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. 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. Such treatments might emerge through the confluence of findings in animal models and children. As such, this protocol holds the hope of generating treatments that will alter clinical practice. Moreover, this protocol can generate understandings of development. This is becasue 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. For example, based on our work demonstrated attention perturbations in anxious youth, we have developed novel computer-based methods for retraining attention in pediatric anxiety disorders. This provides a novel means to achieve clinical benefits. In fact, during the past year, we have enrolled 20 subjects into such a computer-based trial, using a treatment emerging from the current protocol. The central focus of the protocol is on individual differences in neural circuitry function, as they relate to individual differences in behavior. 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. Initial findings from this project actually document the occurence of many such deficits, providing some of the first evidence establishing neuroscientific correlates of pediatric mood and anxiety disorders. In subsequent work, we also replicated these findings, already demonstrating these individual differences in broad groups of disorders more than five times. In the past year, 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. In latter years, we hope 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 coming years will be to contrast neurocognitive profiles 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. As a result, we hypothesize that fMRI attention modulation and emotional memory paradigms will engage these cortico-limbic brain regions in both psychiatrically healthy and impaired subjects. We actually already have confirmed this hypothesis in broad groups of children. 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 be 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 are in the midst of finalizing our first set of studies on new treatments. Finally, we are in the midst of analyzing data acquired with our new fMRI protocols, particularly attention-based and fear-conditioning paradigms;we also have attempted to increase our focus on social fears. Based on the results of these analyses, we also plan to prepare a number of manuscripts. 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. We have also developed a new treatment, based on our initial findings, that we have begun piloting as part of these projects.

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Kircanski, Katharina; White, Lauren K; Tseng, Wan-Ling et al. (2018) A Latent Variable Approach to Differentiating Neural Mechanisms of Irritability and Anxiety in Youth. JAMA Psychiatry 75:631-639
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