Associations between resting-state functional connectivity and treatment response in a randomized clinical trial for posttraumatic stress disorder

Abstract

Background: Alterations in resting-state functional connectivity (rsFC) have been reported in posttraumatic stress disorder (PTSD). Here, we examined pre- and post-treatment rsFC during a randomized clinical trial to characterize alterations and examine predictors of treatment response.

Methods: Sixty-four combat veterans with PTSD were randomly assigned to prolonged exposure (PE) plus placebo, sertraline plus enhanced medication management, or PE plus sertraline. Symptom assessment and resting-state functional magnetic resonance imaging (fMRI) scans occurred before and after treatment. Twenty-nine trauma-exposed combat veterans without PTSD served as a control group at intake. Seed-based and region of interest (ROI)-to-ROI connectivities, as well as an exploratory connectome-based approach were used to analyze rsFC patterns. Based on previously reported findings, analyses focused on Salience Network (SN) and Default-Mode Network (DMN).

Results: At intake, patients with PTSD showed greater DMN-dorsal attention network (DAN) connectivity (between ventromedial prefrontal cortex and superior parietal lobule; family-wise error corrected p = .011), greater SN-DAN connectivity (between insula and middle frontal gyrus; corrected p = .003), and a negative correlation between re-experiencing symptoms and within-DMN connectivity (between posterior cingulate cortex (PCC) and middle temporal gyrus; corrected p < .001). We also found preliminary evidence for associations between rsFC and treatment response. Specifically, high responders (≥50% PTSD symptom improvement), compared with low responders, had greater SN-DMN segregation (i.e., less pre-treatment amygdala-PCC connectivity; p = .011) and lower pre-treatment global centrality (p = .042).

Conclusions: Our findings suggest neural abnormalities in PTSD and may inform future research examining neural biomarkers of PTSD treatment response.

Trial registration: ClinicalTrials.gov NCT01524133.

Keywords: PTSD; fMRI; functional connectivity; prolonged exposure; resting state; sertraline.

Published 2020. This article is a U.S. Government work and is in the public domain in the USA.

Figures

Figure 1.

Visualization of the seeds that were used (Sheynin et al., 2020). Coordinates (De Luca et al., 2006): dACC (±4,−6,40) 10mm rad sphere; PCC (±2,−51,27) 10mm rad sphere; vmPFC (±2,54,−4) 10mm rad sphere; Hippocampus (±20,−19,−18) 5mm rad sphere. Anatomical masks were used for insula (Sripada R.K., King A.P., Welsh, R.C., et al., 2012) and amygdala (Sripada R.K., King A.P., Garfinkel S.N., et al., 2012).

Figure 2.

Significant baseline differences in rsFC between PTSD and control groups (seed-based approach). (A) Insula seed. Patients > controls contrast revealed greater connectivity between SN and DAN in patients, and specifically, between insula and MFG (FWE corrected; p = .003). (B) VmPFC seed. Patients > controls contrast revealed greater connectivity between DMN and DAN in patients, and specifically, between vmPFC and superior parietal lobule (corrected p = .011). (C) PCC seed. Within-DMN connectivity, and specifically, between PCC and anterior MTG, was negatively correlated with PTSD severity, and specifically, with re-experiencing symptoms (corrected p < .001).

Figure 3.

Pre-treatment rsFC is associated with treatment outcome (ROI-ROI analyses). (A) Patients who had high response to treatment ( ≥ 50% change in CAPS) had less amygdala-PCC (SN-DMN) connectivity (i.e. greater segregation) before treatment than patients who had low response to treatment (p = .011). Interestingly, the controls also had a low connectivity value (around zero), and only low responders had a value different (greater) than zero (p = .010). (B) No difference is amygdala-PCC connectivity after treatment.