Pretreatment Rostral Anterior Cingulate Cortex Connectivity With Salience Network Predicts Depression Recovery: Findings From the EMBARC Randomized Clinical Trial

Abstract

Background: Baseline rostral anterior cingulate cortex (rACC) activity is a well-replicated nonspecific predictor of depression improvement. The rACC is a key hub of the default mode network, which prior studies indicate is hyperactive in major depressive disorder. Because default mode network downregulation is reliant on input from the salience network and frontoparietal network, an important question is whether rACC connectivity with these systems contributes to depression improvement.

Methods: Our study evaluated this hypothesis in outpatients (N = 238; 151 female) enrolled in the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) 8-week randomized clinical trial of sertraline versus placebo for major depressive disorder. Depression severity was measured using the Hamilton Rating Scale for Depression, and electroencephalography was recorded at baseline and week 1. Exact low-resolution electromagnetic tomography was used to compute activity from the rACC, and key regions within the default mode network (posterior cingulate cortex), frontoparietal network (left dorsolateral prefrontal cortex), and salience network (right anterior insula [rAI]). Connectivity in the theta band (4.5-7 Hz) and beta band (12.5-21 Hz) was computed using lagged phase synchronization.

Results: Stronger baseline theta-band rACC-rAI (salience network hub) connectivity predicted greater depression improvement across 8 weeks of treatment for both treatment arms (B = -0.57, 95% confidence interval = -1.07, -0.08, p = .03). Early increases in theta-band rACC-rAI connectivity predicted greater likelihood of achieving remission at week 8 (odds ratio = 2.90, p = .03).

Conclusions: Among patients undergoing treatment, theta-band rACC-rAI connectivity is a prognostic, albeit treatment-nonspecific, indicator of depression improvement, and early connectivity changes may predict clinically meaningful outcomes.

Trial registration: ClinicalTrials.gov NCT01407094.

Keywords: Depression; EEG; Functional connectivity; Rostral ACC; Salience network; Sertraline.

Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.

Figure shows the regions of interest (10 mm radius) that were created in the rostral anterior cingulate cortex (rACC), posterior cingulate cortex (PCC), left dorsolateral prefrontal cortex (DLPFC) and right anterior insula (rAI). Resting-state functional connectivity was then computed (by means of lagged phase synchronization) between the rACC, and the PCC (default mode network), left DLPFC (frontoparietal network) and rAI (salience network), in both the theta (4.5-7 Hz) and beta (12.5-21 Hz) frequency bands. For the purposes of visualization, regions of interest shown here are displayed on a 2 × 2 × 2 Montreal Neurological Institute template brain (5 mm resolution is used for analyses in eLORETA).

Figure 2.

Early changes (baseline to week 1) in theta-band connectivity between the rostral anterior cingulate cortex (rACC) and the right anterior insula (rAI) – a major region in the salience network (SN) – as a function of depression remission status. Remission was defined as a Hamilton Depression Rating Scale score of ≤7 at week 8.