Marked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Efforts to unravel sex differences in the brain organization of autism have, however, been challenged by the limited availability of female data. We addressed this gap by using a large sample of males and females with autism and neurotypical (NT) control individuals (ABIDE; Autism: 362 males, 82 females; NT: 409 males, 166 females; 7–18 years). Discovery analyses examined main effects of diagnosis, sex and their interaction across five resting-state fMRI (R-fMRI) metrics (voxel-level Z > 3.1, cluster-level P < 0.01, gaussian random field corrected). Secondary analyses assessed the robustness of the results to different pre-processing approaches and their replicability in two independent samples: the EU-AIMS Longitudinal European Autism Project (LEAP) and the Gender Explorations of Neurogenetics and Development to Advance Autism Research. Discovery analyses in ABIDE revealed significant main effects of diagnosis and sex across the intrinsic functional connectivity of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical regions, largely converging in the default network midline. Sex-by-diagnosis interactions were confined to the dorsolateral occipital cortex, with reduced VMHC in females with autism. All findings were robust to different pre-processing steps. Replicability in independent samples varied by R-fMRI measures and effects with the targeted sex-by-diagnosis interaction being replicated in the larger of the two replication samples—EU-AIMS LEAP. Given the lack of a priori harmonization among the discovery and replication datasets available to date, sample-related variation remained and may have affected replicability. Atypical cross-hemispheric interactions are neurobiologically relevant to autism. They likely result from the combination of sex-dependent and sex-independent factors with a differential effect across functional cortical networks. Systematic assessments of the factors contributing to replicability are needed and necessitate coordinated large-scale data collection across studies.

中文翻译：

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自闭症大脑内在功能中实现稳健且可复制的性别差异


自闭症患病率的显着性别差异凸显了了解生物性别相关因素在自闭症中的作用的必要性。然而，由于女性数据有限，揭示自闭症大脑组织性别差异的努力受到了挑战。我们通过使用大量男性和女性自闭症患者以及神经典型 (NT) 对照个体样本来解决这一差距（ABIDE；自闭症：362 名男性，82 名女性；NT：409 名男性，166 名女性；7-18 岁）。发现分析检查了诊断、性别及其相互作用对五个静息态 fMRI (R-fMRI) 指标的主要影响（体素水平 Z > 3.1，簇水平 P < 0.01，高斯随机场校正）。二次分析评估了结果对不同预处理方法的稳健性及其在两个独立样本中的可复制性：EU-AIMS 纵向欧洲自闭症项目 (LEAP) 和促进自闭症研究的神经遗传学和发展的性别探索。 ABIDE 中的发现分析揭示了诊断和性别对后扣带皮层内在功能连接、几个皮质区域的区域同质性和体素镜像同伦连接 (VMHC) 的显着主要影响，大部分集中在默认网络中线。性别与诊断的相互作用仅限于背外侧枕叶皮层，自闭症女性的 VMHC 减少。所有发现对于不同的预处理步骤都是稳健的。独立样本的可重复性因 R-fMRI 测量和效果而异，目标性别与诊断的相互作用在两个复制样本中较大的一个中被复制 - EU-AIMS LEAP。 鉴于迄今为止可用的发现和复制数据集之间缺乏先验协调，与样本相关的变化仍然存在，并且可能影响可复制性。非典型的跨半球相互作用在神经生物学上与自闭症相关。它们可能是由性别依赖和性别无关因素组合产生的，并且在功能性皮层网络中具有不同的影响。需要对影响可重复性的因素进行系统评估，并且需要跨研究协调大规模数据收集。