The pattern of brain activity in response to tests that examine emotional regulation could help identify which patients with post-traumatic stress disorder (PTSD) would benefit most from a form of psychotherapy, and it may point to novel therapies, new findings suggest.
Two thirds of patients with PTSD who undergo prolonged exposure therapy to improve response to trauma-related memories and situations experience a 50% reduction in symptoms; 80% achieve remission; and about one third of patients drop out of therapy.
In the first of two articles published July 18 in the American Journal of Psychiatry, investigators showed that in patients with PTSD who had the greatest response to exposure therapy, there was a significant difference in patterns of brain activation during the performance of two of three emotional regulation tasks.
In the second article, investigators found that exposure therapy led to significant changes in brain activation, albeit in different circuits, which were related to improvements in PTSD symptom scores and psychological well-being.
“These findings put a place marker in our understanding of psychotherapy writ large. We can really put psychiatric disorders on the map in terms of hard science and help fight the stigma that surrounds these illnesses and their treatment,” study author Amit Etkin, MD, PhD, associate professor, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, California, said in a release.
“Within the field of PTSD, it gives a concrete sense of hope for people undergoing treatment and starts laying the groundwork for new treatments based on understanding brain circuitry,” he added.
In the first study, the researchers examined whether the emotional reactivity and regulation traits of individuals with PTSD could be used to identify those who were most likely to benefit from prolonged exposure therapy.
They initially performed functional MRI (fMRI) on 66 PTSD patients while they performed the following tasks:
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the emotional reactivity task, which assesses goal-irrelevant emotional reactivity to fearful and neutral faces;
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the emotional conflict task, which induces emotional conflict by pairing fearful and happy faces with congruent or incongruent emotion words; and
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the reappraisal task, in which negative or neutral pictures are viewed with either a natural or a reduced emotional response.
Participants were randomly assigned to undergo immediate prolonged exposure treatment, comprising a total of between nine and 12 90-minute sessions once or twice a week (n = 36), or were placed in a wait-list condition (n = 30). Seventeen of the patients who underwent immediate treatment also underwent single-pulse transcranial magnetic stimulation (TMS) during fMRI to examine predictive patterns of activation.
Overall, the immediate-treatment group showed significantly greater reductions in PTSD and depressive symptoms, as well as improvements in quality-of-life domains, in comparison with those in the wait-list group.
Analysis of task effects showed that in the immediate-treatment group, during the emotional reactivity task, greater baseline activation occurred in all prefrontal regions and in the left anterior insula to fearful vs neutral faces in comparison with patients in the wait-list group (P < .001).
The opposite pattern was seen in the wait-list group, in which greater prefrontal activation was associated with less symptom improvement (P < .03).
Moreover, greater symptom improvement in the treatment group was associated with less left amygdala actuation in the fear vs neutral contrast comparison (P = .012). The opposite pattern was seen in the wait-list group (P = .03).
Low Baseline Activation Equals Greater Response
In the emotional conflict task, greater baseline activation in all dorsolateral prefrontal clusters was associated with larger reductions in symptom scores in the treatment group in comparison with the wait-list group (P < .003).
In addition, reduced baseline activation in both right and left dorsolateral prefrontal clusters was associated with greater reductions in symptom scores in the wait-list group (P < .03). Greater baseline dorsal anterior cingulate activation was linked to greater reductions in symptom scores in the treatment group (P < .001).
Further analysis showed that greater ventromedial prefrontal/ventral striatal activation predicted a larger reduction in PTSD symptom scores in the immediate-treatment group (P < .001). Again, the opposite effect was seen in the wait-list group, in which lower baseline activation was predictive of greater symptom reduction (P = .006).
There was no interaction between patient groups and symptom change on the reappraisal task.
Regarding the TMS results, the researchers found that in the treatment group, a reduction of activation in the left amygdala in response to stimulation of the right posterior middle frontal gyrus was associated with greater reductions in PTSD symptoms (P = .003).
