Neurodevelopmental Mechanisms Underlying the Onset of Depression among At-Risk Youth: The Role of Dysregulation in the Negative Valence System

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PROJECT SUMMARY Offspring of mothers with major depressive disorder (MDD) are at substantially elevated risk for developing depression by early adulthood. Devastatingly, 60% of these high risk (HR) youth will meet criteria for MDD by age 25, versus only 16% of individuals in the general population. Recognized by the 2022 NIMH Strategic Plan, the discovery of a reliable, objective marker of MDD risk is critical for earlier detection to facilitate targeted prevention efforts for HR youth. Across studies, HR offspring exhibit maladaptive reactivity and regulatory responses to negative social-emotional stimuli. During functional magnetic resonance imaging (fMRI) tasks probing negative emotion processing (NEP), youth of depressed, versus nondepressed, mothers consistently exhibit dysfunction in brain networks responsible for adaptive NEP, including salience emotional and cognitive control networks (SEN and CCN). Critically, pilot data from the Early-Stage Principal Investigator provide compelling evidence that SEN-CCN network dysfunction during NEP may represent a brain-based marker of depression among HR youth. However, a mechanistic test of this hypothesis has yet to be evaluated in an adequately powered and demographically distributed sample of HR and low risk (LR) youth followed over a sufficient period to detect the emergence of MDD. The current R01 will employ a novel, multimodal, longitudinal study to test whether functional properties of brain networks supporting NEP predict future depression trajectories among HR and LR youth (Aim 1). In doing so, we will examine whether SEN-CCN dysfunction during NEP changes over time once depression emerges. Clarifying the question of stability is critical to determining whether SEN-CCN dysfunction during NEP is modifiable and may represent a novel MDD treatment target in HR youth (Aim 2). Prior work also shows that HR youth exhibit deficits in NEP across physiological (event-related potentials, ERPs), behavioral, and self-report indices. To determine which risk markers should be prioritized for prevention, an innovative aspect of the proposal will be to test if SEN-CCN function during NEP is superior to other cost-effective markers of risk in predicting youth depression, and whether a multi-indicator model including several units of NEP improves MDD prediction indices (Aim 3). Finally, we will explore how biological sex and puberty interact with neurodevelopmental pathways to predict depression trajectories in HR youth. To achieve these aims, we will recruit 250 youth (with and without with a maternal history of recurrent MDD). At baseline, youth (ages 9-14, 50% female) will be lifetime free of MDD to capture the emergence of depression during a period of elevated MDD risk. At baseline, 12-, and 24- months, youth will complete tasks probing negative social- emotional reactivity and regulation to generate multimodal NEP measures (fMRI, ERPs, behavior). Every 6 months, we will assess youth’s depressive symptoms and diagnoses via online surveys and phone interviews (up to 24 months). Findings will contribute to the discovery of biomarkers that are linked to the development and course of MDD among HR youth, which can be utilized in targeted MDD prevention and intervention studies.