Project Summary Major depressive disorder (MDD) is a serious public health problem that has, at best, modest treatment response. One reason for this mixed efficacy is that MDD has a very heterogeneous clinical presentation. One way to parse the heterogeneity is to investigate the role of particular features of MDD, an endeavor that can also help identify novel and focal targets for treatment and prevention efforts. Psychomotor disturbance (e.g., psychomotor agitation [PmA] and retardation [PmR]) has long been viewed as a particularly pernicious feature of MDD, and yet we know surprisingly little about these behaviors. For example, it is unknown if motor disturbance occurs only in active depression, or whether it also continues into remission (potentially signaling vulnerability for relapse). There also has been little work (a) linking PmA & PmR with abnormal neural circuitry mediating these motor behaviors, (b) examining how motor symptoms change over the course of illness, and (c) investigating whether PmR & PmA represent a single underlying process, or reflect distinct mechanisms. The present proposal seeks to test these questions and also identify powerful and easy to administer tools to assess these behaviors in clinical practice. The proposed project will recruit those with current MDD (n = 100), remitted MDD (n = 100) and controls (n = 50) and take a Research Domain Criteria (RDoC) approach by comparing the three groups on multiple indicators of PmR and PmA (Aim 1). Specifically, we will assess PmR and PmA with self and observer- based reports, behavioral assessments in the laboratory (Velocity Scaling [PmR] and Force Variability [PmA]), and behavioral assessments in subjects' natural environment (actigraphy and daily typing behavior on one's smartphone [texting, emailing, etc.]). These behavioral measures are particularly critical as they yield more fine-grained and objective assessments of PmR and PmA that may be missed by traditional diagnostic assessments. Aim 2 seeks to examine the structural (diffusion tensor) and functional (resting state fMRI) connectivity of motor circuitry of the three groups as well as the relation between motor circuitry and the proposed indicators of PmR and PmA. For this aim, we will utilize innovative graph theory metrics of connectivity of the three primary motor circuits identified in animal and human studies (specifically, basal ganglia, cerebellar and cortico-cortical motor circuits) which will provide a comprehensive examination of motor system organization in MDD. Aim 3 seeks to follow-up subjects three times over 18 months to evaluate whether motor symptoms change in tandem with overall depressive symptoms and functioning over time and/or whether baseline PmR/PmA predicts course of depression an functoining. Aim 3 is particularly clinically significant. Finding that motor and overall depression severity co- vary over time, or that motor variables predict subsequent change in overall depression severity, would support the potential clinical utility of the proposed novel, reliable, and easily administered motor assessments.

PROJECT NARRATIVE The goal of this proposal is to better understand slowing and agitated movements that are characteristic of depression, and determine if these movements occur only in active depression, or are also present in individuals whose depression has remitted. We will also evaluate the brain basis for such behaviors, and examine if these abnormalities in movement change over time as currently depressed individuals recover, or as remitted individuals relapse. Taken together, understanding these movement abnormalities may lead to path-breaking early detection strategies, that help to predict the course of depression, and inform treatment strategies.