Atypical genomic cortical patterning in autism with poor early language outcome.

Cortical regionalization develops via genomic patterning along anterior-posterior (A-P) and dorsal-ventral (D-V) gradients. Here, we find that normative A-P and D-V genomic patterning of cortical surface area (SA) and thickness (CT), present in typically developing and autistic toddlers with good early language outcome, is absent in autistic toddlers with poor early language outcome. Autistic toddlers with poor early language outcome are instead specifically characterized by a secondary and independent genomic patterning effect on CT. Genes involved in these effects can be traced back to midgestational A-P and D-V gene expression gradients and different prenatal cell types (e.g., progenitor cells and excitatory neurons), are functionally important for vocal learning and human-specific evolution, and are prominent in prenatal coexpression networks enriched for high-penetrance autism risk genes. Autism with poor early language outcome may be explained by atypical genomic cortical patterning starting in prenatal development, which may detrimentally affect later regional functional specialization and circuit formation.

Pre-treatment clinical and gene expression patterns predict developmental change in early intervention in autism.

Early detection and intervention are believed to be key to facilitating better outcomes in children with autism, yet the impact of age at treatment start on the outcome is poorly understood. While clinical traits such as language ability have been shown to predict treatment outcome, whether or not and how information at the genomic level can predict treatment outcome is unknown. Leveraging a cohort of toddlers with autism who all received the same standardized intervention at a very young age and provided a blood sample, here we find that very early treatment engagement (i.e., <24 months) leads to greater gains while controlling for time in treatment. Pre-treatment clinical behavioral measures predict 21% of the variance in the rate of skill growth during early intervention. Pre-treatment blood leukocyte gene expression patterns also predict the rate of skill growth, accounting for 13% of the variance in treatment slopes. Results indicated that 295 genes can be prioritized as driving this effect. These treatment-relevant genes highly interact at the protein level, are enriched for differentially histone acetylated genes in autism postmortem cortical tissue, and are normatively highly expressed in a variety of subcortical and cortical areas important for social communication and language development. This work suggests that pre-treatment biological and clinical behavioral characteristics are important for predicting developmental change in the context of early intervention and that individualized pre-treatment biology related to histone acetylation may be key.

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

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.

Author Correction: The spatiotemporal organization of episodic memory and its disruption in a neurodevelopmental disorder.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The spatiotemporal organization of episodic memory and its disruption in a neurodevelopmental disorder.

Recent theories of episodic memory (EM) posit that the hippocampus provides a spatiotemporal framework necessary for representing events. If such theories hold true, then does the development of EM in children depend on the ability to first bind spatial and temporal information? And does this ability rely, at least in part, on normal hippocampal function? We investigated the development of EM in children 2-8 years of age (Study 1) and its impairment in Williams Syndrome, a genetic neurodevelopmental disorder characterized by visuospatial deficits and irregular hippocampal function, (Study 2) by implementing a nonverbal object-placement task that dissociates the what, where, and when components of EM. Consistent with the spatiotemporal-framework view of hippocampal EM, our results indicate that the binding of where and when in memory emerges earliest in development, around the age of 3, and is specifically impaired in WS. Space-time binding both preceded and was critical to full EM (what + where + when), and the successful association of objects to spatial locations seemed to mediate this developmental process.