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Imaging Pinpoints Brain Circuits Changed by PTSD Therapy

Findings Can Help Target Treatment, Predict Outcomes

Science Update

Using brain imaging to track the effects of treatment of post-traumatic stress disorder (PTSD), scientists have identified a brain circuit on which a frequently used and effective psychotherapy (prolonged exposure) acts to quell symptoms. The findings help explain why the neural circuit identified is a promising target for additional treatment development, including brain stimulation therapies.

In an accompanying paper, the authors also report that they have identified hallmarks in brain activity of people with PTSD that predict who will benefit from treatment. Both papers appear online July 18 in the American Journal of Psychiatry.

In prolonged exposure treatment for patients with PTSD, trained therapists use deliberate and careful exposure to images, situations, or cues that evoke traumatic memories. The object of the therapy is to reduce fearful associations with these trauma cues and replace them with a sense of safety and control over emotional reactions. The treatment can be very effective, but it has not been clear how it changes brain processes to have a beneficial effect on symptoms.

Amit Etkin, M.D., Ph.D., at Stanford University School of Medicine, led a team of scientists collaborating on this work. The study enrolled 66 individuals with PTSD; all underwent functional magnetic resonance brain imaging (fMRI) at rest and while carrying out tasks that engage different aspects of emotional response and regulation. By tracking blood flow, fMRI reveals areas of the brain that are active. Scientists monitor regional brain activity while a subject is carrying out a given task. Participants were then randomly assigned either to treatment with exposure therapy or a waitlist. All then had fMRI scans either following treatment or, if assigned to waitlist, after a comparable waiting period.

In participants who received exposure therapy, there were changes in activation observed in a part of the brain nearest the front of the cortex—the seat of higher order brain function, including thought and decision making—when they were doing a reappraisal task which instructed them to reduce their level of distress by interpreting or seeing a negative picture (such as a gruesome scene) differently. The post-treatment changes in the frontopolar cortex were only observed during this task, not with two other tasks that required participants to simply react to emotional cues (such as fearful expression faces), or sort conflicting emotional information (for example if they viewed a fearful face labelled happy).

The magnitude of the changes in brain activation observed was greater in participants who had improved to a greater extent in a clinical test of PTSD symptoms. Imaging also revealed an increase in connectivity between the frontopolar cortex and two other brain regions, providing a fuller picture of a brain circuit that exposure therapy acts on. To probe the nature of the connections between these brain regions, the investigators applied magnetic pulses (transcranial magnetic stimulation or TMS) to the frontopolar cortex of healthy subjects; the stimulation deactivated the “downstream” brain areas, confirming a functional connection between the two areas.

The frontopolar area of the cortex plays a role in cognitive flexibility, the ability of the brain to shift between different aims and strategies. The team probed whether PTSD treatment changed patterns of activity in this brain circuit at rest by acquiring fMRI scans of subjects while they let their minds wander. In those who had received therapy, there was more varied, changing activity than in those who had not been treated. The investigators suggest that this variability is a signature of flexibility in mental processes.

In an accompanying paper, this team reports that brain activation patterns observed in conjunction with certain behavioral tasks can predict who will benefit from exposure therapy; by selecting the most informative measures, the team could predict with more than 95 percent accuracy who would experience improvement in symptoms. As with the post-treatment findings, brain activation patterns seen when TMS was used to probe brain responses prior to treatment paralleled those seen with combined fMRI and behavioral tests. In those study participants who would benefit most from therapy, both sets of tests suggested that the prefrontal cortex exerted a greater regulatory effect on an emotional center in the brain (the amygdala).

Tellingly, the elements of brain activation that predicted therapeutic effect were not the same as those that reflected positive effects post-treatment. The brain circuit identified here that predicted whether someone would benefit from therapy was different from the one that changed when therapy was effective, an insight into how multiple circuits may be involved in processes underlying therapeutic change. An important aspect of this study was the use of multiple behavioral tests used to probe brain activation and the inclusion of a control (untreated) group for comparison, allowing the investigators to pinpoint meaningful changes in brain activity and link them, with confidence, to therapy. “This study provides a solid footing for understanding mechanisms so we can start working towards matching people to the treatment most likely to work for them and develop novel therapeutics for directly targeting brain therapy,” said lead author Etkin. “By grounding psychotherapy in brain mechanisms, we can also hopefully decrease stigma, an invisible barrier to care that is so prevalent in psychiatric disorders and prevents people from getting the care that would benefit them.”

One motivation for this work is that understanding the biology of a psychosocial intervention can provide information on which to base the design of direct brain circuit interventions, like TMS. Tools like TMS could also be used in a targeted way to enhance (or even enable) the beneficial effects of psychotherapy. “Perhaps the best way to inform and motivate development of novel brain stimulation-based treatment by necessity comes through studying psychotherapy, the oldest and most interpersonal treatment we have in psychiatry,” said Etkin.

The work is in keeping with NIMH’s efforts to foster research aimed at developing a circuit-based understanding of brain function and psychiatric disorders; Etkin points out that this work shows how the therapeutic effects of psychosocial treatments for brain disorders are, like medication and brain stimulation techniques, grounded in biology.

Reference

Fonzo GA et al. PTSD psychotherapy outcome predicted by brain activation during emotional reactivity and regulation . American Journal of Psychiatry. Published online July 18, 2017.  https://doi.org/10.1176/appi.ajp.2017.16091072 

Fonzo GA et al. Selective effects of psychotherapy on frontopolar cortical function in PTSD . American Journal of Psychiatry. Published online July 18, 2017. https://doi.org/10.1176/appi.ajp.2017.16091073 

Grants: MH091860, 019938

Clinical Trial: NCT01507948

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