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Despite advances in early detection, the average age of autism spectrum disorder (ASD) diagnosis exceeds 4 years and is often later in females. In typical development, biological sex predicts inter-individual variation across multiple developmental milestones, with females often exhibiting earlier progression. The goal of this study was to examine sex differences in caregiver-reported developmental milestones (first word, phrase, walking) and their contribution to timing of initial concerns expressed by caregivers and eventual age of diagnosis. 195 (105 males) children and adolescents aged 8 to 17 years with a clinical diagnosis of ASD were recruited to the study (mean IQ = 99.76). While developmental milestones did not predict timing of diagnosis or age parents first expressed concerns, females had earlier first words and phrases than males. There was a marginal difference in the age of diagnosis, with females receiving their diagnosis 1 year later than males. Despite sex differences in developmental milestones and diagnostic variables, IQ was the most significant predictor in the timing of initial concerns and eventual diagnosis, suggesting children with lower IQ, regardless of sex, are identified and diagnosed earlier. Overall, biological sex and developmental milestones did not account for a large proportion of variance for the eventual age of ASD diagnosis, suggesting other factors (such as IQ and the timing of initial concerns) are potentially more influential. LAY SUMMARY: In this study, a later age of diagnosis in females having ASD was confirmed; however, biological sex was not the stronger predictor of age of diagnosis. Parents reported that females learned language more quickly than males, and parents noted their first concerns when females were older than males. In this sample, the strongest predictor of age of diagnosis was the age of first concerns.

Social motivation is a foundational construct with regard to the etiology, neurobiology, and phenotype of autism spectrum disorder (ASD). Multiple theories suggest that early emerging alterations to social motivation underlie a developmental cascade of social and communication deficits across the lifespan. Despite this significance, methods to measure social motivation vary widely, with little data to date as to how different measures might compare. In this study, we explore three existing caregiver-report measures that have been proposed to quantify social motivation among school-age children with ASD (n = 18; all male) and without ASD (n = 36; 50% female), with the broad goal of characterizing social motivation across measures and specific aims of investigating (a) diagnostic and sex differences in social motivation, (b) correspondence between measures, and (c) relationships between social motivation and broader social outcomes. Across all three measures, individuals with ASD had lower social motivation by caregiver-report. However, they did display individual differences in the degree of social motivation reported. There were no differences in social motivation between males and females without ASD on any of the three measures. For the full sample, measures of social motivation correlated with one another as anticipated, and stronger social motivation was associated with stronger social skills and fewer social difficulties. Our data suggest that social motivation among children with ASD may be best conceptualized as an individual difference that is diminished on average relative to peers but which varies among children and adolescents with ASD, rather than as an absolute absence or uniform deficit. LAY SUMMARY: Several theories suggest that children with autism spectrum disorder (ASD) experience less social motivation than their peers without ASD, contributing to difficulties in social skills. Based on multiple caregiver-report questionnaires, social motivation was reduced on average for school-age children with ASD but also varied among children with ASD. Stronger social motivation was related to stronger social skills and fewer social problems. Future work should include more girls with ASD, consider social motivation across age groups, and include first-hand perspectives from people with ASD.

The balance of excitation and inhibition in neural circuits is hypothesized to be increased in autism spectrum disorder, possibly mediated by altered signaling of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), yet empirical evidence in humans is inconsistent. We used edited magnetic resonance spectroscopy (MRS) to quantify signals associated with both GABA and the excitatory neurotransmitter glutamate in multiple regions of the sensory and sensorimotor cortex, including primary visual, auditory, and motor areas in adult individuals with autism and in neurotypical controls. Despite the strong a priori hypothesis of reduced GABA in autism spectrum disorder, we found no group differences in neurometabolite concentrations in any of the examined regions and no correlations of MRS measure with psychophysical visual sensitivity or autism symptomatology. We demonstrate high data quality that is comparable across groups, with a relatively large sample of well-characterized participants, and use Bayesian statistics to corroborate the lack of any group differences. We conclude that levels of GABA and Glx (glutamate, glutamine, and glutathione) in the sensory and sensorimotor cortex, as measured with MRS at 3T, are comparable in adults with autism and neurotypical individuals. Autism Res 2020, 13: 1111-1129. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: γ-Aminobutyric acid (GABA) and glutamate are the main inhibitory and excitatory neurotransmitters in the human brain, respectively, and their balanced interaction is necessary for neural function. Previous research suggests that the GABA and glutamate systems might be altered in autism. In this study, we used magnetic resonance spectroscopy to measure concentrations of these neurotransmitters in the sensory areas in the brains of young adults with autism. In contradiction to the common hypothesis of reduced GABA in autism, we demonstrate that concentrations of both GABA and glutamate, in all the brain regions examined, are comparable in individuals with autism and in neurotypical adults. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

