Infant Visual Brain Development and Inherited Genetic Liability in Autism

Abstract

Objective: Autism spectrum disorder (ASD) is heritable, and younger siblings of ASD probands are at higher likelihood of developing ASD themselves. Prospective MRI studies of siblings report that atypical brain development precedes ASD diagnosis, although the link between brain maturation and genetic factors is unclear. Given that familial recurrence of ASD is predicted by higher levels of ASD traits in the proband, the authors investigated associations between proband ASD traits and brain development among younger siblings.

Methods: In a sample of 384 proband-sibling pairs (89 pairs concordant for ASD), the authors examined associations between proband ASD traits and sibling brain development at 6, 12, and 24 months in key MRI phenotypes: total cerebral volume, cortical surface area, extra-axial cerebrospinal fluid, occipital cortical surface area, and splenium white matter microstructure. Results from primary analyses led the authors to implement a data-driven approach using functional connectivity MRI at 6 months.

Results: Greater levels of proband ASD traits were associated with larger total cerebral volume and surface area and larger surface area and reduced white matter integrity in components of the visual system in siblings who developed ASD. This aligned with weaker functional connectivity between several networks and the visual system among all siblings during infancy.

Conclusions: The findings provide evidence that specific early brain MRI phenotypes of ASD reflect quantitative variation in familial ASD traits. Multimodal anatomical and functional convergence on cortical regions, fiber pathways, and functional networks involved in visual processing suggest that inherited liability has a role in shaping the prodromal development of visual circuitry in ASD.

Keywords: Autism Spectrum Disorder; Development; Neurodevelopmental Disorders; Neuroimaging.

Figure 1.. Proband autism traits explain significant variation in total cerebral volume and cortical surface area in infant siblings who later develop autism.

Example cerebral volumetric segmentations (A) and surface reconstructions (B) for 6-month structural MRIs are inset into scatterplots depicting bi-variate associations between proband autism traits (Social Communication Questionnaire (SCQ) scores) and each sibling brain feature at 6, 12, and 24 months. Pearson’s correlation coefficients and associated sample size and p-value are reported above the label for each time point for the autism spectrum disorder group (ASD group; red); higher levels of autism traits (indicated by higher SCQ scores) in probands was associated with increased cerebral volume and surface area. Proband SCQ scores were not correlated with measures of cerebral volume or surface in the non-ASD group (gray); see Table S3.

Figure 2.. Greater levels of proband autism traits are associated with larger surface area in the occipital and frontal cortices in infant siblings who develop autism spectrum disorder.

(A) Primary regions of interest included occipital cortical regions shown to exhibit hyper-expansion in autism spectrum disorder (ASD). To speak to specificity, we included the right middle frontal gyrus and left inferior temporal gyrus, which were also found to hyper-expand in ASD. Additionally, two control regions were selected to not overlap with any regions shown to have differential development in ASD during infancy or to contribute to prediction of ASD in Hazlett et al., 2017. Hyper-expanding regions are shown in royal blue, control regions are shown in light blue. (B) Proband SCQ score was positively correlated with surface area in the right middle occipital gyrus at 6 months (r = 0.44, P = 0.010), 12 months (r = 0.38, P = 0.017), and 24 months (r = 0.39, P = 0.007) in the ASD group. This aligned with longitudinal model results indicating that higher proband SCQ score was significantly associated with greater surface area in the right middle occipital cortex in the ASD group during this developmental window (β= 26.82, 95% CI 11.15 to 42.5, df = 267, P < 0.001). Additional correlations were found between proband Social Communication Questionnaire (SCQ) scores and sibling surface area in the right lingual gyrus at 12 months (r = 0.38, P = 0.017), and the left cuneus (r = 0.40, P = 0.006) and right middle frontal gyrus (r = 0.38, P = 0.010) at 24 months. No significant correlations were found between proband SCQ scores and control regions at any age.

Figure 3.. Proband autism traits have an age-specific association with splenium microstructure in ASD siblings.

The reconstructed splenium tract in atlas space is inset into scatterplots depicting bi-variate associations between proband autism traits (Social Communication Questionnaire (SCQ) scores) and sibling splenium fractional anisotropy (FA) at 6, 12, and 24 months. Pearson’s correlation coefficients and associated sample size and p-value are reported above the label for each time point for the ASD group (red). Higher autism trait levels (indicated by higher SCQ scores) in probands was associated with increased splenium fractional anisotropy (FA) at 6 months, but not after. Proband SCQ scores were not correlated splenium FA in the non-ASD group (gray); see Table S6.

Figure 4.. Proband autism traits are associated with functional connectivity in networks including visual cortical regions among siblings at 6 months of age.

Functional connectivity enrichment analyses identified four 6-month network pairs that were associated with proband trait level as measured by the Social Communication Questionnaire (SCQ) score (a), Autism Diagnostic Interview-Revised Reciprocal Social Interaction (ADI-R RSI) score (b), and/or the Vineland Adaptive Behavior Scales Socialization (VABS-Soc) score (c). Lower triangles of each matrix depict heatmaps of Spearman Rho (ρ) correlations between functional connectivity (fc) values and proband behavioral scores; upper triangles are thresholded to display the strongest 5% of sibling brain-proband behavior correlations, with region-to-region connections visualized as dots and colored within enriched network pairs by the direction of effect (blue = negative, red = positive). Network pairs approaching experiment-wide significance (p-values < .001 maintain 5% experiment-wide false-positive rate; p-values < 0.01 are considered trending) are surrounded by bold black boxes and indicated by arrows in the correlation matrices and are depicted in brain space. The color of the lines connecting pairs of regions of interest reflects the proportion of individual functional connectivity values that are above zero (a). Light blue to dark blue to magenta colors represent negative brain-behavior correlations and green to yellow to red colors denote positive brain-behavior correlations. Light blue and green denote that the region-to-region pair contains predominantly negative functional connectivity values; magenta and red reflect region-to-region pairs with predominantly positive functional connectivity. Blue and yellow reflect functional connectivity values that are distributed across zero. High proband scores on the SCQ and ADI-R RSI are indicative of greater levels of autism traits; lower scores on the VABS-Soc are indicative of poorer social functioning. Stronger correlations between pDMN-Vis, pDMN-mVis and pFP-Vis were associated with lower proband trait levels, while stronger correlations between pDMN-SM1 were associated with increased autism traits in probands.