Two clusters of brain regions with distinct age-related profiles of functional connectivity in autism spectrum disorder

Brain functional connectivity changes throughout development, and individuals with autism spectrum disorder (ASD) may follow trajectories that differ from those of typically developing controls. Using large multisite resting-state fMRI cross-sectional datasets, we examined how functional connectivity differences between ASD and typically developing controls change across a broad age range of 5 to 64 y. A data-driven analysis identified two spatially distributed clusters of cortical regions showing distinct age-related profiles of ASD–TD connectivity differences. Cluster 1 was marked by consistent hypoconnectivity across ages, suggesting a stable neural signature of ASD. Cluster 2 was characterized by hypoconnectivity in childhood that gradually diminished with age, suggesting a temporary delay profile. These clusters were systematically organized along the sensory–association axis. Cluster 1 mainly involved lower-rank sensory and sensorimotor cortices, while Cluster 2 mainly involved higher-rank association cortices. Brain–behavior analyses revealed greater and broader ASD symptom associations across ages in the consistent hypoconnectivity profile than the delay profile. Further subtype analyses suggested that social-affect symptoms were associated with greater hypoconnectivity than repetitive behavior symptoms in both clusters. Spatial correlation analyses with neurotransmitter maps revealed associations of Cluster 1 with mGluR5 and of Cluster 2 with GABA A α5, providing insight into the neurobiological basis of the two clusters. In a cross-disorder validation analysis, applying the same analytic framework to attention-deficit/hyperactivity disorder did not reveal comparable results. Together, these findings suggest that ASD-related functional connectivity alterations are developmentally heterogeneous and organized along the cortical hierarchy, providing a developmental perspective for understanding the neurobiology of ASD.