Genetic and Environmental Influences on Cortico-Striato-Thalamo-Cortical Circuits in Twins with Autism

Background:

Cortico-striato-thalamo-cortical (CSTC) circuits are involved with carrying out goal-directed behaviors and disruption of these pathways is associated with aberrant behaviors, such as obsessive thinking and repetitive behaviors. The structures that comprise these circuits include cortical (orbitofrontal (OFC) and anterior cingulate (ACC) cortices), striatal (caudate, putamen, and globus pallidus), and thalamic regions. Although limited, investigations of individuals with autism spectrum disorder (ASD) support a potential relationship between abnormalities in these regions and restricted and repetitive behaviors (RRB).

Objectives:

The goal of the current investigation was to examine CSTC regions in twins with and without ASD to determine whether abnormalities in these circuits are related with RRB symptoms and associated with genetic or environmental influences.

Methods:

Data were acquired as part of a large-scale neuroimaging study of same-sex twin pairs that included monozygotic (MZ) and dizygotic (DZ) twins with ASD and typically-developing (TD) control twins. Measures of autism-related symptom severity included the Social Responsiveness Scale (SRS) and Repetitive Behavior Scale-Revised (RBS-R). A structural T1-weighted spoiled grass gradient recalled (SPGR) 3D MRI was acquired on a 3 Telsa GE scanner and cortical reconstruction/segmentation was performed using FreeSurfer. Morphometric differences between groups were examined with mixed effects models and correlations between regional measurements and RRB symptoms were assessed. Additionally, intra-class correlations (ICC) were compared between MZ and DZ twin pairs. ACE and AE models for broad sense heritability (a²=additive genetics) and environmental influences (c²=shared family environment, e²=unique environment) were then calculated to provide an estimate of the proportion of variation associated with genetic/environmental factors.

Results:

In this preliminary analysis, valid segmentations were available from 48 twin pairs with ASD (21 MZ/27 DZ) and 33 TD pairs (19 MZ/14 DZ). The ASD and TD samples included children and adolescents (age range: 6-15 years) that were adequately matched as there were no group differences in age or gender, p>0.05. Examining volumes of CSTC regions, the largest differences were found in striatal regions with larger volumes in ASD compared to TD, particularly the putamen (M_ASD= 6350.32,SD= 769.94; M_CTRL= 6040.69,SD= 589.86; p<0.001). Within twin pairs discordant for ASD, there were additional indications of volumetric abnormalities with larger volumes in cortical regions, such as the ACC (M_ASD= 2761.50,SD= 524.31; M_CTRL= 2562.67,SD= 575.35; p<0.007), but smaller volumes of thalamic regions, (M_ASD= 8174.92,SD= 1232.92; M_CTRL= 8837.24,SD= 863.91; p<0.007). Additionally, CSTC volumes were associated with RRB symptoms (e.g., OFC and RBS-R Restricted Behaviors, r=0.29, p=0.009). Finally, genetic factors accounted for the largest proportion of variance in the size of striatal and thalamic regions (~0.60-1.00) but exerted less influence on some cortical structures (~0.20-1.00), with potentially relevant differences between twins with ASD and controls.

Conclusions:

Consistent with previous reports, preliminary data from this investigation indicate that children and adolescents with ASD exhibit volumetric abnormalities in CSTC circuits, which may be associated with RRB symptom presentation. More importantly, comparisons between twin pairs indicate that genetic susceptibility for ASD, as opposed to environmental factors, likely influence abnormalities in striatal and thalamic structures but that environmental factors may exert more influence on prefrontal cortex abnormalities.