Is genetic risk of ADHD mediated via dopaminergic mechanism? A study of functional connectivity in ADHD and pharmacologically challenged healthy volunteers with a genetic risk profile

Abstract

Recent GWAS allow us to calculate polygenic risk scores for ADHD. At the imaging level, resting-state fMRI analyses have given us valuable insights into changes in connectivity patterns in ADHD patients. However, no study has yet attempted to combine these two different levels of investigation. For this endeavor, we used a dopaminergic challenge fMRI study (L-DOPA) in healthy participants who were genotyped for their ADHD, MDD, schizophrenia, and body height polygenic risk score (PRS) and compared results with a study comparing ADHD patients and healthy controls. Our objective was to evaluate how L-DOPA-induced changes of reward-system-related FC are dependent on the individual polygenic risk score. FMRI imaging was used to evaluate resting-state functional connectivity (FC) of targeted subcortical structures in 27 ADHD patients and matched controls. In a second study, we evaluated the effect of ADHD and non-ADHD PRS in a L-DOPA-based pharmaco-fMRI-challenge in 34 healthy volunteers. The functional connectivity between the putamen and parietal lobe was decreased in ADHD patients. In healthy volunteers, the FC between putamen and parietal lobe was lower in ADHD high genetic risk participants. This direction of connectivity was reversed during L-DOPA challenge. Further findings are described for other dopaminergic subcortical structures. The FC between the putamen and the attention network showed the most consistent change in patients as well as in high-risk participants. Our results suggest that FC of the dorsal attention network is altered in adult ADHD as well as in healthy controls with higher genetic risk.

Fig. 1. Connectivity in ADHD > HC.

The left column gives the name of the seed region-of-interest. The middle column titled shows an exemplary brain slice depicting a significant brain cluster. Color is given in the color bar which codes effect size in red or blue. The column on the right gives mean extracted beta-values for the respective comparison between ADHD and HC to demonstrate absolute values and direction of the effect. ADHD attention-deficit hyperactivity disorder, HC healthy controls.

Fig. 2. Relation between genetic risk, functional connectivity, and dopaminergic challenge.

The left column gives the name of the seed region-of-interest. The column titled “correlation PRS placebo” shows an exemplary slice of a brain with a significant cluster, the scatterplot gives the direction of the effect. The column on the right “correlation PRS dopaminergic challenge” gives the same, slice with significant cluster and scatterplot, for the intrasubject difference L-DOPA > placebo in dependence of the polygenic risk. The scatterplots show the functional connectivity gives as correlation and the difference between L-DOPA and placebo on the y axis and the polygenic risk on the x axis. PRS polygenic risk, ns not significant.

Fig. 3. Overview results: direction of connectivity for the specific seed region-of-interest.

On the left, a modified overview of the neuronal signal flow from the cortex to the thalamus (and back) gives an impression where in the loop our specific ROI masks are situated. In addition to the well-known motor loop, putamen and caudate are part of an associative and executive loop, whereas the nucleus accumbens is part of the limbic loop. The ventral pallidum is downstream in this loop. The thalamus projects back to the cortex, thus forming a loop (not shown) apart from their motor function. In the middle, a stylized sagittal view gives an impression of neuroanatomical localization. On the right, the matrix gives an abstract overview of the aforementioned results. Green codes a positive direction of the ROI on the left, blue a negative correlation. Each column gives directionality for ADHD > HC, the placebo condition in high-risk participants and in the comparison L-DOPA > placebo in high-risk participants. The main finding. Putamen-derived connectivity shows a directionality switch from the DAN during L-DOPA challenge.