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Maternal nutrition during gestation has been investigated for its role in child neurodevelopment. However, little is known about the potential impact of gestational caffeine exposure on child autistic behaviors. Here, we assess the relation between maternal caffeine intake during pregnancy and children's behavioral traits related to Autism Spectrum Disorder (ASD). We harmonized data from two pregnancy cohorts, Early Autism Risk Longitudinal Investigation (EARLI) (n = 120), an enriched-risk cohort of mothers who previously had a child with ASD, from Pennsylvania, Maryland, and Northern California (2009-2012), and the Health Outcomes and Measures of the Environment (HOME) Study (n = 269), a general population cohort from Cincinnati, Ohio (2003-2006). Mothers self-reported caffeine intake twice during pregnancy. Caregivers reported child behavioral traits related to ASD using the Social Responsiveness Scale (SRS) when children were aged 3-8 years. Higher scores indicate more ASD-related behaviors. We estimated covariate-adjusted differences in continuous SRS T-scores per interquartile range increase in caffeine intake. Self-reported caffeine intake during pregnancy was positively associated with SRS T-scores among children in EARLI (β: 2.0; 95% CI -0.1, 4.0), but to a lesser extent in HOME (β: 0.6; 95% CI -0.5, 1.6). In HOME, pre-pregnancy body mass index (BMI) modified the association between caffeine intake and SRS T-scores, where more positive associations were observed among women with higher BMIs. Our findings suggest gestational caffeine intake may represent a marker of vulnerability to childhood ASD-related behaviors. Additional studies are warranted to extend these findings.

Since 2012, studies in mice, rats, and humans have suggested that abnormalities in purinergic signaling may be a final common pathway for many genetic and environmental causes of autism spectrum disorder (ASD). The current study in mice was conducted to characterize the bioenergetic, metabolomic, breathomic, and behavioral features of acute hyperpurinergia triggered by systemic injection of the purinergic agonist and danger signal, extracellular ATP (eATP). Responses were studied in C57BL/6J mice in the maternal immune activation (MIA) model and controls. Basal metabolic rates and locomotor activity were measured in CLAMS cages. Plasma metabolomics measured 401 metabolites. Breathomics measured 98 volatile organic compounds. Intraperitoneal eATP dropped basal metabolic rate measured by whole body oxygen consumption by 74% ± 6% (mean ± SEM) and rectal temperature by 6.2˚ ± 0.3˚C in 30 minutes. Over 200 metabolites from 37 different biochemical pathways where changed. Breathomics showed an increase in exhaled carbon monoxide, dimethylsulfide, and isoprene. Metabolomics revealed an acute increase in lactate, citrate, purines, urea, dopamine, eicosanoids, microbiome metabolites, oxidized glutathione, thiamine, niacinamide, and pyridoxic acid, and decreased folate-methylation-1-carbon intermediates, amino acids, short and medium chain acyl-carnitines, phospholipids, ceramides, sphingomyelins, cholesterol, bile acids, and vitamin D similar to some children with ASD. MIA animals were hypersensitive to postnatal exposure to eATP or poly(IC), which produced a rebound increase in body temperature that lasted several weeks before returning to baseline. Acute hyperpurinergia produced metabolic and behavioral changes in mice. The behaviors and metabolic changes produced by ATP injection were associated with mitochondrial functional changes that were profound but reversible.

Primary symptoms of adults with autism spectrum disorder (ASD), such as pervasive social deficits in social interaction and communication, cause adults with ASD to adopt a sedentary lifestyle. Meanwhile, gamified and behavioral theory-based interventions have been shown to improve physical activity in a fun and unobtrusive way. In this paper, we describe the iterative design inquiry process of PuzzleWalk, a gamified, physical activity-promoting mobile app designed for adults with ASD. We report the design rationales and lessons learned across four user-centered design phases with ASD experts and adults with ASD, including user requirement gathering, iterative participatory design, usability evaluation, and field deployment. The design insights generated from this work could inform future research focusing on designing sociotechnical systems, games, and interventions for people with ASD.

Animal models have shown that chronic stress increases cortisol, which contributes to overeating of highly palatable food, increased abdominal fat and lower cortisol reactivity. Few studies in humans have simultaneously examined these trajectories. We examined premenopausal women, either mothers of children with a diagnosis of an autism spectrum disorder (n = 92) or mothers of neurotypical children (n = 91). At baseline and 2-years, we assessed hair cortisol, metabolic health, and reward-based eating. We compared groups cross-sectionally and prospectively, accounting for BMI change. Caregivers, relative to controls, had lower cumulative hair cortisol at each time point, with no decreases over time. Caregivers also had stable levels of poor metabolic functioning and greater reward-based eating across both time points, and evidenced increased abdominal fat prospectively (all ps ≤.05), independent of change in BMI. This pattern of findings suggest that individuals under chronic stress, such as caregivers, would benefit from tailored interventions focusing on better regulation of stress and eating in tandem to prevent early onset of metabolic disease, regardless of weight status.

The relationship between viewer individual differences and gaze control has been largely neglected in the scene perception literature. Recently we have shown a robust association between individual differences in viewer cognitive capacity and scan patterns during scene viewing. These findings suggest other viewer individual differences may also be associated with scene gaze control. Here we expand our findings to quantify the relationship between individual differences in clinical traits and scene viewing behavior in a normative sample. The present study used Successor Representation Scanpath Analysis (SRSA) to quantify the strength of the association between individual differences in scan patterns during real-world scene viewing and individual differences in viewer attention-deficit disorder, autism spectrum disorder, and dyslexia scores. The SRSA results revealed individual differences in vertical scan patterns that explained more than half of the variance in attention-deficit scores, a third of the variance in autism quotient scores, and about a quarter of the variance in dyslexia scores. These results suggest that individual differences in attention-deficit disorder, autism spectrum disorder, and dyslexia scores are most strongly associated with vertical scanning behaviors when viewing real-world scenes. More importantly, our results suggest scene scan patterns have promise as potential diagnostic tools and provide insight into the types of vertical scan patterns that are most diagnostic.

Autism spectrum disorder (hereafter referred to as "ASD") is a heterogeneous neurodevelopmental condition characterized by impaired social communication and interactions, and restricted, repetitive activities or interests. Alterations in network connectivity and memory function are frequently observed in autism patients, often involving the hippocampus. However, specific changes during early brain development leading to disrupted functioning remain largely unclear. Here, we investigated the development of dendritic arbor of hippocampal CA1 pyramidal neurons in the BTBR T+tf/J (BTBR) mouse model of autism. BTBR mice display the defining behavioural features of autism, and also exhibit impaired learning and memory. We found that compared to control C57BL/6J (B6) animals, the lengths of both apical and basal dendrites were significantly greater in neonatal BTBR animals. Further, basal dendrites in the BTBR mice had higher branching complexity. In contrast, cross-sectional area of the soma was unchanged. In addition, we observed a similar density of CA1 pyramidal neurons and thickness of the neuronal layer between the two strains. Thus, there was a specific, compartmentalized overgrowth of dendrites during early development in the BTBR animals. Biochemical analysis further showed that the extracellular signal-regulated kinases (ERK) pathway was up-regulated in the hippocampus of neonatal BTBR animals. Since dendritic structure is critical for information integration and relay, our data suggest that altered development of dendrites could potentially contribute to impaired hippocampal function and behavior observed in the BTBR model, and that this might be related to increased activation of the ERK pathway.

Understanding the biological mechanisms underlying human neuropsychiatric disorders, such as autism spectrum disorder (ASD), has been hindered by the lack of a robust, translational animal model. Rhesus monkeys (Macaca mulatta) display many of the same social behaviors that are affected in ASD, making them an excellent animal species in which to model social impairments. However, the social impairments associated with ASD may reflect extreme ends of a continuous distribution of traits. Thus, to validate the rhesus monkey as an animal model for studying social impairments that has strong translational relevance for ASD, researchers need an easily-implemented measurement tool that can quantify variation in social behavior dimensionally. The Social Responsiveness Scale (SRS) is a 65-item survey that identifies both typical and atypical social behaviors in humans that covary with ASD symptom severity. A chimpanzee SRS has already been validated and the current study adapted this tool for use in the rhesus monkey (mSRS). Fifteen raters completed the mSRS for 105 rhesus monkeys living at the Yerkes National Primate Research Center. The mSRS scores showed a unimodal distribution with a positive skew that identified 6 statistical outliers. Inter-rater reliability was very strong, but only 17 of the 36 questions showed positive intra-item reliability. The results of an exploratory factor analysis identified 3 factors that explained over 60% of the variance, with 12 items significantly loading onto the primary factor. These items reflected behaviors associated with social avoidance, social anxiety or inflexibility and social confidence. These initial findings are encouraging and suggest that variability in the social responsiveness of rhesus monkeys can be quantified using the mSRS: a tool that has strong translational relevance for human disorders. With further modification, the mSRS may provide an promising new direction for research on the biological mechanisms underlying social impairments.

