Abstract
A notable characteristic of autism spectrum disorder (ASD) is co-occurring deficits in low-level sensory processing and high-order social interaction. While there is evidence indicating detrimental cascading effects of sensory anomalies on the high-order cognitive functions in ASD, the exact pathological mechanism underlying their atypical functional interaction across the cortical hierarchy has not been systematically investigated. To address this gap, here we assessed the functional organisation of sensory and motor areas in ASD, and their relationship with subcortical and high-order trandmodal systems. In a resting-state fMRI data of 107 ASD and 113 neurotypical individuals, we applied advanced connectopic mapping to probe functional organization of primary sensory/motor areas, together with targeted seed-based intrinsic functional connectivity (iFC) analyses. In ASD, the connectopic mapping revealed topological anomalies (i.e., excessively more segregated iFC) in the motor and visual areas, the former of which patterns showed association with the symptom severity of restricted and repetitive behaviors. Moreover, the seed-based analysis found diverging patterns of ASD-related connectopathies: decreased iFCs within the sensory/motor areas but increased iFCs between sensory and subcortical structures. While decreased iFCs were also found within the higher-order functional systems, the overall proportion of this anomaly tends to increase along the level of cortical hierarchy, suggesting more dysconnectivity in the higher-order functional networks. Finally, we demonstrated that the association between low-level sensory/motor iFCs and clinical symptoms in ASD was mediated by the high-order transmodal systems, suggesting pathogenic functional interactions along the cortical hierarchy. Findings were largely replicated in the independent dataset. These results highlight that atypical integration of sensory-to-high-order systems contributes to the complex ASD symptomatology.
Highlights
The major symptoms defining autism spectrum disorder (ASD) include persistent deficits in social communication and interaction, and restricted/repetitive patterns of behaviors and interests, all of which either fully or at least partly involve high-order transmodal cortical regions [1,2,3,4,5,6,7,8,9,10,11]. Because of such relevance for various phenotypes, high-order cognitive systems have long been a focus of ASD research in the past decades, providing a basis to construct seminal theories centered on atypical theory of mind [12, 13], or executive dysfunction [14,15,16]
Our mediation analyses further enrich the context of this finding, as we demonstrated that the severity of social impairment is mediated by the intrinsic functional connectivity (iFC) of the transmodal systems, which may be in turn affected by atypical development of early sensory areas in ASD
Our findings demonstrate multiple levels of functional connectivity anomalies along the cortical hierarchy, ranging from atypical gradients in primary sensory/motor areas to diverging patterns of hypoand hyper-connectivity among the subcortico-cortical and cortico-cortical networks
Summary
The major symptoms defining autism spectrum disorder (ASD) include persistent deficits in social communication and interaction, and restricted/repetitive patterns of behaviors and interests, all of which either fully or at least partly involve high-order transmodal cortical regions [1,2,3,4,5,6,7,8,9,10,11] Because of such relevance for various phenotypes, high-order cognitive systems have long been a focus of ASD research in the past decades, providing a basis to construct seminal theories centered on atypical theory of mind [12, 13], or executive dysfunction [14,15,16]. Despite the significance of this model, how the interaction between these hierarchically distinct two subsystems contribute to each behavioral symptom of ASD remains poorly understood, mainly because of lack of analytical tools to integrate multiple brain systems and behaviors in a mechanistically meaningful way
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