Synergistic-redundant dysfunction in autism spectrum disorder: Heterogeneity and molecular mechanisms

Delineating the systematic functional integration and regional functional robustness in shared and individual-specific subspaces is critical to elucidating the neural basis underlying social and cognitive deficits in autism spectrum disorder (ASD). Here, integrated information decomposition and common orthogonal basis extraction approaches were combined to map individual synergistic and redundant interactions in shared and individual-specific subspaces based on functional connectivity networks derived from 842 individuals with ASD and 933 typically developing controls (TC), examined across age-stratified groups from a cross-sectional perspective. Results revealed that synergistic interactions were progressively greater in older age groups of individuals with ASD, whereas redundant interactions exhibited an inverted-U-shaped pattern of age-related differences, with the most pronounced between-group differences observed in adolescence and comparatively smaller differences in childhood and adulthood. Moreover, alterations in synergistic and redundant interactions within individual-specific subspaces were associated with clinical symptoms in a developmentally stage-specific manner at the individual level. By integrating neurotransmitter and gene expression datasets, spatial association analyses revealed that dysfunction of the dopaminergic, GABAergic, and opioid neurotransmitter systems, genes regulating synaptic signaling and neuronal projection development, and cell types including astrocytes and microglia may underlie the neuropathology of ASD. Collectively, these findings not only uncover abnormal patterns of information interactions in ASD brain networks, but also offer novel insights into ASD heterogeneity, potentially providing crucial clues for the development of early diagnostic and intervention strategies.