Gray matter asymmetry atypical patterns in subgrouping minors with autism based on core symptoms

Abstract

Abnormal gray matter (GM) asymmetry has been verified in autism spectrum disorder (ASD), which is characterized by high heterogeneity. ASD is distinguished by three core symptom domains. Previous neuroimaging studies have offered support for divergent neural substrates of different core symptom domains in ASD. However, no previous study has explored GM asymmetry alterations underlying different core symptom domains. This study sought to clarify atypical GM asymmetry patterns underlying three core symptom domains in ASD with a large sample of 230 minors with ASD (ages 7-18 years) and 274 matched TD controls from the Autism Brain Imaging Data Exchange I (ABIDE I) repository. To this end, the scores of the revised autism diagnostic interview (ADI-R) subscales were normalized for grouping ASD into three core-symptom-defined subgroups: social interaction (SI), verbal communication (VA), and restricted repetitive behaviors (RRB). We investigated core-symptom-related GM asymmetry alterations in ASD resulting from advanced voxel-based morphometry (VBM) by general linear models. We also examined the relationship between GM asymmetry and age and between GM asymmetry and symptom severity assessed by the Autism Diagnostic Observation Schedule (ADOS). We found unique GM asymmetry alterations underlying three core-symptom-defined subgroups in ASD: more rightward asymmetry in the thalamus for SI, less rightward asymmetry in the superior temporal gyrus, anterior cingulate and caudate for VA, and less rightward asymmetry in the middle and inferior frontal gyrus for RRB. Furthermore, the asymmetry indexes in the thalamus were negatively associated with ADOS_SOCIAL scores in the general ASD group. We also showed significant correlations between GM asymmetry and age in ASD and TD individuals. Our results support the theory that each core symptom domain of ASD may have independent etiological and neurobiological underpinnings, which is essential for the interpretation of heterogeneity and the future diagnosis and treatment of ASD.

Keywords: autism; brain-behavior relationships; core symptom domains; gray matter asymmetry; minors.

FIGURE 1

Differences in GM asymmetry in between-group comparisons. (A) General ASD vs. TD controls: seven clusters with significant differences between general ASD and TD controls. (B) SI vs. TD: four clusters with significant differences between SI and TD controls. (C) VA vs. TD: four clusters with significant differences between VA and TD controls. (D) RRB vs. TD: five clusters with significant differences between RRB and TD controls; the red color indicates the general ASD/SI/VA/RRB group with more rightward asymmetry, and the blue color indicates more leftward asymmetry. The results were corrected for multiple comparisons using the Gaussian random field procedure with the voxel level P-value < 0.005 and the cluster level of P < 0.05. GM, gray matter; ASD, autism spectrum disorder; TD, typically developing; SI, subgroup dominated by social interaction deficits; VA, subgroup dominated by verbal communication abnormalities; RRB, subgroup dominated by restricted repetitive behaviors.

FIGURE 2

The relationship between AIs and symptom severity. AIs of Cluster A4 were negatively associated with social scores measured by the ADOS in the general ASD group. The results were corrected for multiple comparisons using the Gaussian random field procedure with the voxel level P-value < 0.005 and the cluster level of P < 0.05. ASD, autism spectrum disorder; AI, asymmetry index; ADOS, Autism Diagnostic Observation Schedule.

FIGURE 3

The relationship between AIs and age. (A) Cluster V1 exhibited increased leftward asymmetry from age 7 to 18 in the VA subgroup. (B) Cluster A5 presented increased rightward asymmetry with age in the general ASD group. (C) Cluster A2 showed increased rightward asymmetry over time in the TD group. The results were corrected for multiple comparisons using the Gaussian random field procedure with the voxel level P-value < 0.005 and the cluster level of P < 0.05. AI, asymmetry index; ASD, autism spectrum disorder; TD, typically developing; VA, subgroup dominated by verbal communication abnormalities.