However, there was no association between TMS to the right anterior middle frontal gyrus and treatment outcome (P = .141).
In the second article, the team presented the results of a second clinical assessment and fMRI scan that were performed approximately 4 weeks after the final treatment session to determine whether there were any changes in regional brain entropy following psychotherapy.
These scans showed that in the reappraisal task, there was an increase in left lateral frontopolar cortex activation during the cognitive reappraisal of images in the immediate- treatment group (P = .002) but not in the wait-list group.
There was also an increase in connectivity between the ventromedial prefrontal cortex/ventral striatum and the lateral frontopolar cortex after treatment (P = .003), with a nonsignificant decrease in activity seen in the wait-list group (P = .087).
The results also demonstrated that greater increases in left lateral frontopolar reappraisal activation in the immediate-treatment group were associated with significantly greater improvements in symptoms of hyperarousal on the Clinician-Administered PTSD Scale for DSM-IV (P = .005).
Moreover, increases in left lateral frontopolar activation in the treatment group were associated with significant improvements in psychological well-being on the World Health Organization Quality of Life Scale–Brief Version (P < .001).
Following treatment, an analysis of blood-oxygen-level-dependent signals at rest showed that in the immediate-treatment group, there was an increase in entropy in the lateral frontopolar cortex (P < .001), but not in the ventromedial prefrontal cortex/striatum.
The team found that in healthy individuals, TMS in the left frontopolar cortex induced significant deactivation in the ventromedial prefrontal cortex/ventral striatal region (P = .002).
Practical, Clinical Implications
Dr Etkin told Medscape Medical News that although prolonged exposure therapy enhanced certain pathways associated with regulating emotion, these were not the same pathways of emotion regulation that were associated with response to therapy at baseline.
“Most of those are not altered by the therapy itself, and what’s altered seems to a relatively small portion of how you regulate emotion,” he said.
Dr Etkin believes this finding highlights not only the underlying complexity of PTSD but also “our own hubris as a field or as scientists.
“We have this assumption that by treating somebody and their symptoms getting better, we’ve erased all of the evidence of their illness — as it were, the scars of the illness in their brain — and what this has taught us is actually anything but,” he said.
“The thing we see changed during treatment seems not to be there at baseline and is probably compensatory. In other words, we’re teaching them how to adaptively manage their emotions, but we haven’t erased all of the problems that led to PTSD in the first place. It’s still there in their brain, except that they can cope with it better now,” Dr Etkin said.
On the basis of what they have learned, Dr Etkin and his colleagues are developing neurostimulation treatments for PTSD.
“I find it, in many ways, quite ironic that in developing a high-tech brain stimulation treatment, we may use the lowest-tech psychotherapies as our route in. You go where the strength of the data is, but from a history of psychiatry and neuroscience perspective, I just find that appealing. We’re also really interested in pushing into a more clinic-useable biomarker form of treatment prediction.
“So, can we take our understanding of brain circuitry – but now assessed in a way that’s easy to do in the clinic – and bring practical use to the concept of imaging a brain in order to predict outcome?”
The research was supported by the National Institute of Mental Health. Dr Rothbaum has received funding from the Wounded Warrior Project, the Department of Defense, the National Institute of Mental Health, a Brain and Behavior Research Foundation (NARSAD) distinguished investigator grant, the McCormick Foundation, and Transcept Pharmaceuticals; she has served on an advisory board for Genentech, owns equity in Virtually Better, and has received royalties from Oxford University Press, Guilford, American Psychiatric Publishing, and Emory University. Dr Etkin has served as a consultant for Takeda, Otsuka, and Acadia, has received a research grant from Brain Resource, Inc, and owns equity in Akili Interactive. The other authors have disclosed no relevant financial relationships.
Am J Psychiatry. Published online July 18, 2017. Study 1 abstract, Study 2 abstract
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