Search

The development of expectations was investigated by using the Visual Expectations Procedure. In Experiment 1, 128 infants aged 6-, 9-, and 12-months-old saw two 40-trial sequences of a videotaped mechanical toy appearing in various locations. The sequences represented an alternation pattern (i.e., ABAB) or a complex pivot pattern (i.e., ABCBABCB). In Experiment 2, 76 infants aged 4-, 8-, and 12-months-old saw either a left-right alternation or a top-bottom alternation. Reaction time improved and the percentage of anticipations increased between 6 and 9 months in Experiment 1 and between 4 and 8 months in Experiment 2 but not thereafter. Anticipations for the pivot sequence and for younger infants on both sequences were often incorrect (i.e., gaze shifts occurred before stimulus onset but were not directed toward the upcoming stimulus). We conclude that young infants have expectations that reflect some degree of general or procedural knowledge, but it is not clear that this behavior implies specific, articulated expectations about upcoming events. [ABSTRACT FROM AUTHOR]

O autismo é um distúrbio do desenvolvimento (early-onset) marcado por atrasos e desvios nas áreas social, de comunicação e nas habilidades para o jogo (play skills), assim como padrões repetitivos e limitados de interesse e comportamento. Consideráveis evidências empíricas acumuladas nos últimos 5 a 10 anos sugerem que, em geral, quanto mais precoce for a intervenção adequada em crianças autistas, é mais provável maximizar o potencial da criança obtendo melhores resultados. Estes resultados destacam a necessidade de realizar avaliações amplas das deficiências no desenvolvimento nos primeiros anos de vida. Este artigo fornece uma visão geral sobre os princípios e elementos para avaliar crianças pequenas com suspeita de autismo partindo de uma abordagem desenvolvimental ampla na qual os padrões normais de desenvolvimento - paticularmente nos domínios social e de comunicação - sejam a estrutura para compreender os atrasos e desvios na socilaização evidenciados em crianças pequenas com autismo. Também se oferece uma breve síntese das futuras diretrizes para a avaliação dos padrões de socialização em bebês e crianças pequenas que pode aproveitar os avanços tecnológicos atuais que estão surgindo nos estudos de mecanismos básicos de orientação social

Autism is a heterogeneous condition, and functional magnetic resonance imaging-based studies have advanced understanding of neurobiological correlates of autistic features. Nevertheless, little work has focused on the optimal brain states to reveal brain-phenotype relationships. In addition, there is a need to better understand the relevance of attentional abilities in mediating autistic features. Using connectome-based predictive modelling, we interrogate three datasets to determine scanning conditions that can boost prediction of clinically relevant phenotypes and assess generalizability. In dataset one, a sample of youth with autism and neurotypical participants, we find that a sustained attention task (the gradual onset continuous performance task) results in high prediction performance of autistic traits compared to a free-viewing social attention task and a resting-state condition. In dataset two, we observe the predictive network model of autistic traits generated from the sustained attention task generalizes to predict measures of attention in neurotypical adults. In dataset three, we show the same predictive network model of autistic traits from dataset one further generalizes to predict measures of social responsiveness in data from the Autism Brain Imaging Data Exchange. In sum, our data suggest that an in-scanner sustained attention challenge can help delineate robust markers of autistic traits and support the continued investigation of the optimal brain states under which to predict phenotypes in psychiatric conditions.

Background: Reduced social attention-looking at faces-is one of the most common manifestations of social difficulty in autism that is central to social development. Although reduced social attention is well characterized in autism, qualitative differences in how social attention unfolds across time remains unknown., Methods: We used a computational modeling (i.e., hidden Markov modeling) approach to assess and compare the spatiotemporal dynamics of social attention in a large, well-characterized sample of children with autism (n = 280) and neurotypical children (n = 119) (ages 6-11) who completed 3 social eye-tracking assays at 3 longitudinal time points (baseline, 6 weeks, 24 weeks)., Results: Our analysis supported the existence of 2 common eye movement patterns that emerged across 3 eye-tracking assays. A focused pattern was characterized by small face regions of interest, which had high a probability of capturing fixations early in visual processing. In contrast, an exploratory pattern was characterized by larger face regions of interest, with a lower initial probability of fixation and more nonsocial regions of interest. In the context of social perception, children with autism showed significantly more exploratory eye movement patterns than neurotypical children across all social perception assays and all 3 longitudinal time points. Eye movement patterns were associated with clinical features of autism, including adaptive function, face recognition, and autism symptom severity., Conclusions: Decreased likelihood of precisely looking at faces early in social visual processing may be an important feature of autism that is associated with autism-related symptomology and may reflect less visual sensitivity to face information., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Research on attention towards non-social stimuli in preschoolers with autism spectrum disorder (ASD) has increased over the past decade; however, findings have been inconsistent. It has been suggested that stimuli relating to common circumscribed interests (CIs) elicit more attention than non-CI related stimuli. This meta-analysis synthesizes results from 31 studies that compared attention towards non-social stimuli in children with ASD under the age of five with typically developing (TD) controls using eye-tracking. Additional subgroup analysis comparing studies that employed non-social stimuli related to CIs frequently reported in adults with ASD to studies using non-CI related stimuli were conducted. Meta-regressions with age, sex, stimulus dimension, nonverbal DQ, and symptom severity were conducted. Results show small (g = 0.39) but significantly higher attention towards non-social stimuli for the ASD group. However, when studies were split based on stimulus type no significant differences for non-CI related stimuli was found. Meanwhile studies employing CI related stimuli reported significant large effects on attention allocation (g = 0.69). None of the conducted regressions reached significance. The findings show increased non-social attention in children with ASD is driven by CI related content rather than a general non-social attentional bias. The findings and future research directions are discussed., (© 2024 The Author(s). Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Lay Abstract: In some cases, a clinician's perceptions of a child's autism-related behaviors are not the same as the child's caregiver's perceptions. Identifying how these discrepancies relate to the characteristics of the child is critical for ensuring that diagnosis procedures are unbiased and suitable for all children. This study examined whether discrepancies between clinician and caregiver reports of autism features related to the child's sex at birth. We also explored how the discrepancies related to the age at which the child received their autism diagnosis and how much intervention they received. We found that clinicians rated autism features higher than caregivers for boys and rated autism features lower than caregivers for girls. In addition, lower clinician relative to parent ratings was related to being diagnosed at an older age and receiving less intervention. These findings suggest that there is more to learn about the presentation of autism-related behaviors in girls. When caregiver and clinician ratings of autism features do not align, it may be important to consider caregivers' ratings to obtain a more accurate picture of the child's autism features and the support they may need., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: G.D. is on the Scientific Advisory Boards of Akili, Inc., Nonverbal Learning Disability Project, and Tris Pharma, Inc., provided consultation to Apple, Inc., Gerson Lehrman Group, and Guidepoint Global, LLC, received speaker fees from WebMD and book royalties from Guilford Press, Oxford University Press, Springer Nature Press. G.D. reports grant funding from NICHD, NIMH, and the Simons Foundation; G.D. has developed technology, data, and/or products that have been licensed to Apple, Inc. and Cryocell, Inc. and G.D. and Duke University have benefited financially. R.A.B. is currently employed by Apple. F.S. consults for Roche Pharmaceutical Company and Janssen Research and Development. J.C.M. 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.

