PROJECT SUMMARY Attention Deficit Hyperactivity Disorder (ADHD), the most common childhood behavioral diagnosis, is a heterogeneous disorder linked to poor adult outcomes including high rates of academic underachievement, mental illness, substance abuse, and criminal activity. A critical obstacle to improving long-term ADHD outcomes is the current lack of quantitative neurophysiologic markers that could be used to improve precision treatment (behavioral and pharmacologic). In research funded during two grant periods, we addressed this barrier: Leveraging observed associations of ADHD-associated impairments in motor control with core impairments in cognitive and emotional control to pursue motor physiologic biomarkers linked to ADHD diagnosis and symptom severity. Engaging expertise of two research teams in different cities, we developed, refined, and effectively implemented innovative methods for evaluating motor physiology in school-age children with ADHD. During the first grant period we initiated Transcranial Magnetic Stimulation (TMS) investigations of motor cortex, discovering that Short Interval Cortical Inhibition (SICI) is reduced in children with ADHD and that this reduced SICI correlates with parent-ratings of ADHD symptom severity, with consistent findings across the two sites. During the second grant period, we developed (TMS-compatible) child-friendly games as paradigms for evaluation of motor cortex physiology under conditions requiring cognitive and emotional control. We found that SICI is reduced in children with ADHD during action selection and inhibition (as well as rest). Further, we discovered that TMS-evoked increases in motor evoked potential (MEP) amplitude from rest to task engagement (which we have denoted as “Task Related Up Modulation” - TRUM) are significantly diminished in ADHD. Interestingly, while both TRUM and SICI robustly correlate with ADHD severity, they show limited correlation with each other. These published findings, in conjunction promising preliminary analyses of TMS- behavioral associations, suggest a model in which these two promising, distinct physiologic biomarkers reflect differential domains of dysfunction in ADHD, with SICI reflecting mechanisms linked to maintaining attention and filtering distractions, while TRUM reflects the capacity to modulate response control particularly under cognitively and emotionally demanding conditions. To pursue validation of SICI and TRUM as physiologic biomarkers, we now propose: AIM 1 To establish test-retest reliability of SICI and TRUM in children with ADHD and typically developing (TD) controls. AIM 2 To quantify stimulant treatment-induced changes in SICI and TRUM in children with ADHD as a validation of utility of these biomarkers for treatment focused studies. AIM 3 To explore the differential association of SICI and TRUM with ADHD-relevant RDoC constructs of Cognitive Control and Emotional Positive/Negative Valence. Achieving these aims will lay groundwork for future use of SICI and TRUM as a pragmatic and biologically meaningful quantitative measure that can be applied to investigations of precision ADHD treatment, genetics, and risk factors for serious long-term outcomes.

PROJECT NARRATIVE Children with Attention Deficit Hyperactivity Disorder (ADHD) are at substantially increased risk for long- term difficulties into adulthood, including academic underachievement, substance abuse, and criminal behavior. In our effort to improve these outcomes, we have worked on identifying highly-reliable motor measures that could be used to help better guide ADHD treatment, leading to the discovery of two brain- based measures that are abnormal in children with ADHD and, importantly, also predict the severity of ADHD behaviors. We aim to determine whether these two measures, performed with brief and safe Transcranial Magnetic Stimulation (TMS), are reliable and meaningful enough to be used to help improve precision of individually-targeted and effective ADHD treatments.