Adolescent anxiety disorders are prevalent, markedly impairing, and predictive of high risk for adult anxiety, depression, and suicide. Identifying early childhood predictors of anxiety would allow us to target children most in need of intervention. Although behavioral inhibition is not a psychiatric illness, it predicts high risk for adolescent and adult anxiety, particularly social phobia. As such, early behavioral inhibition is a diathesis for anxiety. Investigating patterns of neural functioning associated with behavioral inhibition and social phobia would demonstrate the degree to which an early-life risk factor and an adolescent disorder share underlying biological correlates, data essential for advancing the assessment and prevention of anxiety. The current proposal capitalizes on a rare opportunity to conduct such integrative work. Work in this proposal has been ongoing for five years. Important findings are rapidly emerging, as communicated through a series of publications in high-impact journals. These findings have both stimulated other groups to pursue complimentary research avenues and to increase enthusiasm within the NIMH for continued focus on this area. ? ? The central hypothesis for this study is that adolescents with social phobia or with temperamental risk for the disorder share anomalies in striatal function. ? ? Aim 1: Confirm differences between adolescents with social phobia and psychiatrically healthy controls in striatal response to salient nonsocial incentives. Based on our initial work associating behavioral inhibition and striatal hyperactivation to nonsocial incentives, we hypothesize that socially phobic adolescents will show greater striatal activation to anticipated nonsocial incentives (e.g., monetary gain or avoidance of monetary loss) vs. no incentive, relative to controls. We have successfully documented associations between abnormal processing of monetary rewards in two samples, and we are actively extending this work.? ? Aim 2: Establish differences in striatal response to salient social incentives between adolescents with social phobia and controls. We hypothesize that, during an anticipatory period leading up to potential social interactions vs. a baseline, socially phobic adolescents will show increased striatal activation relative to controls. Preliminary data documenting increased striatal activation to anticipated social interactions in adolescents with heterogeneous anxiety disorders vs. controls supports this hypothesis. Nevertheless, more definitive work is needed in specific anxiety disorders. ? ? Aim 3: Identify differences in striatal response to salient social incentives between adolescents with a temperamental risk for social phobia and those without such a risk. In this area, relatively little work has been completed as part of the current protocol.? ? These hypotheses have been tested in two samples of children, both of which have been follwed since the very first months of life. This work has been conducted through a series of ongoing collaboration with the University of Maryland, led by Dr. Nathan Fox, an expert on temperament. ? ? One of these cohorts, including approximately 200 children followed into early adulthood, has been studies comprehensively. Thus, approximately 90% of these young adults have received comprehensive psychiatric evaluations, studies of molecular genetics, and cognitive neuroscience investigations. Approximately two-thirds have participated in brain imaging research. Studies in this cohort have led to many publications, and the work with this cohort is beginning to slow down.? ? The second cohort includes approximately 500 children, also followed since infancy. However, these children are just entering the school-age years. This provides an unusual opportunity to extend the initial findings in these projects, generated in the first cohort. Namely, the first cohort primarily involved research with older individuals, all typically older than 10. By studying children using current neuroscience methods at younger ages in this protocol, we will have a better chance to appreciate how perturbations in brain functions associated with anxiety begin to manifest. Such work meaningfully extends the studies begun in this proposal, during the past five years.
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