Objective: Electroencephalography (EEG) measures of visual evoked potentials (VEPs) provide a targeted approach for investigating neural circuit dynamics. This study separately analyses phase-locked (evoked) and non-phase-locked (induced) gamma responses within the VEP to comprehensively investigate circuit differences in autism., Methods: We analyzed VEP data from 237 autistic and 114 typically developing (TD) children aged 6-11, collected through the Autism Biomarkers Consortium for Clinical Trials (ABC-CT). Evoked and induced gamma (30-90 Hz) responses were separately quantified using a wavelet-based time-frequency analysis, and group differences were evaluated using a permutation-based clustering procedure., Results: Autistic children exhibited reduced evoked gamma power but increased induced gamma power compared to TD peers. Group differences in induced responses showed the most prominent effect size and remained statistically significant after excluding outliers., Conclusions: Our study corroborates recent research indicating diminished evoked gamma responses in children with autism. Additionally, we observed a pronounced increase in induced power. Building upon existing ABC-CT findings, these results highlight the potential to detect variations in gamma-related neural activity, despite the absence of significant group differences in time-domain VEP components., Significance: The contrasting patterns of decreased evoked and increased induced gamma activity in autistic children suggest that a combination of different EEG metrics may provide a clearer characterization of autism-related circuitry than individual markers alone., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: Autism spectrum disorder (ASD) is estimated to be ∼10 times higher in children with versus without an autistic sibling in population-based studies. Prospective studies of infant siblings have revealed even higher familial recurrence rates. In the current prospective longitudinal study, we provide updated estimates of familial ASD recurrence using a multinational database of infants with older autistic siblings., Methods: Data were collated across 18 sites of the Baby Siblings Research Consortium, an international network studying the earliest manifestations of ASD. A total of 1605 infants with an older autistic sibling were followed from early in life to 3 years, when they were classified as ASD or non-ASD. Hierarchical generalized linear modeling, with site as a random effect, was used to examine predictors of recurrence in families and calculate likelihood ratios., Results: A total of 20.2% of siblings developed ASD, which is not significantly higher than the previously reported rate of 18.7%. Male infant sex and >1 older affected sibling were significant predictors of familial recurrence. Proband sex also influenced recurrence rates, with siblings of female probands significantly more likely to develop ASD than siblings of male probands. Race and maternal education were also associated with recurrence in families., Conclusions: The familial recurrence rate of ASD, as measured in infant sibling studies, has not changed appreciably since previous estimates were made in 2011. Younger siblings of autistic children, particularly those who are male, have an affected female sibling, multiple affected siblings, or are impacted by social inequities, should be closely monitored and promptly referred for diagnostic evaluation., (Copyright © 2024 by the American Academy of Pediatrics.)

Younger siblings (SIBS) of children with autism exhibit a wide range of clinical and subclinical symptoms including social, cognitive, language, and adaptive functioning delays. Identifying factors linked with this phenotypic heterogeneity is essential for improving understanding of the underlying biology of the heterogenous outcomes and for early identification of the most vulnerable SIBS. Prevalence of neurodevelopmental (NDD) and neuropsychiatric disorders (NPD) is significantly elevated in families of children with autism. It remains unknown, however, if the family history associates with the developmental outcomes among the SIBS. We quantified history of the NDDs and NPDs commonly reported in families of children with autism using a parent interview and assessed autism symptoms, verbal, nonverbal, and adaptive skills in a sample of 229 SIBS. Multiple regression analyses were used to examine links between family history and phenotypic outcomes, whereas controlling for birth year, age, sex, demographics, and parental education. Results suggest that family history of schizophrenia, depression, anxiety, bipolar disorder, and intellectual disability associate robustly with dimensional measures of social affect, verbal and nonverbal IQ, and adaptive functioning in the SIBS. Considering family history of these disorders may improve efforts to predict long-term outcomes in younger siblings of children with autism and inform about familial factors contributing to high phenotypic heterogenetity in this cohort., (© 2024 The Author(s). Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Studies utilizing eye-tracking methods have potential to promptly capture real-world dynamics of one of the core areas of vulnerability in autism spectrum disorders (ASD), selective social attention. So far, no studies have successfully reported utilizing the method to examine social attention in toddlers with neurodevelopmental vulnerabilities in real world and challenging settings such as an interactive face-to-face. This study examined the feasibility and validity of live eye-tracking method in response to live interaction occurring in several contexts in toddlers with and without ASD. Forty-seven toddlers with ASD, with atypical development (ATYP), or typically developing (TD), underwent a 30-s live eye-tracking procedure during a face-to-face interaction with a masked stranger using child-directed-speech (16 ASD, 14 ATYP, 17 TD; M age  = 23.44 months, SD = 6.02). Out of this group of toddlers, 29 (10 ASD, 8 ATYP, 11 TD, M age  = 21.97 months, SD = 5.76) underwent the same procedure with one of their maskless parent. Task completion rate, calibration accuracy, and affective response (feasibility measures) as well as attention to the task and the social partner (validity measures) were examined. Task completion rate and calibration accuracy were excellent. Despite the challenging context of face-to-face interaction, the toddlers exhibited a neutral affect, and high attention to the task and the speaker. As anticipated, toddlers with ASD looked less at the social partner compared with control groups. However, attention was comparable between the Stranger and Parent conditions, indicating that the effect was consistent regardless of presence of face covering or the familiarity of the interactive partner. The study demonstrates the high feasibility and validity of a live eye-tracking task involving face-to-face interaction in neurodiverse toddlers with social vulnerabilities. The effect of diminished attention to social partners in toddlers with autism is robust and present when interacting with an unfamiliar person and parent. The results suggest that a brief live eye-tracking method constitutes a promising ecologically valid candidate biomarker and potential intervention outcome in autism., (© 2023 International Society for Autism Research and Wiley Periodicals LLC.)

