Network-specific sex differentiation of intrinsic brain function in males with autism.

The 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. To 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. Across 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. The 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. The online version of this article (10.1186/s13229-018-0192-x) contains supplementary material, which is available to authorized users.

自闭症谱系障碍（ASD）患病率中男性占优势的情况激发了对ASD性别差异的研究。多方面的证据表明，ASD相关特征与典型性别差异在神经表型上存在趋同。现有的两种相互竞争的模型对这种神经表型趋同做出了预测。这两种模型可以通过神经影像学进行检验。具体而言，极端男性大脑（EMB）模型预测，ASD与患有ASD的男性和女性大脑的男性化增强有关（即向男性化转变）。相比之下，性别不一致（GI）模型预测，患有ASD的女性会向男性化转变，而患有ASD的男性则会向女性化转变。 为了阐明这两种模型是否适用于患有ASD的男性大脑的内在功能特性，我们测量了在男性中大量可得的静息态功能磁共振成像（R - fMRI）数据集中典型性别差异与ASD相关异常之间的统计重叠。主要分析集中在两个大规模的R - fMRI样本上：来自1000功能连接组项目的357名神经正常（NT）男性和471名神经正常女性，以及来自自闭症脑成像数据交换项目的360名患有ASD的男性和403名神经正常男性。 在所有R - fMRI指标中，结果显示患有ASD的男性中存在向男性化转变和向女性化转变并存的情况，但具有网络特异性。向男性化转变主要涉及默认网络，而向女性化转变主要发生在躯体运动网络。利用现有的认知本体图谱对相关认知过程进行的探索表明，高阶社会认知功能与向男性化转变相对应，而低阶感觉运动过程与向女性化转变相对应。 目前的研究结果表明，患有ASD的男性大脑的非典型内在特性部分反映了性别分化所涉及的机制。一个基于网络相关的非典型性别嵌合体的模型可以综合先前关于ASD性别分化所涉及因素的相互竞争的理论。 本文的网络版（10.1186/s13229 - 018 - 0192 - x）包含补充材料，授权用户可获取。