Project Summary/Abstract Pediatric ADHD is diagnosed in ~9% of youths in the United States and has long-term debilitating mental health, social, and educational effects. ADHD is primarily characterized by inattentive and hyperactive/impulsive behaviors, and methylphenidate is a first line of treatment to alleviate symptoms. While generally effective, 20-30% of youth with ADHD do not respond to methylphenidate. It is currently unknown why methylphenidate does not successfully treat a subset of youth with ADHD, nor is it known who will respond before treatment is initiated. The proposed work aims to fill this knowledge gap by testing the effects of methylphenidate on two neurobiological systems thought to be disrupted in ADHD, with a goal of identifying biomarkers of methylphenidate response. The dual pathway model of ADHD proposes that dysfunction in neurobiological pathways underlying cognitive control and motivational processing gives rise to ADHD symptoms, providing two candidate pathways that methylphenidate may act upon. We propose to examine this framework at the whole brain level by employing functional connectivity and graph theoretical tools to test the effects of methylphenidate on brain organization during tasks that tax cognitive control and reward responsivity in medication naïve children with ADHD. This work will use cutting edge methods that model whole brain functional connectivity on the order of seconds to investigate dynamic changes in brain organization of the hypothesized pathways across the cognitive tasks. Using dynamic functional connectivity approaches we can measure flexibility of connections between brain regions, indexed by how often functional connectivity patterns change across the course of a task. We predict that during a cognitive control task, regions belonging to cognitive control networks (fronto-parietal, cingulo-opercular, default mode) will become less hyperconnected and more flexible on methylphenidate (Specific Aim 1). We further predict that when reward is introduced to a cognitive control task, networks supporting motivational processing (reward, salience, default mode) will reconfigure and become more flexible; we further predict that this reconfiguration will be more pronounced on methylphenidate (Specific Aim 2). Lastly, we predict that flexibility of brain regions from these hypothesized pathways will be powerful predictors of response to methylphenidate (operationalized by performance improvement on control demanding cognitive tasks) above and beyond baseline behavioral measures of ADHD symptomology (Exploratory Aim 3). This work combines new tools (dynamic functional connectivity) with new approaches (modeling brain organization across cognitive task states) to form a comprehensive model of the effects of methylphenidate in pediatric ADHD. By identifying features of brain network organization that change on methylphenidate and testing how these features predict behavioral change, we stand to identif...