Dana L. McMakin, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Depressive disorders in young adulthood are highly prevalent and have been associated with serious deficits in psychosocial and global functioning. Treatments for depression that employ cognitive-behavioral techniques to address the dysregulation of negative emotion have been moderately successful. However, research in clinical psychology and affective neuroscience indicates that the dysregulation of positive emotion characterizes depression and distinguishes it from other mood disorders. The goal of the current study is to develop a treatment aimed at improving positive emotion regulation among individuals with depression. The intervention will be adapted from the written disclosure paradigm (WDP). The traditional WDP focuses on writing about past traumatic events and demonstrates improvements in physical and psychological health. Researchers have recently urged the exploration of WDP as a clinical intervention for psychopathology. The present study will adapt the WDP to direct dysphoric individuals to savor positive events in several writing sessions in order to enhance and extend the experience of positive emotion. Treatment efficacy will be assessed by examining post-intervention changes in depressive symptomatology as well as changes in positive emotion, savoring and attribution skills, pleasant life events and the behavioral activation system. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Rates of depression rise sharply during adolescence, becoming a leading cause of lifetime disability with high rates of recurrence and chronic impairment. Despite progress in efficacious treatments, only 50% of treated adolescents attain sustained remission. Recent insights from developmental affective neuroscience suggest that there may be windows of brain plasticity during adolescence when certain skills for effectively managing affect (emotions and motivations) may best be acquired. To this end, the candidate's long term career objective is to develop more effective treatments for affective disorders among youth by utilizing a developmental affective neuroscience framework to guide this effort. The candidate's immediate focus is to target positive affective functioning among adolescents with depression, and to investigate growing evidence that adolescence may be an opportune maturational period for intervention. Normative remodeling of key neural substrates of positive affect and reward systems at puberty plays a role in the development of depression during adolescence. These changes may signal a relatively sensitive period (surrounding pubertal maturation) when practicing key skills for managing positive affect may have an enduring impact on brain-behavior mechanisms of depression. The current Mentored Patient Oriented Career Development Award will uniquely position the candidate to advance this agenda. Her background includes specialized training in child clinical psychology, treatment development for adolescent depression, psychosocial approaches to affective functioning, basic multivariate statistics, and a broad exposure to the basics of developmental affective neuroscience. To most effectively bridge developmental affective neuroscience with treatment innovation she seeks to deepen and extend her training to include: 1) a more intricate understanding of brain-behavior theories of positive affective functioning, particularly as they relate to the development of depression, 2) advanced statistics and methods for examining brain-behavior mechanisms in the context of pediatric treatment trials, and 3) strategies for treatment development that translate these brain-behavior theories and methods to clinical practice. The University of Pittsburgh is an outstanding environment in which to engage in the interdisciplinary training required to achieve these training goals. The candidate's mentors-David Brent, Ronald Dahl and Greg Siegle-have combined expertise in adolescent depression and treatment development, neuro-developmental pathways to affective disorders, and multi-method approaches to measuring brain-behavior mechanisms of treatment response. In addition to their individual productivity and strong mentoring histories, this team of investigators has collaborated on large-scale, interdisciplinary projects to advance the scientific understanding and treatment of affective disorders among youth. The proposed project draws on this training and expertise to develop a treatment module (6 sessions) for improving features of positive affective functioning among adolescents with depression. The Positive Affect Stimulation and Sustainment [PASS] module teaches strategies for sustaining positive affective states, with the goal of strengthening key neural circuitry during this period of developmental plasticity. Relative deficits in features of positive affective functioning are central to the development and clinical course of depression;yet, few treatments target these deficits. Behavioral activation increases exposure and reinforcement related to pleasant events, but emerging evidence suggests that affective states quickly fade for depressed individuals following positive experiences. As