The laboratory rat is emerging as an attractive preclinical animal model of autism spectrum disorder (ASD), allowing investigators to explore genetic, environmental and pharmacological manipulations in a species exhibiting complex, reciprocal social behavior. The present study was carried out to compare two commonly used strains of laboratory rats, Sprague-Dawley (SD) and Long-Evans (LE), between the ages of postnatal day (PND) 26-56 using high-throughput behavioral phenotyping tools commonly used in mouse models of ASD that we have adapted for use in rats. We detected few differences between young SD and LE strains on standard assays of exploration, sensorimotor gating, anxiety, repetitive behaviors, and learning. Both SD and LE strains also demonstrated sociability in the 3-chamber social approach test as indexed by spending more time in the social chamber with a constrained age/strain/sex matched novel partner than in an identical chamber without a partner. Pronounced differences between the two strains were, however, detected when the rats were allowed to freely interact with a novel partner in the social dyad paradigm. The SD rats in this particular testing paradigm engaged in play more frequently and for longer durations than the LE rats at both juvenile and young adult developmental time points. Results from this study that are particularly relevant for developing preclinical ASD models in rats are threefold: (i) commonly utilized strains exhibit unique patterns of social interactions, including strain-specific play behaviors, (ii) the testing environment may profoundly influence the expression of strain-specific social behavior and (iii) simple, automated measures of sociability may not capture the complexities of rat social interactions.

BackgroundDuplications of 15q11.2-q13.1 (Dup15q syndrome) are highly penetrant for autism spectrum disorder (ASD). A distinct electrophysiological (EEG) pattern characterized by excessive activity in the beta band has been noted in clinical reports. We asked whether EEG power in the beta band, as well as in other frequency bands, distinguished children with Dup15q syndrome from those with non-syndromic ASD and then examined the clinical correlates of this electrophysiological biomarker in Dup15q syndrome.MethodsIn the first study, we recorded spontaneous EEG from children with Dup15q syndrome (n = 11), age-and-IQ-matched children with ASD (n = 10) and age-matched typically developing (TD) children (n = 9) and computed relative power in 6 frequency bands for 9 regions of interest (ROIs). Group comparisons were made using a repeated measures analysis of variance. In the second study, we recorded spontaneous EEG from a larger cohort of individuals with Dup15q syndrome (n = 27) across two sites and examined age, epilepsy, and duplication type as predictors of beta power using simple linear regressions.ResultsIn the first study, spontaneous beta1 (12-20 Hz) and beta2 (20-30 Hz) power were significantly higher in Dup15q syndrome compared with both comparison groups, while delta (1-4 Hz) was significantly lower than both comparison groups. Effect sizes in all three frequency bands were large (|d| > 1). In the second study, we found that beta2 power was significantly related to epilepsy diagnosis in Dup15q syndrome.ConclusionsHere, we have identified an electrophysiological biomarker of Dup15q syndrome that may facilitate clinical stratification, treatment monitoring, and measurement of target engagement for future clinical trials. Future work will investigate the genetic and neural underpinnings of this electrophysiological signature as well as the functional consequences of excessive beta oscillations in Dup15q syndrome.

BackgroundSibling sex ratios have been applied as an indirect test of a hypothesized association between prenatal testosterone levels and risk for autism, a developmental disorder disproportionately affecting males. Differences in sibling sex ratios between those with and without autism would provide evidence of a shared risk factor for autism and offspring sex. Conclusions related to prenatal testosterone, however, require additional assumptions. Here, we used directed acyclic graphs (DAGs) to clarify the elements required for a valid test of the hypothesis that sibling sex ratios differ between children with and without autism. We then conducted such a test using a large, population-based sample of children.MethodsOver 1.1 million subjects, born in California from 1992-2007, and identified through birth records, were included. The association between autism diagnosis, determined using the administrative database of the California Department of Developmental Services, and the sex of the subsequent sibling was examined using generalized estimating equations. Sources of potential bias identified using DAGs were addressed.ResultsAmong male children with autism, 52.2% of next-born siblings were brothers, versus 51.0% for unaffected males. For females with autism, 50.2% of following siblings were brothers versus 51.2% among control females. The relative risk of a subsequent male sibling associated with autism diagnosis was 1.02 (95% confidence interval: 0.99, 1.04).ConclusionsIn a large, population-based sample we failed to find evidence suggesting an excess of brothers among children with autism while controlling for several threats to validity. This test cannot rule out a role of any given exposure, including prenatal testosterone, in either risk of autism or offspring sex ratio, but suggests against a common cause of both.

Background22q11.2 Deletion Syndrome (22q11DS) represents one of the greatest known genetic risk factors for the development of psychotic illness, and is also associated with high rates of autistic spectrum disorders (ASD) in childhood. We performed integrated genomic analyses of 22q11DS to identify genes and pathways related to specific phenotypes.MethodsWe used a high-resolution aCGH array to precisely characterize deletion breakpoints. Using peripheral blood, we examined differential expression (DE) and networks of co-expressed genes related to phenotypic variation within 22q11DS patients. Whole-genome transcriptional profiling was performed using Illumina Human HT-12 microarrays. Data mining techniques were used to validate our results against independent samples of both peripheral blood and brain tissue from idiopathic psychosis and ASD cases.ResultsEighty-five percent of 22q11DS individuals (N = 39) carried the typical 3 Mb deletion, with significant variability in deletion characteristics in the remainder of the sample (N = 7). DE analysis and weighted gene co-expression network analysis (WGCNA) identified expression changes related to psychotic symptoms in patients, including a module of co-expressed genes which was associated with psychosis in 22q11DS and involved in pathways associated with transcriptional regulation. This module was enriched for brain-expressed genes, was not related to antipsychotic medication use, and significantly overlapped with transcriptional changes in idiopathic schizophrenia. In 22q11DS-ASD, both DE and WGCNA analyses implicated dysregulation of immune response pathways. The ASD-associated module showed significant overlap with genes previously associated with idiopathic ASD.ConclusionThese findings further support the use of peripheral tissue in the study of major mutational models of diseases affecting the brain, and point towards specific pathways dysregulated in 22q11DS carriers with psychosis and ASD.

Persons with autism regularly exhibit executive dysfunction (ED), including problems with deliberate goal-directed behavior, planning, and flexible responding in changing environments. Indeed, this array of deficits is sufficiently prominent to have prompted a theory that executive dysfunction is at the heart of these disorders. A more detailed examination of these behaviors reveals, however, that some aspects of executive function remain developmentaly appropriate. In particular, while people with autism often have difficulty with tasks requiring cognitive flexibility, their fundamental cognitive control capabilities, such as those involved in inhibiting an inappropriate but relatively automatic response, show no significant impairment on many tasks. In this article, an existing computational model of the prefrontal cortex and its role in executive control is shown to explain this dichotomous pattern of behavior by positing abnormalities in the dopamine-based modulation of frontal systems in individuals with autism. This model offers excellent qualitative and quantitative fits to performance on standard tests of cognitive control and cognitive flexibility in this clinical population. By simulating the development of the prefrontal cortex, the computational model also offers a potential explanation for an observed lack of executive dysfunction early in life.

Developmental delay and/or intellectual disability (DD/ID) affects 1-3% of all children. At least half of these are thought to have a genetic etiology. Recent studies have shown that massively parallel sequencing (MPS) using a targeted gene panel is particularly suited for diagnostic testing for genetically heterogeneous conditions. We report on our experiences with using massively parallel sequencing of a targeted gene panel of 355 genes for investigating the genetic etiology of eight patients with a wide range of phenotypes including DD/ID, congenital anomalies and/or autism spectrum disorder. Targeted sequence enrichment was performed using the Agilent SureSelect Target Enrichment Kit and sequenced on the Illumina HiSeq2000 using paired-end reads. For all eight patients, 81-84% of the targeted regions achieved read depths of at least 20×, with average read depths overlapping targets ranging from 322× to 798×. Causative variants were successfully identified in two of the eight patients: a nonsense mutation in the ATRX gene and a canonical splice site mutation in the L1CAM gene. In a third patient, a canonical splice site variant in the USP9X gene could likely explain all or some of her clinical phenotypes. These results confirm the value of targeted MPS for investigating DD/ID in children for diagnostic purposes. However, targeted gene MPS was less likely to provide a genetic diagnosis for children whose phenotype includes autism.

