Broadly Reduced Intrinsic Functional Connectivity in Girls Compared to Boys with Autism Spectrum Disorders

Background: The high male:female prevalence ratio of autism spectrum disorders (ASDs) has been recognized dating back to Leo Kanner’s initial description in 1943 (Kanner, 1943). The majority of research studies in autism reflect this strong male bias. Although a growing body of research suggests that ASDs may affect females differently than males (Werling & Geschwind, 2013), little is known about possible female variants. Further research with adequate samples is necessary to inform our understanding of gender-related neurobiological differences in ASDs. Knowledge of gender-specific differences in ASDs promises to inform novel, targeted therapeutic interventions (Constantino, 2017).

Objectives: Investigate gender-based differences in iFC, and within- versus between-domain connectivity, in children and adolescents with and without ASDs.

Methods:

Resting-state functional MRI data for 142 children and adolescents (ages 7-18 years) were selected from the Autism Brain Imaging Database Exchange (ABIDE I and II; n = 111; DiMartino et al., 2014 & 2017) and an in-house sample (n = 31), with 70 datasets from children with ASDs (36 females) and 72 datasets from typically developing (TD) children (36 females). Within each diagnostic group, boys and girls were matched on age, handedness, cognitive functioning, head motion, and study site. Group independent component analysis (ICA) and dual-regression were used to generate intrinsic functional networks for each subject. The spatial maps were thresholded at 90^th percentile to extract separate functional clusters (ROIs). Functional connectivity (FC) was estimated by generating intra-individual ROI-ROI correlation matrices, with mean connectivity matrices averaged across participants. ROIs were categorized into three domains: sensorimotor, default mode, and executive. Chi-square tests of independence were used to test for differences in the proportion of significant within- and between-domain ROI-ROI correlations (rs > |0.4|).

Results: Within the TD group, boys (TD-B) showed significantly more positive correlations within the sensorimotor domain than girls (TD-G) (X² = 14.7, p <0.001). TD-B and TD-G did not differ in their within- or between-domain connectivity for any other domains. In contrast, girls with ASDs (ASD-G) showed broad underconnectivity compared to boys with ASDs (ASD-B). Specifically, ASD-G showed fewer positive correlations between the sensory networks and executive and default mode networks (X² = 5.11, p = 0.02); fewer positive correlations within the DMN (X² = 5.00, p = 0.03); fewer positive correlations between the DMN and other domains (X² = 15.78, p = < 0.0001); fewer positive correlations within the executive domain (X² = 6.12, p = 0.01); and fewer positive correlations between executive and other domains (X² = 10.85, p < 0.0001).

Conclusions: We found a pattern of pervasive underconnectivity in girls compared to boys with ASDs, whereas in the TD group, gender differences in connectivity were seen only within the sensorimotor domain. Our study includes a substantially larger sample than previous reports. Use of ABIDE data, however, precluded inclusion of puberty status and hormonal changes, which are likely to affect brain organization.