As the diagnosis and treatment of Autism Spectrum Disorder (ASD) becomes a greater public health concern, access to professionals and expert assessment becomes increasingly more challenging. Novel techniques to improve efficiency of assessment of young children with social communication concerns are desperately needed to address significant barriers to accessing diagnostic evaluations. Utilizing crowdsourcing technology, we compared ratings by experts and crowdworkers of social communication behaviors in videos of 18-month-old children. Of note, 563 crowdworkers and 24 expert responses were collected in approximately 7 hr and 57 days, respectively. Summed scores of social communication behaviors observed by crowdworkers showed high correlation to those of experts. These data introduce a novel and perhaps efficient way in which to examine of social communication impairments in toddlers. Autism Research 2018, 11: 1629-1634. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This research compared crowdsourced assessments of social communication behaviors to assessments by experts, for toddlers whose behaviors ranged in severity from typical to atypical. Results showed that crowdsourced rankings of social communication behavior significantly correlate with those of experts.

Rates of autism spectrum disorder (ASD) and age at first diagnosis vary considerably across the United States and are moderated by children's sex, race, ethnicity, and availability of services. We additionally suggest that degree of caregiver-clinician agreement on ASD symptoms may play a role in ASD assessment. Since gold standard ASD assessment integrates caregiver-reported developmental history with clinician observations, differential agreement between reporters across demographic groups may contribute to a host of detrimental outcomes. Here, we investigate whether caregiver-clinician agreement on ASD symptoms varies according to child and family characteristics. Comprehensive data from 2,759 families in the Simons Simplex Collection were analyzed. Linear models were created with caregiver reports predicting clinician reports, and moderating effects of child characteristics and family factors were examined. Poorer reporter correspondence was observed when children had higher IQ scores, stronger adaptive behavior, and more behavioral difficulties. Greater disagreement was also associated with African American racial status (for younger children), lower household income, and paternal social difficulties (for older children). Children's biological sex did not moderate caregiver-clinician agreement. Marked disagreement between caregivers and clinicians could lead to suboptimal or insufficient intervention services and negative experiences for families throughout development. Such families may also be less likely to qualify for research studies, and therefore be underrepresented in the ASD literature. Modified assessment procedures may be required to improve assessment accuracy and family experiences. Autism Res 2018, 11: 476-487. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay summary Evaluation of autism spectrum disorder (ASD) incorporates both caregiver and clinician perspectives of symptoms, and disagreement between these perspectives could lead to poorer outcomes for families. Using data from 2,759 families, we show that caregiver-clinician agreement on ASD symptoms is poorer for children with higher cognitive and adaptive skills, more behavioral difficulties, lower household income, and African American racial status. These children may be at higher risk for misdiagnosis, poorer family experiences during evaluations, and poorer representation in ASD research.

