Open Access

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that typically begins in childhood and is associated with the cardinal symptoms of inattentiveness, hyperactivity, and impulsiveness. In a significant number of cases, ADHD persists into adulthood and leads to profound psychosocial impairment and costs to the population. The course of the disorder and the severity of psychosocial impairment are further influenced by the presence of comorbidities. The risk of developing psychiatric comorbidities such as affective disorders, personality disorders and substance use disorders is increased compared to the general population. Studies also indicate that ADHD is associated with a higher burden of somatic disorders such as obesity, diabetes mellitus, asthma and migraine. In the last decades, there has been a growing body of research that identified sex-related differences in ADHD, but there is still insufficient evidence on specific issues. In addition to the sex-ratio, which is more balanced in adulthood compared to childhood, there are also indications that differences exist at the symptom level and that the comorbid disorders that occur more frequently in ADHD also seem to differ in men and women, although the studies are not yet clear on this. Using resting-state analyses of functional magnetic resonance imaging (fMRI), we aimed to address the question of whether we can detect sex differences in ADHD and selected comorbidities (substance use disorder, depression, obesity) based on altered functional connectivity profiles. A central role for the pathogenesis of ADHD is the dysregulation of dopaminergic neurotransmission, specifically altered reward processing, as an expression of impaired impulse control. In the present study, we focused on a neuroanatomical hub, namely, the external part of the globus pallidus (GPe), which we defined as a "region of interest" for the analyses performed. There is growing evidence that the globus pallidus not only plays a role in the extrapyramidal motor system, but also integrates cognitive and reward-related information, functions that are impaired in ADHD. In a first step, we looked for sex differences in ADHD patients (n=137) and separately in healthy controls (HC) (n=45), then we compared a similar group of HC and ADHD patients to compare sex-differences in ADHD patients and HC. In a second step, we investigated whether the neural basis of comorbidity patterns differed between male and female patients. Analysis of the images of 182 participants was performed using the SPM-based CONN toolbox V 18.b. When comparing subjects with ADHD and HC, we observed an interaction between the GPe and the middle left temporal gyrus, with the effect being more pronounced in healthy subjects. When analyzing the large ADHD sample, an interaction between the GPe and the frontal pole/middle right frontal gyrus was observed. The connectivity between the GPe and the frontal and temporal brain areas appeared to be more pronounced in female ADHD patients than in males, with the sex-effect being reversed and more pronounced in healthy subjects. The results suggest that in patients with ADHD there is a loss of sex-specialization in GPe-connectivity. Males with ADHD and depression showed lower functional connectivity between the GPe and parts of the occipital cortex than females with ADHD and depression. To our knowledge, this is the first study to investigate sex-specific functional connectivity networks using a seed-based connectivity analysis of the external globus pallidus in adult ADHD patients with and without comorbidities. The study serves to improve our knowledge of GPe involvement in ADHD and sex-specific recruitment of this network. Taken as a whole, this study contributes to our understanding of the neurobiological correlates of ADHD and suggests possible differences between males and females with ADHD centered on altered connectivity with the GPe, helping to provide a different perspective on current research and new ideas for further studies.