Impact of Gender on Resting-State Network Connectivity in Youth with ASD

Background: Autism spectrum disorder (ASD) is consistently shown to have a higher prevalence rate in males than females (Fombonne, 2009), and nearly all neuroimaging studies in ASD to date have used samples that are predominantly or entirely male (Philip et al., 2012). Such neuroimaging studies in males have found differences in resting-state functional connectivity between participants with ASD and typically developing (TD) controls, with multiple studies particularly implicating the salience network in ASD (Uddin et al., 2015). However, genetic and behavioral evidence suggests that findings from males with ASD may not generalize to their female counterparts, as females require a greater genetic load to develop ASD (Werling & Geschwind, 2013) and may display differences in symptom profiles relative to males with ASD (Lai et al., 2015). Furthermore, a couple of recent neuroimaging studies have reported some gender differences in brain connectivity among individuals with ASD (Alaerts et al., 2016; Ypma et al., 2016), underscoring the importance of further investigations into the impact of gender on functional connectivity in ASD.

Objectives: Examine how functional connectivity findings within the salience network differ between girls and boys with ASD, as well as how girls and boys with ASD differ from gender-matched TD controls.

Methods: As part of an NIH-funded multi-site network, resting-state functional magnetic resonance imaging (fMRI) data was collected from a total of 195 individuals with ASD and TD controls. An approximately equal number of girls and boys contributed data to each group, and all subjects were between the ages of 8 and 17 years old. Salience network connectivity was examined using a seed located in the anterior insula (Seeley et al., 2007), with nuisance regressors and ICA-AROMA used to reduce potential motion confounds (Pruim et al., 2015). Site, IQ, and pubertal development were included as covariates at the group level. Comparisons between the female and male subjects of the ASD and TD groups were completed in FSL and prethreshold masked to focus on those areas which displayed significant positive or negative connectivity with the SN seed. Connectivity z-scores from significant group clusters were subsequently extracted and correlated with behavioral measures.

Results: Relative to boys with ASD, girls with ASD displayed greater positive connectivity with premotor regions and reduced positive connectivity with insular and frontal areas. Girls with ASD furthermore demonstrated increased negative connectivity with sensorimotor regions compared to boys with ASD, who instead had greater negative connectivity with temporal and cerebellar structures. When comparing girls and boys with ASD to their TD counterparts, there were no significant differences between girls with and without ASD. However, relative to TD boys, boys with ASD displayed significant reductions in both positive and negative connectivity with temporal and parietal regions.

Conclusions: These findings suggest that brain regions associated with salience detection and sensorimotor processing are differentially connected in males and females with ASD. Furthermore, our results demonstrate that brain alterations found in males with ASD may not generalize to females with ASD and emphasize the necessity of considering gender when investigating brain-based phenotypes in ASD.