Increased Functional Segregation Related to the Salience Network in Unaffected Siblings of Youths With Attention-Deficit/Hyperactivity Disorder

Objective Although there are frequent reports of shared neurofunctional and neurostructural alterations among probands with attention-deficit/hyperactivity disorder (ADHD) and their unaffected siblings, there is little knowledge regarding whether abnormalities in the resting-state functional connectivity of ADHD probands is also expressed in unaffected siblings, or whether this unaffected (but at-risk) cohort manifests distinct patterns. Method We used a multivariate connectome-wide association study examining intrinsic functional connectivity with resting-state functional magnetic resonance imaging (MRI) in a sample (aged 8−17 years) of medication-naive ADHD probands (n = 56), their unaffected siblings (n = 55), and typically developing (TD) youths (n = 106). Results ADHD probands showed, relative to TD youths, increased connectivity between the default-mode network (DMN) and task-positive networks. Relative to ADHD and TD groups, respectively, unaffected siblings showed increased connectivity within the salience network and reduced connectivity between the DMN and salience network. No shared alterations in functional connectivity among ADHD probands and their unaffected siblings were identified. These findings were largely confirmed by complementary pairwise connectomic comparisons. However, the main connectivity differences between ADHD and unaffected siblings were not replicated in a tightly age- and sex-matched subsample (20 proband−sibling pairs and 60 TD youths). Conclusion Our findings suggest that increased functional segregation related to the attention networks, especially the salience (ventral attention) system, may be a potential feature of at-risk siblings who remain unaffected by ADHD expression. Further replications are needed in other larger and sex-matched samples. Clinical trial registration information: Structural and Functional Connectivity of Frontostriatal and Frontoparietal Networks as Endophenotypes of ADHD; https://clinicaltrials.gov/; NCT01682915. Although there are frequent reports of shared neurofunctional and neurostructural alterations among probands with attention-deficit/hyperactivity disorder (ADHD) and their unaffected siblings, there is little knowledge regarding whether abnormalities in the resting-state functional connectivity of ADHD probands is also expressed in unaffected siblings, or whether this unaffected (but at-risk) cohort manifests distinct patterns. We used a multivariate connectome-wide association study examining intrinsic functional connectivity with resting-state functional magnetic resonance imaging (MRI) in a sample (aged 8−17 years) of medication-naive ADHD probands (n = 56), their unaffected siblings (n = 55), and typically developing (TD) youths (n = 106). ADHD probands showed, relative to TD youths, increased connectivity between the default-mode network (DMN) and task-positive networks. Relative to ADHD and TD groups, respectively, unaffected siblings showed increased connectivity within the salience network and reduced connectivity between the DMN and salience network. No shared alterations in functional connectivity among ADHD probands and their unaffected siblings were identified. These findings were largely confirmed by complementary pairwise connectomic comparisons. However, the main connectivity differences between ADHD and unaffected siblings were not replicated in a tightly age- and sex-matched subsample (20 proband−sibling pairs and 60 TD youths). Our findings suggest that increased functional segregation related to the attention networks, especially the salience (ventral attention) system, may be a potential feature of at-risk siblings who remain unaffected by ADHD expression. Further replications are needed in other larger and sex-matched samples.