Children with autism spectrum disorder (ASD) often exhibit externalizing problems, which have been linked with increased anxiety and depression, peer rejection, and parental stress. Identification of early predictors of externalizing behaviors in autism will facilitate identification of vulnerable children and implementation of early preventative interventions. There is ample evidence that executive functioning, social functioning, and temperament are predictive of later externalizing problems in general populations, but less is known about these relations in ASD and other neurodiverse populations, particularly in the early preschool years. To address this gap, we assessed the relations between executive functioning, social functioning, and temperament at age 3 and externalizing problems at age 5 in a sample of neurodiverse children with ASD and other neurodevelopmental disorders and delays. Analyses revealed that severity of early executive functioning impairment predicted increased externalizing problems. Severity of social autism symptoms moderated this relationship such that the effect of executive functioning on externalizing problems decreased as autism symptoms increased. These findings suggest that executive functioning is an important target for identifying and developing interventions for vulnerable children and underscore the necessity of considering severity of autism symptoms when researching the development of externalizing problems in children with neurodevelopmental disorders., (© 2024 International Society for Autism Research and Wiley Periodicals LLC.)

The Selective Social Attention (SSA) task is a brief eye-tracking task involving experimental conditions varying along socio-communicative axes. Traditionally the SSA has been used to probe socially-specific attentional patterns in infants and toddlers who develop autism spectrum disorder (ASD). This current work extends these findings to preschool and school-age children. Children 4- to 12-years-old with ASD (N = 23) and a typically-developing comparison group (TD; N = 25) completed the SSA task as well as standardized clinical assessments. Linear mixed models examined group and condition effects on two outcome variables: percent of time spent looking at the scene relative to scene presentation time (%Valid), and percent of time looking at the face relative to time spent looking at the scene (%Face). Age and IQ were included as covariates. Outcome variables' relationships to clinical data were assessed via correlation analysis. The ASD group, compared to the TD group, looked less at the scene and focused less on the actress' face during the most socially-engaging experimental conditions. Additionally, within the ASD group, %Face negatively correlated with SRS total T-scores with a particularly strong negative correlation with the Autistic Mannerism subscale T-score. These results highlight the extensibility of the SSA to older children with ASD, including replication of between-group differences previously seen in infants and toddlers, as well as its ability to capture meaningful clinical variation within the autism spectrum across a wide developmental span inclusive of preschool and school-aged children. The properties suggest that the SSA may have broad potential as a biomarker for ASD., (© 2023 International Society for Autism Research and Wiley Periodicals LLC.)

Idiopathic autism spectrum disorder (ASD) is highly heterogeneous, and it remains unclear how convergent biological processes in affected individuals may give rise to symptoms. Here, using cortical organoids and single-cell transcriptomics, we modeled alterations in the forebrain development between boys with idiopathic ASD and their unaffected fathers in 13 families. Transcriptomic changes suggest that ASD pathogenesis in macrocephalic and normocephalic probands involves an opposite disruption of the balance between excitatory neurons of the dorsal cortical plate and other lineages such as early-generated neurons from the putative preplate. The imbalance stemmed from divergent expression of transcription factors driving cell fate during early cortical development. While we did not find genomic variants in probands that explained the observed transcriptomic alterations, a significant overlap between altered transcripts and reported ASD risk genes affected by rare variants suggests a degree of gene convergence between rare forms of ASD and the developmental transcriptome in idiopathic ASD., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Difficulty with attention is an important symptom in many conditions in psychiatry, including neurodiverse conditions such as autism. There is a need to better understand the neurobiological correlates of attention and leverage these findings in healthcare settings. Nevertheless, it remains unclear if it is possible to build dimensional predictive models of attentional state in a sample that includes participants with neurodiverse conditions. Here, we use 5 datasets to identify and validate functional connectome-based markers of attention. In dataset 1, we use connectome-based predictive modeling and observe successful prediction of performance on an in-scan sustained attention task in a sample of youth, including participants with a neurodiverse condition. The predictions are not driven by confounds, such as head motion. In dataset 2, we find that the attention network model defined in dataset 1 generalizes to predict in-scan attention in a separate sample of neurotypical participants performing the same attention task. In datasets 3-5, we use connectome-based identification and longitudinal scans to probe the stability of the attention network across months to years in individual participants. Our results help elucidate the brain correlates of attentional state in youth and support the further development of predictive dimensional models of other clinically relevant phenotypes., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Lay Abstract: Children with autism spectrum disorder are prescribed a variety of medications that affect the central nervous system (psychotropic medications) to address behavior and mood. In clinical trials, individuals taking concomitant psychotropic medications often are excluded to maintain homogeneity of the sample and prevent contamination of biomarkers or clinical endpoints. However, this choice may significantly diminish the clinical representativeness of the sample. In a recent multisite study designed to identify biomarkers and behavioral endpoints for clinical trials (the Autism Biomarkers Consortium for Clinical Trials), school-age children with autism spectrum disorder were enrolled without excluding for medications, thus providing a unique opportunity to examine characteristics of psychotropic medication use in a research cohort and to guide future decisions on medication-related inclusion criteria. The aims of the current analysis were (1) to quantify the frequency and type of psychotropic medications reported in school-age children enrolled in the ABC-CT and (2) to examine behavioral features of children with autism spectrum disorder based on medication classes. Of the 280 children with autism spectrum disorder in the cohort, 42.5% were taking psychotropic medications, with polypharmacy in half of these children. The most commonly reported psychotropic medications included melatonin, stimulants, selective serotonin reuptake inhibitors, alpha agonists, and antipsychotics. Descriptive analysis showed that children taking antipsychotics displayed a trend toward greater overall impairment. Our findings suggest that exclusion of children taking concomitant psychotropic medications in trials could limit the clinical representativeness of the study population, perhaps even excluding children who may most benefit from new treatment options.

