Revealing the Multivariate Associations Between Autistic Traits and Principal Functional Connectome

Autism Spectrum Disorder (ASD) is a multifaceted neurodevelopmental condition characterized by a spectrum of behavioral and cognitive traits. As the characteristics of ASD are highly heterogeneous across individuals, a dimensional approach that overcomes the limitation of the categorical approach is preferred to reveal the symptomatology of ASD. Previous neuroimaging studies demonstrated strong links between large-scale brain networks and autism phenotypes. However, the existing studies have primarily focused on univariate association analysis, which limits our understanding of autism connectopathy. Using resting-state functional magnetic resonance imaging data from 309 participants (168 individuals with ASD and 141 typically developing controls) across a discovery dataset and two independent validation datasets, we identified multivariate associations between high-dimensional neuroimaging features and diverse phenotypic measures (20 or 7 measures). We generated low-dimensional representations of functional connectivity (i.e., gradients) and assessed their multivariate associations with autism-related phenotypes of social, behavioral, and cognitive problems using sparse canonical correlation analysis (SCCA). We selected three functional gradients that represented the cortical axes of the sensory-transmodal, motor-visual, and multiple demand-rests of the brain. The SCCA revealed multivariate associations between gradients and phenotypic measures, which were noted as linked dimensions. We identified three linked dimensions: the links between (1) the first gradient and social impairment, (2) the second and internalizing/externalizing problems, and (3) the third and metacognitive problems. Our findings were partially replicated in two independent validation datasets, indicating robustness. Multivariate association analysis linking high-dimensional neuroimaging and phenotypic features may offer promising avenues for establishing a dimensional approach to autism diagnosis.