A clinical trial led by BBRF grantees has demonstrated for the first time that personalized targeting of non-invasive TMS brain stimulation therapy can reduce the brain’s reactivity to threat in patients with PTSD.

Noting robust reductions in PTSD symptoms after a follow up period of 3 to 6 months in those who received the therapy, the researchers said that TMS as they administered it “may induce a brain state where approaching trauma-related memories and triggers is more acceptable” to patients, and that over time following the treatments, this may lead “naturally to reduced PTSD symptoms as patients take their lives back.”

It’s a potentially important development in PTSD therapy, since many who receive standard evidence-based psychotherapy (e.g., “exposure therapy”) or drug therapy (only two medicines, paroxetine and sertraline, are approved for PTSD) either do not respond, drop out of treatment, or relapse over time.

The trial, recently reported in the American Journal of Psychiatry, involved 7 BBRF grantees and was led by Sanne J.H. van Rooij, Ph.D., a 2021 and 2018 BBRF Young Investigator. Among the paper’s senior authors were William M. McDonald, M.D., a 1999 BBRF Young Investigator, and Kerry J. Ressler M.D., Ph.D., a BBRF Scientific Council member, 2017 BBRF Distinguished Investigator, 2009 BBRF Freedman Prize winner, and 2005 and 2002 BBRF Young Investigator. All are at the Emory University School of Medicine.

This was the first clinical trial seeking to demonstrate the impact of personalized TMS targeting a specific portion of the amygdala that has been shown to mediate reactivity to perceived threat. “Dysregulation within the brain’s threat neurocircuitry, particularly hyperactivity of the amygdala, is a central mechanism underlying clinical symptoms in PTSD” as well as the related condition called hyperarousal, the researchers noted. Hyperarousal is a state of chronic, heightened physiological and emotional alertness that can lead to severe anxiety, irritability, hypervigilance, insomnia, and intense reactivity to triggers—all features of PTSD.

In neuroimaging studies, greater reactivity of the amygdala to perceived threat has been associated with nonresponse to trauma-focused therapy. In addition, when the right portion of the amygdala has been deactivated in surgeries addressing treatment-resistant epilepsy, doctors have noted the amelioration of PTSD in patients who suffered PTSD symptoms in addition to epilepsy. These and other observations have led to the theory that over-engagement of the right amygdala is a main driver of PTSD symptoms.

TMS cannot reach far enough into the brain to directly alter neural activity in the amygdala. But in the newly reported clinical trial, the team wanted TMS, which directs magnetic pulses into the brain, to be focused on an area of the cortex (the dorsolateral prefrontal cortex, or DLPFC) lying a little less than one inch below the scalp—specifically, a spot that is most robustly connected, functionally, with the right amygdala. Their premise was that low-frequency TMS—known to reduce cortical excitability—would also have the effect of reducing right amygdala reactivity to perceived threat, provided it were focused on that functionally connected spot in the cortex.

The trial was double-blinded and randomized, meaning that none of the participants or those administering or assessing treatments would know which trial participants were receiving active targeted TMS and which were receiving a placebo version that looks and feels like TMS but does not stimulate the brain.

The patient cohort consisted of 50 people, average age about 40, 86% of whom were female and 60% were White. The average score on a scale called PCL-5 to measure PTSD symptoms was 37.7 prior to treatments. (Scores of 31-33 indicate probable PTSD.) All received a pre-treatment fMRI scan, which enabled precise targeting in each patient of the spot in the DLPFC most robustly connected, functionally, to the right amygdala.

Twenty-six randomly selected participants received active low-frequency TMS treatments, at 1-Hz, in twice-daily sessions given over 10 consecutive weekdays. The two daily sessions, separated by 10 minutes, delivered a total of 1,800 magnetic pulses to the cortex (36,000 total pulses over the 10 treatment days.) This is considered “accelerated” TMS, as opposed to the much slower schedule of treatments, with similar numbers of pulses delivered over 4-6 weeks, in standard TMS. Twenty-four participants received a placebo treatment, using the same treatment schedule and procedure over 10 days, albeit delivering no active brain stimulation.

The primary outcome measured in the trial was right amygdala reactivity, measured before and immediately after 10 days of TMS/placebo treatments. In those receiving active TMS therapy, the hypothesis was validated: after 10 days of treatment, the right amygdala became less reactive when participants were scanned while being asked to view a series of faces with expressions ranging from fearful to neutral.

The team reported that clinical PTSD symptoms were also “significantly” reduced with active TMS. Hyperarousal symptoms “significantly decreased” in the active TMS group from pre-TMS to the assessment made immediately following the treatment course (“post-TMS”), but not in the group receiving placebo. Total PTSD symptoms “significantly decreased” in the active TMS group from pre-TMS to post-TMS, and from pre-TMS to the assessment made at follow-up. Importantly, the continued improvement at long-term follow-up was not observed in the placebo group.

At the 3- to 6-month follow-up, “a clear separation [in results] was observed” between those who had received active TMS and those who had received placebo. Starting from a pre-TMS PCL-5 score of 39.9, the active treatment group had a 19.5-point reduction, on average (to about 20). Scores below the high 20s indicate symptoms that are below the threshold of clinical PTSD. In the placebo group, after an initial decline in total symptoms (a score decrease from about 37 to about 30, possibly due to the placebo effect seen in most clinical trials), there was no further reduction in the long follow-up period. Hyperarousal symptoms were also markedly lower in the active TMS group at 3-6 months post-therapy, compared with those in the placebo group.

“We think that the full behavioral effects of active stimulation may take some time to emerge,” Dr. Sanne commented, “as many PTSD symptoms reflect learned or adaptive behaviors, such as avoidance, and behavioral change takes time.” The team also noted that a delayed or continued therapeutic clinical response in the period following TMS and other forms of brain stimulation for PTSD as well as depression has been previously noted.

It is in the light of this data that the team suggested that targeted treatment with accelerated TMS like that delivered in the trial may, over time, change the brain in ways that render trauma-related memories less likely to result in hyperarousal, and more likely that trauma memories can be accepted and lived with, resulting in an ability of patients to “take their lives back.”

Larger trials are needed to confirm the findings in this trial, the team said. They also noted that in this trial, the participants represented a range of PTSD severity and trauma types, were mostly female, and had a number of comorbid disorders. All of these factors potentially influence the results obtained, and must be explored in future studies with different participant profiles.

The team also included: Tanja Jovanovic, Ph.D., 2015 BBRF Independent Investigator, 2010 Young Investigator; Paul E. Holtzheimer M.D., 2016 BBRF Independent Investigator, 2007 Young Investigator; Joan A. Camprodon, M.D., Ph.D., 2010 BBRF Young Investigator; and Vince D. Calhoun, Ph.D., 2004 BBRF Young Investigator.