Sex Difference in Structural Hemispheric Asymmetry in ASD

Background: Autism spectrum disorder (ASD) is characterized by a striking male preponderance with three times more males being affected than females. While neuroimaging studies have started to pick up on studying sex differences in ASD, none has addressed the question of sex differences with respect to hemispheric specialization. ASD is characterized by a disruption of specialization in the brain with findings pointing to atypical hemispheric asymmetry across hemispheres (Herbert et al., 2002; Floris et al., 2016). Sex differences in hemispheric specialization have frequently been reported in neurotypical (NT) individuals with males showing more pronounced patterns of lateralization than females, however, no study has addressed this question in ASD.

Objectives:

We aimed to explore sex differences in hemispheric lateralization across individuals with ASD and NT controls.

Methods:

We selected high quality structural T1-weighted MRI data from the Longitudinal European Autism Project dataset including 94 females with ASD aged 6-30 years, 260 IQ-and age-matched males with ASD as well as 166 age-matched NT males and 90 NT females. T1-weighted images were preprocessed using SPM12 and the CAT12 toolbox. Specific preprocessing steps were adopted to meet requirements for the analysis of asymmetry: 1) images were segmented using a symmetric tissue probability map; 2) segmented images were flipped along the x-axis; 3) original (OI) and flipped images (FI) were used to create a symmetric DARTEL template and subsequently registered to it; 4) laterality indices was calculated at each voxel by the formula:(OI–FI)/(OI+FI)*2. Laterality images were restricted to the right hemisphere (RH) and smoothed with a 4mm FWHM kernel. Main effects and interactions were tested by regression of a GLM at each voxel with group and sex as fixed factors and age and scanning sites as nuisance covariates. Significance levels for clusters were set at a voxel-level cluster-forming p<0.001 and by their number of expected voxels (spatial extent threshold) according to Gaussian Random Field theory. Statistical outcomes were corrected for multiple comparisons at the cluster-level by controlling the topological false discovery rate (FDR) at q<0.05. Significant results were correlated with symptom measures such as the ADOS and ADI.

Results:

Voxel-wise analysis of laterality in the RH revealed significant group-by-sex-interactions in the posterior cingulate cortex and the pars trinagularis. Males with ASD showed reduced leftward asymmetry compared to NT males, while ASD females showed increased leftward asymmetry compared to NT females. The opposite pattern was evident in the angular gyrus and supplementary motor area with ASD females showing reversed rightward asymmetry compared to NT females and ASD males showing reversed leftward asymmetry compared to NT males. Results remained the same when including handedness and FIQ as nuisance covariates. Correlation analyses with ADI- and ADOS-subscales did not yield any significant results.

Conclusions:

Males and females with ASD exhibit differential patterns of structural hemispheric lateralisation compared to NT controls in language processing regions and default network hubs. While males with ASD show patterns that resemble those in NT females, females with ASD exhibit neural masculinization suggesting that models of ‘gender-incoherence’ of ASD also apply to atypical hemispheric lateralization.