Abstract
BackgroundMarked 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.MethodsWe 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.ResultsDiscovery 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.LimitationsGiven the lack of a priori harmonization among the discovery and replication datasets available to date, sample-related variation remained and may have affected replicability.ConclusionsAtypical 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.
Highlights
Marked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism
Discovery analyses: Autism Brain Imaging Data Sharing Exchange (ABIDE) Main effects of diagnosis Analyses revealed a total of seven clusters showing a significant effect of diagnosis for three of the five resting-state functional magnetic resonance imaging (R-fMRI) metrics: posterior cingulate cortex (PCC)-intrinsic functional connectivity (iFC), voxel-mirrored homotopic connectivity (VMHC) and regional homogeneity (ReHo); Fig. 1 and Additional file 1: Figure S2
Autism-related hyper-connectivity was only evident for PCC-iFC with left superior lateral occipital cortex, temporal occipital fusiform cortex and occipital fusiform gyrus (Additional file 1: Figure S2)
Summary
Marked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Autism spectrum disorder (autism) is characterized by a marked male preponderance in prevalence with three times more males being diagnosed than females [1] This pronounced sex-differential prevalence implies that sexrelated biological factors are likely implicated in the neurobiology of autism. Little is known about the differential underlying neural expressions in males and females with autism Such knowledge could widen our understanding of potential underlying mechanisms of autism and related neurodevelopmental conditions [2]. This has motivated research into the impact of biological sex on brain organization in autism [2,3,4,5]. While the exact nature of the intrinsic brain organization in autism remains to be established [6], research on the impact of biological sex differences in autism is just beginning to emerge
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