Dopamine D4 Receptor Gene Associated with the Frontal-Striatal-Cerebellar Loop in Children with ADHD: A Resting-State fMRI Study

Abstract

Attention deficit hyperactivity disorder (ADHD) is a common childhood neuropsychiatric disorder that has been linked to the dopaminergic system. This study aimed to investigate the effects of regulation of the dopamine D4 receptor (DRD4) on functional brain activity during the resting state in ADHD children using the methods of regional homogeneity (ReHo) and functional connectivity (FC). Resting-state functional magnetic resonance imaging data were analyzed in 49 children with ADHD. All participants were classified as either carriers of the DRD4 4-repeat/4-repeat (4R/4R) allele (n = 30) or the DRD4 2-repeat (2R) allele (n = 19). The results showed that participants with the DRD4 2R allele had decreased ReHo bilaterally in the posterior lobes of the cerebellum, while ReHo was increased in the left angular gyrus. Compared with participants carrying the DRD4 4R/4R allele, those with the DRD4 2R allele showed decreased FC to the left angular gyrus in the left striatum, right inferior frontal gyrus, and bilateral lobes of the cerebellum. The increased FC regions included the left superior frontal gyrus, medial frontal gyrus, and rectus gyrus. These data suggest that the DRD4 polymorphisms are associated with localized brain activity and specific functional connections, including abnormality in the frontal-striatal-cerebellar loop. Our study not only enhances the understanding of the correlation between the cerebellar lobes and ADHD, but also provides an imaging basis for explaining the neural mechanisms underlying ADHD in children.

Keywords: Attention deficit hyperactivity disorder; Dopamine D4 receptor; Frontal-striatal-cerebellar loop; Functional connectivity; Regional homogeneity; Resting-state functional magnetic resonance imaging.

Fig. 1

The left angular gyrus was selected as the region of interest for functional connectivity.

Fig. 2

Brain areas with ReHo differences between carriers of the DRD4 4R/4R allele and carriers of the DRD4 2R allele. Hot and cold colors indicate increased and decreased ReHo values in carriers of the DRD4 4R/4R allele. Color bar represents t-values ranging from − 3.64 to 4.16.

Fig. 3

Brain areas with functional connectivity differences between carriers of the DRD4 4R/4R allele and carriers of the DRD4 2R allele. Hot and cold colors indicate increased and decreased functional connectivity carriers of the DRD4 4R/4R allele, respectively. Color bar represents t-values ranging from − 4.23 to 4.85.