Clinical trials in autism spectrum disorder (ASD) often rely on clinician rating scales and parent surveys to measure autism-related features and social behaviors. To aid in the selection of these assessments for future clinical trials, the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) directly compared eight common instruments with respect to acquisition rates, sensitivity to group differences, equivalence across demographic sub-groups, convergent validity, and stability over a 6-week period. The sample included 280 children diagnosed with ASD (65 girls) and 119 neurotypical children (36 girls) aged from 6 to 11 years. Full scale IQ for ASD ranged from 60 to 150 and for neurotypical ranged from 86 to 150. Instruments measured clinician global assessment and autism-related behaviors, social communication abilities, adaptive function, and social withdrawal behavior. For each instrument, we examined only the scales that measured social or communication functioning. Data acquisition rates were at least 97.5% at T1 and 95.7% at T2. All scales distinguished diagnostic groups. Some scales significantly differed by participant and/or family demographic characteristics. Within the ASD group, most clinical instruments exhibited weak (≥ |0.1|) to moderate (≥ |0.4|) intercorrelations. Short-term stability was moderate (ICC: 0.5-0.75) to excellent (ICC: >0.9) within the ASD group. Variations in the degree of stability may inform viability for different contexts of use, such as identifying clinical subgroups for trials versus serving as a modifiable clinical outcome. All instruments were evaluated in terms of their advantages and potential concerns for use in clinical trials., (© 2023 International Society for Autism Research and Wiley Periodicals LLC.)

Objective: Numerous candidate EEG biomarkers have been put forward for use in clinical research on autism spectrum disorder (ASD), but biomarker development has been hindered by limited attention to the psychometric properties of derived variables, inconsistent results across small studies, and variable methodology. The authors evaluated the basic psychometric properties of a battery of EEG assays for their potential suitability as biomarkers in clinical trials., Methods: This was a large, multisite, naturalistic study in 6- to 11-year-old children who either had an ASD diagnosis (N=280) or were typically developing (N=119). The authors evaluated an EEG battery composed of well-studied assays of resting-state activity, face perception (faces task), biological motion perception, and visual evoked potentials (VEPs). Biomarker psychometrics were evaluated in terms of acquisition rates, construct performance, and 6-week stability. Preliminary evaluation of use was explored through group discrimination and phenotypic correlations., Results: Three assays (resting state, faces task, and VEP) show promise in terms of acquisition rates and construct performance. Six-week stability values in the ASD group were moderate (intraclass correlations ≥0.66) for the faces task latency of the P1 and N170, the VEP amplitude of N1 and P1, and resting alpha power. Group discrimination and phenotype correlations were primarily observed for the faces task P1 and N170., Conclusions: In the context of a large-scale, rigorous evaluation of candidate EEG biomarkers for use in ASD clinical trials, neural response to faces emerged as a promising biomarker for continued evaluation. Resting-state activity and VEP yielded mixed results. The study's biological motion perception assay failed to display construct performance. The results provide information about EEG biomarker performance that is relevant for the next stage of biomarker development efforts focused on context of use.

Background: Due to familial liability, siblings of children with ASD exhibit elevated risk for language delays. The processes contributing to language delays in this population remain unclear., Methods: Considering well-established links between attention to dynamic audiovisual cues inherent in a speaker's face and speech processing, we investigated if attention to a speaker's face and mouth differs in 12-month-old infants at high familial risk for ASD but without ASD diagnosis (hr-sib; n = 91) and in infants at low familial risk (lr-sib; n = 62) for ASD and whether attention at 12 months predicts language outcomes at 18 months., Results: At 12 months, hr-sib and lr-sib infants did not differ in attention to face (p = .14), mouth preference (p = .30), or in receptive and expressive language scores (p = .36, p = .33). At 18 months, the hr-sib infants had lower receptive (p = .01) but not expressive (p = .84) language scores than the lr-sib infants. In the lr-sib infants, greater attention to the face (p = .022) and a mouth preference (p = .025) contributed to better language outcomes at 18 months. In the hr-sib infants, neither attention to the face nor a mouth preference was associated with language outcomes at 18 months., Conclusions: Unlike low-risk infants, high-risk infants do not appear to benefit from audiovisual prosodic and speech cues in the service of language acquisition despite intact attention to these cues. We propose that impaired processing of audiovisual cues may constitute the link between genetic risk factors and poor language outcomes observed across the autism risk spectrum and may represent a promising endophenotype in autism., (© 2022 Association for Child and Adolescent Mental Health.)

Autism is a heterogeneous neurodevelopmental condition, and functional magnetic resonance imaging-based studies have helped advance our understanding of its effects on brain network activity. We review how predictive modeling, using measures of functional connectivity and symptoms, has helped reveal key insights into this condition. We discuss how different prediction frameworks can further our understanding of the brain-based features that underlie complex autism symptomatology and consider how predictive models may be used in clinical settings. Throughout, we highlight aspects of study interpretation, such as data decay and sampling biases, that require consideration within the context of this condition. We close by suggesting exciting future directions for predictive modeling in autism., (Copyright © 2022. Published by Elsevier Inc.)

Altered resting state functional connectivity (FC) involving the anterior insula (aINS), a key node in the salience network, has been reported consistently in autism. Here we examined, for the first time, FC between the aINS and the whole brain in a sample of full-term, postmenstrual age (PMA) matched neonates (mean 44.0 weeks, SD = 1.5) who due to family history have high likelihood (HL) for developing autism (n = 12) and in controls (n = 41) without family history of autism (low likelihood, LL). Behaviors associated with autism were evaluated between 12 and 18 months (M = 17.3 months, SD = 2.5) in a subsample (25/53) of participants using the First Year Inventory (FYI). Compared to LL controls, HL neonates showed hypoconnectivity between left aINS and left amygdala. Lower connectivity between the two nodes was associated with higher FYI risk scores in the social domain (r(25) = -0.561, p = .003) and this association remained robust when maternal mental health factors were considered. Considering that a subsample of LL participants (n = 14/41) underwent brain imaging during the fetal period at PMA 31 and 34 weeks, in an exploratory analysis, we evaluated prospectively development of the LaINS-Lamy connectivity and found that the two areas strongly coactivate throughout the third trimester of pregnancy. The study identifies left lateralized anterior insula-amygdala connectivity as a potential target of further investigation into neural circuitry that enhances likelihood of future onset of social behaviors associated with autism during neonatal and potentially prenatal periods., (© 2022. The Author(s).)

