The neurobehavioral, environmental and genetic factors impacting ADHD.

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

This report details progress towards our overarching aim of understanding the interplay between behavioral, social, genetic and brain factors in development. Much of research focuses on how attention deficit hyperactivity disorder (ADHD) may impact on brain development. In 2020-2021, our group has focused on (1) predicting the course of childhood ADHD symptoms, using genomic, neural and cognitive features; (2) parsing how changes in the brains functional architecture with age might relate to (a) changes in ADHD symptoms with age, and (b) response to psychostimulant medication. 1. Predicting the course of ADHD symptoms through the integration of childhood genomic, neural, and cognitive features (Sudre et al, Molecular Psychiatry, 2020) . Childhood attention deficit hyperactivity disorder (ADHD) shows a highly variable course with age: some individuals show improving, others stable or worsening symptoms. The ability to predict symptom course could help individualize treatment and guide interventions. By studying a cohort of 362 youth, we asked if common genetic variant (polygenic) risk for ADHD, combined with baseline neural and cognitive features could aid in the prediction of the course of symptoms over an average period of 4.8 years. Compared to a never-affected comparison group, we find that participants with worsening symptoms carried the highest polygenic risk for ADHD, followed by those with stable symptoms, then those whose symptoms improved. Participants with worsening symptoms also showed atypical baseline cognition. Atypical microstructure of the cingulum bundle and anterior thalamic radiation was associated with improving symptoms while reduction of thalamic volume was found in those with stable symptoms. Machine-learning algorithms, trained and tested on independent groups, performed well in classifying those never affected against groups with worsening, stable, and improving symptoms (area under the curve >0.79). We conclude that some measures of polygenic risk, cognition, and neuroimaging show significant associations with the future course of ADHD symptoms and may have modest predictive power. These features warrant further exploration as prognostic tools. 2(a). An examination of the relationships between ADHD symptoms and functional connectivity over time (Norman et al 2021, Neuropsychopharmacology). Previous cross-sectional work has demonstrated resting-state connectivity abnormalities in children and adolescents with ADHD, compared to typically developing controls. However, it is unclear to what extent these neural anomalies confer risk for later symptoms of the disorder, or represent the downstream effects of symptoms on functional connectivity. Here, we studied 167 children and adolescents with varying levels of ADHD symptoms. All participants underwent resting-state functional magnetic resonance imaging and ADHD symptom assessments on two occasions during development. Resting-state functional connectivity was quantified using eigenvector centrality mapping. Using voxelwise cross-lag modeling, we found that less connectivity at baseline within right inferior frontal gyrus was associated with more follow-up symptoms of inattention. By contrast, symptoms of inattention at baseline were not associated with later anomalies in resting state functional connectivity. Findings suggest that previously reported cross-sectional abnormalities in functional connectivity within inferior frontal gyrus in patients with ADHD may represent a longitudinal risk factor for the disorder, in line with efforts to target this region with novel therapeutic methods. 2 (b). A longitudinal study of resting-state connectivity and response to psychostimulant treatment in ADHD. (Norman et al, American Journal of Psychiatry, 2021). Psychostimulants are the first-line pharmacological treatments for ADHD, although symptom reduction varies widely between patients and these individual differences in treatment response are poorly understood. We examined whether psychostimulant medication response was associated with differences over development in the brains functional architectures. We captured brain function by measuring resting-state functional connectivity within and between some of the cardinal brain functional networks (specifically the cingulo-opercular, striato-thalamic, and default mode networks). We studied 110 individuals with ADHD and 142 unaffected individuals. Starting at an average age of 10.6 years, participants underwent functional neuroimaging on up to five occasions during development (age range, 617 years). For those with ADHD, symptoms were assessed on and off psychostimulant medication using a clinician led interview with parents. We found that several aspects of the brains functional architecture were associated with psychostimulant medication responses. Specifically, worse responses to treatment were associated with an atypical increase with age in cingulo-opercular connectivity in the resting state. This work delineates how the brains functional architecture, as captured by resting-state connectivity may be associated over development with response to psychostimulants in ADHD. Functioning and development within the cingulo-opercular network may warrant further investigation as a contributor to differential response to psychostimulants.