Sex-related differences in adult attention-deficit hyperactivity disorder patients – An analysis of external globus pallidus functional connectivity in resting-state functional MRI

In the last two decades, there has been a growing body of research that identified sex-related differences in attention-deficit hyperactivity disorder (ADHD). Our objective was to quantify whether these sex differences are based on altered functional brain connectivity profiles. In addition, we investigated whether the presence of comorbid disorders, including depression, substance use disorder (SUD) and overweight, influenced these sex differences. A seed-based connectivity analysis of the external globus pallidus (GPe), an important inhibitory relay hub of the fronto-thalamo-striatal-loop, was performed. In a first step, we searched for sex-related differences in ADHD patients (N = 137) and separately in healthy controls (HC) (N = 45), after that, we compared an equal group of HC and ADHD patients to compare sex-related differences in ADHD patients and HC. In a second step, we studied whether the neural basis of comorbidity patterns is different between male and female patients. We observed that male ADHD patients demonstrated a decrease in functional connectivity (FC) from the GPe to the left middle temporal gyrus compared to female ADHD patients. Moreover, within the full ADHD group (N = 137), there was a lower FC in male patients from GPe to the right frontal pole/middle frontal gyrus compared to female patients. Male ADHD patients with depression demonstrated decreased FC from the GPe to parts of the occipital cortex compared to female ADHD patients with depression. No such effect was demonstrated for overweight or SUD. The current study reveals different FC profiles in males and females with ADHD, which are centered around altered connectivity with the GPe. An improved understanding of sex-differences in ADHD, and the role of comorbid disorders, therein can result in improved diagnostic and therapeutic opportunities for ADHD patients.