DESCRIPTION (provided by applicant): Depression is one of the most debilitating diseases worldwide, and the social and economic burden is a major public health challenge. Childhood maltreatment is a common risk factor for depression and when present further compromises adaptive functioning. Important clinical differences exist between depression with and without maltreatment, suggesting that they constitute two distinct phenotypes and require different treatment guidelines. Preliminary data from genetic and neurobiological studies in adults also support this notion. The aim of this proposal is to determine whether adolescents with depression and a history of maltreatment have distinct differences in structural and functional neural circuits compared to depressed adolescents without maltreatment. The study will focus on adolescence because, except for infancy, it is the greatest period of neural change and maturation, and the effects of maltreatment on the brain appear during this developmental stage. Four groups will be recruited: adolescents with clinical depression and a history of childhood maltreatment, adolescents with clinical depression and no maltreatment history, adolescents with no psychiatric disorder but have a history of childhood maltreatment, and adolescents with no psychiatric disorder or maltreatment history. The participants will undergo structural magnetic resonance imaging and diffusion tensor imaging studies to measure macro- and micro-structural connectivity/tractography profiles in key neural networks that are associated with core symptoms of depression (specifically the fronto-limbic circuit for negative mood and the fronto-striatal circuit for anhedonia). They will undergo resting-state and task-based functional magnetic resonance imaging studies to measure functional connectivity profiles in these neural networks. In addition to identifying group differences between the two depression subtypes/phenotypes, we will assess whether maltreatment moderates the associations between dimensional ratings of specific depressive symptom profiles (e.g., anhedonia, negative affect, rumination) and neural circuits. To our knowledge, this study is the first to utilize multi-modal imaging to differentiate structural and functional neural substrates associated with the combination of depression and maltreatment relative to those associated with depression. The four group (2 x 2) design will enable us to determine if the observed differences between the two depressed groups are a function of a main (additive) effect of maltreatment or an interaction effect (i.e., the neural characteristics associated with depression are altered by maltreatment). The results of the study will increase our understanding of the existing neural models of depression and have the potential to improve clinical practice by enhancing treatment guidelines and algorithms. Differentiation of the neural markers associated with the two depression subtypes could be used to predict treatment outcome more effectively and to more selectively index clinical responses to treatment. Identifying the unique neural substrates associated with depression in victims of maltreatment would also facilitate the development and testing of new treatments for those who do not respond well to current approaches (as observed in some clinical trials).

PUBLIC HEALTH RELEVANCE: Depressive illness is the leading cause of disability world-wide, and it frequently begins during adolescence. Child abuse/neglect is a major risk factor for depression, and depression resulting from abuse/neglect may be different from depression due to other causes. We will identify the brain changes in these two subtypes of depression in adolescents which will increase our understanding of their biological bases and improve treatment guidelines.