12 month peak alpha frequency is a correlate but not a longitudinal predictor of non-verbal cognitive abilities in infants at low and high risk for autism spectrum disorder

Although studies of PAF in individuals with autism spectrum disorder (ASD) report group differences and associations with non-verbal cognitive ability, it is not known how PAF relates to familial risk for ASD, and whether similar associations with cognition in are present in infancy. Using a large multi-site prospective longitudinal dataset of infants with low and high familial risk for ASD, metrics of PAF at 12 months were extracted and growth curves estimated for cognitive development between 12-36 months. Analyses tested whether PAF 1) differs between low and high risk infants, 2) is associated with concurrent non-verbal/verbal cognitive ability and 3) predicts developmental change in non-verbal/verbal ability. Moderation of associations between PAF and cognitive ability by familial risk status was also tested. No differences in 12-month PAF were found between low and high risk infants. PAF was associated with concurrent non-verbal cognitive ability, but did not predict change in non-verbal cognitive over development. No associations were found between PAF and verbal ability, along with no evidence of moderation. PAF is not related to familial risk for ASD, and is a neural marker of concurrent non-verbal cognitive ability, but not verbal ability, in young infants at low and high risk for ASD.

Keywords: Autism spectrum disorder; Cognitive development; EEG; Infant siblings; Peak alpha frequency.

Objective: To examine the emergence and trajectory of feeding difficulties in young children who are later diagnosed with autism spectrum disorder (ASD).

Methods: The Behavioral Pediatrics Feeding Assessment Scale (BPFAS) was administered to a sample of 93 toddlers with an older sibling with ASD-the high-risk group-and 62 toddlers with no known familial ASD-the low-risk group-as part of a larger infant sibling study. The BPFAS was completed by parents at 15, 18, 24, and 36 months of age. At 36 months, participants underwent a diagnostic assessment and were classified into 1 of the following 4 outcome groups: ASD, nontypical development, high-risk typically developing, and low-risk typically developing. The BPFAS was scored for total frequency of feeding difficulties and autism-specific factor scores previously described in the literature.

Results: The frequency of feeding difficulties increased significantly more rapidly in the ASD group between 15 and 36 months of age, and by 36 months, they exhibited a significantly higher total frequency score than all other groups. Analysis of the factor scores revealed a similar pattern for the food acceptance and mealtime behavior domains but no significant differences in the medical/oral motor domain.

Conclusion: Feeding difficulties develop significantly more rapidly in children with ASD, with longitudinal monitoring revealing the steeper trajectory earlier than can be detected with cross-sectional analysis. Children with ASD are at risk of health and social consequences of poor feeding behavior that may potentially be minimized if addressed early and appropriately.

Background: Recent large-scale initiatives have led to systematically collected phenotypic data for several rare genetic conditions implicated in autism spectrum disorder (ASD). The onset of developmentally expected skills (e.g. walking, talking) serve as readily quantifiable aspects of the behavioral phenotype. This study’s aims were: (a) describe the distribution of ages of attainment of gross motor and expressive language milestones in several rare genetic conditions, and (b) characterize the likelihood of delays in these conditions compared with idiopathic ASD.

Methods: Participants aged 3 years and older were drawn from two Simons Foundation Autism Research Initiative registries that employed consistent phenotyping protocols. Inclusion criteria were a confirmed genetic diagnosis of one of 16 genetic conditions (Simons Searchlight) or absence of known pathogenic genetic findings in individuals with ASD (SPARK). Parent-reported age of acquisition of three gross motor and two expressive language milestones was described and categorized as on-time or delayed, relative to normative expectations.

Results: Developmental milestone profiles of probands with genetic conditions were marked by extensive delays (including nonattainment), with highest severity in single gene conditions and more delays than idiopathic ASD in motor skills. Compared with idiopathic ASD, the median odds of delay among the genetic groups were higher by 8.3 times (IQR 5.8-16.3) for sitting, 12.4 times (IQR 5.3-19.5) for crawling, 26.8 times (IQR 7.7-41.1) for walking, 2.7 times (IQR 1.7-5.5) for single words, and 5.7 times (IQR 2.7-18.3) for combined words.

