Project Summary/Abstract High prevalence rates of attention-deficit/ hyperactivity disorder (ADHD) (5-11% of children 4-17 years), combined with its high societal cost, strong persistence and pernicious effects on quality of life, warrant continued efforts to understand its underlying neural mechanisms and find efficacious treatments. Clinical heterogeneity is a major challenge, likely related to multiple causal paths, and contributes to variability in clinical presentation, underlying neural mechanisms, and treatment response. Although psychostimulants are the gold standard of treatment for ADHD, problems with suboptimal response, adverse side effects and non-compliance occur for a significant minority of those with ADHD. As a result, there is a critical need for empirically supported non- pharmacological interventions for ADHD. In addition, a reliable method for predicting response to treatment interventions in ADHD (and psychiatry in general), both medication and non-pharmacological approaches alike, remains elusive. This inability to prospectively predict whether a treatment approach will be effective for a given individual is costly and time consuming for professionals and patients, and often inconclusive due to disagreement between informants. In this project, we will conduct a large, multisite randomized clinical trial to test the efficacy of external trigeminal nerve stimulation (TNS), a novel, minimal risk, non-invasive neuromodulation treatment, for ADHD in children ages 7-12 years old (N=180). This high impact project will contribute significantly to the literature for empirically-supported nonpharmacological interventions for ADHD, identify underlying neural mechanisms, and test clinically useful behavioral and cognitive predictors of treatment response. Confirming the efficacy of TNS for ADHD could provide millions of families a viable non- pharmacological treatment option, and in some cases, as first-line treatment strategy for patients with ADHD, if supported by this research. The validation of a behavioral profile that is significantly predictive of treatment response will make identification of patients appropriate for TNS treatment simple and extremely cost effective as well as enhance dissemination of treatment into the community. This proposal is consistent with several NIMH priorities, including the development of innovative interventions, assessment of the mechanisms of action of efficacious interventions in the brain and identification of behavioral and cognitive characteristics to guide treatment approaches.