Individualized cortical thickness asymmetry in Autism Spectrum Disorders and Schizophrenia

Abstract

Introduction Cortical thickness asymmetry has been proposed as a latent biomarker for Autism Spectrum Disorders (ASD) and schizophrenia (SZ). However, the degree of abnormal asymmetry at the individual level in ASD and SZ remains unclear. To investigate this, we applied normative modeling. Methods Normative means for the whole brain and regional (160 cortical parcels) cortical thickness asymmetry index (AI) were established using a training set of healthy subjects (n=4,904, 45.15% male, age range: 6-95 years), controlling for age, sex, image quality and scanner. We calculated z-scores to quantify individual deviations from the normative mean in a test set consisting of healthy controls (HCtest, n=526, 40% male), participants with ASD (n=135, 83% male) and SZ (n=287, 81% male). Regional deviance was assessed by counting the number of individuals with significant deviations below (infra-normal, z-score ≤ -1.96) or above (supra-normal, z-score ≥ 1.96) normative means in each parcel. We also evaluated individual deviance by counting the number of regions with significant deviations for each participant. A data-driven multivariate approach was employed to determine whether joint regional deviance was associated with diagnosis. Results There were no differences for deviance of whole brain AI between any of the groups. Distributions of individual deviances overlapped across all 160 regions, with only one superior temporal region in which SZ individuals showed a higher proportion of supra-normal AI values compared to HCtest (HCtest = 1.14%, SZ = 5.92%, χ2 = 15.45, PFDR< 0.05, ω = 0.14). The SZ group also had a higher average number of regions with significant deviations than HCtest (infra-normal: z = -4.21, p < 0.01; supra-normal: z = -4.33, p < 0.01). Multivariate analysis showed no association between inter-regional heterogeneity of AI and diagnosis. Results were consistent when using a higher resolution parcellation, alternative asymmetry calculations, analysis restricted to males, and after controlling for handedness and IQ. Conclusions Our findings indicate that whole brain, regional and inter-regional variability in cortical thickness AI among those with ASD is entirely accounted for by normative variation. This study challenges the utility of cortical thickness asymmetry as a biomarker for ASD.