The Influence of Biological Sex on Neurobiological Mechanisms Underlying Autism Spectrum Disorder

Background:  Autism spectrum disorder (ASD) is highly heterogeneous condition, particularly when considering neurobiological function. There is, however, evidence to suggest that biological sex contributes to this neurobiological heterogeneity, and that females may be more profoundly affected. 

Objectives:  This study investigated the role of biological sex on neural mechanisms underlying ASD, including neural activity and connectivity, with a specific focus on brain regions and mechanisms underlying social cognition.

Methods:  66 males and female adults with high-functioning ASD and age, sex and IQ matched controls took part in this study. Participants completed various measures, including: neurocognitive/neurobehavioural assessment; structural (anatomical and diffusion weighted imaging [DWI]), functional (resting state [investigating the default mode network; DMN], and task related [investigating ToM]) magnetic resonance imaging (MRI); and combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG; TMS-EEG) of right lateralised dorsolateral-prefrontal cortex (rDLPFC), primary motor cortex (rM1) and temporo-parietal junction (rTPj). 

Results:  : DWI data revealed no differences between groups in any major white matter (WM) tracts throughout the brain. At rest, we did not identify any differences in functional connectivity (FC) between the key DMN structures, between groups, nor any effect of sex. Reduced FC in the ASD group, however, was noted between the posterior cingulate cortex (PCC) and the right lateralised somatosensory and temporal cortices. While processing social interactions, there were no group differences in hemodynamic response in core “mentalising” regions (medial prefrontal cortex, rTPj), but the ASD group displayed a reduced response in the neighbouring right posterior superior temporal sulcus (pSTS). Gender analysis indicated that this was apparent for males with ASD, but not females with ASD. TMS-EEG data did not reveal any group differences in neurobiological response to TMS at any of the sites investigated, or any effect of sex.

Conclusions:  These findings provide important information with regard to the heterogeneity of ASD, specifically around the notion of a mediating role of biological sex in ASD. The findings of this study indicate that the perceived sex differences in ASD are not consistently replicated across measures of neurobiological mechanisms. This highlights the importance of investigating sex differences in ASD across a variety of measures and mechanisms, and also across different domains implicated in the autism spectrum.