Amygdala and Insula Connectivity Changes Following Psychotherapy for Posttraumatic Stress Disorder: A Randomized Clinical Trial

Abstract

Background: Exposure-based psychotherapy is a first-line treatment for posttraumatic stress disorder (PTSD), but its mechanisms are poorly understood. Functional brain connectivity is a promising metric for identifying treatment mechanisms and biosignatures of therapeutic response. To this end, we assessed amygdala and insula treatment-related connectivity changes and their relationship to PTSD symptom improvements.

Methods: Individuals with a primary PTSD diagnosis (N = 66) participated in a randomized clinical trial of prolonged exposure therapy (n = 36) versus treatment waiting list (n = 30). Task-free functional magnetic resonance imaging was completed prior to randomization and 1 month following cessation of treatment/waiting list. Whole-brain blood oxygenation level-dependent responses were acquired. Intrinsic connectivity was assessed by subregion in the amygdala and insula, limbic structures key to the disorder pathophysiology. Dynamic causal modeling assessed evidence for effective connectivity changes in select nodes informed by intrinsic connectivity findings.

Results: The amygdala and insula displayed widespread patterns of primarily subregion-uniform intrinsic connectivity change, including increased connectivity between the amygdala and insula; increased connectivity of both regions with the ventral prefrontal cortex and frontopolar and sensory cortices; and decreased connectivity of both regions with the left frontoparietal nodes of the executive control network. Larger decreases in amygdala-frontal connectivity and insula-parietal connectivity were associated with larger PTSD symptom reductions. Dynamic causal modeling evidence suggested that treatment decreased left frontal inhibition of the left amygdala, and larger decreases were associated with larger symptom reductions.

Conclusions: PTSD psychotherapy adaptively attenuates functional interactions between frontoparietal and limbic brain circuitry at rest, which may reflect a potential mechanism or biosignature of recovery.

Keywords: Connectivity; Imaging; PTSD; Psychotherapy; Resting; fMRI.

Copyright © 2020 Society of Biological Psychiatry. All rights reserved.

Figures

Figure 1.

Treatment-related increases in intrinsic connectivity of the insula and amygdala with each other and with the posterior ventromedial prefrontal cortex. Figure depicts regions of the insula displaying treatment-related increases in intrinsic connectivity with the amygdala (A), and regions of the posterior ventromedial prefrontal cortex displaying increased connectivity with both the amygdala and insula (B). FDR-corrected Z values for the treatment arm x time effect are rendered on an average brain surface with signs indicating the directionality of change in the prolonged exposure arm. Positive Z values indicate greater connectivity in the prolonged exposure arm at post-treatment vs. pre-treatment, whereas negative signs indicate greater connectivity at pre-treatment vs. post-treatment. Seed regions are displayed on the MNI average brain. Error bars indicate ± 1 S.E. PE = prolonged exposure; PFC = prefrontal cortex; Post = post-treatment; Pre = pre-treatment; WL = waiting list.

Figure 2.

Treatment-related decreases in intrinsic connectivity of both the amygdala and insula with fronto-parietal regions and associations with treatment response. Figure depicts regions of the left IFJ and left IPS that displayed treatment-related decreases in connectivity with both the amygdala and insula, identified via conjunction analysis (A). Solid lines are the prolonged exposure arm and dotted lines represent the waiting list arm. Of these effects, greater decreases in amygdala-left IFJ connectivity and greater decreases in insula-left IPS connectivity were associated with larger reductions in CAPS Total scores from pre- to post-treatment (B). Graphs in B display changes in CAPS total scores from pre- to post-treatment with separate plots for individuals from each treatment arm above and below the grand mean for the connectivity decreases. Note this median split is done for visual purposes only, and the analysis treated connectivity change as a continuous variable. Scatter plots depicting the relationships between change in connectivity (post-treatment vs. pre-treatment) and change in Clinician-Administered PTSD Scale total scores (pre-treatment vs. post-treatment) are also displayed for additional visualization of relationships. Note that these reflect data from completers only and are thus not directly comparable to results from the mixed model analyses. Areas from conjunction analysis are rendered on an average brain surface with signs indicating the directionality of change in the prolonged exposure arm (blue denoting less connectivity at post-treatment, yellow denoting greater connectivity at post-treatment). Seed regions are displayed on the MNI average brain. Error bars indicate ± 1 S.E. CAPS = Clinician-Administered PTSD Scale; IFJ = inferior frontal junction; IPS = intraparietal sulcus; PE = prolonged exposure; Pre = pre-treatment; Post = post-treatment; WL = waiting list.

Figure 3.

Baseline effective connectivity parameters of DCM network and differential modulation of time-related changes by treatment arm. The picture in A depicts the baseline effective connectivity parameters of the DCM network encompassing the left and right amygdala and insula as well as the left IFJ and left IPS regions found to display uniform treatment-related decreases in intrinsic connectivity that were associated with PTSD symptom changes. Only connections with strong evidence (posterior probabilities > 0.95) are depicted. Blue lines indicate inhibitory influences while red lines indicate excitatory influences. Shaded blue circles indicate inhibitory self -connections with strong evidence. Lines are scaled by the strength of the parameter from 0 to 0.5 Hz. Picture in B depicts the same network structure overlaid with parameters that displayed strong evidence (posterior probabilities > 0.95) for differential time-related modulation as a function of treatment arm, i.e. a treatment arm x time effect. Connections overlaid with an additional red arrow indicate a greater time-related shift from pre- to post-treatment towards more excitation/less inhibition for prolonged exposure vs. waiting list, while connections overlaid with an additional blue arrow indicate a greater time-related shift from pre- to post-treatment towards more inhibition/less excitation for prolonged exposure vs. waiting list. Connections in black/grey indicate no strong evidence for a differential time-related modulation of connection strength as a function of treatment arm. Amyg = amygdala; DCM = dynamic causal modeling; Hz = hertz; IFJ = inferior frontal junction; IPS = intraparietal sulcus; Ins = Insula; L = left; PE = prolonged exposure; R = right; WL = waiting list.