A new study led by researchers at the Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, suggests that using neurostimulation therapies on a specific brain network could treat post-traumatic stress disorder (PTSD) in veterans. Evaluating 193 participants in the Vietnam Head Injury Study with penetrating traumatic brain injury, the research team found that those individuals with damage connected to their amygdala, the fear center of the brain, were less likely to develop PTSD.
“Unfortunately, people sometimes assume PTSD has to do with how mentally strong or weak a person is, but it has nothing to do with moral character,” said Shan Siddiqi, MD, a psychiatrist in the Brigham’s Center for Brain Circuit Therapeutics and an assistant professor of psychiatry at Harvard Medical School. “This is a very real brain disease, and we can localize it to certain brain circuits.”
Siddiqi is corresponding and first author of the team’s published paper in Nature Neuroscience, titled “A potential target for noninvasive neuromodulation of PTSD symptoms derived from focal brain lesions in veterans,” in which the researchers stated, “This lesion-based ‘PTSD circuit’ may serve as a target for clinical trials of neuromodulation in veterans with PTSD.”
PTSD may affect up to 30% of trauma survivors and military combat veterans, and is associated with disabling comorbidities such as depression, substance use and suicidality, the authors noted. Drugs and psychotherapy are only “modestly effective,” they continued, “… so targeted neuromodulation has been proposed as a new treatment approach, building on its established efficacy for depression.”
Techniques for neuromodulation aim to activate or inhibit those brain circuits that are causally implicated in particular symptoms or disorders. However, the team noted, “Neuromodulation trials for the treatment of posttraumatic stress disorder (PTSD) have yielded mixed results, and the optimal neuroanatomical target remains unclear.”
For their reported research Siddiqi and colleagues analyzed three datasets to study brain circuitry that might be causally linked to PTSD in military veterans. The study involved a collaboration with other researchers from the Brigham’s Center for Brain Circuit Therapeutics, as well as investigators from the Feinberg School of Medicine at Northwestern University, Brown University Alpert School of Medicine, and Duke University School of Medicine.
Siddiqi noted that previous studies have shown people with damage to the amygdala are less likely to get PTSD, but the team wanted to find a therapeutic target for the disease. “The amygdala is deep in the brain, making it hard to hit precisely with a stimulation modality without doing surgery,” Siddiqi said. The authors further noted, “Noninvasive modulation of brain circuitry is possible using transcranial magnetic stimulation (TMS), but TMS cannot directly access deep targets such as the amygdala.”
Researchers in the Center for Brain Circuit Therapeutics had previously uncovered networks to successfully treat depression and addiction using transcranial magnetic stimulation (TMS). Michael Fox, MD, PhD, co-author on the newly published Nature Neuroscience paper and director of the Center for Brain Circuit Therapeutics, said the team hoped to build on their success by identifying targets for conditions such as PTSD.
“One of the big gaps for developing a brain stimulation treatment for PTSD is identifying the correct therapeutic target,” commented Fox, noting that previous trials have tried to use the same circuit his team derived for depression, but that the target failed in trials for PTSD. “Thus, we sought to identify TMS targets based on functional connectivity (FC) of lesion locations that affect PTSD symptoms, independently of depression,” the investigators stated.
“Rather than continue with a trial-and-error approach of testing different targets, we turned to brain lesions to map out the circuit,” Fox said. For their newly reported work the team examined 193 patients with penetrating traumatic brain injuries from the Vietnam Head Injury Study led by co-author, Jordan Grafman, PhD, at Northwestern. They looked at whether those veterans developed PTSD 20 years after the war in Vietnam. “First, in 193 military veterans with penetrating traumatic brain injury (TBI), we derived and cross-validated a brain circuit functionally connected to lesions that reduce probability of developing PTSD,” the team wrote.
“Some of these veterans who got shrapnel in their head went on to develop PTSD, but many of them did not,” Fox said. “The patients actually developed PTSD less than other veterans who did not get damage to their brain.”
Fox commented that the data Grafman gathered was key for this study because he had mapped the exact location of damage in each patient and what the neurological effects of the damage were.
The researchers hypothesized that a circuit may exist that, when damaged, protects against PTSD. They used their wiring diagram, the human connectome, to map where brain damage had occurred and where each lesion connected. From there, they compared the data to 180 veterans who did not have brain damage, some of whom have PTSD and some whom do not. “… in 180 veterans without brain lesions, we assessed whether FC in this circuit was associated with PTSD,” they stated. They found connectivity within the circuit correlated with whether they had PTSD or not. Finally, the team looked at whether this circuit would be a good target for treatment by examining previous trials using TMS for PTSD.
“The trials where stimulation was hitting the circuit we identified tended to be the trials that had good outcomes in patients,” Fox said. “We also asked whether or not our results could inform how to stimulate the targets, leading to what we believe is a therapeutic target for treatment using TMS.”
During the study, a patient with severe PTSD requested TMS at Acacia Mental Health in California. Siddiqi was consulted to help plan the treatment. After a careful informed consent process, clinicians at Acacia used the circuit found in the study to treat the patient, ultimately improving his symptoms. “Reduced functional connectivity within this circuit after transcranial magnetic stimulation correlated with symptom reduction, even though the circuit was not directly targeted,” the researchers noted.
Fox said that while this result is in only one patient, the case provides an illustration for how the results of the study might translate into a clinical setting. “This lesion-based ‘PTSD circuit’ may serve as a target for clinical trials of neuromodulation in veterans with PTSD,” the team stated in their paper. Before it can be accessible to a larger population, they will have to conduct a randomized controlled trial targeting the circuit to gain FDA approval.
The authors concluded, “In veterans with penetrating traumatic brain injury, lesion locations that reduced probability of PTSD were preferentially connected to a circuit including the medial prefrontal cortex, amygdala and anterolateral temporal lobe.” This circuit, they said, was reproducible, predicted PTSD outcomes in out-of-sample validation and was not dependent on any single brain region or network. “The peak superficial node in this circuit, the mPFC, may serve as a promising target for TMS clinical trials in PTSD.”
Siddiqi said one limitation to the study is they don’t yet know how the treatment results could change if a person is in a state of PTSD-induced fear at the time of treatment compared to relaxation. Fox added the study included only veterans, so they are unsure if PTSD in non-veterans would map onto the same circuit.
“While more work remains to be done, we’ve taken an important step here to identify a therapeutic target for a condition in patients who desperately need better treatments,” Fox said.