The neuronal differences contributing to the etiology of autism spectrum disorder (ASD) are still not well defined. Previous studies have suggested that myelin and axons are disrupted during development in ASD. By combining structural and diffusion MRI techniques, myelin and axons can be assessed using extracellular water, aggregate g-ratio, and a new approach to calculating axonal conduction velocity termed aggregate conduction velocity, which is related to the capacity of the axon to carry information. In this study, several innovative cellular microstructural methods, as measured from magnetic resonance imaging (MRI), are combined to characterize differences between ASD and typically developing adolescent participants in a large cohort. We first examine the relationship between each metric, including microstructural measurements of axonal and intracellular diffusion and the T1w/T2w ratio. We then demonstrate the sensitivity of these metrics by characterizing differences between ASD and neurotypical participants, finding widespread increases in extracellular water in the cortex and decreases in aggregate g-ratio and aggregate conduction velocity throughout the cortex, subcortex, and white matter skeleton. We finally provide evidence that these microstructural differences are associated with higher scores on the Social Communication Questionnaire (SCQ) a commonly used diagnostic tool to assess ASD. This study is the first to reveal that ASD involves MRI-measurable in vivo differences of myelin and axonal development with implications for neuronal and behavioral function. We also introduce a novel formulation for calculating aggregate conduction velocity, that is highly sensitive to these changes. We conclude that ASD may be characterized by otherwise intact structural connectivity but that functional connectivity may be attenuated by network properties affecting neural transmission speed. This effect may explain the putative reliance on local connectivity in contrast to more distal connectivity observed in ASD., Competing Interests: Dr. James C. McPartland consults with Customer Value Partners, Bridgebio, Determined Health, and BlackThorn Therapeutics, has received research funding from Janssen Research and Development, serves on the Scientific Advisory Boards of Pastorus and Modern Clinics, and receives royalties from Guilford Press, Lambert, Oxford, and Springer. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Other authors declare no conflicts of interest., (Copyright: © 2024 Newman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The integration of a service dog can have numerous benefits for children with Autism Spectrum Disorder (ASD). However, although integration takes place within a family, little is known about the dynamics of these benefits on the family microsystem. Thus, the aim of our study was to propose a more systemic perspective, not only by investigating the benefits of SD integration, but also by exploring the relationships between improvements in children with ASD, parents' well-being, parenting strategies and the quality of the child-dog relationship. Twenty parent-child with ASD dyads were followed before, as well as 3 and 6 months after service dog integration. At each stage, parents completed an online survey which included: the Autism Behavior Inventory (ABI-S), the State-Trait Anxiety Inventory (STAI-Y), the Parenting Stress Index Short Version (PSI-SF), the Monash Dog Owner Relationship Scale (MDORS) and the Parenting Styles and Dimensions Questionnaire (PSDQ). First, repeated measure one-way ANOVAs revealed that both children's ASD symptoms and parents' anxiety decreased significantly after service dog integration. Additionally, Spearman correlations revealed that the more ASD symptoms decreased, the more parent's anxiety and parenting stress also decreased. Second, the quality of the child-dog relationship appeared to contribute to those benefits on both children's ASD symptoms and parents' well-being. Interestingly, parenting strategies seemed to adapt according to these benefits and to the quality of the child-dog relationship. Through a more systemic perspective, this study highlighted that the integration of a service dog involved reciprocal and dynamic effects for children with ASD and their parents, and shed new light on the processes that may underlie the effects of a service dog for children with ASD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Dollion et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Self-owned items are better remembered than other-owned items; this ownership effect reflects privileged processing of self-related information. The size of this ownership effect has been shown to decrease in neurotypical adults as the number of autistic traits increases, and is reduced in autistic adults. However, emerging evidence has questioned the reliability of these findings. This paper aimed to replicate previous work using well-powered, pre-registered designs, and Bayesian analyses. Experiment 1 (N = 100) found a significant ownership effect in neurotypical adults; however, the size of this was unrelated to individual differences in autistic traits. Experiment 2 (N = 56) found an ownership effect in neurotypical but not autistic adults. The findings suggest that individual differences in autistic traits in the neurotypical population do not impact the ownership effect, but a clinical diagnosis of autism might. We discuss how these findings can be explained by differences in psychological self-awareness in autism., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Smith et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Early life stress (ELS) can impact brain development and is a risk factor for neurodevelopmental disorders such as schizophrenia. Post-weaning social isolation (SI) is used to model ELS in animals, using isolation stress to disrupt a normal developmental trajectory. We aimed to investigate how SI affects the expression of genes in mouse hippocampus and to investigate how these changes related to the genetic basis of neurodevelopmental phenotypes. BL/6J mice were exposed to post-weaning SI (PD21-25) or treated as group-housed controls (n = 7-8 per group). RNA sequencing was performed on tissue samples from the hippocampus of adult male and female mice. Four hundred and 1,215 differentially-expressed genes (DEGs) at a false discovery rate of < 0.05 were detected between SI and control samples for males and females respectively. DEGS for both males and females were significantly overrepresented in gene ontologies related to synaptic structure and function, especially the post-synapse. DEGs were enriched for common variant (SNP) heritability in humans that contributes to risk of neuropsychiatric disorders (schizophrenia, bipolar disorder) and to cognitive function. DEGs were also enriched for genes harbouring rare de novo variants that contribute to autism spectrum disorder and other developmental disorders. Finally, cell type analysis revealed populations of hippocampal astrocytes that were enriched for DEGs, indicating effects in these cell types as well as neurons. Overall, these data suggest a convergence between genes dysregulated by the SI stressor in the mouse and genes associated with neurodevelopmental disorders and cognitive phenotypes in humans., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Laighneach et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Understanding the overall utility of biological testing for autism spectrum disorder (ASD) is essential for the development and integration of biomarkers into routine care. One measure related to the overall utility of biological testing is the knowledge that a person has about the condition he/she suffers from. However, a major gap towards understanding the role of knowledge in overall utility is the absence of studies that have assessed knowledge of autism along with its predictors within a representative sample of families within the context of routine care. The objective of this study was to measure knowledge of ASD among families within the routine care pathway for biological testing in ASD by examining the association between knowledge with potential correlates of knowledge namely sociodemographic factors, parental stress and distress, and time since diagnosis among parents whose child with ASD is undergoing clinical genetic testing. Parents of a child diagnosed with ASD (n = 85, Mage = 39.0, SD = 7.7) participating in an ongoing prospective genomics study completed the ASD Quiz prior to undergoing genetic testing for clinical and research purposes. Parents also completed self-reported measures of stress and distress. Parent stress and distress was each independently correlated with knowledge of ASD, rs ≥ 0.26, ps < 0.05. Stepwise regression analysis revealed a significant model accounting for 7.8% of the variance in knowledge, F (1, 82) = 8.02, p = 0.006. The only factor significantly associated with knowledge was parental distress, β = 0.30, p = 0.006. Parental stress, time since diagnosis, and sociodemographic factors were not significant predictors in this model. We concluded that families require tailored support prior to undergoing genetic testing to address either knowledge gaps or high distress. Ongoing appraisal of the testing process among families of diverse backgrounds is essential in offering optimal care for families undergoing genetic testing. [ABSTRACT FROM AUTHOR]

Objective: The Centers for Disease Control and Prevention (CDC) coordinates a labor-intensive process to measure the prevalence of autism spectrum disorder (ASD) among children in the United States. Random forests methods have shown promise in speeding up this process, but they lag behind human classification accuracy by about 5%. We explore whether more recently available document classification algorithms can close this gap. Materials and methods: Using data gathered from a single surveillance site, we applied 8 supervised learning algorithms to predict whether children meet the case definition for ASD based solely on the words in their evaluations. We compared the algorithms’ performance across 10 random train-test splits of the data, using classification accuracy, F1 score, and number of positive calls to evaluate their potential use for surveillance. Results: Across the 10 train-test cycles, the random forest and support vector machine with Naive Bayes features (NB-SVM) each achieved slightly more than 87% mean accuracy. The NB-SVM produced significantly more false negatives than false positives (P = 0.027), but the random forest did not, making its prevalence estimates very close to the true prevalence in the data. The best-performing neural network performed similarly to the random forest on both measures. Discussion: The random forest performed as well as more recently available models like the NB-SVM and the neural network, and it also produced good prevalence estimates. NB-SVM may not be a good candidate for use in a fully-automated surveillance workflow due to increased false negatives. More sophisticated algorithms, like hierarchical convolutional neural networks, may not be feasible to train due to characteristics of the data. Current algorithms might perform better if the data are abstracted and processed differently and if they take into account information about the children in addition to their evaluations. Conclusion: Deep learning models performed similarly to traditional machine learning methods at predicting the clinician-assigned case status for CDC’s autism surveillance system. While deep learning methods had limited benefit in this task, they may have applications in other surveillance systems. [ABSTRACT FROM AUTHOR]

