Characterizing Subcortical Structural Heterogeneity in Autism

Abstract

Autism presents with significant phenotypic and neuroanatomical heterogeneity, and neuroimaging studies of the thalamus, globus pallidus and striatum in autism have produced inconsistent and contradictory results. These structures are critical mediators of functions known to be atypical in autism, including sensory gating and motor function. We examined both volumetric and fine-grained localized shape differences in autism using a large (n=3145, 1045-1318 after strict quality control), cross-sectional dataset of T1-weighted structural MRI scans from 32 sites, including both males and females (assigned-at-birth). We investigated three potentially important sources of neuroanatomical heterogeneity: sex, age, and intelligence quotient (IQ), using a meta-analytic technique after strict quality control to minimize non-biological sources of variation. We observed no volumetric differences in the thalamus, globus pallidus, or striatum in autism. Rather, we identified a variety of localized shape differences in all three structures. Including age, but not sex or IQ, in the statistical model improved the fit for both the pallidum and striatum, but not for the thalamus. Age-centered shape analysis indicated a variety of age-dependent regional differences. Overall, our findings help confirm that the neurodevelopment of the striatum, globus pallidus and thalamus are atypical in autism, in a subtle location-dependent manner that is not reflected in overall structure volumes, and that is highly non-uniform across the lifespan.

Figure 1:

Forest plots showing results of random-effects meta-analysis across sites for all structures. Hedges g* effect sizes are reported for main effect of diagnosis in model structure_volume ~ diagnosis + total_brain_volume + age + sex. No main effect of diagnosis was observed. Columns are: site name, forest plot, site weight, Hedges g* estimate and 95% confidence intervals. Site codes are: CAM - Cambridge Family Study of Autism; Cambridge - UKAIMS Cambridge site; IoP - UKAIMS Institute of Psychiatry site; IP - ABIDE Institut Pasteur; KKI - ABIDE Kennedy Krieger Institute; MAX_MUN - ABIDE Ludwig Maximilians University Munich; OHSU - ABIDE Oregon Health and Science University; SDSU – ABIDE San Diego State University; TORONTO - SickKids / University of Toronto; UM – ABIDE University of Michigan

Figure 2:

Hedges’ g* main effect of autism diagnosis on vertex-wise surface area and displacement in the left and right striatum, thalamus, and globus pallidus, when controlling for total structure volume, age, and sex. Warm colours indicate positive effects, cool colours indicate negative effects (g* range −0.3 to 0.3). Surface area is the Voronoi area surrounding a vertex; displacement represents relative convexity (positive) or concavity (negative).

Figure 3:

Main effect of diagnosis on vertex-wise surface area (top) and displacement (bottom) in striatum, thalamus, and globus pallidus. Green spheres indicate vertices with peak effect sizes. Forest plots show meta-analytic results at vertices where peak effects were observed for thalamic displacement (positive, left) and pallidal displacement (negative, right).

Figure 4:

Age-centered analysis, centered on five-year intervals from ages 6–46. Hedges’ g* main effect of autism diagnosis on vertex-wise displacement in the left and right thalamus, when controlling for total structure volume and sex. Warm colours indicate positive effects, cool colours indicate negative effects (g* range −0.33 to 0.33). Displacement represents relative convexity (positive) or concavity (negative).