Longitudinal Changes in Cortical Thickness in Adolescents with Autism Spectrum Disorder and Their Association with Restricted and Repetitive Behaviors

Abstract

The neuroanatomy of autism spectrum disorder (ASD) shows highly heterogeneous developmental trajectories across individuals. Mapping atypical brain development onto clinical phenotypes, and establishing their molecular underpinnings, is therefore crucial for patient stratification and subtyping. In this longitudinal study we examined intra- and inter-individual differences in the developmental trajectory of cortical thickness (CT) in childhood and adolescence, and their genomic underpinnings, in 33 individuals with ASD and 37 typically developing controls (aged 11–18 years). Moreover, we aimed to link regional atypical CT development to intra-individual variations in restricted and repetitive behavior (RRB) over a two-year time period. Individuals with ASD showed significantly reduced cortical thinning in several of the brain regions functionally related to wider autism symptoms and traits (e.g., fronto-temporal and cingulate cortices). The spatial patterns of the neuroanatomical differences in CT were enriched for genes known to be associated with ASD at a genetic and transcriptomic level. Further, intra-individual differences in CT correlated with within-subject variability in the severity of RRBs. Our findings represent an important step towards characterizing the neuroanatomical underpinnings of ASD across development based upon measures of CT. Moreover, our findings provide important novel insights into the link between microscopic and macroscopic pathology in ASD, as well as their relationship with different clinical ASD phenotypes.

Connectivity-Based Brain Network Supports Restricted and Repetitive Behaviors in Autism Spectrum Disorder Across Development

“…Stereotyped behaviors, ritualistic behaviors, and restricted behaviors improved greatly after childhood. These finding corroborated previous studies that reported a broad range of trajectories of RRBIs in ASD patients (8)(9)(10)24). For children, RRBIs are relatively stable between 2 and 7 years of age (9).…”

“…We found that significant reductions of FC among brain regions in the temporal lobe, occipital lobe, and cingulate might contribute to the trajectory of RRBIs over time, especially stereotyped behaviors and overall RRBIs (evaluated by the RBSR-6). Previous studies that examined associations between cortical thickness and RRBI severity over time found that gray matter thickness of the orbital frontal cortex and middle frontal cortex correlated with self-injurious behaviors in adolescent patients (24). In the present study, core brain regions that were responsible for stereotyped behaviors included the superior occipital gyrus, insula, rolandic operculum, angular, caudate, and cingulum.…”

Developing Gene-Based Personalised Interventions in Autism Spectrum Disorders

“…For example, the role of mutations in the mTOR or RAS signalling pathways show similar neuropathological characteristics in human and rodent models [ 16 ]. Gene expression pattern, neural synaptic function, or the imbalance of inhibitory and excitatory neural functions are other well-studied aspects which can be compared between rodent and human models [ 13 , 17 , 18 ]. Additionally, the role of somatic mutations has been the focus of recent exciting developments, especially in the field of treatment-resistant epilepsy, as documented both in humans and in animal models [ 19 , 20 ].…”

From Genes to Therapy in Autism Spectrum Disorder

“…For example, Bieneck et al, show that the physiological cortical thinning in individuals with ASD during adolescence was decreased compared to typical controls; this possibly indicates abnormalities in the process of synaptic pruning. Interestingly, the observed differences in cortical thinning correlated with synaptic genes [ 21 ]. These findings echo previous observations, indicating an association between synaptic genes and differences in cortical thickness in individuals with ASD [ 22 , 23 ].…”

“…These findings echo previous observations, indicating an association between synaptic genes and differences in cortical thickness in individuals with ASD [ 22 , 23 ]. Bieneck et al, reported altered cortical thinning predominantly in fronto-temporal brain regions and the cingulate cortex in individuals with ASD [ 21 ]. In addition, these developmental changes were associated with severity of repetitive behaviors, while the most affected brain regions were enriched for genes involved in synaptic function, corroborating earlier studies indicating the involvement of synaptic genes in cortical thickness [ 22 ].…”