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 and comparing findings in these syndromes with findings in adult anxiety disorders as well as in other pediatric mental disorders, particularly mood disorders. While studies conducted at the NIH as part of this protocol focus most narrowly and deeply on pediatric anxiety disorders, studies conducted with collaborators focus most deeply on adult anxiety disorders and mood or other psychiatric disorders in children and adolescents. Collaborative work therefore allows us to examine the similarities and differences between pediatric and adult mood and anxiety disorders. The current protocol has generated key insights on novel treatments, which are now being studied in the context of brain-imaging research. The protocol also focuses deeply on the manner in which effective treatment changes 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 disorders deeply undermine 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 pressing need to use new understandings from neuroscience to generate new ideas about treatment. Work in this protocol holds the hope of generating new insights in ways that will lead to novel treatment discovery. For example, replicable perturbations, identified through the confluence of findings in animal models and children, might be targeted by novel treatments. In the current protocol, such work has focused on extinction as it relates to cognitive behavioral therapy, and on 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 five years, we have published multiple papers that demonstrate such promise by targeting aspects of attention and plasticity in fear responses, extending research completed in prior years. Four randomized controlled trials were published in this area through work with collaborators and following on from highly similar randomized controlled trials published in prior years. For work completed at the NIH, we target randomized controlled trials where data are acquired from brain imaging. We have enrolled 110 patients from a trial that will finish when we have reached 120 patients. Enrollment did stall with the COVID-19 pandemic, but we saw an increase during the past year, to the point where we should be able to finish the trial in the coming year. Moreover, we have also developed an alternative form of attention bias modification that we have successfully piloted in the past year. Once our main randomized control trial finishes, we will evaluate the possibility of improving our current approach through the alternative form of treatment piloted in the past year. Finally, we have been actively analyzing our data on neurobiology, which we will relate to clinical response in the coming year. As such, this protocol demonstrates the potential importance of embedding a clinical trial within a brain imaging study. 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. Particularly exciting work from the past year focuses on aspects of attention and on multivariate statistical approaches to brain imaging. These efforts involve considerable attempts to replicate findings generated in patients seen on campus with findings generated in extramural research. As in past years, we continue to show that neural circuitry specifically related to anxiety can be differentiated from the neural circuitry that anxiety shares with other forms of psychopathology. 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. This work relies on fMRI attention modulation and emotional memory paradigms, where we find different patterns of engagement of cortico-limbic brain regions in psychiatrically healthy and anxious, impaired participants. These studies are ongoing in more than 750 participants. For these participants, each received neurocognitive examinations, and a subset received fMRI examinations. Each also received standardized assessments of response to treatment. This has allowed our group to use our data as part of international collaborations, where our group is playing an increasingly large role. As part of our studies in healthy individuals, 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. 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 creation of large-scale collaborations. This collaboration is supported by an extramural grant that allows Creighton 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 completing our study of novel treatment and preparing for the trial that will extend the results from this study.