Podcast: Autism means different things to different people

At this year’s International Society of Autism Research meeting in Austin, TX, there was a variety of themes explored. From early development and milestones, to intervention and supports, to different features like sensory issues, treatment, and how to solve the problem of heterogeneity. It comes down to this: Autism means different things to different people. This is just a small subset of everything that was presented at INSAR 2022 and I hope that if you want to see more, you advocate to have the presentations posted online or even have the program book made available publicly. In the meantime, enjoy the 30 minute summary here.

www.autism-insar.org

This year’s Day of Learning was a huge success, with topics ranging from biological sex differences to mobile technologies all the way to the importance and documented value of leisure activities in people on the spectrum. the speakers included a discussion of the IACC, sex differences, the value of prevalence data, mobile technologies, leisure activities, and a recognition of two advocates who made or make a difference in families: Samantha Els and Suzanne Wright. Listen to this week’s podcast here for a quickie, but don’t let it prevent you from watching the longer videos, a link to which can be found below.

2022 Day of Learning presentations in full

http://www.babynavigator.com

http://www.autismnavigator.com

Autism spectrum disorder (ASD) is an early-onset developmental disorder characterized by deficits in communication and social interaction and restrictive or repetitive behaviours1,2. Family studies demonstrate that ASD has a substantial genetic basis with contributions both from inherited and de novo variants3,4. It has been estimated that de novo mutations may contribute to 30% of all simplex cases, in which only a single child is affected per family5. Tandem repeats (TRs), defined here as sequences of 1 to 20 base pairs in size repeated consecutively, comprise one of the major sources of de novo mutations in humans6. TR expansions are implicated in dozens of neurological and psychiatric disorders7. Yet, de novo TR mutations have not been characterized on a genome-wide scale, and their contribution to ASD remains unexplored. Here we develop new bioinformatics methods for identifying and prioritizing de novo TR mutations from sequencing data and perform a genome-wide characterization of de novo TR mutations in ASD-affected probands and unaffected siblings. We infer specific mutation events and their precise changes in repeat number, and primarily focus on more prevalent stepwise copy number changes rather than large expansions. Our results demonstrate a significant genome-wide excess of TR mutations in ASD probands. Mutations in probands tend to be larger, enriched in fetal brain regulatory regions, and are predicted to be more evolutionarily deleterious. Overall, our results highlight the importance of considering repeat variants in future studies of de novo mutations.

Despite a growing understanding of the molecular and developmental basis of autism spectrum disorder (ASD), how the neuronal encoding of social information is disrupted in ASD and whether it contributes to abnormal social behavior remains unclear. Here, we disrupted and then restored expression of the ASD-associated gene Shank3 in adult male mice while tracking the encoding dynamics of neurons in the medial prefrontal cortex (mPFC) over weeks. We find that Shank3 disruption led to a reduction of neurons encoding the experience of other mice and an increase in neurons encoding the animal’s own experience. This shift was associated with a loss of ability by neurons to distinguish other from self and, therefore, the inability to encode social agency. Restoration of Shank3 expression in the mPFC reversed this encoding imbalance and increased sociability over 5-8 weeks. These findings reveal a neuronal-encoding process that is necessary for social behavior and that may be disrupted in ASD.

Keywords: Computational biology and bioinformatics; Genetics; Genomics.

Background: Marked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Efforts to unravel sex differences in the brain organization of autism have, however, been challenged by the limited availability of female data.

Methods: We addressed this gap by using a large sample of males and females with autism and neurotypical (NT) control individuals (ABIDE; Autism: 362 males, 82 females; NT: 409 males, 166 females; 7-18 years). Discovery analyses examined main effects of diagnosis, sex and their interaction across five resting-state fMRI (R-fMRI) metrics (voxel-level Z > 3.1, cluster-level P < 0.01, gaussian random field corrected). Secondary analyses assessed the robustness of the results to different pre-processing approaches and their replicability in two independent samples: the EU-AIMS Longitudinal European Autism Project (LEAP) and the Gender Explorations of Neurogenetics and Development to Advance Autism Research.

Results: Discovery analyses in ABIDE revealed significant main effects of diagnosis and sex across the intrinsic functional connectivity of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical regions, largely converging in the default network midline. Sex-by-diagnosis interactions were confined to the dorsolateral occipital cortex, with reduced VMHC in females with autism. All findings were robust to different pre-processing steps. Replicability in independent samples varied by R-fMRI measures and effects with the targeted sex-by-diagnosis interaction being replicated in the larger of the two replication samples-EU-AIMS LEAP.

Limitations: Given the lack of a priori harmonization among the discovery and replication datasets available to date, sample-related variation remained and may have affected replicability.

Conclusions: Atypical cross-hemispheric interactions are neurobiologically relevant to autism. They likely result from the combination of sex-dependent and sex-independent factors with a differential effect across functional cortical networks. Systematic assessments of the factors contributing to replicability are needed and necessitate coordinated large-scale data collection across studies.

