Given concerns about the appropriate diagnosis for children with chronic, severe irritability, we defined the syndrome of severe mood dysregulation(SMD)to capture youth with extremely severe irritability and symptoms of hyperarousal. Our SMD phenotype formed the basis for the new pediatric diagnosis of mood dysregulation disorder with dysphoria(DMDD)in DSM-5. Since the inception of this project, approximately 350 youth with SMD/DMDD have been recruited into the project. Approximately 40 new patients were recruited this year. The youth with DMDD that we study suffer very severe psychiatric impairment, as assessed by medications received, number of psychiatric hospitalizations, and standardized measures of function. As noted above, we demonstrated differences between youth with SMD and those with bipolar disorder (BD) in clinical course, family history, and brain mechanisms associated with symptoms. In the course of this work, we became increasingly interested in the pathophysiology of irritability, not just in comparison to that of BD, but also in its own right. This is because irritability is one of the most common, impairing psychiatric symptoms in children, but there has been little research devoted to it, and there are remarkably few evidence-based treatments. This year, we published a translational mechanistic model of irritability that suggests that core deficits in pediatric irritability include aberrant responses to frustration, aberrant approach responses to threat, and deficits in instrumental learning that prevent them from adapting appropriately to changes in environmental contingencies. The construct of irritability is particularly well-suited for the transdiagnostic, translational approach of the Research Domain Criteria (RDoC). Much of our work now involves examining irritability, not only in DMDD, but also in other groups exhibiting irritability, including youth with anxiety disorders or ADHD. With the arrival of a new Unit in our Branch focused on adolescent depression, we will include such youth also in our studies. (Also, as explained under MH002778-18, in the upcoming year will discontinue our work with youth with bipolar disorder.) Across groups, we characterize irritability as a continuous variable. A focus of our neuroimaging work includes the use of frustrating tasks, since a hallmark of irritability is difficulty tolerating frustration. Previously, we demonstrated behavioral and neural differences between irritable and non-irritable youth during a frustrating attentional task. We improved that paradigm and obtained fMRI data from approximately 200 youth with DMDD, ADHD, and/or anxiety disorders, as well as healthy youth. Our results show that irritability is associated with increased prefrontal and striatal engagement when youth attempt an attention orienting task after receiving frustrating feedback. Since prefrontal engagement is important in emotion regulation, one interpretation of this finding is that such prefrontal emotion regulation mechanisms are less efficient in irritable than non-irritable youth. Alternatively, in irritable youth, increased prefrontal engagement may be required after frustration to down-regulate exaggerated subcortical limbic responses e.g., in the striatum. These effects of irritability are present even when the effects of ADHD and anxiety are taken into account. We have also piloted two additional frustration tasks. The second frustration task differs from the one described above in the timing of frustration (short blocks of frustration, occurring in randomized order with non-frustrating blocks, vs. a long block of non-frustration followed by a long bout of frustration) and in the task involved (attention orienting in the first task, cognitive flexibility in the second). The development of this second task thus allows us to test whether, across task timing differences and cognitive tasks, increased irritability is associated with increased prefrontal engagement after frustration. Our third frustration task will allow us to determine whether irritability is associated with instrumental learning deficits at baseline and after frustration. Instrumental learning is the process by which people learn which of their behaviors will be rewarded. Deficits in such learning could lead to increased frustration in irritable youth. Children typically present with multiple symptoms and diagnoses. It is important to identify pathophysiological mechanisms that are specific to different symptoms, and also how the neural mechanisms mediating different symptoms interact. Such research is important to further efforts toward personalized medicine. We are particularly interested in neural mechanisms that differentiate anxiety and irritability, given cross-sectional and longitudinal associations between these traits and possible shared circuitry mediating them. Both irritable and anxious youth have an attention bias toward threatening faces. Therefore, we scanned approximately 200 children with a range of common symptoms, including anxiety, irritability, and ADHD, while they completed an attention bias task. We found that irritability is associated with increased amygdala, striatal, and prefrontal engagement when subjects were asked to attend away from threat. In contrast, anxiety was associated with normal neural activity but abnormal connectivity between prefrontal and limbic regions. A major focus of our work is treatment. We continue our double-blind trial designed to ascertain whether citalopram (a serotonergic reuptake inhibitor (SRI) antidepressant that is effective in the treatment of pediatric anxiety) plus stimulant is more effective than placebo plus stimulant in the treatment of severe irritability. Stimulant and SRI treatment tend to have fewer side-effects than atypical antipsychotic treatment, which is considered first-line treatment for BD, yet stimulants and SRI's are relatively contraindicated in patients with BD because of concern about possibly inducing a manic episode. Therefore, this work has considerable public health importance. We have randomized approximately 55 children into the trial, and youth are tolerating the treatment well. We are now developing and testing two novel psychosocial approaches to treating irritability. The first involves computer-based training designed to shift a subject's perception of ambiguous faces from angry toward happy. In work published last year, we found that youth with DMDD tend to judge ambiguous faces as angry rather than happy; that we can change this judgment with computer-based training; and that this is associated with decreased irritability. This was an open trial, without a control condition. We have begun a controlled trial of this new Interpretation Bias Treatment, along with brain imaging before and after training. Recruitment has been robust, and approximately 25 youth have completed the trial. Youth complete neuroimaging on a task assessing interpretation bias pre and post treatment. We are also now completing an open pilot study of a manual-based cognitive behavioral treatment targeting irritability. This treatment has a strong emphasis on behavioral techniques i.e., exposing the child to tolerable, but frustrating situations, to improve the child's ability to tolerate such situations. The treatment is based on our neuroscience-based model of irritability, including irritable children's hypothesized deficits in the process and content of instrumental learning, and their aberrant responses to frustration. We will soon begin a multiple baseline design study of this new treatment, since such a design more structured piloting whose results can be subjected to statistical analysis. Imaging on the first frustration paradigm, described above, will be conducted pre and post treatment.