This work is conducted under protocol 01-M-0192, NCT00018057. 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. This involves a particularly deep interest in the relationships between pediatric anxiety and mood disorders. Through collaborative work, this allows us to examine 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 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, identified through the confluence of findings in animal models and children. In the current protocol, such work has focused closely on extinction, as it relates to cognitive behavioral therapy, and attention bias, as it relates to cognitive training. As such, this protocol is beginning to generate treatments that will alter clinical practice. In the past year, this work has continued to focus very deeply on aspects of attention, extending research completed in prior years; one randomized controlled trial was published in this area through work with collaborators; a second randomized controlled trial, conducted on site at NIH, has been completed, and this most recent study, unlike all prior studies in this area among youth, includes data from brain imaging. Data analysis has been finalized, and the paper is nearing completion. This most recent work suggests that research on attention might identify targets for novel treatments in anxiety, a potential significant breakthrough that is directly relevant to patient care. As such, this protocol demonstrates the potential importance of embedding a clinical trial within a brain imaging study. Finally, we have increasingly incorporated novel treatment approaches into this protocol. During the past five years, we completed five randomized controlled trials, and this work has generated considerable other work in extramural settings focused on novel therapeutics. 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. 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 brain function. In the past four 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 devoted considerable time in the protocol to questions on disorder specificity, with a particular focus on comparing fears that are elicited by social and non-social stimuli. However, in the past year, this focus has shifted to emphasize more strongly differences between anxiety and mood disorders as opposed to differences among distinct types of anxiety, such as social and non-social anxiety. 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 show 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 also 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. Moreover, our paradigms have been adopted by many other laboratories around the world. This includes many of our attention, fear-conditioning, and face-viewing paradigms. This facilitates attempts to replicate findings in multiple contexts with diverse patient groups. During the coming year, we will devote most of our time to reporting results from recently completed studies and we will begin to initiate a new series of studies that extend work performed as the initial part of this protocol.
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