Over the last two decades, non-invasive brain stimulation, especially rTMS (repetitive transcranial magnetic stimulation), has become a widely used therapy for psychiatric disorders, most especially depression. In recent years, rapid-acting versions have been successfully introduced to treat severe, treatment-resistant major depressive disorder, while in other applications, non-invasive stimulation has been tested to address other conditions, including PTSD and OCD.

In a paper published in Molecular Psychiatry, researchers led by Gregory A. Fonzo, Ph.D., a 2019 BBRF Young Investigator at the University of Texas at Austin Dell Medical School, report on a pilot study of low-intensity transcranial focused ultrasound (tFUS), which they tested for safety and therapeutic potential in 29 patients with a variety of mood, anxiety, and trauma-related disorders, as well as in 23 healthy controls.

While rTMS uses magnetic pulses to alter the activity of cortical cells just beneath the skull, tFUS uses focused high-frequency soundwaves to reach areas of the brain that lie beneath the cortex—so-called subcortical areas. rTMS can affect subcortical structures such as the amygdala and hippocampus, but only indirectly, via connections forged by stimulated cortical cells with those structures. In tFUS, there is no cortical intermediary; focused sound waves reach directly into the subcortical brain and can be targeted with considerable precision.

The study performed by Dr. Fonzo and colleagues, who included Charles B. Nemeroff, M.D., Ph.D., a BBRF Scientific Council member, 1997 Selo Prize-winner, and two-time Distinguished Investigator (1996, 2003), focused on tFUS’s impact on the amygdala, a subcortical structure centrally involved in the processing of emotions. Hyperactivity in the amygdala is thought to be implicated in a range of psychiatric conditions.

The experiments, in addition to testing an application of tFUS technology, reflect an approach advanced at the National Institutes of Health that encourages researchers to think of psychiatric symptoms across diagnostic boundaries. Called RDoC, or Research Domain Criteria, it regards the amygdala, for example, as a key mediator of “all negative valence subdomains,” i.e., brain areas involved in generating negative feelings that include perceptions of acute threat (fear), potential threat (anxiety), sustained threat, loss, and lack of reward. These constructs are interconnected and relate to responses to aversive situations or contexts, and some or all of them may be involved in various mood, anxiety, and trauma-related disorders.

The team’s premise was: if tFUS is capable of safely and therapeutically modifying the amygdala, specifically in reducing hyperactivity in the structure, it could conceivably be used transdiagnostically—across diagnoses—as a form of therapy. Current therapies including SSRI antidepressants and psychotherapy may act across diagnoses to some important extent. But many who receive these and other therapies don’t respond or don’t respond fully or in a durable way. Hence, the continuing search for new approaches.

A single application of focused ultrasound (“sonication”) has been shown to alter neurobiological function in monkeys which can last over one hour. These and other tests indicate that tFUS alters neuroplasticity, i.e., the ability of neurons to change the strength of their connections, one of the mechanisms though which antidepressants are thought to deliver therapeutic results.

A test of tFUS to inhibit neural activation in the amygdala across a range of mood, anxiety and trauma-related disorders had not yet been attempted. Dr. Fonzo and colleagues recruited 29 patients with such disorders, as well as 23 healthy controls. They conducted a double-blinded, placebo-controlled “target engagement study” in the 52 participants, designed to test whether tFUS could indeed modulate activity in a targeted area, the left amygdala. Afterward, they conducted an unblinded pilot clinical trial in which the 29 participants with psychiatric diagnoses received daily repetitive tFUS (rtFUS) over 3 weeks (5 treatments per week) targeting the left amygdala.

The ”target engagement” tests were successful. In two sessions separated by one week, patients and controls received an active tFUS session and a placebo, or “sham,” version. The treatment was guided by MRI, and effects were observed when the participants were receiving a functional MRI scan. These experiments showed that active tFUS (versus ”sham”) reduced activation in the left amygdala, while modulating connectivity between that area and interconnected limbic and prefrontal circuitry. There was considerable variability in the magnitude of such reduction among recipients of tFUS, a result to be taken up in future studies. These tests also established to the team’s satisfaction that tFUS as administered was safe and “feasible as an intervention approach.” No serious adverse events were reported.

Of the 29 participants in the unblinded pilot clinical trial, most of them in the early 20s, diagnoses were overlapping: 16 had been diagnosed with major depression; 10 with bipolar disorder; 4 with alcohol use disorder; 2 with panic disorder; 23 with an anxiety disorder; and 10 with PTSD. The primary outcome measure was the Mood and Anxiety Symptom Questionnaire—General Distress (MASQ-GD) scale, on which the average participant had a score of about 30 prior to the 3 weeks of tFUS treatments, and 21 following the treatment course, a reduction, the team said, that was statistically significant, despite the small size of the cohort.

“The pilot trial provides initial evidence of safety, feasibility and possible utility of daily rtFUS as a transdiagnostic intervention,” the team reported. “We observed a significant reduction in our primary outcome, a general measure of negative-affect symptoms” in the disorders affecting the participants. “Following the entire treatment course the effect size [of the benefit] was moderate-to-large for the primary outcome as well as for several secondary outcomes, including depression and PTSD symptom severity.”

The researchers say these results justify a much larger, double-blinded ”sham”-controlled clinical trial. Such a trial would not have the disadvantage of the current pilot of lacking a control group—which makes it difficult to assess the possible benefit of the tested rtFUS protocol. Future tests might also explore the dosing—whether sessions 5 days per week are optimal, or if fewer sessions or a different treatment duration might be advantageous. There is also no data yet on the durability of the therapeutic effects of rtFUS, another subject for exploration in future tests.