We examined the emotional and psychophysiological underpinnings of social interaction in the context of autism spectrum disorder, more specifically, involving participants diagnosed with Asperger syndrome (AS). We recorded participants’ autonomic nervous system (ANS) activation (electrodermal activity, heart rate, and heart rate variability) and facial muscle activation during conversations in two different types of male dyads: (1) ten dyads where one participant has been diagnosed with AS (AS/NT dyads) and (2) nine dyads where both participants are neurotypical (NT/NT dyads). Afterwards, three independent raters assessed continuously each participant’s affiliative and dominant behaviors during the first and last 10 minutes of the conversations. The relationship between the assessed data and ANS responses was examined. We found that, in the NT/NT dyads, a high level of affiliation displayed by the conversational partner calms down the participant when they are actively dominating the interaction. In contrast, when the participants themselves expressed affiliation, their psychophysiological responses indicated increase in arousal, which suggests that the giving of affiliation is physiologically “hard work.” The affiliation-related ANS responses were similar in those NT participants whose conversational partner had AS, while some differences in facial muscle activation did occur in comparison to NT/NT dyads. In the AS participants, in contrast, a high level of affiliation provided by the conversational partner was associated with increase in arousal, suggesting heightened alertness and stress. As for their own affiliative behavior, the AS participants exhibited similar indicators of alertness and stress as the NT participants, but only when their own level of dominance was low. Our results increase understanding of how individuals with AS experience social interaction at the physiological level, and how this experience differs from that in NT individuals. Moreover, our results confirm and further specify our earlier results, where we proposed that affiliation involves the type of “sharing of the burden” that also reverberates in the participants’ bodies. [ABSTRACT FROM AUTHOR]

Background: Although eating difficulties are known to be common in children on the autism spectrum, there is a lack of research on whether these behaviours persist or change into adulthood. Emerging evidence suggests that autistic adults may experience higher levels of disordered eating than the general population, indicating the impact of autism on eating in this adult population warrants further exploration. Method: This study interviewed 12 autistic adults about their eating habits, with a focus on the continuing or changing presence of behaviours often seen in autistic children such as sensory sensitivity or a preference for routines. Interviews were transcribed and analysed using thematic analysis. Results: Overall, participants suggested that autism did continue to impact their eating into adulthood, particularly in the areas of sensory sensitivity, medical difficulties, executive functioning difficulties, and rigidity, but that they had learned to adapt so that these issues no longer represented a problem. However, a minority of participants did feel that their autism had a negative effect on their eating, particularly those diagnosed with eating disorders. Additionally, eating behaviours associated with autism were identified as potentially contributing to having an unhealthy body weight. Conclusions: Certain traits associated with autism, such as cognitive rigidity and sensory sensitivity, could potentially continue to influence the eating behaviours of autistic adults. These traits are typically experienced as differences which can be adapted around and managed, rather than specific problems. However, these traits can potentially contribute to difficulties such as disordered eating and weight gain, and the implications of these should be explored by future research. [ABSTRACT FROM AUTHOR]

Background: Prenatal antibiotic exposure induces changes in infants’ gut microbiota composition and is suggested as a possible contributor in the development of autism spectrum disorders (ASD). In this study, we examined the association between prenatal antibiotic exposure and the risk of ASD. Methods: This was a population-based cohort study utilizing the Manitoba Population Research Data Repository. The cohort included 214 834 children born in Manitoba, Canada between April 1, 1998 and March 31, 2016. Exposure was defined as having filled one or more antibiotic prescription during pregnancy. The outcome was autism spectrum disorder diagnosis. Multivariable Cox proportional hazards regression was used to estimate the risk of developing ASD in the overall cohort and in a sibling cohort. Results: Of all subjects, 80 750 (37.6%) were exposed to antibiotics prenatally. During follow-up, 2965 children received an ASD diagnosis. Compared to children who were not exposed to antibiotics prenatally, those who were exposed had a higher risk of ASD: (adjusted HR 1.10 [95% CI 1.01, 1.19]). The association was observed in those exposed to antibiotics in the second or third trimester (HR 1.11 [95% CI 1.01, 1.23] and 1.17 [95% CI 1.06, 1.30], respectively). In the siblings’ cohort, ASD risk estimate remained unchanged (adjusted HR 1.08 [95% CI 0.90, 1.30], although it was not statistically significant. Conclusions: Prenatal antibiotic exposure is associated with a small increase in the risk of ASD. Given the potential of residual confounding beyond what it was controlled through our study design and because of possible confounding by indication, such a small risk increase in the population is not expected to be clinically significant. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorders (ASD) are a set of neurodevelopmental disorders characterised by behavioural, communication and social impairments. The prevalence of sleep disturbances in children with ASD is 40–80%, with significant effects on quality of life for the children and carers. This systematic review aimed to synthesise evidence of the effects of behavioural interventions to improve sleep among children with ASD. Methods: Databases (MEDLINE, PsycINFO, CINAHL, ScienceDirect, Autism Data, CENTRAL, ClinicalTrials.gov and Current Controlled Trials) were searched for published, unpublished and ongoing randomised controlled trials evaluating the effect of non-pharmacological interventions for insomnia in children with autism spectrum conditions. Results: Three studies met the inclusion criteria, one provided actigraphy data, one Children’s Sleep Habits Questionnaire (CSHQ) data, and one both actigraphy and CSHQ data for use in meta-analyses. There were significant differences between the behavioural intervention and comparison groups (actigraphy data) for total sleep time (24.41 minutes, 95% CI 5.71, 43.11, P = 0.01), sleep latency (-18.31 minutes, 95% CI -30.84, -5.77, P = 0.004) and sleep efficiency (5.59%, 95% CI 0.87, 10.31, P = 0.02). There was also a favourable intervention effect evident for the subjective CSHQ data (-4.71, 95% CI -6.70, -2.73, P<0.00001). Risk of bias was low across several key domains (randomisation, allocation concealment and reporting), with some studies being unclear due to poor reporting. Conclusions: There are very few high quality randomised controlled trials in this area. Here we provide initial synthesised quantitative evidence of the effectiveness of behavioural interventions for treating sleep problems in children with ASD. Trial registration: Protocol was registered () on the International Prospective Register of Systematic Reviews (). [ABSTRACT FROM AUTHOR]

Introduction: Although caring for a child with intellectual and developmental disabilities (IDD) can have positive outcomes, parents may be at a greater risk of depression and anxiety, due to a number of associated stressors, such as increased caregiver demands and financial strain. This systematic review updates previous data, exploring the relationship between parenting a child with IDD and parental depression and anxiety. Methods: Five electronic databases were searched for eligible English-language articles, published between January 2004 and July 2018. All epidemiological study designs were eligible, provided the level of depression and/or anxiety was compared between parents of children (aged <18) with and without IDD. No limit was placed on geographic location. The proportion of positive associations between parenting a child with IDD and depression/anxiety were disaggregated by disability type, geographic region, and sample size. The percentage of parents at risk of moderate depression or anxiety were calculated using recognised clinical cut-off scores for each screening tool. Meta-analyses, in which pooled effect sizes of elevated depression and anxiety symptoms were calculated, were conducted across two IDD conditions, autism and cerebral palsy. Results: Of the 5,839 unique records screened, 19 studies fulfilled the inclusion criteria. The majority of studies were conducted in high-income (n = 8, 42%) or upper-middle income countries (n = 10, 53%). Of the 19 studies, 69% focused on parents of children with cerebral palsy (n = 7, 37%) or autism (n = 6, 32%). Nearly all studies found a positive association between parenting a child with IDD and depression (n = 18, 95%) and anxiety (n = 9, 90%) symptoms. Factors associated with higher levels of depression symptoms amongst parents of children with IDD included disability severity (n = 8, 78%) and lower household income (n = 4, 80%). Approximately one third (31%) of parents of children with IDD reach the clinical cut-off score for moderate depression, compared with 7% of parents of children without IDD. 31% of parents of children with IDD reach the cut-off score for moderate anxiety, compared with 14% of parents of children without IDD. The meta-analyses demonstrated moderate effect sizes for elevated depression amongst parents of children with autism and cerebral palsy. Conclusions: Results indicate elevated levels of depressive symptoms amongst parents of children with IDD. Quality concerns amongst the existing literature support the need for further research, especially in low- and middle-income countries. [ABSTRACT FROM AUTHOR]