such, PASS may augment behavioral activation by extending affective experiences. The candidate's prior research supports the feasibility of PASS, as well as changes in subjective positive emotion and depressive symptoms. The current study proposes to extend this work with a randomized controlled trial (RCT) in which adolescents with depression (n=60;ages 12-17) will be randomized to PASS or Cognitive Therapy (a comparison treatment that does not target positive affective functioning) for 6 weeks. Participants will complete self report and behavioral assessments of targeted mechanisms and symptoms, and 34 participants will complete neuroimaging tasks designed to elicit positive affect and activate underlying neural circuitry (e.g. fronto-mesolimbic circuits). The primary goals of the current trial include: 1) establish feasibility and acceptability of PASS, 2) employ a multi-method approach to measure PASS related change in targeted mechanisms, and 3) explore PASS-related changes in sustainability and connectivity in key circuits within the fronto-mesolimbic network. All of these goals will inform iterative refinements of the manual, and will generate more specific hypotheses and methods for a future, large-scale RCT. Based on the results of this work, future trials may, e.g., include an augmentation design to determine if PASS adds value above and beyond behavioral activation, and may test hypotheses regarding opportune developmental windows (e.g. early vs. mid puberty) for the treatment approach. PUBLIC HEALTH RELEVANCE: Rates of depression rise sharply during adolescence, becoming a leading cause of lifetime disability with high rates of recurrence and chronic impairment. Despite progress in efficacious treatments, only 50% of treated adolescents attain sustained remission. By developing novel approaches for intervening during key periods of development and brain maturation, the proposed research and training carries potential not only to alleviate immediate symptoms, but also to reduce mortality, and alter morbidity and well being across the lifetime.

PROJECT SUMMARY Up to 50% of peripubertal youth with anxiety have unmet clinical needs, leaving these youth at high risk for suicide, depression and substance abuse across adolescence. In accord with the NIMH strategic plan, we aim to deepen mechanistic understanding of anxiety during the sensitive period of peripuberty to inform novel treatments and reduce health risks. This proposal focuses on negative overgeneralization, which is a core dimension of anxiety that is poorly understood, and refers to the tendency to generalize aversive responses from one context (house fire) to other contexts (camp-fire) that share features. Amygdala activity, induced by heightened emotional arousal, enhances plasticity in associative learning mechanisms, facilitating the binding of contextual features in memory that are only loosely related. We posit that sleep plays a critical role in negative overgeneralization. Specifically, we draw from basic neuroscience to propose a model by which heightened amygdala reactivity during wakefulness, induced by increased emotional arousal, facilitates replay of negative memories during sleep. This facilitated replay leads to the stabilization and integration (consolidation) of negative memories into long-term memory networks via slow wave oscillatory events during NREM sleep. We further propose that facilitated replay of negative memories during sleep promotes generalization by influencing underlying neurocomputational mechanisms (i.e., pattern completion ? a computational process that makes neural representations similar). Finally, we propose that sleep-dependent consolidation is malleable, such that Targeted Memory Reactivation (TMR) of positive memories during sleep can competitively displace consolidation of negative memories, and reduce negative overgeneralization. The current proposal tests this model using a novel multi-method approach combining neuroimaging, polysomnography, and a memory task that captures behavioral generalization and its underlying neural mechanisms (i.e. pattern completion). Aim 1 examines 200 peripubertal youth (ages 10-13 years) across a full continuum of anxious symptoms in a randomized sleep (n=140) versus wake (n=60) design to demonstrate sleep-dependent effects on behavioral and neural mechanisms of negative overgeneralization. Aim 2 focuses on the 140 youth in the sleep condition to evaluate amygdala reactivity at encoding and sleep neurophysiology during post-encoding sleep as mediators between anxiety and negative overgeneralization. Aim 3 uses the same design as the sleep condition but recruits a new sample of youth with elevated anxiety (n=60) to enroll in a randomized trial in which positive memories are cued during sleep (TMR, n=30), or sham cues are presented during sleep (n=30), to examine malleability of sleep-dependent mechanisms of negative overgeneralization. This project will set the stage for the long-term goal of developing novel interventions that manipulate sleep (e.g. via TMR) not only to improve existing symptoms, but also to positively shape neurodevelopment and reduce risk in the sensitive period of peripuberty.