Imbalanced social-communicative and restricted repetitive behavior subtypes of autism spectrum disorder exhibit different neural circuitry

Abstract

Social-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here, we developed a phenotypic stratification model that makes highly accurate (97–99%) out-of-sample SC = RRB, SC > RRB, and RRB > SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset (n = 509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show replicable differences within some networks compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC > RRB and visual association circuitry in SC = RRB. The SC = RRB subtype show hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these networks show a differential enrichment pattern with known autism-associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share many commonalities, but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry.

Cerebellar demyelination and neurodegeneration associated with mTORC1 hyperactivity may contribute to the developmental onset of autism‐like neurobehavioral phenotype in a rat model

“…The latter involves coordinated top‐down and bottom‐up interactions of cerebellar circuits with different forebrain networks, via abundant sensorimotor and associative connections (Ito, 2006; Ovsepian et al, 2013; Schmahmann, 2019). Through these communication routes, the cerebellum also contributes to the regulation and coordination of complex social interactions and stereotypic behaviors, which are affected in ASDs (Bertelsen et al, 2021; D'Mello & Stoodley, 2015). Clinical reports of TSC loss‐of‐function cases reveal a range of developmental retardation, epilepsy, and signs of cerebellar deficiency associated with autistic symptoms (Jurkiewicz et al, 2006; Weisenfeld et al, 2013).…”

Broken or socially-mistuned mirror neurons in autism? An investigation via transcranial magnetic stimulation

“…These findings are of particular importance in the current pursuit of distinct neurobiological subtypes of ASD (e.g. Bertelsen et al, 2021).…”

The link between autism and sex-specific neuroanatomy, and associated cognition and gene expression

“…To isolate genes that are highly expressed in spatial patterns throughout the brain and similar to the sex prediction RAP-imaging-t-maps, we used the gene expression decoding functionality integrated in Neurosynth (41) and NeuroVault (42). This approach has been previously used in several autism-related studies (32, 33, 43, 44). It uses the six donor brains from the Allen Human Brain Gene Expression atlas (45) and statistically test the similarity between spatial gene expression patterns of all 20,787 protein decoding genes and our input maps.…”