Neurophysiological Markers of Pediatric Irritability and Its Response to Intervention

There has been an increasing focus on the adverse impacts of irritability, defined as increased tendency towards anger. Irritability worsens peer relationships, family functioning, academic performance and is a risk factor for depression, suicide and substance use and is one of the main reasons why children get referred for treatment. It has been identified as transdiagnostic entity meriting investigation as a treatment target for personalized intervention given its prevalence and morbidity. Most children with prominent irritability also meet criteria for Attention Deficit Hyperactivity Disorder (ADHD) but only a subset of children with ADHD manifest impairing levels of irritability. Irritability levels are only minimally correlated with severity of ADHD symptoms suggesting that irritability is not simply a manifestation of severe ADHD. The first line treatment for irritability in children with ADHD is to optimize the dose of the CNS stimulant. However, there is great heterogeneity in response, with baseline mood lability being the best marker for both improving and worsening irritability. In addition, increased irritability is one of the most common reasons why parents stop these medications. The unpredictability in response to CNS stimulants has led to the increasing use of antipsychotics and other non-evidence based treatments for ADHD. It is unknown what drives this heterogeneity in response in part because little is known about the underlying causal mechanisms for irritability in youth with ADHD. Two areas theorized to contribute to irritability include impairments in learning from experience (instrumental learning) and sensitivity to reward and loss.1 There are objective methods for measuring these domains in children through the use of even-related potentials (ERPs)- synchronous neural activity in response to a stimulus. Reward positivity (RewP) is an ERP component occurring in response to feedback on task performance that can be broken down to separate reward and loss components. Irritability is thought to arise due to the combination of an enhanced drive for reward coupled with an excessive response to loss. No prior work has examined associations of RewP with irritability in ADHD. However, abnormalities in RewP and elevated irritability have both been established as risk factors for depression, suggesting that RewP may also predict irritability. Error related negativity (ERN) reflects the preconscious detection of potential conflict serving as an early warning signal for errors. Error detection is one of the first steps for instrumental learning. It is impaired in some youth with ADHD, with a suppressed ERN correlated with reduced error processing. CNS stimulants improve ERN amplitude and impaired error processing. We theorize that abnormalities in RewP and ERN in children with ADHD will serve as respective markers for severity of irritability and subsequent treatment response to CNS stimulants. If successful, we will have identified a causal pathway for irritability that will aide treatment development and identified a reliable biomarker for the current first line treatment for irritability in ADHD (CNS Stimulants), while providing care to a significantly impaired group of local children for whom few evidence-based treatments exist.