Project Summary Major depressive disorder (MDD) is a leading cause of disability worldwide and has a peak period of onset during adolescence. Most individuals with MDD will experience multiple episodes over their life course, relating to poor outcomes, suicide risk, and large personal and public health burden. Thus, identifying mechanisms of MDD illness and course is critical to identify novel intervention targets. MDD is characterized by deficits within the RDoC Positive Valence System (PVS), particularly reward-related and motivational alterations that rely on dopamine (DA) brain systems. While DA functioning has been examined in adults using Position Emission Tomography (PET), the use of radioisotope tracers makes PET invasive and untenable for pediatric research. As an alternative, the current study leverages a novel, fast, and non-invasive MRI acquisition sensitive to neuromelanin (NM) to probe midbrain DA function in youth with remitted MDD. Further, we expect midbrain DA to contribute to alterations in key PVS domains disrupted in depression. Specifically, the current study examines effort discounting–the process by which individuals calculate the cost- benefit of expending effort to achieve reward. Effort discounting is shown in animal work to rely on midbrain DA and to activate striatal regions in human MRI studies. Deficits in effort discounting, a critical part of motivation, likely contributes to anhedonic symptoms in depression. Although alterations are noted in adult MDD, the neural encoding of effort discounting has yet to be tested in adolescents with depression. The current R21 aims to address several critical gaps by probing the PVS across multiple units of analysis in 14-17-year-olds with depression (MDD = 30) and matched healthy controls (HC = 30), capitalizing on a recently funded R01 (MH119771-01A1) for recruitment and clinical assessment. First, Aim 1 will test, for the first time, whether adolescents with MDD exhibit hypothesized reductions in DA functioning in key midbrain regions, the substantia nigra and ventral tegmental area, as indexed by NM-MRI. Further, we will examine whether adolescents with MDD exhibit blunted neural encoding of effort discounting in the ventral striatum via fMRI and will explore whether midbrain NM mediates these differences. Second, Aim 2 will test whether these neural markers improve prediction of real-world functioning in these adolescents using an innovative smartphone app for deep, digital phenotyping. This will include both unobtrusive, passive sensing of daily physical activity, as an index for motivational capacity, as well as repeated self-report of positive affective and anhedonic symptoms during everyday functioning via ecological momentary assessment. Last, Aim 3 will test the ability of these neural markers to predict the worsening of depressive and anhedonic symptoms over a 6-month follow-up. In summary, this project has the promise to identify DA and PVS deficits that contribute to depression, which, ultimately, will lead to clinical translation for innovative biological risk markers and intervention targets.

Project Narrative Research in adults with depression implicates dopaminergic deficits that may contribute to core hedonic and motivational alterations; however, this has not been tested in adolescents. The current study takes an RDoC approach to test dopamine and reward-related deficits in adolescents with depression to identify how these factors predict real-world affective and motivational deficits and the longitudinal course of depressive symptoms.