Biological Psychiatry, 2019, 85(10), 872-880.

Pre-treatment rostral anterior cingulate cortex connectivity with salience network predicts depression recovery: Findings from the EMBARC randomized clinical trial

Alexis E. Whitton^a,c, Christian A. Webb^a,c, Daniel G. Dillon^a,c, Jürgen Kayser^d, Ashleigh Rutherford^c, Franziska Goer^c, Maurizio Fava^a,b, Patrick McGrath^d, Myrna Weissman^d, Ramin Parsey^e, Phil Adams^d, Joseph M. Trombello^f, Crystal Cooper^f, Patricia Deldin^g, Maria A. Oquendo^h, Melvin G. McInnis^g, Thomas Carmody^f, Gerard Bruder^d, Madhukar H. Trivedi^f, Diego A. Pizzagalli^a,c

^aDepartment of Psychiatry, Harvard Medical School, Boston, Massachusetts; ^bDepartment of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; ^cCenter for Depression, Anxiety and Stress Research, McLean Hospital, Belmont, Massachusetts; ^dNew York State Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, New York; ^e Department of Psychiatry, Stony Brook University, Stony Brook, New York; ^fDepartment of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas; ^gDepartment of Psychiatry, University of Michigan, Ann Arbor, Michigan; ^hDepartment of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania

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 (DMN), which prior studies indicate is hyperactive in major depressive disorder (MDD). As DMN downregulation is reliant on input from the salience network (SN) and frontoparietal network (FPN), an important question is whether rACC connectivity with these systems contributes to depression improvement. Method: Our study evaluated this hypothesis in outpatients (N=238; 151 females) enrolled in the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care) 8-week randomized clinical trial of sertraline versus placebo for MDD. 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 (eLORETA) was used to compute activity from the rACC, and key regions within the DMN (posterior cingulate cortex), FPN (left dorsolateral prefrontal cortex) and SN (right anterior insula; rAI). Connectivity in the theta (4.5-7 Hz) and beta (12.5-21 Hz) bands was computed using lagged phase synchronization. Results: Stronger baseline theta-band rACC-rAI (SN hub) connectivity predicted greater depression improvement across 8 weeks of treatment for both treatment arms (B=-0.57, 95% CI=-1.07, -0.08, p=0.03). Early increases in theta-band rACC-rAI connectivity predicted a greater likelihood of achieving remission at week 8 (odds ratio=2.90, p=0.03). Conclusion: Among patients undergoing treatment, theta-band rACC-rAI connectivity is a prognostic, albeit treatment non-specific indicator of depression improvement, and early connectivity changes may predict clinically meaningful outcomes. Trial Registration: clinicaltrials.gov; http://clinicaltrials.gov; NCT01407094.

Key Words: depression; sertraline; rostral ACC; functional connectivity; salience network; EEG

psychophysiology article abstract