Katherine R Luking, Ph.D. - US grants

DESCRIPTION (provided by applicant): This proposal explores how the neural and behavioral mechanisms involved in reward/punishment processing may be affected in pre-puberty onset Major Depressive Disorder (MDD). Problems experiencing pleasure, anhedonia, is one of the core components of MDD. It is thought that this symptom is related to changes in processing within the reward circuitry. Namely adults and adolescents with MDD show attenuated response to reward in brain regions such as the dorsal and ventral striatum, orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (PFC), all known to be involved in reward processing. There is less evidence for alterations in punishment processing at the neural level, but girls at increased risk for developing MDD show increased insula activity when receiving punishments, which aligns with behavioral evidence that individuals with MDD are hypersensitive to punishment. While it seems clear that adolescents and adults with MDD, and even adolescents at risk for MDD, experience changes in reward processing, it has yet to be determined whether pre- puberty cases of MDD are characterized by similar reward/punishment processing deficits. Regions involved in reward processing such as the OFC and striatum undergo significant development over the course of puberty and some researchers have hypothesized that this developmental process could contribute to the rapid rise in incidence of MDD through adolescence. The current proposal tests the hypothesis that pre-puberty children (7-10 years) with MDD, prior to adolescent development of reward systems, are hyper-responsive to punishments and hypo-responsive to rewards compared to healthy peers. We will test this hypothesis both behaviorally and at the neural level in a two-session experiment (using state-of-the-art functional magnetic resonance imaging methods and analytical techniques) that examines whether these children are able to adjust their behavior based on reward/punishment feedback and whether activity within brain regions associated with reward/punishment processing is different between groups during receipt of candy rewards and punishments. Success in this work would provide important information about the continuity of the neurobiological and behavioral symptoms of MDD over the course of development. This information could impact development of future treatment options tailored to the specific developmental and clinical needs of this population struggling with MDD.) PUBLIC HEALTH RELEVANCE: This project has high relevance for the understanding and future treatment of childhood Major Depressive Disorder (MDD). Investigating reward and punishment processing within pre- pubertal MDD cases will give information regarding the continuity of changes in behavioral and neural responses to reward/punishment within adolescent and adult MDD. This is of particular importance given that the neuro-circuitry involved in reward/punishment processing undergoes significant development over adolescence. Understanding whether changes in reward processing occurs in MDD cases prior to the neural development associated with puberty will provide a more complete view of childhood MDD which is critical given the lack of safe and effective treatment options for this population. This information may help drive the development of more effective interventions in this population.

ABSTRACT Changes in reward system structure and function are thought to underlie many of the behavioral features, both positive and negative, that characterize adolescence. While increasing striatal response to reward during adolescence putatively supports positive and age typical behaviors such as greater exploration and peer affiliation, blunted striatal response to reward is observed in adolescent Major Depressive Disorder (MDD), maternally defined MDD-risk, and prospective worsening of depressive symptoms. Although it is clear that functional response to reward changes dramatically over normative development, and that blunted reward responding is linked to negative outcomes, it is unclear how depression risk may impact longitudinal trajectories of positive valence system function over adolescence. Understanding how and why maternally defined depression risk may interact with typical developmental processes could lead to a better understanding of the etiopathogenesis of depression and the development of prevention/intervention programs. To investigate these questions the proposed study aims to employ longitudinal functional neuroimaging methods to first examine whether blunted striatal reward responding is a consistent correlate of MDD-risk from childhood through adolescence (i.e. relates to the intercept rather than the slope of striatal reward response) or whether such blunting emerges/strengthens over development (i.e. relates to the rate of change in striatal reward response). Whether maternal neurobiological features, including striatal response to reward and structural integrity of reward-related white matter tracts, mediate relationships between maternal MDD history and offspring function will also be examined. To investigate these questions the proposed study capitalizes on an existing longitudinal data set where neural (fMRI) response to reward feedback was evaluated in a large sample of 8-14 year-old girls, with a second fMRI scan to be collected at a two-year follow up. Functional measures of maternal neural response to reward (fMRI) as well as white matter structural integrity (Diffusion Spectrum Imaging ? DSI) will also be collected at the two-year follow up, and are novel contributions of the proposed study. Analyses will focus on the never-depressed daughters of mothers with either a history of depression or without a history of any Axis I disorder. The proposed study will provide training in advanced neuroimaging techniques (DSI and fMRI), models of risk and developmental psychopathology, as well as advanced statistical techniques for both mediation and longitudinal analyses. This research will provide an enhanced understanding of a core dysfunctional mechanism in depression risk, reward responsiveness, and its trajectory across development.