Identification of Neural Markers of Aggression and Irritability and Their Capacity to Predict Treatment Response to CNS Stimulant Medication in Youth with ADHD - Abstract Impulsive aggression and chronic irritability (IACI) often occur together and are some of the most common reasons why children present for behavioral health (BH) care. ADHD is frequently associated with IACI as upwards of 50% of youth with ADHD manifest impairing levels of it. IACI is the most common reason that children with ADHD are prescribed antipsychotics and admitted to inpatient BH units. Systematic dose optimization of CNS stimulants improves levels of IACI, reducing the need for these more intensive and burdensome treatments. However, response varies, with over half of children with ADHD showing meaningful improvement, upwards of 40% receiving minimal benefit and 3 to 10% exhibiting increased IACI levels. Phenotypic and demographic variables are of limited utility for predicting response, suggesting the need to move beyond symptoms in the search for treatment predictors. Youth with ADHD and IACI struggle with multiple aspects reinforcement learning (RL), defined as learning from interactions with the environment to reach a goal. Successful RL efforts tap multiple cognitive functions. In controlled laboratory tasks, youth with IACI and ADHD exhibit abnormal behavioral and neural response to reward (reward responsiveness), difficulty processing environmental cues to adapt behavior (set shifting/goal updating) and impaired attentional allocation when blocked from a goal (frustrative nonreward). Event-related potentials (ERP) exist for each of these research domain criteria (RDOC) that serve as established neural measures offering a child friendly means to assess their contribution to observable levels of IACI. CNS stimulants improve functioning in these specific realms and impact these associated ERPs to the degree that differences between ADHD and non- ADHD youth disappear. In response to NIMH’s Notice of Special Interest on aggression (NOT-MH-22-095), we will examine the capacity of these ERPs to predict levels of IACI in naturalistic settings. We will then assess if interindividual variance in the capacity of CNS stimulants to impact RL associated ERPs accounts for differences in the clinical effects of these medications on IACI at home using a multimethod battery integrating ERPs, guardian report and task performance. Specifically, we will examine variance in the reward positivity (RewP) ERP when receiving reward feedback, the switch positivity (SwP) ERP measuring mental effort when cued to shift set and the change in P3b amplitude measuring attention allocation when transitioning from reward to nonreward on a go-no-go task. To achieve these aims, 136 children with ADHD and elevated IACI will have their CNS stimulant dose optimized over six weeks and then complete a two week within subjects crossover trial of placebo versus optimal dose. ERP collection will be completed within each blinded week. Guardian ratings will be gathered 3x per day including during peak and off-peak times of medication effect to capture variance in IACI levels within the day and disentangle reports of worsening IACI related to loss of previously beneficial medication effects versus those most likely due to a direct adverse response to drug.