Although the neural scaffolding for language is putatively present before birth, the maturation of functional connections among the key nodes of the language network, Broca's and Wernicke's areas, is less known. We leveraged longitudinal and cross-sectional data from three sites collected through six studies to track the development of functional circuits between Broca's and Wernicke's areas from 30 weeks of gestation through 30 months of age in 127 unique participants. Using resting-state fMRI data, functional connectivity was calculated as the correlation between fMRI time courses from pairs of regions, defined as Broca's and Wernicke's in both hemispheres. The primary analysis evaluated 23 individuals longitudinally imaged from 30 weeks postmenstrual age (fetal) through the first postnatal month (neonatal). A secondary analysis in 127 individuals extended these curves into older infants and toddlers. These data demonstrated significant growth of interhemispheric connections including left Broca's and its homolog and left Wernicke's and its homolog from 30 weeks of gestation through the first postnatal month. In contrast, intrahemispheric connections did not show significant increases across this period. These data represent an important baseline for language systems in the developing brain against which to compare those neurobehavioral disorders with the potential fetal onset of disease., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Executive functioning (EF) deficits co-occur frequently with autism spectrum disorder (ASD) and have a long-term detrimental impact on quality of life of children and their families. Timely identification of risk for EF vulnerabilities may hasten access to early intervention and alleviate their long-term consequences. This study examines (1) if EF deficits are elevated in toddlers with ASD compared to nonautistic siblings of children with ASD, typically developing (TYP) toddlers, and toddlers with atypical developmental presentation; and (2) if EF deficits have a detrimental effect on adaptive functioning in ASD. Participants were recruited between September 2014 and October 2019 and included 73 toddlers with ASD, 33 nonautistic siblings of children with ASD, 35 toddlers with atypical development, and 28 TYP toddlers matched on chronological age (M = 39.01 months, SD = 3.11). EF deficits were measured using the BRIEF-P; adaptive skills were measured using the VABS-II. Whenever appropriate, analyses were controlled for MSEL verbal and nonverbal developmental quotient, ADOS-2 autism severity scores, and sex. Analyses revealed that toddlers with ASD exhibited elevated BRIEF-P scores across all domains compared to each of the three comparison groups. Higher BRIEF-P scores were associated with lower adaptive social, communication, and daily living skills while controlling for symptom severity, verbal and nonverbal functioning, and sex. In conclusion, marked vulnerabilities in EF are already present in 3-year-old toddlers with ASD and are predictive of the level of adaptive functioning in ASD. EF vulnerabilities in toddlers should be targeted for intervention to improve long-term outcomes in ASD. LAY SUMMARY: Many children with autism experience vulnerabilities in executive functioning (EF), which may include challenges with inhibition, working memory, cognitive flexibility, and planning. The study shows that these vulnerabilities can already be detected at age three and that their presence is linked with lower social, communication, and daily living skills. Screening children with ASD for EF challenges and helping those who have difficulties may improve their long-term outcomes., (© 2022 International Society for Autism Research and Wiley Periodicals LLC.)

While previous work has identified the early predictors of language skills in infants at elevated familial risk (ER) and low familial risk (LR) for autism spectrum disorder (ASD), no studies to date have explored whether these predictors vary based on diagnostic outcome of ASD or no ASD. The present study used a large, multisite dataset to examine associations between a set of commonly studied predictor variables (infant gesture abilities, fine motor skills, nonverbal cognition, and maternal education level), measured at 12 months, and language skills, measured at 3 years, across three diagnostic outcome groups-infants with ASD ("ASD"), ER infants without ASD ("ER-no ASD"), and LR infants without ASD ("LR-no ASD"). Findings revealed that the predictors of language skills differed across groups, as gesture abilities were positively associated with language skills in the ER-no ASD group but negatively associated with language skills in the ASD group. Furthermore, maternal education level was positively associated with language skills in the ASD and LR-no ASD groups only. Variability in these early predictors may help explain why language skills are heterogeneous across the autism spectrum, and, with further study, may help clinicians identify those in need of additional and/or specialized intervention services that support language development. LAY SUMMARY: The present study identified predictors of language skills in infants with and without autism spectrum disorder (ASD). Maternal education level and 12-month gesture abilities predicted 3-year language skills in infants with ASD. Measuring these predictors early in life may help identify infants and families in need of additional and/or specialized intervention services that support language development., (© 2022 International Society for Autism Research and Wiley Periodicals LLC.)

When designing and interpreting results from clinical trials evaluating treatments for children on the autism spectrum, a complicating factor is that most children receive a range of concurrent treatments. Thus, it is important to better understand the types and hours of interventions that participants typically receive as part of standard of care, as well as to understand the child, family, and geographic factors that are associated with different patterns of service utilization. In this multi-site study, we interviewed 280 caregivers of 6-to-11-year-old school-aged children on the autism spectrum about the types and amounts of interventions their children received in the prior 6 weeks. Reported interventions were coded as " evidence-based practice" or " other interventions," reflecting the level of empirical support. Results indicated that children received a variety of interventions with varying levels of empirical evidence and a wide range of hours (0 to 79.3 hours/week). Children with higher autism symptom levels, living in particular states, and who identified as non-Hispanic received more evidence-based intervention hours. Higher parental education level related to more hours of other interventions. Children who were younger, had lower cognitive ability, and with higher autism symptom levels received a greater variety of interventions overall. Thus, based on our findings, it would seem prudent when designing clinical trials to take into consideration a variety of factors including autism symptom levels, age, cognitive ability, ethnicity, parent education and geographic location. Future research should continue to investigate the ethnic, racial, and socioeconomic influences on school-aged intervention services., Competing Interests: Conflict of Interest The authors [AS, JK, SF, MSD, JIN, CN, SW, RB, SJ, KC, CS, AN, JD] declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Dr. Dawson is on the Scientific Advisory Boards of Janssen Research and Development, Akili Interactive, Inc, LabCorp, Inc, Roche Pharmaceutical Company, and Tris Pharma, and is a consultant to Apple, Gerson Lehrman Group, Guidepoint Global, Inc, and is CEO of DASIO, LLC. Dr. Dawson has stock interests in Neuvana, Inc. Dr. Dawson has the following patent No. 10,912,801 and patent applications: 62,757,234, 25,628,402, and 62,757,226. Dr. Dawson has developed technology, data, and/or products that have been licensed to Apple, Inc. and Cryocell, Inc. and Dawson and Duke University have benefited financially. 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, and Springer. Frederick Shic consults for Janssen Research and Development, Roche Pharmaceuticals, and BlackThorn Therapeutics.

