Abnormal Association Between Neural Activity and Genetic Expressions of Impulsivity in Attention-Deficit/Hyperactivity Disorder: An Adolescent Brain Cognitive Development Study

Abstract

Background: Impulsivity in highly heritable attention-deficit/hyperactivity disorder (ADHD) has been studied using neural activity via functional magnetic resonance imaging (fMRI) or genetic data, but rarely with multivariate methods that link both. We investigated coupled neural activity and gene expression signatures, using parallel independent component analysis (pICA) and ABCD (Adolescent Brain Cognitive Development) Study data.

Methods: Children with ADHD (n = 394; 63% male) and healthy control children (n = 1000; 47% male) of European ancestry were included. The participants were randomly divided into 80% discovery and 20% replication datasets with demographic stratification. We analyzed neural activity and gene expressions from the discovery datasets using pICA and extracted paired independent components (pICs). The loading coefficients of the pICs were utilized to predict behavioral and cognitive data for a stop signal task (SST) in replication datasets.

Results: We identified 3 pICs estimated from gene expression in the cortex, cerebellum, and nucleus accumbens. Significant neural activity was mainly localized to the orbital/inferior/middle frontal gyri, rectal gyrus, precuneus, inferior temporal gyrus, inferior parietal lobule, and cerebellum. Significant gene components were associated with immunoglobulin-, taste receptor-, and immunity-related terms and overlapped with ADHD-related genes. The extracted fMRI-/gene-ICs were significantly correlated with mean reaction time, stop signal reaction time on the SST, and behavioral inhibition, with a large boost in sensitivity when both the paired fMRI-/gene-ICs and their interaction were used in a multimodal regression analysis.

Conclusions: We reported biologically plausible pairs of neural activity and gene sets using pICA, which were significantly associated with ADHD impulsivity-related behavioral and cognitive data.

Keywords: Attention-deficit/hyperactivity disorder; Functional magnetic resonance imaging; Gene expression; Imaging genetics; Parallel independent component analysis; Stop signal task.