Autism is a complex genetic disorder where both de-novo and inherited genetics factors play a role. Next generation sequencing approaches have been extensively used to identify rare variants associated with autism. To date, all such studies were focused on nuclear genome; thereby leaving the role of mitochondrial DNA (mtDNA) variation in autism unexplored. Recently, analytical tools have been developed to evaluate mtDNA in whole-exome data. We have analyzed the mtDNA sequence derived from whole-exome sequencing in 10 multiplex families. In one of the families we have identified two variants of interest in MT-ND5 gene that were previously determined to impair mitochondrial function. In addition in a second family we have identified two VOIs; mtDNA variant in MT-ATP6 and nuclear DNA variant in NDUFS4, where both VOIs are within mitochondrial Respiratory Chain Complex. Our findings provide further support for the role of mitochondria in ASD and confirm that whole-exome sequencing allows for analysis of mtDNA, which sets a stage for further comprehensive genetic investigations of the role of mitochondria in autism. Autism Res 2017, 10: 1338-1343. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Current research suggests that incidence and heterogeneity of autism spectrum disorder (ASD) symptoms may arise through a variety of exogenous and/or endogenous factors. While subject to routine clinical practice and generally considered safe, there exists speculation, though no human data, that diagnostic ultrasound may also contribute to ASD severity, supported by experimental evidence that exposure to ultrasound early in gestation could perturb brain development and alter behavior. Here we explored a modified triple hit hypothesis [Williams & Casanova, ] to assay for a possible relationship between the severity of ASD symptoms and (1) ultrasound exposure (2) during the first trimester of pregnancy in fetuses with a (3) genetic predisposition to ASD. We did so using retrospective analysis of data from the SSC (Simon's Simplex Collection) autism genetic repository funded by the Simons Foundation Autism Research Initiative. We found that male children with ASD, copy number variations (CNVs), and exposure to first trimester ultrasound had significantly decreased non-verbal IQ and increased repetitive behaviors relative to male children with ASD, with CNVs, and no ultrasound. These data suggest that heterogeneity in ASD symptoms may result, at least in part, from exposure to diagnostic ultrasound during early prenatal development of children with specific genetic vulnerabilities. These results also add weight to on-going concerns expressed by the FDA about non-medical use of diagnostic ultrasound during pregnancy. Autism Res 2017, 10: 472-484. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Executive function and play skills develop in early childhood and are linked to cognitive and language ability. The present study examined these abilities longitudinally in two groups with autism spectrum disorder-a group with higher initial language (n = 30) and a group with lower initial language ability (n = 36). Among the lower language group, concurrent nonverbal cognitive ability contributed most to individual differences in executive function and play skills. For the higher language group, executive function during preschool significantly predicted play ability at age 6 over and above intelligence, but early play did not predict later executive function. These results suggested that factors related to the development of play and executive function differ for subgroups of children with different language abilities and that early executive function skills may be critical in order for verbal children with autism to develop play. Autism Res 2016, 9: 1274-1284. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Social deficits are fundamental to autism spectrum disorder (ASD), and a growing body of research implicates altered functioning of the autonomic nervous system (ANS), including both sympathetic and parasympathetic branches. However, few studies have explored both branches concurrently in ASD, particularly within the context of social interaction. The current study investigates patterns of change in indices of sympathetic (pre-ejection period; PEP) and parasympathetic (respiratory sinus arrhythmia; RSA) cardiac influence as boys (ages 8-11 years) with (N = 18) and without (N = 18) ASD engage in dyadic social interaction with novel and familiar social partners. Groups showed similar patterns of autonomic change during interaction with the novel partner, but differed in heart rate, PEP, and RSA reactivity while interacting with a familiar partner. Boys without ASD evinced decreasing sympathetic and increasing parasympathetic influence, whereas boys with ASD increased in sympathetic influence. Boys without ASD also demonstrated more consistent ANS responses across partners than those with ASD, with parasympathetic responding differentiating familiar and novel interaction partners. Finally, PEP slopes with a familiar partner correlated with boys' social skills. Implications include the importance of considering autonomic state during clinical assessment and treatment, and the potential value of regulation strategies as a complement to intervention programs aiming to support social cognition and behavior. Autism Res 2016, 9: 579-591. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Pervasive social difficulties among individuals with autism spectrum disorder (ASD) are often construed as deriving from reduced sensitivity to social stimuli. Behavioral and neurobiological evidence suggests that typical individuals show preferential processing of social (e.g., voices, faces) over nonsocial (e.g., nonvocal sounds, images of objects) information, whereas individuals with ASD may not. This reduction in sensitivity may reflect disrupted reward processing [Dawson & Bernier, ], with significant developmental consequences for affected individuals. In this study, we explore effects of social and monetary reward on behavioral and electrodermal responses (EDRs) among 8- to 12-year-old boys with (n = 18) and without (n = 18) ASD, with attention to the potential moderating effects of stimulus familiarity. During a simple matching task, participants with and without ASD had marginally slower reactions during social vs. nonsocial reward, and boys with ASD had less accurate responses than controls. Compared to baseline, reward and non-reward conditions elicited more frequent and larger EDRs for participants as a whole, and both groups showed similar patterns of EDR change within reward blocks. However, boys with and without ASD differed in their EDRs to non-reward, and response amplitude was correlated with social and emotional functioning. These findings provide some support for altered reward responding in ASD at the autonomic level, and highlight the discontinuation of reward as an important component of reward-based learning that may play a role in shaping behavior and guiding specialized brain development to subserve social behavior and cognition across the lifespan.