Keywords: Autism spectrum disorder; Replication; Resting-state functional connectivity; Robustness; Sex differences; Voxel-mirrored homotopic connectivity.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders associated with deficits in social communication and restrictive, repetitive patterns of behavior, that affect up to 1 in 54 children. ASDs clearly demonstrate a male bias, occurring ~4 times more frequently in males than females, though the basis for this male predominance is not well-understood. In recent years, ASD risk gene discovery has accelerated, with many whole-exome sequencing studies identifying genes that converge on common pathways, such as neuronal communication and regulation of gene expression. ASD genetics studies have suggested that there may be a “female protective effect,” such that females may have a higher threshold for ASD risk, yet its etiology is not well-understood. Here, we review common biological pathways implicated by ASD genetics studies as well as recent analyses of sex differential processes in ASD using imaging genomics, transcriptomics, and animal models. Additionally, we discuss recent investigations of ASD risk genes that have suggested a potential role for estrogens as modulators of biological pathways in ASD, and highlight relevant molecular and cellular pathways downstream of estrogen signaling as potential avenues for further investigation.

Keywords: animal models; autism spectrum disorder; estrogens; female protective effect; genetics; imaging genomics.

Multimodal exploration of objects during toy play is important for a child’s development and is suggested to be abnormal in children with autism spectrum disorder (ASD) due to either atypical attention or atypical action. However, little is known about how children with ASD coordinate their visual attention and manual actions during toy play. The current study aims to understand if and in what ways children with ASD generate exploratory behaviors to toys in natural, unconstrained contexts by utilizing head-mounted eye tracking to quantify moment-by-moment attention. We found no differences in how 24- to 48-mo children with and without ASD distribute their visual attention, generate manual action, or coordinate their visual and manual behaviors during toy play with a parent. Our findings suggest an intact ability and willingness of children with ASD to explore toys and suggest that context is important when studying child behavior.

A recent theory posits that prediction deficits may underlie the core symptoms in autism spectrum disorder (ASD). However, empirical evidence for this hypothesis is minimal. Using a visual extrapolation task, we tested motion prediction abilities in children and adolescents with and without ASD. We examined the factors known to be important for motion prediction: the central-tendency response bias and smooth pursuit eye movements. In ASD, response biases followed an atypical trajectory that was dominated by early responses. This differed from controls who exhibited response biases that reflected a gradual accumulation of knowledge about stimulus statistics. Moreover, while better smooth pursuit eye movements for the moving object were linked to more accurate motion prediction in controls, in ASD, better smooth pursuit was counterintuitively linked to a more pronounced early response bias. Together, these results demonstrate atypical visual prediction abilities in ASD and offer insights into possible mechanisms underlying the observed differences.

Keywords: Autism; eye movements; perception; prediction; vision.

Keywords: abnormal social behavior; animal models; behavioral neuroscience; group behavior; psychosocial illness; social neuroscience.

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by primary difficulties in social function. Individuals with ASD display slowed neural processing of faces, as indexed by the latency of the N170, a face-sensitive event-related potential. Currently, there are no objective biomarkers of ASD useful in clinical care or research. Efficacy of behavioral treatment is currently evaluated through subjective clinical impressions. To explore whether the N170 might have utility as an objective index of treatment response, we examined N170 before and after receipt of an empirically validated behavioral treatment in children with ASD. Method: Electroencephalography (EEG) data were obtained on a preliminary cohort of preschool-aged children with ASD before and after a 16-week course of PRT and in a subset of participants in waitlist control (16-weeks before the start of PRT) and follow-up (16-weeks after the end of PRT). EEG was recorded while participants viewed computer-generated faces with neutral and fearful affect. Results: Significant reductions in N170 latency to faces were observed following 16 weeks of PRT intervention. Change in N170 latency was not observed in the waitlist-control condition. Conclusions: This exploratory study offers suggestive evidence that N170 latency may index response to behavioral treatment. Future, more rigorous, studies in larger samples are indicated to evaluate whether the N170 may be useful as a biomarker of treatment response.

Keywords: N170; autism spectrum disoder; biomarker; electroencephalography; pivotal response treatment.

Human stem-cell-derived models provide the promise of accelerating our understanding of brain disorders, but not knowing whether they possess the ability to mature beyond mid- to late-fetal stages potentially limits their utility. We leveraged a directed differentiation protocol to comprehensively assess maturation in vitro. Based on genome-wide analysis of the epigenetic clock and transcriptomics, as well as RNA editing, we observe that three-dimensional human cortical organoids reach postnatal stages between 250 and 300 days, a timeline paralleling in vivo development. We demonstrate the presence of several known developmental milestones, including switches in the histone deacetylase complex and NMDA receptor subunits, which we confirm at the protein and physiological levels. These results suggest that important components of an intrinsic in vivo developmental program persist in vitro. We further map neurodevelopmental and neurodegenerative disease risk genes onto in vitro gene expression trajectories to provide a resource and webtool (Gene Expression in Cortical Organoids, GECO) to guide disease modeling