18.4 IMAGING THE TREATMENT OF ADHD

Abstract

ADHD is one of the most common mental health disorders affecting children. Psychostimulants are a first-line treatment for ADHD, but common side effects often result in discontinuation. Moreover, the long-term efficacy of psychostimulants remains unclear. Identifying the neural mechanisms by which psychostimulants attenuate ADHD symptoms may guide the development of more refined and tolerable therapeutics. In this work, we aim to identify causal effects of psychostimulants on brain connectivity in individuals with ADHD and their relationship with symptom improvement. In a 12-week, randomized, placebo-controlled trial of lisdexamfetamine (LDEX), 49 out of 58 eligible participants (12.6 [5.7] years; 33 [67%] males; 25 LDEX and 24 placebo) completed both pre– and post–randomized controlled trial MRI scanning with adequate data quality. The primary clinical outcome measures are T scores on ADHD symptom scales assessed with the Conners’ Parent Rating Scale and the Conners’ Adult ADHD Rating Scale. Treatment effects on striatal and thalamic functional connectivity (FC) are identified using both static (time-averaged) and dynamic (time-varying) measures and then correlated with symptom improvement. We also examined whether treatment-induced connectivity changes acted on connections that differed between those with ADHD and healthy controls (HCs). An HC group (n = 46) matched on age and sex was included for comparison. Analyses were then repeated in independent samples from the ABCD study (n = 103) and the New York University ADHD-200 Consortium cohort (n = 213). We found that LDEX resulted in increasing static and decreasing dynamic FC. However, there were only dynamic mediated therapeutic effects of LDEX. Additionally, at baseline, dynamic FC was elevated in unmedicated-ADHD participants relative to HCs. Independent samples yielded similar findings: ADHD was associated with increased dynamic FC, and psychostimulants with reduced dynamic FC. We found that changes in dynamic, not static, FC accounted for therapeutic effects of psychostimulants. Altered dynamic FC may represent a reliable target for new ADHD interventions aimed at stabilizing network dynamics.