The FMR1 premutation (PM) is relatively common in the general population. Evidence suggests that PM carriers may exhibit subtle differences in specific cognitive and language abilities. This study examined potential mechanisms underlying such differences through the study of gaze and language coordination during a language processing task (rapid automatized naming; RAN) among female carriers of the FMR1 PM. RAN taps a complex set of underlying neuropsychological mechanisms, with breakdowns implicating processing disruptions in fundamental skills that support higher order language and executive functions, making RAN (and analysis of gaze/language coordination during RAN) a potentially powerful paradigm for revealing the phenotypic expression of the FMR1 PM. Forty-eight PM carriers and 56 controls completed RAN on an eye tracker, where they serially named arrays of numbers, letters, colors, and objects. Findings revealed a pattern of inefficient language processing in the PM group, including a greater number of eye fixations (namely, visual regressions) and reduced eye-voice span (i.e., the eyes’ lead over the voice) relative to controls. Differences were driven by performance in the latter half of the RAN arrays, when working memory and processing load are the greatest, implicating executive skills. RAN deficits were associated with broader social-communicative difficulties among PM carriers, and with FMR1-related molecular genetic variation (higher CGG repeat length, lower activation ratio, and increased levels of the fragile X mental retardation protein; FMRP). Findings contribute to an understanding of the neurocognitive profile of PM carriers and indicate specific gene-behavior associations that implicate the role of the FMR1 gene in language-related processes. [ABSTRACT FROM AUTHOR]

“Why are neurotypicals so pig-ignorant about autism?” an autistic person wrote on the Curtin Autism Research Group’s on-line portal as a response to a call for research questions. Co-produced with an autistic researcher, knowledge about and attitudes towards autism were analysed from 1,054 completed surveys, representing the Australian neurotypical adult population. The majority, 81.5% of participants had a high level of knowledge and 81.3% of participants had a strong positive attitude towards autism. Neither age, nor education level had an impact on attitudes. However, attitudes were influenced by knowledge about ‘Societal Views and Ideas’; ‘What it Could be Like to Have Autism’; and the demographic variables ‘Knowing and having spent time around someone with autism’; and gender (women having more positive attitudes than men). Thus, targeted interventions, geared more towards men than women, to increase knowledge about autism could further improve attitudes and increase acceptance of the autistic community. [ABSTRACT FROM AUTHOR]

In recent years there has been increased attention to child neurodevelopment in studies on medication safety in pregnancy. Neurodevelopment is a multifactorial outcome that can be assessed by various assessors, using different measures. This has given rise to a debate on the validity of various measures of neurodevelopment. The aim of this review was twofold. Firstly we aimed to give an overview of studies on child neurodevelopment after prenatal exposure to central nervous system acting medications using psychotropics and analgesics as examples, giving special focus on the use and validity of outcome measures. Secondly, we aimed to give guidance on how to conduct and interpret medication safety studies with neurodevelopment outcomes. We conducted a systematic review in the MEDLINE, Embase, PsycINFO, Web of Science, Scopus, and Cochrane databases from inception to April 2019, including controlled studies on prenatal exposure to psychotropics or analgesics and child neurodevelopment, measured with standardised psychometric instruments or by diagnosis of neurodevelopmental disorder. The review management tool Covidence was used for data-extraction. Outcomes were grouped as motor skills, cognition, behaviour, emotionality, or “other”. We identified 110 eligible papers (psychotropics, 82 papers, analgesics, 29 papers). A variety of neurodevelopmental outcome measures were used, including 27 different psychometric instruments administered by health care professionals, 15 different instruments completed by parents, and 13 different diagnostic categories. In 23 papers, no comments were made on the validity of the outcome measure. In conclusion, establishing neurodevelopmental safety includes assessing a wide variety of outcomes important for the child’s daily functioning including motor skills, cognition, behaviour, and emotionality, with valid and reliable measures from infancy through to adolescence. Consensus is needed in the scientific community on how neurodevelopment should be assessed in medication safety in pregnancy studies. Review registration number: CRD42018086101 in the PROSPERO database. [ABSTRACT FROM AUTHOR]

The variability in the own-gender bias (OGB) in face-recognition is thought to be based on experience and the engagement of expert face processing mechanisms for own-gender faces. Experience is also associated with personality characteristics such as extraversion and Autism, yet the effects of these variables on the own-gender bias has not been explored. We ran a face recognition study exploring the relationships between own-gender experience, holistic processing (measured using the face-inversion effect, composite face effect, and the parts-and-wholes test), personality characteristics (extraversion and Autism Quotient) and the OGB. Findings did not support a mediational account where experience increases holistic processing and this increases the OGB. Rather, there was a direct relationship between extraversion and Autism Quotient and the OGB. We interpret this as personality characteristics having an effect on the motivation to process own-gender faces more deeply than opposite-gender faces. [ABSTRACT FROM AUTHOR]

During development, motor skills are fundamental in supporting interactions with the external world. The ability to plan actions is a particularly important aspect of motor skill since it is involved in many daily activities. In this work, we studied the development of motor planning longitudinally in children with an older sibling with Autism Spectrum Disorder (ASD) who are at heightened risk (HR) for the disorder and children with no such risk (low risk; LR) using a shape sorter task. Children were observed at 14, 18, 24 and 36 months. Three HR children with a later diagnosis of ASD (HR-ASD) were analyzed separately from the rest of the sample. Behavioral and kinematic data indicated that precision demands significantly influenced children’s actions, and that children’s performance improved with age. No differences were found between the HR and LR groups, but a descriptive analysis of data from the three HR-ASD suggested differences in the variables describing children’s action (as reaching time and acceleration) as well as variables describing children’s performance (as the adjustment of the shapes). [ABSTRACT FROM AUTHOR]

The study of Autism Spectrum Disorder (ASD) in the United States has identified a growing prevalence of the disorder across the country, a high economic burden for necessary treatment, and important gaps in insurance for individuals with autism. Confronting these facts, states have moved quickly in recent years to introduce mandates that insurers provide coverage for autism care. This study analyzes these autism insurance mandates and demonstrates that while states have moved swiftly to introduce them, the generosity of the benefits they mandate insurers provide varies dramatically across states. Furthermore, our research finds that controlling for policy need, interest group activity, economic circumstances, the insurance environment, and other factors, the passage of these mandates and differences in their generosity are driven by the ideology of state residents and politicians–with more generous benefits in states with more liberal citizens and increased Democratic control of state government. We conclude by discussing the implications of these findings for the study of health policy, politics, and autism in America. [ABSTRACT FROM AUTHOR]

The ability to selectively respond to one’s own name is important for social and language development, and is disrupted in atypically developing populations (e.g., autism spectrum disorder). Research with typically developing samples using event-related potentials (ERPs) has demonstrated that the subject’s own name (SON) is differentiated from other stimuli at both early sensory and later cognitive stages of auditory processing. While neural indices of response to name have been researched extensively in adults, no such studies have been conducted with typically developing preschool children or children with autism spectrum disorder (ASD). The present study investigated ERP response to name in a sample of typically developing (TD) preschoolers (n = 19; mean age = 4.3 years) as well as a small, exploratory comparison group of preschoolers with ASD (n = 13; mean age = 4.4 years). TD preschoolers exhibited significantly greater negativity to SON over frontal regions than to an unfamiliar nonsense name, consistent with the adult SON negativity component. This component was present whether the name was spoken by a parent or an unfamiliar adult, suggesting that it reflects SON-specific processing rather than broad self-relevant information processing. Comparing preschoolers with ASD to the TD children revealed a significant SON negativity component across both groups. The amplitude of the SON negativity response was significantly correlated with social variables in the ASD group, though these correlations did not survive correction for multiple comparisons. This study is the first to demonstrate the presence of the SON component in preschool children with and without ASD. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorders (ASD) are lifelong neurodevelopmental disorders. It is not clear whether working memory (WM) deficits are commonly experienced by individuals with ASD. Aim: To determine whether individuals with ASD experience significant impairments in WM and whether there are specific domains of working memory that are impaired. Methods: We conducted a meta-analysis using four electronic databases EMBASE (OVID), MEDLINE (OVID), PsychINFO (EBSCOHOST), and Web of Science, to examine the literature to investigate whether people with ASD experience impairments related to WM. Meta-analyses were conducted separately for phonological and visuospatial domains of WM. Subgroup analyses investigated age and intelligence quotient as potential moderators. Results: A total of 29 papers containing 34 studies measuring phonological and visuospatial domains of WM met the inclusion criteria. WM scores were significantly lower for individuals with ASD compared to typically developed (TD) controls, in both the visuospatial domain when investigating accuracy (d: -0.73, 95% CI -1.04 to -0.42, p < 0.05) and error rates (d: 0.56, 95% CI 0.25 to 0.88, p<0.05), and the phonological domain when investigating accuracy (d:-0.67, 95% CI -1.10 to -0.24, p>0.05) and error rate (d: 1.45, 95% CI -0.07 to 2.96, p = 0.06). Age and IQ did not explain the differences in WM in ASD. Conclusions: The findings of this meta-analysis indicate that across the lifespan, individuals with ASD demonstrate large impairments in WM across both phonological and visuospatial WM domains when compared to healthy individuals. [ABSTRACT FROM AUTHOR]

