Abstract
Autism spectrum disorder (ASD) encompasses a set of neurodevelopmental conditions whose striking sex-related disparity (with an estimated male-to-female ratio of 4:1) remains unknown. Here we use magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) to identify the brain structure correlates of the sex-by-ASD diagnosis interaction in a carefully selected cohort of 110 ASD patients (55 females) and 83 typically-developing (TD) subjects (40 females). The interaction was found to be predicated primarily upon white matter connectivity density innervating, bilaterally, the lateral aspect of the temporal lobe, the temporo-parieto-occipital junction and the medial parietal lobe. By contrast, regional gray matter (GM) thickness and volume are not found to modulate this interaction significantly. When interpreted in the context of previous studies, our findings add considerable weight to three long-standing hypotheses according to which the sex disparity of ASD incidence is (A) due to WM connectivity rather than to GM differences, (B) modulated to a large extent by temporoparietal connectivity, and (C) accompanied by brain function differences driven by these effects. Our results contribute substantially to the task of unraveling the biological mechanisms giving rise to the sex disparity in ASD incidence, whose clinical implications are significant.
Highlights
One in ~68 children in the US suffers from autism spectrum disorder (ASD), which is a highly-heritable neurodevelopmental mental condition characterized by difficulty in communicating, forming relationships with other individuals, using language and manipulating abstract concepts
We use magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) to investigate the effects of sex, ASD diagnosis and their interaction upon regional cortical area, cortical thickness, cortical curvature, gray matter (GM) volume and white matter (WM) connectivity density (CD) in a carefully-selected cohort consisting of 110 ASD and 83 typically developing (TD) volunteers (95 females)
The WM connectivity density of temporal and parietal brain areas is found to be modulated, to a statistically significant extent, by the statistical interaction between sex and ASD diagnosis, which suggests that differences in brain circuitry in these brain regions are strongly associated with the sex disparity in ASD incidence
Summary
One in ~68 children in the US suffers from autism spectrum disorder (ASD), which is a highly-heritable neurodevelopmental mental condition characterized by difficulty in communicating, forming relationships with other individuals, using language and manipulating abstract concepts. The hyper-connectivity patterns in ASD females were interpreted as reflective of neural masculinization, whereas hypo-connectivity patterns observed in ASD males were found to exhibit the features of neural feminization, which prompted Alaerts et al to propose that, contrary to the predictions of EMB theory, ASD is a disorder of sexual differentiation rather than masculinization in both genders Such potentially contradictory findings across studies suggest that the ongoing debate regarding the relationship between ASD modulators, ASD diagnosis and brain structure remains far from settled. Our results suggest powerful strategies for future research into this puzzling, mysterious and clinically significant phenomenon
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