Conclusions: Delays in developmental milestones, particularly in gross motor skills, are frequent and may be among the earliest indicators of differentially affected developmental processes in specific genetically defined conditions associated with ASD, as compared with those with clinical diagnoses of idiopathic ASD. The possibility of different developmental pathways leading to ASD-associated phenotypes should be considered when deciding how to employ specific genetic conditions as models for ASD.

Keywords: copy number variant; developmental phenotype; intellectual disability.

Environmental health, toxic chemicals, autism, environment

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.

Background: Although autism spectrum disorders (ASD) are among the most heritable of all neuropsychiatric syndromes, most affected children are born to unaffected parents. Recently, we reported an average increase of 3-5% over general population risk of ASD among offspring of adults who have first-degree relatives with ASD in a large epidemiologic family sample. A next essential step is to investigate whether there are measurable characteristics of individual parents placing them at higher or lower recurrence risk, as this information could allow more personalized genetic counseling.

Methods: We assembled what is to our knowledge the largest collection of data on the ability of four measurable characteristics of unaffected prospective parents to specify risk for autism among their offspring: (1) sub clinical autistic trait burden, (2) parental history of a sibling with ASD, (3) transmitted autosomal molecular genetic abnormalities, and (4) parental age. Leveraging phenotypic and genetic data in curated family cohorts, we evaluate the respective associations between these factors and child outcome when autism is present in the family in the parental generation.

Results: All four characteristics were associated with elevation in offspring risk; however, the magnitude of their predictive power-with the exception of isolated rare inherited pathogenic variants -does not yet reach a threshold that would typically be considered actionable for reproductive decision-making.

Conclusions: Individual specification of risk to offspring of adults in ASD-affected families is not straightforwardly improved by ascertainment of parental phenotype, and it is not yet clear whether genomic screening of prospective parents in families affected by idiopathic ASD is warranted as a clinical standard. Systematic screening of affected family members for heritable pathogenic variants, including rare sex-linked mutations, will identify a subset of families with substantially elevated transmission risk. Polygenic risk scores are only weakly predictive at this time but steadily improving and ultimately may enable more robust prediction either singly or when combined with the risk variables examined in this study.

Keywords: Early detection; Family studies; Genetic counseling; Personalized medicine; Reproductive health planning.

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.

Purpose Reading involves the ability to decode and draw meaning from printed text. Reading skill profiles vary widely among learners with autism spectrum disorder (ASD). One fairly common pattern is relative strength in decoding combined with weak comprehension skills-indicators of this profile emerge as early as the preschool years. In order for children with ASD to develop a facility with language that prepares them for reading success, practitioners must intentionally create and provide appropriate instruction practices. Method In this tutorial, we describe ways in which practitioners can support language development and comprehension skills for children with ASD within the context of shared reading activities. We begin by providing known information about the reading performance of children with ASD using the Simple View of Reading as our guiding conceptual framework. Next, we present a number of practical, evidence-based strategies that educators can implement within the context of shared book reading activities. Case studies are embedded throughout the tutorial to demonstrate how practitioners may apply these strategies in their instructional settings. Conclusions Shared book reading interventions are a well-studied, developmentally appropriate approach for bringing about change in language and literacy in early childhood. The success of shared reading depends upon rich communication and interaction between the adult reader and the child. Many children with ASD will require strategies to support social communication and emergent literacy skill development (e.g., vocabulary knowledge, language comprehension) that are specifically linked to future reading comprehension.

The Pandemic has required teachers to find ways to provide high-quality instruction in a virtual format. Video-based instruction (VBI) is a version of technology-aided instruction that has been effectively used in classrooms to improve mathematical outcomes for students with disabilities. This manuscript describes how a special education teacher can utilized VBI through free online platforms (i.e., SeeSaw, Loom) to implement a mathematical problem solving instructional strategy (modified schema-based instruction; MSBI) for students with autism spectrum disorder (ASD) while at home. MSBI utilizing VBI has successfully been used by teachers and researchers to improve additive and multiplicative problem solving skills for students with ASD. This manuscript describes how special education teachers can support students and their caregivers by providing high-quality problem solving instruction in a virtual environment.

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.