Sex-Related Neurocircuitry Supporting Camouflaging in Adults with Autism: Female Protection Insights

The male preponderance in autism led to the hypothesis that aspects of female biology are protective against autism. Females with autism report engaging in more compensatory behaviors (i.e., "camouflaging") to overcome autism-related social differences, which may be a downstream result of protective pathways. No studies have examined sex-related brain pathways supporting camouflaging in females with autism, despite its potential to inform mechanisms underlying the sex bias in autism. This case-control design included 45 non-intellectually-disabled adults with autism (male/female: 21/24) and 40 neurotypical adults (male/female: 19/21) ages 18-71. We used group multivariate voxel pattern analysis to conduct a data-driven, connectome-wide characterization of "sex-atypical" (sex-by-diagnosis) and "sex-typical" (sex) brain functional connectivity features linked to camouflaging, and validated findings in females with autism multi-modally via structural connectometry. Exploratory associations with cognitive control, memory, emotion recognition, and depression/anxiety examined the adaptive nature of functional connectivity patterns supporting camouflaging in females with autism. We found 1) "sex-atypical" functional connectivity patterns predicting camouflaging in the hypothalamus and precuneus and 2) "sex-typical" patterns in the anterior cingulate and right anterior parahippocampus. Higher hypothalamic functional connectivity with a limbic reward cluster was the strongest predictor of camouflaging in females with autism (a "sex-atypical" pattern), and also predicted better cognitive control/emotion recognition. Structural connectometry validated functional connectivity results with consistent brain pathways/effect patterns implicated across multi-modal findings in females with autism. This data-driven, connectome-wide characterization of "sex-atypical" and "sex-typical" brain connectivity features supporting compensatory social behavior in autism suggests hormones may play a role in the autism sex bias. Furthermore, both "male-typical" and "female-typical" brain connectivity patterns are implicated in camouflaging in females with autism in circuits associated with reward, emotion, and memory processing. "Sex-atypical" results are consistent with the fetal steroidogenic hypothesis, which would result in masculinized brain features in females with autism. However, female genetics/biology may contribute to "female-typical" patterns implicated in camouflaging.