145. Cortical thinning and hippocampal expansion as brain signatures of ADHD symptom trajectories

Abstract

Abstract Background Attention-deficit/hyperactivity disorder (ADHD) affects around 5% of children and adolescents world-wide and is characterized by its significant clinical heterogeneity, including different symptom courses, such as persistent, remitting, and emergent trajectories during adolescence and adulthood, which may be affected by pharmacological treatments. More importantly, the neurodevelopmental mechanisms underlying heterogeneity in ADHD-symptom trajectories remain unclear. Therefore, a critical question remains unanswered: Do current medications influence symptom trajectories and their underlying neurodevelopmental processes toward sustained remission? A deeper understanding of these neurodevelopmental processes could inform novel intervention strategies that may alter symptom courses and promote sustained remission. Aims & Objectives To address these gaps, we aim to investigate three questions: (1) Are ADHD symptom trajectories associated with distinct behavioural developmental profiles and ADHD medication use? (2) Can we identify distinct brain signatures for each symptom trajectory and their neurobiological associations? (3) Can these brain signatures predict subsequent ADHD symptoms and generalize to other independent samples? Method We utilized two longitudinal population-based cohorts (ABCD [n = 7,436] and IMAGEN [n =109]) and three independent clinical datasets (ADHD-200 [n = 263], ADHD-1000[n = 742], and ADHD-Shanghai [n = 1,868]). These datasets collected genetic data, ADHD symptoms, structural MRI, ADHD medication information, and multiple functional assessments (Figure 1). First, in the ABCD study, we examined the relationship between ADHD symptom trajectories and distinct behavioural developmental profiles, as well as ADHD medication use. Next, we identified distinct brain signatures for each symptom trajectory between ages 10 and 12 and their key neurobiological processes. Third, we tested whether these brain signatures predict subsequent ADHD symptoms at age 13 and whether these findings could generalize to other independent samples. Results Here, using a longitudinal cohort of adolescents (ABCD, n=7,436) to show that persistent, remitting, and emergent ADHD symptom trajectories correlated with persistent, improving, and worsening behavioral changes (e.g., school performance, sleep quality, and pro-social behaviour), respectively. Each trajectory had distinct brain signatures: faster cortical thinning (persistence), slower thinning (emergence), and faster subcortical expansion (remission). Slower cortical thinning in right posterior cingulate cortex was associated with inattention symptom increase, while faster hippocampal volumetric expansion associated with inattention symptom decrease. The persistent and emergent groups showed significant higher polygenic risk scores for ADHD as compared with the control group. The above findings were not affected by ADHD medication. Notably, these signatures associated with neurobiological processes, such as synaptic pruning, and enhanced ADHD symptom prediction at age 13 and generalized to young adults (age 23) in IMAGEN cohort. More importantly, the hippocampal signature for remitting symptoms was replicated in IMAGEN and two clinical cohorts (ADHD-200, ADHD-1000). Given that baseline ADHD medication use was not significantly associated with the remitting trajectory, our findings suggest that current treatments may not facilitate sustained remission, highlighting the potential for new interventions. Discussion & Conclusions In summary, our findings highlight the importance of long-term clinical monitoring following the current pharmacotherapy for ADHD. The observed cortical thinning and hippocampal volumetric expansion as brain signatures for distinct trajectories of ADHD symptoms may inform new interventions, targeting these brain signatures to alter symptom trajectories and facilitate sustained remission.