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, particularly 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, the current protocol also has generated key insights on novel treatments. Moreover, these new treatments are now being studied in the context of brain-imaging research. As a result, the protocol also focuses quite 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. There is a particularly pressing need to use understandings from neuroscience to generate new ideas about treatment. Work in this protocol holds the hope of generating these insights, specifically in ways that will lead to novel treatment discovery. This hope has increased in recent years for various reasons. For example, work in this protocol and related studies has discovered 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 on extinction, as it relates to cognitive behavioral therapy, and attention bias, as it relates to both cognitive behavioral therapy and cognitive training. As such, this protocol defines a promising pathway for generating treatments that may alter clinical practice. In the past three years, we have published multiple papers that demonstrate such promise, by targeting aspects of attention, extending research completed in prior years; three randomized controlled trials were published in this area through work with collaborators; this follows from highly similar randomized controlled trials published in prior years. For work completed at the NIH, we target randomized controlled trials where data also are acquired using data from brain imaging. In this way, we are directly connecting a measure of brain function to a measure of treatment response, one very important potential 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, in the current year, we devoted considerable efforts to another randomized controlled trial that is heavily recruiting subjects. Currently, we have randomized more than 60 subjects in a study that will be completed after we have randomized 120 subjects. 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 five 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 mood and anxiety-related problems in the past two years. 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 500 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. We have a particularly strong interest in studying reliability of brain function, as assessed with fMRI. In recent years, we have been able to develop paradigms with acceptable levels of reliability. In the past year, we used such paradigms to focus our work in patients on brain functions that we have found to be reliable. Such work is highly important, since treatment-related brain imaging research benefits greatly from the ability to identify reliable perturbations in brain function among patients. As noted above, using these methods, 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 focus has led to the publication of two notable brain-imaging papers in the past year that compare findings in anxiety and mood-related psychopathology among youth. Finally, within the past year, we have begun a large-scale collaboration. This collaboration is supported by an extramural grant that allows Vanderbilt University and the University of Wisconsin to work with our NIMH site to attempt to replicate findings across our three groups. This will generate data in approximately 500 young people on the biology of anxiety, as delineated in our work over the past 15 years. These efforts have already generated a series of important publications. During the coming year, we will devote most of our time to building on the successes of our past work. This includes continuing our recently initiated studies of novel treatments, monitoring ongoing efforts in our multi-site study, and implementing additional studies of disorder specificity.
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