ADHD-related sex differences in fronto-subcortical intrinsic functional connectivity and associations with delay discounting

Abstract

Background: Attention-deficit/hyperactivity disorder (ADHD) is associated with atypical fronto-subcortical neural circuitry and heightened delay discounting, or a stronger preference for smaller, immediate rewards over larger, delayed rewards. Recent evidence of ADHD-related sex differences in brain structure and function suggests anomalies in fronto-subcortical circuitry may differ among girls and boys with ADHD. The current study examined whether the functional connectivity (FC) within fronto-subcortical neural circuitry differs among girls and boys with ADHD compared to same-sex typically developing (TD) controls and relates to delay discounting.

Methods: Participants include 8-12-year-old children with ADHD (n = 72, 20 girls) and TD controls (n = 75, 21 girls). Fronto-subcortical regions of interest were functionally defined by applying independent component analysis to resting-state fMRI data. Intrinsic FC between subcortical components, including the striatum and amygdala, and prefrontal components, including ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), and anterior dorsolateral prefrontal cortex (dlPFC), was compared across diagnostic groups overall and within sex. Correlations between intrinsic FC of the six fronto-subcortical pairs and delay discounting were also examined.

Results: Both girls and boys with ADHD show atypical FC between vmPFC and subcortical regions including the striatum (stronger positive FC in ADHD) and amygdala (weaker negative FC in ADHD), with the greatest diagnostic effects among girls. In addition, girls with ADHD show atypical intrinsic FC between the striatum and dlPFC components, including stronger positive FC with ACC and stronger negative FC with dlPFC. Further, girls but not boys, with ADHD, show heightened real-time delay discounting. Brain-behavior correlations suggest (1) stronger negative FC between the striatal and dlPFC components correlated with greater money delay discounting across all participants and (2) stronger FC between the amygdala with both the dlPFC and ACC components was differentially related to heightened real-time discounting among girls and boys with and without ADHD.

Conclusions: Our findings suggest fronto-subcortical functional networks are affected in children with ADHD, particularly girls, and relate to delay discounting. These results also provide preliminary evidence of greater disruptions in fronto-subcortical FC among girls with ADHD that is not due to elevated inattention symptom severity, intellectual reasoning ability, age, or head motion.

Keywords: ADHD; Delay discounting; Functional connectivity; ICA; Resting-state; Reward; Temporal discounting; fMRI.

Fig. 1

Intrinsic fronto-subcortical FC in girls and boys with attention-deficit/hyperactivity disorder (ADHD) and typically developing (TD) controls. a Topography of fronto-subcortical networks estimated from the functional magnetic resonance imaging data using group-independent component analysis. Components with the strongest spatial correlation with anatomical fronto-subcortical regions of interest (ROIs) are shown. Frontal components include F1 (ventromedial PFC; pink), F2 (anterior cingulate cortex; purple), and F3 (anterior dorsolateral prefrontal cortex; blue). Subcortical components include S1 (striatum; green) and S2 (amygdala/hippocampus; red). b Dot plots and 95% confidence intervals of the intrinsic synchronization of each pair of the participant-specific fronto-subcortical networks for each diagnostic group separately for boys (top) and girls (bottom). Typically developing (TD, n = 75) children are in blue; children with attention-deficit hyperactivity disorder (ADHD, n = 72) are in green. Synchronization was calculated as the Pearson correlation between component time courses and converted to a Z-score using Fisher’s transform. Confidence intervals are based on comparing the mean of each group to 0. Significant diagnostic group differences within sex were observed among girls only (Table 2) in FC of the S1 (striatum) component with all of the prefrontal components and F1-S2 (vmPFC-amygdala components) FC. *Significant effect after FDR correction applied for six tests; ^†significant effect without FDR correction

Fig. 2

Scatterplot of the partial correlation between intrinsic fronto-subcortical FC and delay discounting. Across groups, children who displayed greater negative F3-S1 (anterior dlPFC-striatum components) FC showed greater monetary delay discounting (p = .004)

Fig. 3

Plot of the regression results showing the conditional effects of F3-S2 (dlPFC-amygdala) FC (left) and F2-S2 (ACC-amygdala) FC (right) in relation to real-time delay discounting for each diagnosis by sex subgroup