Project Summary/Abstract The goal of this career development award is to provide the candidate with additional knowledge and skills in the implementation and analysis of event-related fMRI and brain connectivity. This knowledge and skill set will be used to explore the neural basis of emotion regulation in healthy adolescents with and without trauma exposure, and its dysfunction in adolescent post-traumatic stress disorder (PTSD). PTSD is a debilitating illness for youth and their families, and is often comorbid with other anxiety disorders and depression. Adult PTSD related to childhood trauma carries additional risk for depression, anxiety, substance abuse, and suicide. Treatment of pediatric PTSD is largely limited to psychotherapy, which shows moderate effect sizes, leaving many youth with persistent illness even when such treatment is accessible. While evidence is limited, medications have shown little benefit for pediatric PTSD. In light of these factors, it is of great importance to understand how PTSD may alter neurodevelopmental trajectories, with the aim of instituting biologically informed, early interventions that may avert negative outcomes in childhood and subsequent adulthood. Pediatric PTSD is characterized clinically and behaviorally by abnormal emotion regulation, but few studies have examined the neural basis of emotion regulation in this illness. Functional brain studies in adult PTSD offer a testable model of limbic and prefrontal changes that that may underlie impaired emotion regulation. This includes increased activation of the amygdala and the dorsal anterior cingulate (dACC) cortex, which promote fear responses. At the same time, there is impaired engagement of the ventromedial prefrontal cortex (vmPFC), which normally suppresses fear and anxiety responses. Adolescence is a particularly sensitive period of prefrontal cortical development, with the potential for even greater prefrontal-limbic imbalance associated with PTSD. This could be reflected, for example, by diminished age-related activity in the prefrontal cortex. In contrast, healthy trauma-exposed adolescents may show even greater age-related ventral prefrontal recruitment. Successful treatment, in turn, for youth with PTSD may engage compensatory or resilient mechanisms seen in healthy trauma-exposed youth. However, these models remain largely untested. The proposed research plan will examine the functional neural correlates of implicit emotion regulation in healthy youth with and without trauma exposure, and youth with PTSD, with an emphasis on amygdala and prefrontal cortical regions. This research will focus on initially on baseline (pre-treatment) brain differences compared to healthy youth, with a longitudinal one-year follow up as an exploratory aim. Forty youth, ages 12- 18, will be recruited for each group. Validated fMRI paradigms and behavioral measures will be employed. The fMRI tasks include two complementary paradigms to explore implicit emotion regulation, using emotional faces and emotional pictures, respectively. In Aim 1, we predict that healthy youth will engage both amygdala and prefrontal areas during emotion regulation, and that prefrontal-amygdala connectivity will increase with age. Healthy trauma-exposed youth will show greater amygdala activation, but greater vmPFC activation and connectivity in compensation. In Aim 2, we predict that pediatric PTSD and healthy trauma youth, compared to healthy non-trauma youth, will show increased amygdala and dACC activation. However pediatric PTSD will be differentiated from both comparison groups by impaired vmPFC activation and connectivity during emotion regulation. This will be reflected by diminished age-associated increases in vmPFC function in PTSD. Exploratory analyses will examine longitudinal changes in amygdala and prefrontal function in healthy and PTSD adolescents, and how PTSD symptom changes correlate with brain function change over time. The candidate is a pediatric psychiatrist and affective neuroscientist, with a long-standing interest in stress- induced changes in brain and behavior. His clinical specialization includes the use of trauma-focused cognitive behavioral therapy to treat traumatized youth. The candidate has conducted initial fMRI studies of emotion regulation in a traumatized, young adult population, with experience in the analysis of block design tasks. Immediate career development goals during the award period include additional training in conducting fMRI in youth, analysis of event related fMRI and functional/effective connectivity, and training in clinical trials for a future R01 fMRI treatment study. Acquisition of these skills and knowledge will allow the candidate to become an independent investigator in the affective neuroscience of pediatric PTSD. Long-term career goals include the development of expertise in delineating neurodevelopmental trajectories of trauma-resilient vs. trauma- vulnerable emotion regulation as related to pediatric PTSD, and pioneering research exploring treatment- induced changes in emotion regulation circuitry in pediatric PTSD. The proposed program of training and research will be conducted at the University of Wisconsin-Madison, which is a leading institution in the neuroscientific study of emotion, featuring state-of-the art neuroimaging facilities and distinguished faculty. These include Drs. Richard Davidson (mentor) and Ned Kalin (co-mentor), both of whom are pioneers in the study of the neural circuitry underlying emotion regulation in health and psychopathology. This cross- disciplinary research plan therefore allows for a stepwise approach to a career in the affective neuroscience of pediatric PTSD.

Project Narrative This research will explore how the brain regulates emotion in healthy adolescents and adolescents with post-traumatic stress disorder (PTSD) using functional magnetic resonance imaging (fMRI). Increasing knowledge in this area would be expected to eventually aid in the detection, diagnosis, and treatment of youth with PTSD.