Objectives: Improving mental health outcomes for children and young people has become a priority for policy makers in the developed world. In Australia, up to half of all children and adolescents meeting criteria for mental health disorders receive suboptimal levels of treatment (or no treatment at all) despite the availability of effective treatments. Children with complex mental health conditions are particularly at risk of inadequate treatment as optimal care requires coordination from medical, educational and social services. In Australia, clinicians including pediatricians, psychologists and child and adolescent psychiatrists deliver the bulk of mental health care for children with complex mental health conditions. We aimed to determine perspectives of these Australian clinicians on barriers and enablers within the current system and components of an optimal model of care. Methods: Inductive content analysis was used to analyse 30 semi-structured interviews with key clinicians managing the care of children with complex mental health conditions across Australia. Interviews were conducted using vignettes with Attention Deficit Hyperactivity Disorder (ADHD) and Autism as exemplars. Findings: Multiple barriers to optimal care exist at a systemic, clinician and family level. However, regional health systems provide an enabling environment from which metropolitan models could learn. Transitioning to adult services was highlighted as the most compromised area of care. Clinicians identified short (e.g. empowering parents to advocate for and deliver their child’s care, case conferencing with schools) and long term (e.g. co-locating disciplines to deliver care, workforce training) solutions. Conclusions: Whilst multiple barriers to optimal care for children with complex mental health conditions exist, clinicians identify several enablers including developing networks with other disciplines and empowering parents to advocate for and co-ordinate care. Systemic changes based on multidisciplinary, co-located and integrated care services should be developed as longer term solutions. [ABSTRACT FROM AUTHOR]

Background: The mechanisms underlying autism spectrum disorder (ASD) remain unclear, and clinical biomarkers are not yet available for ASD. Differences in dysregulated proteins in ASD have shown little reproducibility, which is partly due to ASD heterogeneity. Recent studies have demonstrated that subgrouping ASD cases based on clinical phenotypes is useful for identifying candidate genes that are dysregulated in ASD subgroups. However, this strategy has not been employed in proteome profiling analyses to identify ASD biomarker proteins for specific subgroups. Methods: We therefore conducted a cluster analysis of the Autism Diagnostic Interview-Revised (ADI-R) scores from 85 individuals with ASD to predict subgroups and subsequently identified dysregulated genes by reanalyzing the transcriptome profiles of individuals with ASD and unaffected individuals. Proteome profiling of lymphoblastoid cell lines from these individuals was performed via 2D-gel electrophoresis, and then mass spectrometry. Disrupted proteins were identified and compared to the dysregulated transcripts and reported dysregulated proteins from previous proteome studies. Biological functions were predicted using the Ingenuity Pathway Analysis (IPA) program. Selected proteins were also analyzed by Western blotting. Results: The cluster analysis of ADI-R data revealed four ASD subgroups, including ASD with severe language impairment, and transcriptome profiling identified dysregulated genes in each subgroup. Screening via proteome analysis revealed 82 altered proteins in the ASD subgroup with severe language impairment. Eighteen of these proteins were further identified by nano-LC-MS/MS. Among these proteins, fourteen were predicted by IPA to be associated with neurological functions and inflammation. Among these proteins, diazepam-binding inhibitor (DBI) protein was confirmed by Western blot analysis to be expressed at significantly decreased levels in the ASD subgroup with severe language impairment, and the DBI expression levels were correlated with the scores of several ADI-R items. Conclusions: By subgrouping individuals with ASD based on clinical phenotypes, and then performing an integrated transcriptome-proteome analysis, we identified DBI as a novel candidate protein for ASD with severe language impairment. The mechanisms of this protein and its potential use as an ASD biomarker warrant further study. [ABSTRACT FROM AUTHOR]

Introduction: Cerebral Visual Impairment (CVI) is the most common cause of visual impairment in children in the developed world and appears to be more prevalent in children with additional support needs (ASN). There is an urgent need for routine screening for CVI, particularly in children with ASN, however, current screening questionnaires for CVI have limited validation. The aim of this study was to evaluate two screening tools: the Five Questions and the CVI Questionnaire. Additionally, the distribution of CVI across neurodevelopmental disorders is unknown. This too was investigated. Methods: An online survey was completed by 535 parents. The survey was advertised via social media, CVI websites and parent email systems of four schools. The survey comprised of the Five Questions, the CVI Questionnaire and additional questions regarding the child’s diagnoses. Whether or not a child had a diagnosis of CVI and/or additional neurodevelopmental disorders was based on parental report. Results: Based on parent reports, both the screening tools accurately screened for CVI diagnoses in children. The Five Questions and the CVI Questionnaire have construct validity (as determined through factor analysis), high internal consistency (as determined by Cronbach’s alpha) and convergent validity (as determined by correlation analysis of the raw scores of each questionnaire). This study also highlights that among children with neurodevelopmental disorders, a large proportion have parent-reported CVI (23%-39%) and potential CVI (6.59–22.53%; as identified by the questionnaires). Conclusion: The current study demonstrates that the Five Questions and CVI Questionnaire have good convergent validity, internal consistency and a reliable factor structure and may therefore be suitable as screening tools. The study also highlights that reported or potential CVI is evident in a large proportion of children with neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

The development of executive function is necessary for flexible and voluntary control of behavior. Deficits in executive function are purported to be a primary cause of behavioral inflexibility—a core clinical symptom—in Autism Spectrum Disorder (ASD). Attentional set-shifting has traditionally been measured with the Dimensional Change Card Sort, however, this task requires following verbal instructions. Here, we used a novel visual search task that does not require verbal instructions in conjunction with eye-tracking to test attentional set-shifting in 2-year-old toddlers diagnosed with ASD (N = 29) and chronological age-matched typically developing controls (N = 30). On each trial, a relevant and an irrelevant target were embedded in a set of feature-conjunction distractors, and toddlers were tasked with searching for the relevant target. Critically, after a set of trials the targets switched roles (i.e., the previously relevant target became irrelevant, and the previously relevant target became irrelevant). We measured visual search performance prior to and following a target switch. We found that both groups of toddlers could readily switch targets, and found strikingly similar performance between typically developing toddlers and toddlers with ASD. Our results challenge the centrality of deficits in attentional set-shifting to early behavioral inflexibility in ASD. [ABSTRACT FROM AUTHOR]

The relationships of spirituality with human social cognition, as exemplified in autism spectrum and schizophrenia spectrum cognitive variation, remain largely unstudied. We quantified non-clinical levels of autism spectrum and schizotypal spectrum traits (using the Autism Quotient and the Schizotypal Personality Questionnaire-Brief Revised) and dimensions of spirituality (using the Hardt Spirituality Questionnaire) in a large sample of undergraduate students. We tested in particular the hypothesis, based on the diametrical model of autism and psychosis, that autism should be negatively associated, and positive schizotypal traits should be positively associated, with spirituality. Our primary findings were threefold. First, in support of the diametric model, total Spirituality score was significantly negatively correlated with total Autism Quotient score, and significantly positively correlated with Positive Schizotypal traits (the Schizotypal Personality Cognitive-Perceptual subscale), as predicted. Second, these associations were driven mainly by opposite patterns regarding the Search for Meaning Spirituality subscale, which was the only subscale that was significantly negatively associated with autism, and significantly positively associated with Positive Schizotypal traits. Third, Belief in God was positively correlated with Positive Schizotypal traits, but was uncorrelated with autism traits. The opposite findings for Search for Meaning can be interpreted in the contexts of well-supported cognitive models for understanding autism in terms of weak central coherence, and understanding Positive Schizotypal traits in terms of enhanced salience. [ABSTRACT FROM AUTHOR]

X-linked ichthyosis (XLI) is a rare X-linked dermatological condition arising from deficiency for the enzyme steroid sulfatase (STS). STS is normally expressed in the brain, and males with XLI exhibit personality differences from males in the general population, and are at increased risk of developmental and mood disorders. As the STS gene escapes X-inactivation, female carriers of XLI-associated genetic mutations have reduced STS expression/activity relative to non-carrier females, and could manifest similar behavioural phenotypes to males with XLI. Additionally, as STS activity normally increases in female tissues towards late pregnancy and into the puerperium, carrier females could theoretically present with increased rates of postpartum psychopathology. Using a worldwide online survey comprising custom-designed demographic questionnaires and multiple validated psychological questionnaires, we collected detailed self-reported information on non-postpartum and postpartum behaviour in confirmed adult (>16yrs) female carriers of genetic mutations associated with XLI (n = 94) for statistical comparison to demographically-matched previously-published normative data from female controls (seven independent studies, 98≤n≤2562), adult males with XLI (n = 58), and to newly-obtained online survey data from a general population sample of mothers from the United Kingdom and United States of America (n = 263). The pattern of results in carrier females relative to controls was remarkably similar to that previously observed in males with XLI, with evidence for increased rates of developmental and mood disorders, and elevated levels of inattention, impulsivity, autism-related traits and general psychological distress. Carrier females exhibited a significantly elevated rate of postpartum mental health conditions (notably mild depression) relative to controls which could not be accounted for by social factors. Our data confirm the psychological profile associated with XLI-associated mutations, and suggest that female carriers may be at increased risk of psychopathology, including in the postpartum period. These findings are relevant to families affected by XLI, to clinicians involved in the care of these families, and to genetic counsellors. [ABSTRACT FROM AUTHOR]

