Abstract
BackgroundThe male predominance in the prevalence of autism spectrum disorder (ASD) has motivated research on sex differentiation in ASD. Multiple sources of evidence have suggested a neurophenotypic convergence of ASD-related characteristics and typical sex differences. Two existing, albeit competing, models provide predictions on such neurophenotypic convergence. These two models are testable with neuroimaging. Specifically, the Extreme Male Brain (EMB) model predicts that ASD is associated with enhanced brain maleness in both males and females with ASD (i.e., a shift-towards-maleness). In contrast, the Gender Incoherence (GI) model predicts a shift-towards-maleness in females, yet a shift-towards-femaleness in males with ASD.MethodsTo clarify whether either model applies to the intrinsic functional properties of the brain in males with ASD, we measured the statistical overlap between typical sex differences and ASD-related atypicalities in resting-state fMRI (R-fMRI) datasets largely available in males. Main analyses focused on two large-scale R-fMRI samples: 357 neurotypical (NT) males and 471 NT females from the 1000 Functional Connectome Project and 360 males with ASD and 403 NT males from the Autism Brain Imaging Data Exchange.ResultsAcross all R-fMRI metrics, results revealed coexisting, but network-specific, shift-towards-maleness and shift-towards-femaleness in males with ASD. A shift-towards-maleness mostly involved the default network, while a shift-towards-femaleness mostly occurred in the somatomotor network. Explorations of the associated cognitive processes using available cognitive ontology maps indicated that higher-order social cognitive functions corresponded to the shift-towards-maleness, while lower-order sensory motor processes corresponded to the shift-towards-femaleness.ConclusionsThe present findings suggest that atypical intrinsic brain properties in males with ASD partly reflect mechanisms involved in sexual differentiation. A model based on network-dependent atypical sex mosaicism can synthesize prior competing theories on factors involved in sex differentiation in ASD.
Highlights
The male predominance in the prevalence of autism spectrum disorder (ASD) has motivated research on sex differentiation in ASD
In recent years, resting-state functional magnetic resonance imaging (R-fMRI) has demonstrated its feasibility in capturing typical sex differences in various aspects of the intrinsic connectome [7,8,9] and has emerged as a robust tool for substantiating the functional dysconnectivity hypothesis of ASD [1, 2]. This has motivated initial R-fMRI studies to characterize the contribution of biological sex to the neurobiology of ASD [10, 11]
We focused on five key whole-brain voxel-wise R-fMRI indices in regard to (a) typical sex differences in a neurotypical (NT) sample from the 1000 Functional Connectome Project (FCP) [19] and (b) ASD-related differences among males from Autism Brain Imaging Data Exchange (ABIDE) I [1]
Summary
The male predominance in the prevalence of autism spectrum disorder (ASD) has motivated research on sex differentiation in ASD. In recent years, resting-state functional magnetic resonance imaging (R-fMRI) has demonstrated its feasibility in capturing typical sex differences in various aspects of the intrinsic connectome [7,8,9] and has emerged as a robust tool for substantiating the functional dysconnectivity hypothesis of ASD [1, 2]. This has motivated initial R-fMRI studies to characterize the contribution of biological sex to the neurobiology of ASD [10, 11]. Preliminary evidence suggests that both sex-dependent and sex-independent dysconnections coexist in ASD [12]
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