Sex-Specific Alterations in Motor Network Morphology in Relation to Repetitive Behaviours: A Twin Study

Background:

Restricted and repetitive behaviors and interests (RRBI’s) are core symptoms of autism spectrum disorder (ASD) (DSM-5) that are thought to be less prevalent in females than males (Van Wijngaarden-Cremers et al., 2014). Differences in the phenotypic expression and etiology of ASD, including structural morphology of the brain, might underlie this prevalence difference (Supekar and Menon, 2015, Lai et al., 2015). However, for results to be generalizable, the heterogenous expression of ASD, related to variability in environmental and epigenetic factors, needs to be controlled for.

Objectives:

The current study, within the Roots of Autism and ADHD Twin Study Sweden (RATSS) (Bölte et al., 2014), implemented a within-twin pair design to investigate sex differences in the relation between RRBI’s and detailed structural morphology of neocortical motor networks.

Methods:

T1-weighted images from 29 female and 39 male MZ and DZ twin pairs (i.e. 134 participants including neurotypicals and individuals across the whole ASD spectrum), aged 9-24 years, were analysed using surface-based morphology software (Freesurfer) to obtain estimates of cortical volume, surface-area and thickness of gyri and sulci involved in the motor network: central, pre-and post-central, superior frontal (including the supplementary motor area), supramarginal, angular, intra-parietal and superior parietal areas. RRBI’s were assessed using the subscale from the Autism Diagnostic Interview – Revised (Rutter et al. 2003). Within-pair differences in surface-based estimates were correlated to differences in RRBI’s using generalized estimating equation linear models, while controlling for total brain volume and handedness (Edinburgh handedness inventory).

Results:

Behaviourally, males and females did not differ in within-twin pair differences in RRBI’s (Kruskal-Wallis χ2(1) = 0.007, p = 0.9). Neuroanatomically, RRBI scores were primarily associated with alterations in bilateral primary motor cortex, left SMA and intraparietal sulcus in females, but with alterations in left sensory cortex and the corresponding sensory associative parietal region in males. In females, the associations were mostly negative, indicating that an increase of RRBI symptoms was related to a decrease in brain morphological features. In males, the findings were differentially positively or negatively related to RRBIs. The details of the within-pair association between brain estimates and symptom is reported in table 1.

Conclusions:

Although females did not differ from males on RRBI symptoms, we report different and more regions of the neocortical motor network to be associated with RRBI’s in females, supporting the female protective hypothesis. Females were particularly affected in primary motor and SMA in accordance with previous research showing that gray matter in these regions was related to RRBI’s in girls, but not boys with autism (Supekar and Menon, 2015). Moreover, we show that RRBIs are associated with anatomical differences of the neocortical motor network even while controlling for genetic and shared environmental factors, indicating that these effects are partly due to non-shared environmental factors. Taken together, our findings suggest that the autistic phenotype is associated with different underlying neurobiology in females.