Selective Effects of Psychotherapy on Frontopolar Cortical Function in PTSD

Abstract

Objective: Exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD), but a comprehensive, emotion-focused perspective on how psychotherapy affects brain function is lacking. The authors assessed changes in brain function after prolonged exposure therapy across three emotional reactivity and regulation paradigms.

Method: Individuals with PTSD underwent functional MRI (fMRI) at rest and while completing three tasks assessing emotional reactivity and regulation. Individuals were then randomly assigned to immediate prolonged exposure treatment (N=36) or a waiting list condition (N=30) and underwent a second scan approximately 4 weeks after the last treatment session or a comparable waiting period, respectively.

Results: Treatment-specific changes were observed only during cognitive reappraisal of negative images. Psychotherapy increased lateral frontopolar cortex activity and connectivity with the ventromedial prefrontal cortex/ventral striatum. Greater increases in frontopolar activation were associated with improvement in hyperarousal symptoms and psychological well-being. The frontopolar cortex also displayed a greater variety of temporal resting-state signal pattern changes after treatment. Concurrent transcranial magnetic stimulation and fMRI in healthy participants demonstrated that the lateral frontopolar cortex exerts downstream influence on the ventromedial prefrontal cortex/ventral striatum.

Conclusions: Changes in frontopolar function during deliberate regulation of negative affect is one key mechanism of adaptive psychotherapeutic change in PTSD. Given that frontopolar connectivity with ventromedial regions during emotion regulation is enhanced by psychotherapy and that the frontopolar cortex exerts downstream influence on ventromedial regions in healthy individuals, these findings inform a novel conceptualization of how psychotherapy works, and they identify a promising target for stimulation-based therapeutics.

Trial registration: ClinicalTrials.gov NCT01507948.

Keywords: Brain Imaging Techniques; Emotion Regulation; Frontopolar Cortex; Posttraumatic Stress Disorder; Psychotherapy; Transcranial Magnetic Stimulation.

Figure 1. Prolonged exposure increases left frontopolar cortex activation during cognitive reappraisal

A schematic of the task contrast is displayed at the top of the figure, which compares brain activation while individuals deliberately and consciously reduce negative emotion in response to an affectively charged picture relative to when they simply look at the picture and experience their natural emotional response. The line graph depicts the mean individual mixed model-derived predicted values for activation within each treatment arm and at each timepoint. The interaction effect of time and treatment arm is rendered on a template surface, in which individuals in the prolonged exposure group (N = 36) displayed significantly greater increase in activation over time relative to those in waitlist (N = 30). Pre= pre-treatment; Post = post-treatment; ** = p < 0.01.

Figure 2. Prolonged exposure increases connectivity between the left frontopolar cortex and the ventromedial prefrontal cortex/ventral striatum: A circuit conveying downstream influence in healthy individuals

Panel A depicts the treatment arm × time interaction effect in which individuals in the prolonged exposure group (N = 36) displayed significantly greater increases in connectivity from the left frontopolar cortex to the ventromedial prefrontal cortex/ventral striatum during cognitive reappraisal relative to individuals in waitlist (N = 30). The line graph depicts the mean individual mixed model-derived predicted values for connectivity within each treatment arm and at each timepoint. The activation change and its connectivity target are rendered on average surfaces. Panel B depicts the causal effect of left frontopolar stimulation in healthy individuals (N = 14) on blood oxygenation-level dependent signal change in this same ventromedial prefrontal/striatal region relative to right motor cortex stimulation, which was used as a comparison site. The bar graph depicts the mean individual ventromedial prefrontal/ventral striatal activation values for each stimulation site. The top left brain depicts frontopolar stimulation site, and the top right brain depicts right motor cortex stimulation site, both rendered on an average surface. fMRI = functional magnetic resonance imaging; Fp = frontopolar cortex; M1 = primary motor cortex; PFC = prefrontal cortex; Pre = pre-treatment; Post = post-treatment; TMS = transcranial magnetic stimulation; ** = p < 0.01, *** = p < 0.001.

Figure 3. Treatment-related changes in left frontopolar activation during reappraisal relate to improvements in PTSD hyperarousal symptoms and psychological well-being

Diagram at the top depicts the reappraisal contrast from the task, and the treatment arm × time interaction effect in the left frontopolar cortex is rendered on an average brain surface below. Scatterplots depict relationships between average within-subject activation increases over time in left frontopolar cortex during reappraisal (pre-treatment subtracted from post-treatment) and within-subject changes (post-treatment subtracted from pre-treatment) in: Panel A) hyperarousal symptoms assessed by the Clinician-Administered PTSD Scale; and Panel B) Psychological Health subscale from the WHO Quality of Life BREF measure. CAPS = Clinician-Administered PTSD Scale for DSM-IV; Psych = psychological; WHO-QoL = WHO-Quality of Life BREF.

Figure 4. Prolonged exposure increases resting regional brain entropy of the same lateral frontopolar region displaying treatment-related change in functional activation during cognitive reappraisal

Panel A depicts a brain map of the mean regional brain entropy distribution across the entire PTSD sample at baseline, with regions displaying regional entropy values greater than the whole brain mean displayed in red and those displaying regional entropy values lower than the whole brain mean displayed in blue. Image is overlaid on the Montreal Neurological Institute 152-person average T1 structural. Panel B depicts the reappraisal frontopolar activation effect rendered on an average brain surface. The line graph depicts the mean individual mixed model-derived predicted entropy values within each treatment arm and timepoint. Pre= pre-treatment; Post = post-treatment; ** = p < 0.01; *** = p < 0.001.