Background: Word comprehension across semantic categories is a key area of language development. Using online automated eye-tracking technology to reduce response demands during a word comprehension test may be advantageous in children with autism spectrum disorder (ASD). Objectives: To measure online accuracy of word recognition across eleven semantic categories in preschool children with ASD and in typically developing (TD) children matched for gender and developmental age. Methods: Using eye-tracker methodology we measured the relative number of fixations on a target image as compared to a foil of the same category shown simultaneously on screen. This online accuracy measure was considered a measure of word understanding. We tested the relationship between online accuracy and offline word recognition and the effects of clinical variables on online accuracy. Twenty-four children with ASD and 21 TD control children underwent the eye-tracking task. Results: On average, children with ASD were significantly less accurate at fixating on the target image than the TD children. After multiple comparison correction, no significant differences were found across the eleven semantic categories of the experiment between preschool children with ASD and younger TD children matched for developmental age. The ASD group showed higher intragroup variability consistent with greater variation in vocabulary growth rates. Direct effects of non-verbal cognitive levels, vocabulary levels and gesture productions on online word recognition in both groups support a dimensional view of language abilities in ASD. Conclusions: Online measures of word comprehension across different semantic categories show higher interindividual variability in children with ASD and may be useful for objectively monitor gains on targeted language interventions. [ABSTRACT FROM AUTHOR]

Serotonin-1B receptors (5-HT1BRs) modulate perseverative behaviors and prepulse inhibition (PPI) in humans and mice. These inhibitory G-protein-coupled receptors signal through a canonical G-protein-coupled pathway that is modulated by GSK-3β, and a noncanonical pathway mediated by the adaptor protein β-arrestin2 (Arrb2). Given the development of biased ligands that differentially affect canonical versus noncanonical signaling, we examined which signaling pathway mediates 5-HT1BR agonist-induced locomotor perseveration and PPI deficits, behavioral phenotypes observed in both obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD). To assess the role of canonical 5-HT1BR signaling, mice received acute pretreatment with a GSK-3 inhibitor (SB216763 or AR-A014418) and acute treatment with the 5-HT1A/1B receptor agonist RU24969 prior to assessing perseverative locomotor behavior in the open field, and PPI. To determine the role of noncanonical 5-HT1BR signaling, Arrb2 wild-type (WT), heterozygous (HT), and knockout (KO) mice received acute RU24969 treatment prior to behavioral testing. GSK-3 inhibition increased locomotor perseveration overall, and also failed to influence the RU24969-induced perseverative locomotor pattern in the open field. Yet, GSK-3 inhibition modestly reduced RU24969-induced PPI deficits. On the other hand, Arrb2 HT and KO mice showed reduced locomotion and no changes in perseveration overall, in addition to modest reductions in RU24969-induced locomotion and PPI deficits. In conclusion, our data do not support use of either GSK-3 inhibitors or β-arrestin2 inhibition in treatment of perseverative behaviors. [ABSTRACT FROM AUTHOR]

Dysfunctions in the GABAergic system are associated with the pathogenesis of autism spectrum disorder (ASD). However, the mechanisms by which GABAergic system dysfunctions induce the pathophysiology of ASD remain unclear. We previously demonstrated that a selective type I 5α-reductase inhibitor SKF105111 (SKF) induced ASD-like behaviors, such as impaired sociability-related performance and repetitive grooming behaviors, in male mice. Moreover, the effects of SKF were caused by a decrease in the endogenous levels of allopregnanolone (ALLO), a positive allosteric modulator of the GABAA receptor. In this study, we used SKF-treated male mice as a putative animal model of ASD and examined the effects of Kami-shoyo-san (KSS) as an experimental therapeutic strategy for ASD. KSS is a traditional Kampo formula consisting of 10 different crude drugs and has been used for the treatment of neuropsychiatric symptoms. KSS dose-dependently attenuated sociability deficits and suppressed an increase in grooming behaviors in SKF-treated mice without affecting ALLO content in the prefrontal cortex. The systemic administration of the dopamine D1 receptor antagonist SCH23390 reversed the ameliorative effects of KSS. On the other hand, the dopamine D2 receptor antagonist sulpiride and GABAA receptor antagonist bicuculline only attenuated the ameliorative effect of KSS on repetitive self-grooming behaviors. The present results indicate that KSS improves SKF-induced ASD-like behaviors by facilitating dopamine receptor-mediated mechanisms and partly by neurosteroid-independent GABAA receptor-mediated neurotransmission. Therefore, KSS is a potential candidate for the treatment of ASD. [ABSTRACT FROM AUTHOR]

Misinformation poses significant challenges to evidence-based practice. In the public health domain specifically, treatment misinformation can lead to opportunity costs or direct harm. Alas, attempts to debunk misinformation have proven sub-optimal, and have even been shown to “backfire”, including increasing misperceptions. Thus, optimized debunking strategies have been developed to more effectively combat misinformation. The aim of this study was to test these strategies in a real-world setting, targeting misinformation about autism interventions. In the context of professional development training, we randomly assigned participants to an “optimized-debunking” or a “treatment-as-usual” training condition and compared support for non-empirically-supported treatments before, after, and six weeks following completion of online training. Results demonstrated greater benefits of optimized debunking immediately after training; thus, the implemented strategies can serve as a general and flexible debunking template. However, the effect was not sustained at follow-up, highlighting the need for further research into strategies for sustained change. [ABSTRACT FROM AUTHOR]

The deficit in speech sound production in some children with autism spectrum disorder (ASD) adds to their communication barriers. The 3-D virtual environments have been implemented to improve their communication abilities. However, there were no previous studies on the use of a 3-D virtual pronunciation tutor designed specifically to train pronunciation for children with ASD. To fill this research gap, the current study developed and evaluated a 3-D virtual tutor which served as a multimodal and real-data-driven speech production tutor to present both places and manners of Mandarin articulation. Using an eye-tracking technique (RED 5 Eye Tracker), Experiment 1 objectively investigated children’s gauged attention distribution online while learning with our computer-assisted 3-D virtual tutor in comparison to a real human face (HF) tutor. Eye-tracking results indicated most participants showed more interests in the visual speech cues of the 3-D tutor, and paid some degree of absolute attention to the additional visual speech information of both articulatory movements and airflow changes. To further compare treatment outcomes, training performance was evaluated in Experiment 2 with the ASD learners divided into two groups, with one group learning from the HF tutor and the other from the 3-D tutor (HF group vs. 3-D group). Both groups showed improvement with the help of computer-based training in the post-intervention test based on the calculation of a 5-point Likert scale. However, the 3-D group showed much higher gains in producing Mandarin stop and affricate consonants, and apical vowels. We conclude that our 3-D virtual imitation intervention system provides an effective approach of audiovisual pronunciation training for children with ASD. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social interactions, difficulty with communication, and repetitive behavior patterns. In humans affected by ASD, there is a male pre-disposition towards the condition with a male to female ratio of 4:1. In part due to the complex etiology of ASD including genetic and environmental interplay, there are currently no available medical therapies to improve the social deficits of ASD. Studies in rodent models and humans have shown promising therapeutic effects of oxytocin in modulating social adaptation. One pharmacological approach to stimulating oxytocinergic activity is the melanocortin receptor 4 agonist Melanotan-II (MT-II). Notably the effects of oxytocin on environmental rodent autism models has not been investigated to date. We used a maternal immune activation (MIA) mouse model of autism to assess the therapeutic potential of MT-II on autism-like features in adult male mice. The male MIA mice exhibited autism-like features including impaired social behavioral metrics, diminished vocal communication, and increased repetitive behaviors. Continuous administration of MT-II to male MIA mice over a seven-day course resulted in rescue of social behavioral metrics. Normal background C57 male mice treated with MT-II showed no significant alteration in social behavioral metrics. Additionally, there was no change in anxiety-like or repetitive behaviors following MT-II treatment of normal C57 mice, though there was significant weight loss following subacute treatment. These data demonstrate MT-II as an effective agent for improving autism-like behavioral deficits in the adult male MIA mouse model of autism. [ABSTRACT FROM AUTHOR]

