Neuroticism and Individual Differences in Neural Function in Unmedicated Major Depression: Findings from the EMBARC Study

Abstract

Background: Personality dysfunction represents one of the only predictors of differential response between active treatments for depression to have replicated. In this study, we examine whether depressed patients with higher neuroticism scores, a marker of personality dysfunction, show differences versus depressed patients with lower scores in the functioning of two brain regions associated with treatment response, the anterior cingulate and anterior insula cortices.

Methods: Functional magnetic resonance imaging data during an emotional Stroop task were collected from 135 adults diagnosed with major depressive disorder at four academic medical centers participating in the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) study. Secondary analyses were conducted including a sample of 28 healthy individuals.

Results: In whole-brain analyses, higher neuroticism among depressed adults was associated with increased activity in and connectivity with the right anterior insula cortex to incongruent compared to congruent emotional stimuli (ks>281, ps<0.05 FWE corrected), covarying for concurrent psychiatric distress. We also observed an unanticipated relationship between neuroticism and reduced activity in the precuneus (k=269, p<0.05 FWE corrected). Exploratory analyses including healthy individuals suggested that associations between neuroticism and brain function may be nonlinear over the full range of neuroticism scores.

Conclusions: This study provides convergent evidence for the importance of the right anterior insula cortex as a brain-based marker of clinically meaningful individual differences in neuroticism among adults with depression. This is a critical next step in linking personality dysfunction, a replicated clinical predictor of differential antidepressant treatment response, with differences in underlying brain function.

Keywords: Emotion Regulation; Major Depressive Disorder; Neuroticism; Precuneus; Right Anterior Insula; fMRI.

Figures

Figure 1

Neural Correlates of the Incongruence Effect in Major Depression. Significant clusters (p

Figure 2

Effect of Neuroticism on BOLD Response in Major Depression. Significant clusters of positive (Panel A) and negative (Panel B) relationships between neuroticism and brain activity among adults with major depressive disorder, covarying for the effects of site, sex, age, depression, anhedonia, and anxiety. Scatter plots are provided for display purposes only. They depict the bivariate relationships between neuroticism (abscissa) and BOLD response in the significant clusters (ordinate), represented by the beta coefficient associated with the incongruent (I) - congruent (C) contrast. Insets display slope estimates (standardized βs from regression models of extracted data, covarying for the above variables) representing the relationship between neuroticism and BOLD response to each stimulus type.

Figure 3

Effect of Neuroticism on Functional Connectivity with the Dorsal Right Anterior Insula in Major Depression. Significant clusters represent results of generalized psychophysiological interaction analyses using a dorsal right anterior insula seed derived from a recent parcellation study (51). To aid interpretation, clusters have been overlaid on the seven-network parcellation of large-scale cortical networks derived by (56). Scatter plots are provided for display purposes only. They depict the bivariate relationships between neuroticism (abscissa) and parameter estimates (ordinate) of the contrast in connectivity during the incongruent (I) versus congruent (C) conditions. Insets display slope estimates (standardized βs from regression models of extracted data, covarying for the above variables) representing the relationship between neuroticism and connectivity parameter estimates for each stimulus type.