Reward-Related Neural Circuitry in Depressed and Anxious Adolescents: A Human Connectome Project

Abstract

Objective: Although depression and anxiety often have distinct etiologies, they frequently co-occur in adolescence. Recent initiatives have underscored the importance of developing new ways of classifying mental illness based on underlying neural dimensions that cut across traditional diagnostic boundaries. Accordingly, the aim of the study was to clarify reward-related neural circuitry that may characterize depressed-anxious youth.

Method: The Boston Adolescent Neuroimaging of Depression and Anxiety Human Connectome Project tested group differences regarding subcortical volume and nucleus accumbens activation during an incentive processing task among 14- to 17-year-old adolescents presenting with a primary depressive and/or anxiety disorder (n = 129) or no lifetime history of mental disorders (n = 64). In addition, multimodal modeling examined predictors of depression and anxiety symptom change over a 6-month follow-up period.

Results: Our findings highlighted considerable convergence. Relative to healthy youth, depressed-anxious adolescents exhibited reduced nucleus accumbens volume and activation following reward receipt. These findings remained when removing all medicated participants (∼59% of depressed-anxious youth). Subgroup analyses comparing anxious-only, depressed-anxious, and healthy youth also were largely consistent. Multimodal modeling showed that only structural alterations predicted depressive symptoms over time.

Conclusion: Multimodal findings highlight alterations within nucleus accumbens structure and function that characterize depressed-anxious adolescents. In the current hypothesis-driven analyses, however, only reduced nucleus accumbens volume predicted depressive symptoms over time. An important next step will be to clarify why structural alterations have an impact on reward-related processes and associated symptoms.

Keywords: anhedonia; connectomics; internalizing disorders; striatum; subcortical volume.

Figure 1.. Group Differences in Subcortical Volumes and Nucleus Accumbens Activation

Note. Panel A displays d effect size values for all subcortical regions from the regression models denoted in the main text controlling for intracranial volume, age, sex, IQ, pubertal status, handedness, ADHD, medication, and head motion during the T1. These values are derived from models examining left and right hemisphere volume separately. Negative Cohen’s d values indicate smaller volume among adolescents diagnosed with depressive and/or anxiety disorders versus healthy control subjects. Panel B displays scatterplots, boxplots, and density plots for differences in average accumbens volumes (residualized for all covariates) for healthy (HC; grey squares) and depressed-anxious participants (DA; red circles). Panel C scatterplots, boxplots, and density plots for differences in average accumbens activity to the Reward-Baseline contrast (residualized for all covariates) for healthy (HC; grey squares) and depressed-anxious participants (DA; red circles).

Figure 2.. Multimodal Prediction Model Fit

Note. Panel A presents adjusted R² (gray) and R² (black) values for the three models tested in the multimodal prediction section predicting MFQ (Mood and Feelings Questionnaire) depression scores at the 6-month follow-up. The first model includes baseline MFQ scores and all covariates. The second model adds average accumbens volumes (sMRI). The third model adds average accumbens Reward vs. Baseline activation (fMRI). Panel B displays the association between residualized accumbens volumes and residualized MFQ (Mood and Feelings Questionnaire) depression scores from the 6-month follow-up, also residualized for all covariates including baseline depression. These represent results from the multimodal prediction model 2 (sMRI) indicating that smaller accumbens volume predict worsening depression symptoms at 6-month follow-up. HC = healthy controls; DA = depressed-anxious.