Heterogeneous functional state dynamics and its structural substrates in male individuals with autism spectrum disorder.

Neuroimaging studies have revealed altered functional connectome dynamics in autism spectrum disorder (ASD) and linked these alterations to clinical symptoms. However, most studies have emphasized population-level contrasts, leaving interindividual variability in connectome dynamics and its structural underpinnings poorly understood. To address this gap, we analyzed resting-state functional and structural MRI data from 939 male participants (440 with ASD, 499 typically developing controls) across 18 sites in the Autism Brain Imaging Data Exchange (ABIDE). Whole-brain functional state dynamics was characterized using five leading activity modes and their expressions via eigen-microstate analysis. Age-related trajectories of mode expressions were constructed for typically developing controls using normative modeling, enabling quantification of individual-level deviations in functional dynamics. Compared with controls, ASD individuals showed greater interindividual variability in functional deviation profiles. Unsupervised clustering of these profiles identified two robust ASD subtypes with distinct mode-specific dysfunctions. One subtype primarily involved the visual, default-mode, frontoparietal, and dorsal attention networks, whereas the other subtype primarily involved the somatomotor, visual, frontoparietal, and ventral attention networks. These subtypes were clinically dissociable, differing in restricted and repetitive behaviors and social impairments, and exhibited mode-specific brain-symptom associations. Furthermore, the subtypes exhibited distinct cortical thickness alterations, and individual subtype membership was predicted with high accuracy (83%) using a random forest classifier based on cortical thickness. The main findings were replicated in an independent cohort outside ABIDE. This study delineates two reproducible and clinically dissociable ASD subtypes and links functional connectome dynamics to structural substrates, offering novel insights into the neurobiological basis behind ASD heterogeneity.