the treatment.
Beyond the amygdala, focused ultrasound also affected other brain regions. It altered activity and connectivity in parts of the hippocampus, insula, and prefrontal cortex—areas known to work together with the amygdala in emotional processing. These effects were different between patients and healthy individuals, particularly in the right hemisphere of the brain. This pattern may reflect disrupted communication between brain hemispheres in people with mental health disorders, though further research is needed to understand the underlying mechanisms.
The second phase of the study examined what happened when the ultrasound treatment was repeated daily over three weeks. This part showed that the intervention was well tolerated and that most participants completed the full course of treatment. Side effects were generally mild and temporary, with no serious adverse events reported. The most common complaints were brief headaches, lightheadedness, or tingling sensations, most of which occurred during the first session inside the MRI scanner.
Importantly, patients showed improvements in symptoms after the full treatment. The main measure of improvement was a questionnaire assessing general emotional distress, which showed moderate to large reductions in symptom severity. Nearly half of the patients experienced symptom relief that exceeded what would be expected from measurement error alone. Many also reached scores that were more similar to healthy participants.
Additional improvements were found in measures of depression, anxiety, trauma symptoms, and quality of life. Some of these effects remained significant even after adjusting for multiple comparisons, strengthening the evidence that the treatment may be helpful across a range of psychiatric symptoms.
Changes were also seen in how the brain responded to emotional images after the three-week treatment. In particular, both the left and right amygdalae showed reduced activity across several emotional conditions. The most notable decrease was in response to angry faces, a type of stimulus known to strongly activate the amygdala in people with depression, anxiety, and posttraumatic stress. Patients who showed greater decreases in amygdala activity also tended to report larger improvements in their symptoms, suggesting a possible brain-based marker of treatment response.
“I was quite pleasantly surprised that we saw such a broad ranging degree of benefit across multiple different types of psychiatric symptoms,” Fonzo told PsyPost. “This suggests that our brain target, the amygdala, is ripe for future efforts to optimize our initial approach. It also underscores the idea that a common treatment approach can be beneficial across many different diagnoses that are characterized by similar symptoms (and similar brain circuits).”
“There are new and exciting opportunities on the horizon to improve psychiatric treatments through integration and optimization of novel technologies. Low-intensity focused ultrasound is one such promising approach, and scientists are constantly working to improve and optimize our available options. I would hope this inspires hope in the typical mental health consumer that there is hope for relief from depression, anxiety, and posttraumatic stress disorder.”
Although the findings are promising, the researchers emphasize that this was an early-stage trial and several limitations remain. The most important is that the repeated treatment phase did not include a control group. Everyone knew they were receiving the real treatment, which makes it impossible to rule out placebo effects or improvements due to other factors, such as increased attention or hope.
The sample size was also relatively small, and although the study included people with a variety of diagnoses, this made it difficult to assess whether the treatment works better for some conditions than others. In addition, the researchers relied on self-report questionnaires rather than clinical interviews to track symptom changes. While these are useful tools, future studies would benefit from combining them with more comprehensive clinician assessments.
Another limitation is that the technology itself is still being refined. The researchers did not use advanced modeling tools to predict exactly how the ultrasound energy would interact with each person’s skull and brain anatomy, which could affect how precisely the treatment reached the amygdala. They also noted that the effects of treatment might vary depending on how active the brain is before stimulation, how precisely the ultrasound is targeted, and how well different brain regions are connected.
“We need to conduct a larger study using a randomized design with a placebo comparator condition to truly demonstrate potential efficacy of low-intensity focused ultrasound neuromodulation,” Fonzo explained. “Our results are encouraging but do require additional studies until we can be more confident in the therapeutic potential of this approach.”
Despite these limitations, the study represents an important step forward. It is the first to show that low-intensity focused ultrasound can directly target the amygdala and reduce its activity in people with emotional disorders. It also provides early evidence that repeated stimulation may lead to meaningful symptom improvements without serious side effects.
“The next steps would be to see if we can optimize or enhance our existing findings through testing additional sets of stimulation parameters as well as examining other factors that might impact the magnitude and durability of symptom reductions,” Fonzo said. “The longer-term goal would be to conduct one or more randomized controlled trials to assess efficacy of this approach in the most rigorous design.”
The study, “Low-intensity transcranial focused ultrasound amygdala neuromodulation: a double-blind sham-controlled target engagement study and unblinded single-arm clinical trial,” was authored by Bryan R. Barksdale, Lauren Enten, Annamarie DeMarco, Rachel Kline, Manoj K. Doss, Charles B. Nemeroff, and Gregory A. Fonzo.