Recent proposals have suggested the potential for neural biomarkers to improve clinical trial processes in neurodevelopmental conditions; however, few efforts have identified whether chronological age-based adjustments will be necessary (as used in standardized behavioral assessments). Event-related potentials (ERPs) demonstrate early differences in the processing of faces vs. objects in the visual processing system by 4 years of age and age-based improvement (decreases in latency) through adolescence. Additionally, face processing has been proposed to be related to social skills as well as autistic social-communication traits. While previous reports suggest delayed latency in individuals with autism spectrum disorder (ASD), extensive individual and age based heterogeneity exists. In this report, we utilize a sample of 252 children with ASD and 118 children with typical development (TD), to assess the N170 and P100 ERP component latencies (N170L and P100L, respectively), to upright faces, the face specificity effect (difference between face and object processing), and the inversion effect (difference between face upright and inverted processing) in relation to age. First, linear mixed models (LMMs) were fitted with fixed effect of age at testing and random effect of participant, using all available data points to characterize general age-based development in the TD and ASD groups. Second, LMM models using only the TD group were used to calculate age-based residuals in both groups. The purpose of residualization was to assess how much variation in ASD participants could be accounted for by chronological age-related changes. Our data demonstrate that the N170L and P100L responses to upright faces appeared to follow a roughly linear relationship with age. In the ASD group, the distribution of the age-adjusted residual values suggest that ASD participants were more likely to demonstrate slower latencies than would be expected for a TD child of the same age, similar to what has been identified using unadjusted values. Lastly, using age-adjusted values for stratification, we found that children who demonstrated slowed age-adjusted N170L had lower verbal and non-verbal IQ and worse face memory. These data suggest that age must be considered in assessing the N170L and P100L response to upright faces as well, and these adjusted values may be used to stratify children within the autism spectrum., Competing Interests: GD is on the Scientific Advisory Boards of Janssen Research and Development, Akili Interactive, Inc, LabCorp, Inc, Roche Pharmaceutical Company, and Tris Pharma, and is a consultant to Apple, Gerson Lehrman Group, and Guidepoint Global, Inc. JMconsults 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, and Springer. FS consults for Roche Pharmaceutical Company, Janssen Research and Development, and BioStream LLC. SW consults for Janssen Research and Development. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Webb, Emerman, Sugar, Senturk, Naples, Faja, Benton, Borland, Carlos, Levin, McAllister, Santhosh, Bernier, Chawarska, Dawson, Dziura, Jeste, Kleinhans, Murias, Sabatos-DeVito, Shic, McPartland and the Autism Biomarkers Consortium for Clinical Trials.)

Autism spectrum disorder (ASD) is characterized by atypical connectivity lateralization of functional networks. However, previous studies have not directly investigated if differences in specialization between ASD and typically developing (TD) peers are present in infancy, leaving the timing of onset of these differences relatively unknown. We studied the hemispheric asymmetries of connectivity in children with ASD and infants later meeting the diagnostic criteria for ASD. Analyses were performed in 733 children with ASD and TD peers and in 71 infants at high risk (HR) or normal risk (NR) for ASD, with data collected at 1 month and 9 months of age. Comparing children with ASD (n = 301) to TDs (n = 432), four regions demonstrated group differences in connectivity: posterior cingulate cortex (PCC), posterior superior temporal gyrus, extrastriate cortex, and anterior prefrontal cortex. At 1 month, none of these regions exhibited group differences between ASD (n = 10), HR-nonASD (n = 15), or NR (n = 18) infants. However, by 9 months, the PCC and extrastriate exhibited atypical connectivity in ASD (n = 11) and HR-nonASD infants (n = 24) compared to NR infants (n = 22). Connectivity did not correlate with symptoms in either sample. Our results demonstrate that differences in network asymmetries associated with ASD risk are observable prior to the age of a reliable clinical diagnosis., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

The present study objectives were to examine the performance of the new M-CHAT-R algorithm to the original M-CHAT algorithm. The main purpose was to examine if the algorithmic changes increase identification of children later diagnosed with ASD, and to examine if there is a trade-off when changing algorithms. We included 54,463 screened cases from the Norwegian Mother and Child Cohort Study. Children were screened using the 23 items of the M-CHAT at 18 months. Further, the performance of the M-CHAT-R algorithm was compared to the M-CHAT algorithm on the 23-items. In total, 337 individuals were later diagnosed with ASD. Using M-CHAT-R algorithm decreased the number of correctly identified ASD children by 12 compared to M-CHAT, with no children with ASD screening negative on the M-CHAT criteria subsequently screening positive utilizing the M-CHAT-R algorithm. A nonparametric McNemar's test determined a statistically significant difference in identifying ASD utilizing the M-CHAT-R algorithm. The present study examined the application of 20-item MCHAT-R scoring criterion to the 23-item MCHAT. We found that this resulted in decreased sensitivity and increased specificity for identifying children with ASD, which is a trade-off that needs further investigation in terms of cost-effectiveness. However, further research is needed to optimize screening for ASD in the early developmental period to increase identification of false negatives., (© 2021 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Diminished visual attention to faces of social partners represents one of the early characteristics of autism spectrum disorder (ASD). Here we examine if the introduction of puppets as social partners alters attention to speakers' faces in young children with ASD and typically developing (TD) controls. Children with ASD (N = 37; M age  = 49.44 months) and TD (N = 27; M age  = 40.66 months) viewed a video depicting a puppet and a human engaged in a conversation. Dwell time on these faces was analyzed as a function of group and speaker's identity. Unlike TD controls, the ASD group exhibited limited visual attention to and chance-level visual preference for the human speaker. However, attention to and preference for the puppet speaker's face was greater than chance and comparable across the two groups. While there was a strong association between low human speaker preference and high autism severity, no association with autism severity was found for puppet speaker preference. Unlike humans, expressive and verbal puppets attracted the attention of children with ASD at levels comparable to that of TD controls. Considering that puppets can engage in reciprocal interactions and deliver simplified, salient social-communicative cues, they may facilitate therapeutic efforts in children with ASD. LAY SUMMARY: While studies have shown support for therapeutic uses of robots with children with autism, other similar agents such as puppets remain to be explored. When shown a video of a conversation between a puppet and a person, young children with ASD paid as much attention to the puppet's face as typically-developing (TD) children. Since puppets can engage in back-and-forth interactions and model social interactions and communication, they may play a promising role in therapeutic efforts for young children with ASD., (© 2021 International Society for Autism Research and Wiley Periodicals LLC.)

