Through a series of three protocols, we are using functional magnetic resonance imaging (fMRI) to examine neurocognitive correlates of pediatric anxiety disorders. Through ongoing collaborative studies, we also have increasingly compared findings in these syndromes with findings in adult anxiety disorders as well as findings in other pediatric mental disorders. Through collaborative work, we have a particularly strong interest in examining the similarities and differences between pediatric and adult mood and anxiety disorders. From this vantage point, studies conducted at the NIH as part of this protocol focus most narrowly and deeply on pediatric anxiety disorders. On the other hand, studies conducted with collaborators both within the NIH and at extramural sites focus most deeply on adult anxiety disorders and mood or other psychiatric disorders in children and adolescents. Finally, as the neural correlates of anxiety have been defined increasingly precisely through work in this protocol, we have begun to focus more deeply on the manner in which effective treatment changes these neural correlates so that research on novel therapeutics might target such neural correlates. The work performed under this protocol and with the many associated collaborators holds the potential to dramatically impact public health, for various reasons. Mood and anxiety disorder dramatically alter the well-being of children and adolescents. Nevertheless, relatively little work has been conducted on the underlying pathophysiology of these conditions, using methods that allow direct extensions to work in basic neuroscience. fMRI research is vital for work in this area. Such research assesses brain function in children using methods that are directly comparable to the techniques used to study brain function in animal models. Work in this protocol holds the hope of generating insights on pathophysiology in a way that will lead to novel treatment discovery. This hope has increased in recent years, with discovery of replicable perturbations that might be targeted by novel treatments. This suggests that novel treatments have begun to emerge through the confluence of findings in animal models and children. As such, this protocol is beginning to generate treatments that will alter clinical practice. In the past year, this work has focused most deeply on aspects of attention. Moreover, this protocol can generate understandings of development. This is because most adult mood and anxiety disorders also emerge from earlier disorders, manifest in childhood. Therefore, not only might this protocol dramatically alter the well-being of youth, but it also holds the hope of improving the lives of adults. Finally, we have increasingly incoroporated novel treatment approaches into the body of work implemented under this protocol. This applies most directly to the a novel computer-based method for retraining attention in pediatric anxiety disorders. This provides a novel means to achieve clinical benefits. In fact, during the past two years, we completed one randomized controlled trial in 30 subjects with an anxiety disorder, and we are in the midst of a second trial designed to extend findings from this first study. Moreover, through collaborative research, we have completed an additional three trials using similar methods. The central focus of the protocol is on individual differences in neural circuitry function, as they relate to individual differences in behavior and clinical response to treatment. Thus, in the most important aspect of the protocols, we are attempting to document deficits in brain systems mediating reward-related processes, attention bias, and emotional memory in pediatric mood and anxiety disorders. Replicated findings from this project clearly implicate many such deficits in anxiety, moving research on developmental psychopathology into the domain of neuroscience. This shows that individual differences in behavior firmly relate to individual differences in brainfunction. In the past two years, our focus has been on extending attention-based and fear-conditioning work, in ways that most directly inform therapeutics. As noted above, this has led us to implement novel therapies. We have also just begin to return to questions on disorder specificity, with a particular focus on comparing fears that are elicited by social and non-social stimuli. Thus, a particularly important goal in our current studies among individual groups of anxiety disorders. Prior neuropsychological studies in children as well as in adults note that mood and anxiety disorders are associated with deficits in attention modulation and emotional memory. We have found consistent evidence of such deficits in the current protocol. Moreover, prior imaging studies in healthy adults note that tasks requiring attention modulation or emotional memory engage cortico-limbic brain regions previously implicated in adult mood and anxiety disorders. These regions include the amygdala, ventral prefrontal cortex, cingulate gyrus, and hippocampus. Once again, we also find such evidence in the current set of projects, with multiple, replicated reports of cortico-limbic dysfunction in both pediatric and adult anxiety disorders. This shows that fMRI attention modulation and emotional memory paradigms differentially engage cortico-limbic brain regions in psychiatrically healthy and anxious, impaired subjects. These studies are ongoing in more than 400 subjects. For these subjects, each received neurocognitive examinations, and a subset received fMRI examinations. Each received standardized assessments of response to treatment. As part of our studies in healthy subjects, we also successfully developed each of the fMRI protocols that will be used in the current project. As noted above, many of our initial hypotheses have been confirmed, and our studies are now moving forward to examine issues of specificity and to consider how our findings might be used to inform advances in treatment. This involves a particularly deep focus on fear conditioning. During the coming year, we will continue the process of analyzing the extensive data emerging from the fMRI studies performed as part of this protocol;we also will continue to analyze data from behavioral studies in patient groups. Moreover, we also have finalized one randomized controlled trial;we have submitted the results of this trial for publication, and we have begun a second trial. Finally, we have analyzed data acquired with our new fMRI protocols, particularly attention-based and fear-conditioning paradigms;we also have submitted results from these analyses for publication, and we have initiated new studies that extend this recently-completed work. Beyond these ongoing behavioral and fMRI studies, our group is also involved in various collaborations that have led to analyses of other data sets and reporting of research findings. This also has led to a number of recently published papers and manuscripts that are under review.

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Tanofsky-Kraff, Marian; Engel, Scott; Yanovski, Jack A et al. (2013) Pediatric disinhibited eating: toward a research domain criteria framework. Int J Eat Disord 46:451-5
Richards, Jessica M; Plate, Rista C; Ernst, Monique (2013) A systematic review of fMRI reward paradigms used in studies of adolescents vs. adults: the impact of task design and implications for understanding neurodevelopment. Neurosci Biobehav Rev 37:976-91
Shechner, Tomer; Wakschlag, Naomi; Britton, Jennifer C et al. (2013) Empirical examination of the potential adverse psychological effects associated with pediatric FMRI scanning. J Child Adolesc Psychopharmacol 23:357-62
Mueller, Sven C; Aouidad, Aveline; Gorodetsky, Elena et al. (2013) Gray matter volume in adolescent anxiety: an impact of the brain-derived neurotrophic factor Val(66)Met polymorphism? J Am Acad Child Adolesc Psychiatry 52:184-95
Jarcho, Johanna M; Leibenluft, Ellen; Walker, Olga Lydia et al. (2013) Neuroimaging studies of pediatric social anxiety: paradigms, pitfalls and a new direction for investigating the neural mechanisms. Biol Mood Anxiety Disord 3:14
Wakschlag, L S; Kistner, E O; Pine, D S et al. (2010) Interaction of prenatal exposure to cigarettes and MAOA genotype in pathways to youth antisocial behavior. Mol Psychiatry 15:928-37
Beesdo, Katja; Knappe, Susanne; Pine, Daniel S (2009) Anxiety and anxiety disorders in children and adolescents: developmental issues and implications for DSM-V. Psychiatr Clin North Am 32:483-524
Andrews, G; Pine, D S; Hobbs, M J et al. (2009) Neurodevelopmental disorders: cluster 2 of the proposed meta-structure for DSM-V and ICD-11. Psychol Med 39:2013-23
Williams, Lela Rankin; Degnan, Kathryn A; Perez-Edgar, Koraly E et al. (2009) Impact of behavioral inhibition and parenting style on internalizing and externalizing problems from early childhood through adolescence. J Abnorm Child Psychol 37:1063-75
Pine, Daniel S; Helfinstein, Sarah M; Bar-Haim, Yair et al. (2009) Challenges in developing novel treatments for childhood disorders: lessons from research on anxiety. Neuropsychopharmacology 34:213-28

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