Multimodal Developmental Neuroimaging of Girls with Autism

Background:  Autism Spectrum Disorder (ASD) disproportionately affects ♂ relative to ♀. Clear explanations for this bias have not emerged because of inconsistent and incomplete phenotyping and small sample sizes. Girls and boys with ASD may well differ in terms of etiological pathways, developmental profiles, symptom expression, and response to treatment.

Objectives: Using structural magnetic resonance imaging (sMRI), functional MRI (fMRI), diffusion tensor imaging (DTI), and electroencephalography (EEG), we are identifying sex differences in brain structure, function, connectivity, and temporal dynamics in ASD.

Methods:  We will present the results from two data sets to illustrate some of the earliest findings from this ongoing, five-year study. First, using sMRI at 3 Tesla, we performed in vivo evaluation and comparison of cortical thickness among 209, 4- to 12-year-old children with ASD (n=25♀,75♂) and age- and IQ-matched typically developing children (TD, n=28♀,42♂), and unaffected siblings (US, n=17♀,22♂). We evaluated sex differences in: a) state regions, where the cortical thickness in ASD was thinner than TD and US; b) trait regions, where cortical thickness in TD children was thicker than ASD and US; and c) compensatory regions, where cortical thickness in US was thicker than both ASD and TD. Second, using fMRI and a task involving the visual perception of point-light displays (PLDs) of coherent and scrambled biological motion, we discovered sex differences in the normative development of neural systems for social perception in a sample of 38 (19♀) TD children and adolescents (9–14 years old).

Results:  Regarding sMRI, state and compensatory regions were localized mainly to the temporal and frontal lobes as well as the insular cortex. Among the state regions, the cortical thickness of the right posterior superior temporal sulcus (pSTS) and that of the right lateral orbitofrontal cortex were negatively correlated with ADOS module 3 social affect scores (p < .01, corrected), suggesting that cortical thickness in these regions is a sensitive biomarker of social dysfunction in ASD. Sex differences consisted of a trend toward ♀ US exhibiting increased cortical thickness in the compensatory regions relative to ♂ US. Regarding the fMRI data, we conducted a voxel-wise Sex (male, female) x Condition (biological, scrambled) ANOVA to identify sex differences in the brain response to biological versus scrambled motion (p< 0.01, k =21, whole-brain corrected). ♀ relative to ♂ TD children and adolescents exhibited an enhanced response to biological > scrambled motion in the amygdala and ventromedial prefrontal cortex (vmPFC). Psychophysiological interactions analyses revealed increased functional connectivity among the vmPFC, amygdala, and pSTS in ♀ relative to ♂ TD children and adolescents.

Conclusions:  With the sMRI dataset, we generally replicated our prior fMRI findings (Kaiser et al., 2010, PNAS), while identifying additional state and compensatory regions and providing initial evidence for sex differences in cortical thickness in boys and girls with ASD. Our fMRI findings suggest that the robust, potentially protective, neural circuitry supporting social perception in TD ♀, which normally diverges from males in early adulthood, may underlie a sex bias in ASD.