Background: Fetal exposure risk factors are associated with increased autism spectrum disorder (ASD) risk. New hypotheses regarding multigenerational risk for ASD have been proposed, but epidemiological evidence is largely lacking. We evaluated whether parental birth characteristics, including preterm birth and low birthweight, were associated with ASD risk in offspring., Methods: We conducted a nationwide register-based cohort study that included 230 174 mother-child and 157 926 father-child pairs in Denmark. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for offspring ASD according to parental preterm (<37 weeks) and low birthweight (<2500 g) status, with or without adjustment for certain grandmaternal sociodemographic factors. Mediation analyses were performed for selected parental and offspring health-related factors., Results: Offspring of mothers or fathers with adverse birth characteristics had about 31-43% higher risk for ASD (maternal preterm birth, OR = 1.31, 95% CI= 1.12, 1.55; maternal low birthweight, OR = 1.35, 95% CI: 1.17,1.57; paternal preterm birth, OR = 1.43, 95% CI = 1.18, 1.73; paternal low birthweight, OR = 1.38, 95% CI= 1.13, 1.70). Parents born very preterm (<32 weeks) marked a nearly 2-fold increase in ASD risk in their children. These associations were slightly attenuated upon adjustment for grandmaternal sociodemographic factors. Mediation analyses suggested that parental social-mental and offspring perinatal factors might explain a small magnitude of the total effect observed, especially for maternal birth characteristic associations., Conclusions: Offspring of parents born with adverse characteristics had an elevated risk for ASD. Transmission of ASD risk through maternal and paternal factors should be considered in future research on ASD aetiology., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Differential emotional reactivity to social and nonsocial stimuli has been hypothesized but rarely examined empirically in ASD despite its potential importance for development of social motivation, cognition, and comorbid psychopathology. This study examined emotional reactivity, regulation, and attention to social and nonsocial threat in toddlers with ASD (n = 42, M age : 22 months) and typically developing (TD) toddlers (n = 22, M age : 23 months), and their mutual associations with autism symptom severity. Participants were exposed to social (stranger), nonsocial (mechanical objects), and ambiguous (masks) threats, and their intensity of distress (iDistress), attention to threat (Attention), and presence of emotion regulation (ER) strategies were measured. Autism symptom severity was quantified using the Autism Diagnostic Observation Schedule-2. In response to social threat, toddlers with ASD exhibited elevated iDistress (P < 0.038) but lower Attention (P < 0.002) and a wider variety of ER strategies (P < 0.040) compared to TD controls, though their ER strategies were less likely to be social. However, nonsocial and ambiguous threat elicited lower iDistress in ASD than in TD toddlers (P = 0.012 and P = 0.034, respectively), but comparable Attention and ER strategy use. Autism severity was not associated with iDistress. The study demonstrates elevated emotional salience but diminished attentional salience of social threat in ASD. A failure to attend adequately to social threats may restrict opportunities to appraise their threat value and engender often observed in ASD negative emotional responses to novel social situations. Early atypical emotional reactivity may independently contribute to the shaping of complex autism phenotypes and may be linked with later emerging affective and behavioral symptoms. LAY SUMMARY: Compared to typically developing toddlers, toddlers with ASD show diminished attention yet enhanced distress in response to social threat. Poor attention to potential social threat may limit opportunities to assess its threat value and thus contribute to often observed negative emotional responses to novel social situations. Identifying the precursors of atypical emotional reactivity in infancy and its links with later psychopathology will inform about novel treatment targets and mechanisms of change in the early stages of ASD. Autism Res 2021, 14: 1025-1036. © 2020 International Society for Autism Research, Wiley Periodicals, LLC., (© 2020 International Society for Autism Research, Wiley Periodicals, LLC.)

Early identification of autism spectrum disorder (ASD) is regarded as crucial for swift access to early intervention and, subsequently, better outcomes later in life. However, current instruments miss large proportions of children who later go on to be diagnosed with ASD, raising a question of what these instruments measure. The present study utilized data from the Norwegian Mother, Father, and Child Cohort Study and the Autism Birth Cohort study to explore the subsequent developmental and diagnostic characteristics of children raising developmental concern on the six-critical discriminative item criterion of the M-CHAT (DFA6) at 18 months of age (N = 834). The DFA6 identified 28.8% of children diagnosed with ASD (N = 163), but 4.4% with language disorder (N = 188) and 81.3% with intellectual disability (N = 32) without ASD. Scoring in the «at-risk» range was associated with lower IQ, impaired functional language, and greater severity of autism symptoms whether children had ASD or not.

A growing body of evidence supports a potential link between autism spectrum disorder (ASD) and gender dysphoria, yet few studies have looked at sex differences in the co-occurrence of gender diversity and ASD. The aim of this study was to characterize sex differences in gender-diverse expressions and identities, as well as gender-related concerns, in youth with ASD. Parents of youth with ASD ages 6-21 (n = 163) completed an online questionnaire about their child's gender expression and identity. Sex-typed behaviors during childhood were measured using the Gender Identity Questionnaire (GIQ). Semi-partial Kendall correlations and chi-square tests were used to compare gender non-conformity, gender-diverse identities, and gender-related concerns between sexes. Sex-based differences in mean GIQ score and individual GIQ items were evaluated using a linear regression and semi-partial Kendall correlations, respectively. All regressions and correlations controlled for child age. Parents of girls were more likely to report child appearances and mannerisms that were less concordant with their child's birth sex. Based on parent-report, girls had lower mean GIQ scores, indicating greater cross-gendered/fewer same-gendered behaviors in childhood. Lastly, parents of girls with ASD were more likely to report that their daughters experienced anxiety due to gender-related concerns and discomfort during puberty than parents of boys. These findings suggest that girls with ASD seem more likely have gender-diverse preferences, mannerisms, and appearances that fall outside of traditional gender norms. Gender-related concerns appear to be a source of real distress in girls with ASD, highlighting the need for individualized support, especially during puberty. LAY SUMMARY: Despite evidence of a potential link between autism and gender diversity, few studies have explored differences in gender identity/expression between boys and girls with autism. Based on parent responses, we found that girls with autism are more likely than boys to have appearances and mannerisms, as well as behaviors during childhood, that fall outside of the traditional gender role. The unique profile of girls with autism and their elevated distress over gender-related concerns call for individualized support during adolescence., (© 2020 International Society for Autism Research, Wiley Periodicals, LLC.)

