Sex differences of the triple network model in children with autism: A resting-state fMRI investigation of effective connectivity.

Autism spectrum disorder (ASD) has a pronounced male predominance, but the underlying neurobiological basis of this sex bias remains unclear. Gender incoherence (GI) theory suggests that ASD is more neurally androgynous than same-sex controls. Given its central role, altered structures and functions, and sex-dependent network differences in ASD, the triple network model, including the central executive network (CEN), default mode network (DMN), and salience network (SN), has emerged as a candidate for characterizing this sex difference. Here, we measured the sex-related effective connectivity (EC) differences within and between these three networks in 72 children with ASD (36 females, 8-14 years) and 72 typically developing controls (TCs) (36 females, 8-14 years) from 5 sites of the Autism Brain Imaging Data Exchange repositories using a 2 × 2 analysis of covariance factorial design. We also assessed brain-behavior relationships and the effects of age on EC. We found significant diagnosis-by-sex interactions on EC: females with ASD had significantly higher EC than their male counterparts within the DMN and between the SN and CEN. The interaction pattern supported the GI theory by showing that the higher EC observed in females with ASD reflected a shift towards the higher level of EC displayed in male TCs (neural masculinization), and the lower EC seen in males with ASD reflected a shift towards the lower level of EC displayed in female TCs (neural feminization). We also found significant brain-behavior correlations and significant effects of age on EC.

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

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.

Sex differences in structural brain asymmetry of children with autism spectrum disorders.

Previous studies have confirmed the sex difference of gray matter asymmetry in typically developing controls and the abnormal gray matter asymmetry in autism spectrum disorders. However, whether and how sex differences of gray matter asymmetry exist in autism spectrum disorders remains studied. This paper analyzes the above issues and explores correlations between gray matter asymmetry and autistic symptoms. Data from 72 children (36 males and 36 females) with autism spectrum disorders and 72 typically developing-controls (36 males and 36 females) between 8 and 14 years were included and obtained from the autism brain imaging data exchange repository (autism brain imaging data exchange I and autism brain imaging data exchange II). The voxel-based morphometry approach was used to assess gray matter asymmetry in T1-weighted brain data, and gray matter asymmetry was quantified as asymmetry index. A 2 × 2 analysis of covariance was used to identify asymmetry index differences among the four groups. Pearson correlation analysis was performed for asymmetry index values extracted from the clusters with significant differences between the four groups and autistic symptoms (social impairments, communication difficulties, and restricted, repetitive behaviors) measured by the revised autism diagnostic interview scale. Results showed that specific brain regions showed significant main effects for diagnosis in which autism spectrum disorders patients had more leftward asymmetry than typically developing-controls for the parahippocampal gyrus and the postcentral gyrus; specific brain regions showed significant main effects for sex in which females showed more rightward asymmetry for the middle temporal gyrus, inferior frontal gyrus, angular gyrus, and postcentral gyrus and minor rightward asymmetry for the superior frontal gyrus than males; significant diagnosis × sex interaction effects were identified in the angular gyrus and middle occipital gyrus. Pearson correlation analysis showed that males with autism spectrum disorders had a positive association between the asymmetry index value in the middle occipital gyrus and more significant verbal impairment measured by the revised autism diagnostic interview (r = 0.387, p = 0.026). The asymmetry index value in the parahippocampal gyrus was positively associated with more severe social impairment in females with autism spectrum disorders (r = 0.422, p = 0.020). We identified that the sex difference of gray matter asymmetry in children with autism spectrum disorders is qualitative rather than quantitative, which is relatively novel. Our findings provide the theoretical basis for conducting separate studies and using sex-specific diagnostic methods and treatments for males and females children with autism spectrum disorders.

Core-Symptom-Defined Cortical Gyrification Differences in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a heterogeneous disease that is characterized by abnormalities in social communication and interaction as well as repetitive behaviors and restricted interests. Structural brain imaging has identified significant cortical folding alterations in ASD; however, relatively less known is whether the core symptoms are related to neuroanatomical differences. In this study, we aimed to explore core-symptom-anchored gyrification alterations and their developmental trajectories in ASD. We measured the cortical vertex-wise gyrification index (GI) in 321 patients with ASD (aged 7-39 years) and 350 typically developing (TD) subjects (aged 6-33 years) across 8 sites from the Autism Brain Imaging Data Exchange I (ABIDE I) repository and a longitudinal sample (14 ASD and 7 TD, aged 9-14 years in baseline and 12-18 years in follow-up) from ABIDE II. Compared with TD, the general ASD patients exhibited a mixed pattern of both hypo- and hyper- and different developmental trajectories of gyrification. By parsing the ASD patients into three subgroups based on the subscores of the Autism Diagnostic Interview-Revised (ADI-R) scale, we identified core-symptom-specific alterations in the reciprocal social interaction (RSI), communication abnormalities (CA), and restricted, repetitive, and stereotyped patterns of behavior (RRSB) subgroups. We also showed atypical gyrification patterns and developmental trajectories in the subgroups. Furthermore, we conducted a meta-analysis to locate the core-symptom-anchored brain regions (circuits). In summary, the current study shows that ASD is associated with abnormal cortical folding patterns. Core-symptom-based classification can find more subtle changes in gyrification. These results suggest that cortical folding pattern encodes changes in symptom dimensions, which promotes the understanding of neuroanatomical basis, and clinical utility in ASD.