Over half of all children with autism spectrum disorders (ASD) have gastrointestinal (GI) co-morbidities including chronic constipation, diarrhea, and irritable bowel syndrome. The severity of these symptoms has been correlated with the degree of GI microbial dysbiosis. The study objective was to assess tolerability of a probiotic (Bifidobacterium infantis) in combination with a bovine colostrum product (BCP) as a source of prebiotic oligosaccharides and to evaluate GI, microbiome and immune factors in children with ASD and GI co-morbidities. This pilot study is a randomized, double blind, controlled trial of combination treatment (BCP + B. infantis) vs. BCP alone in a cross-over study in children ages 2–11 with ASD and GI co-morbidities (n = 8). This 12-week study included 5 weeks of probiotic-prebiotic supplementation, followed by a two-week washout period, and 5 weeks of prebiotic only supplementation. The primary outcome of tolerability was assessed using validated questionnaires of GI function and atypical behaviors, along with side effects. Results suggest that the combination treatment is well-tolerated in this cohort. The most common side effect was mild gassiness. Some participants on both treatments saw a reduction in the frequency of certain GI symptoms, as well as reduced occurrence of particular aberrant behaviors. Improvement may be explained by a reduction in IL-13 and TNF-α production in some participants. Although limited conclusions can be drawn from this small pilot study, the results support the need for further research into the efficacy of these treatments. [ABSTRACT FROM AUTHOR]

Behaviors characterized as restricted and repetitive (RRBs) in autism manifest in diverse ways, from motor mannerisms to intense interests, and are diagnostically defined as interfering with functioning. A variety of early autism interventions target RRBs as preoccupying young autistic children to the detriment of exploration and learning opportunities. In an exploratory study, we developed a novel stimulating play situation including objects of potential interest to autistic children, then investigated repetitive behaviors and object explorations in 49 autistic and 43 age-matched typical young children (20–69 months). Autistic children displayed significantly increased overall frequency and duration of repetitive behaviors, as well as increased specific repetitive behaviors. However, groups did not significantly differ in frequency and duration of overall object explorations, in number of different objects explored, or in explorations of specific objects. Exploratory analyses found similar or greater exploration of literacy-related objects in autistic compared to typical children. Correlations between repetitive behaviors and object explorations (their frequency and duration) revealed positive, not negative, associations in both groups. Our findings, from a novel situation incorporating potential autistic interests, suggest that RRBs do not necessarily displace exploration and its possibilities for learning in autism. [ABSTRACT FROM AUTHOR]

The aim of the present study was to test the hypothesis that individuals with higher Autism Spectrum Quotient (AQ) scores would be more permissive of pragmatic impairments than those with lower AQ scores. We investigated the presence of a correlation between the AQ scores of mothers with children in grades 1 to 6 and their evaluation of assumed pragmatic impairments in children using the Maternal Evaluation of Pragmatic Impairments in Children (MEPC) measure. Mothers were asked to rate how they would feel if their child showed the communication behaviors listed in scales D (coherence), E (inappropriate initiation), F (stereotyped language), G (use of context), and H (nonverbal communication) of the Children’s Communication Checklist-2, which measures pragmatic impairments. All responses were given on a five-point Likert scale. The results indicated that the higher the maternal AQ score, the less the mother tended to evaluate pragmatic impairments as a problem. We also examined whether the age and gender of assumed children influenced the correlation between AQ and MEPC scores, but found no significant correlation. The partial correlation coefficients were calculated for each subscale, none of which was significant. A negative correlation was found between AQ and MEPC scores as a whole. [ABSTRACT FROM AUTHOR]

Identifying disease genes from a vast amount of genetic data is one of the most challenging tasks in the post-genomic era. Also, complex diseases present highly heterogeneous genotype, which difficult biological marker identification. Machine learning methods are widely used to identify these markers, but their performance is highly dependent upon the size and quality of available data. In this study, we demonstrated that machine learning classifiers trained on gene functional similarities, using Gene Ontology (GO), can improve the identification of genes involved in complex diseases. For this purpose, we developed a supervised machine learning methodology to predict complex disease genes. The proposed pipeline was assessed using Autism Spectrum Disorder (ASD) candidate genes. A quantitative measure of gene functional similarities was obtained by employing different semantic similarity measures. To infer the hidden functional similarities between ASD genes, various types of machine learning classifiers were built on quantitative semantic similarity matrices of ASD and non-ASD genes. The classifiers trained and tested on ASD and non-ASD gene functional similarities outperformed previously reported ASD classifiers. For example, a Random Forest (RF) classifier achieved an AUC of 0. 80 for predicting new ASD genes, which was higher than the reported classifier (0.73). Additionally, this classifier was able to predict 73 novel ASD candidate genes that were enriched for core ASD phenotypes, such as autism and obsessive-compulsive behavior. In addition, predicted genes were also enriched for ASD co-occurring conditions, including Attention Deficit Hyperactivity Disorder (ADHD). We also developed a KNIME workflow with the proposed methodology which allows users to configure and execute it without requiring machine learning and programming skills. Machine learning is an effective and reliable technique to decipher ASD mechanism by identifying novel disease genes, but this study further demonstrated that their performance can be improved by incorporating a quantitative measure of gene functional similarities. Source code and the workflow of the proposed methodology are available at . [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Maternal separation (MS) stress is an established model of early-life stress associated with autistic-like behaviors. Altered glutamatergic and nitrergic neurotransmissions may contribute to the pathophysiology of ASD. However, the specific mechanisms underlying these alterations and their relationship to MS-induced autistic-like behaviors remain unclear. Addressing this knowledge gap, this study aims to elucidate the involvement of the nitric oxide (NO)/ N-methyl-D-aspartate (NMDA) pathway in MS-induced autistic-like behaviors in mice. This knowledge has the potential to guide future research, potentially leading to the development of targeted interventions or treatments aimed at modulating the NO/NMDA pathway to ameliorate ASD symptoms. Ninety male Naval Medical Research Institute (NMRI) mice were assigned to six groups (n = 15) comprising a control group (treated with saline) and five groups subjected to MS and treated with saline, ketamine, NMDA, L-NAME, and L-arginine. Behavioral tests were conducted, including the three-chamber test, shuttle box, elevated plus-maze, and marble burying test. Gene expression of iNOS, nNOS, and NMDA-R subunits (NR2A and NR2B), along with nitrite levels, was evaluated in the hippocampus. The findings demonstrated that MS induced autistic-like behaviors, accompanied by increased gene expression of iNOS, nNOS, NR2B, NR2A, and elevated nitrite levels in the hippocampus. Modulation of the NO/NMDA pathway with activators and inhibitors altered the effects of MS. These results suggest that the NO/NMDA pathway plays a role in mediating the negative effects of MS and potentially contributes to the development of autistic-like behaviors in maternally separated mice., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Khaledi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Most vertebrate offspring must transition from the relative security of parental care (nutrition and protection) to independent foraging. Offspring face many challenges during this critical period, particularly in species where parental care ends at weaning, such as the grey seal (Halichoerus grypus). We studied the development of movement behaviour in naïve grey seal pups from their first trips to sea to about five months of age. Twenty-five (12 males and 13 females) newly-weaned pups were fitted with satellite-linked GPS tags on Sable Island, Nova Scotia, Canada in January 2016. The influence of fixed effects (pup size, sex, week) and the random effect of pup identity on trip characteristics were examined. Movement behaviour was analyzed using a move persistence mixed-effects model. Habitat use was highly variable among individuals and covered much of the geographic distribution of the population. Unlike older juveniles, subadults, and adults in this population, most naïve pups used multiple haulout sites to begin and end trips. There was little evidence of area-restricted search behaviour during trips, suggesting that naïve pups were using an opportunistic foraging tactic that may result in more variable foraging success than that of older, experienced animals. Naïve pups made longer trips with longer haulout durations between them than observed for older greys seals. Males and females differed in some trip characteristics, but sex effects were small over the first few months of life. Offspring size at weaning was not a useful predictor of trip characteristics. Move persistence of grey seal pups was initially high and then decreased over time as individuals gained experience. Both intrinsic and extrinsic factors were influential on the movements of grey seal pups. Greater body length at weaning, longer duration spent on shore after weaning, shallower water column depth, and farther distance from shore were all associated with lower move persistence. Female grey seal pups had lower move persistence than males. Overall, the movements of naïve grey seal pups during the first few months of life were characterized by extensive exploration, but move persistence decreased over time suggesting they may be using an exploration-refinement foraging tactic., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Nowak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)