Objective: Although some eye-tracking studies demonstrate atypical attention to faces by 6 months of age in autism spectrum disorder (ASD), behavioral studies in early infancy return largely negative results. We examined the effects of context and diagnosis on attention to faces during face-to-face live interactions in infants at high familial risk (HR) and low familial risk (LR) for ASD., Method: Participants were 6-, 9-, and 12-month-old siblings of children with ASD who were later determined to have ASD (n = 21), other developmental challenges (HR-C; n = 74), or typical development (TD) (HR-TD; n = 32), and low-risk, typically developing controls (LR-TD; n = 49). Infants were administered the social orienting probes task, consisting of five conditions: dyadic bid, song, peek-a-boo, tickle, and toy play. Attention to an unfamiliar examiner's face was coded by blinded raters from video recordings., Results: At all ages, the ASD group spent less time looking at the examiner's face than the HR-C, HR-TD, and LR-TD groups during the Dyadic Bid and Tickle conditions (all p <.05), but not during the Song, Peek-a-Boo, or Toy Play conditions (all p >.23). Lower attention to faces during Dyadic Bid and Tickle conditions was significantly correlated with higher severity of autism symptoms at 18 months., Conclusion: During the prodromal stages of the disorder, infants with ASD exhibited subtle impairments in attention to faces of interactive partners during interactions involving eye contact and child-directed speech (with and without physical contact), but not in contexts involving singing, familiar anticipatory games, or toy play. Considering the convergence with eye-tracking findings on limited attention to faces in infants later diagnosed with ASD, reduced attention to faces of interactive partners in specific contexts may constitute a promising candidate behavioral marker of ASD in infancy., (Copyright © 2020 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Performing functional magnetic resonance imaging (fMRI) scans of children can be a difficult task, as participants tend to move while being scanned. Head motion represents a significant confound in fMRI connectivity analyses. One approach to limit motion has been to use shorter MRI protocols, though this reduces the reliability of results. Hence, there is a need to implement methods to achieve high-quality, low-motion data while not sacrificing data quantity. Here we show that by using a mock scan protocol prior to a scan, in conjunction with other in-scan steps (weighted blanket and incentive system), it is possible to achieve low-motion fMRI data in pediatric participants (age range: 7-17 years old) undergoing a 60 min MRI session. We also observe that motion is low during the MRI protocol in a separate replication group of participants, including some with autism spectrum disorder. Collectively, the results indicate it is possible to conduct long scan protocols in difficult-to-scan populations and still achieve high-quality data, thus potentially allowing more reliable fMRI findings.

Past studies in autism spectrum disorder (ASD) indicate atypical peripheral physiological arousal. However, the conditions under which these atypicalities arise and their link with behavioral emotional expressions and core ASD symptoms remain uncertain. Given the importance of physiological arousal in affective, learning, and cognitive processes, the current study examined changes in skin conductance level (ΔSCL) in 41 toddlers with ASD (mean age: 22.7 months, SD: 2.9) and 32 age-matched toddlers with typical development (TD) (mean age: 21.6 months, SD: 3.6) in response to probes designed to induce anger, joy, and fear emotions. The magnitude of ΔSCL was comparable during anger (P = 0.206, d = 0.30) and joy (P = 0.996, d = 0.01) conditions, but significantly lower during the fear condition (P = 0.001, d = 0.83) in toddlers with ASD compared to TD peers. In the combined samples, ΔSCL positively correlated with intensity of behavioral emotional expressivity during the anger (r[71] = 0.36, P = 0.002) and fear (r[68] = 0.32, P = 0.007) conditions, but not in the joy (r[69] = -0.15, P = 0.226) condition. Finally, ΔSCL did not associate with autism symptom severity in any emotion-eliciting condition in the ASD group. Toddlers with ASD displayed attenuated ΔSCL to situations aimed at eliciting fear, which may forecast the emergence of highly prevalent internalizing and externalizing problems in this population. The study putatively identifies ΔSCL as a dimension not associated with severity of autism but with behavioral responses in negatively emotionally challenging events and provides support for the feasibility, validity, and incipient utility of examining ΔSCL in response to emotional challenges in very young children. LAY SUMMARY: Physiological arousal was measured in toddlers with autism exposed to frustrating, pleasant, and threatening tasks. Compared to typically developing peers, toddlers with autism showed comparable arousal responses to frustrating and pleasant events, but lower responses to threatening events. Importantly, physiological arousal and behavioral expressions were aligned during frustrating and threatening events, inviting exploration of physiological arousal to measure responses to emotional challenges. Furthermore, this study advances the understanding of precursors to emotional and behavioral problems common in older children with autism. Autism Res 2020, 13: 1476-1488. © 2020 International Society for Autism Research, Wiley Periodicals, Inc., (© 2020 International Society for Autism Research and Wiley Periodicals LLC.)

Importance: Enhanced selective attention toward nonsocial objects and impaired attention to social stimuli constitute key clinical features of autism spectrum disorder (ASD). Yet, the mechanisms associated with atypical selective attention in ASD are poorly understood, which limits the development of more effective interventions. In typically developing individuals, selective attention to social and nonsocial stimuli is associated with the informational value of the stimuli, which is typically learned over the course of repeated interactions with the stimuli., Objective: To examine value learning (VL) of social and nonsocial stimuli and its association with selective attention in preschoolers with and without ASD., Design, Setting, and Participants: This case-control study compared children with ASD vs children with developmental delay (DD) and children with typical development (TD) recruited between March 3, 2017, and June 13, 2018, at a university-based research laboratory. Participants were preschoolers with ASD, DD, or TD., Main Outcomes and Measures: Procedure consisted of an eye-tracking gaze-contingent VL task involving social (faces) and nonsocial (fractals) stimuli and consisting of baseline, training, and choice test phases. Outcome measures were preferential attention to stimuli reinforced (high value) vs not reinforced (low value) during training. The hypotheses were stated before data collection., Results: Included were 115 preschoolers with ASD (n = 48; mean [SD] age, 38.30 [15.55] months; 37 [77%] boys), DD (n = 31; mean [SD] age, 45.73 [19.49] months; 19 [61%] boys), or TD (n = 36; mean [SD] age, 36.53 [12.39] months; 22 [61%] boys). The groups did not differ in sex distribution; participants with ASD or TD had similar chronological age; and participants with ASD or DD had similar verbal IQ and nonverbal IQ. After training, the ASD group showed preference for the high-value nonsocial stimuli (mean proportion, 0.61 [95% CI, 0.56-0.65]; P < .001) but not for the high-value social stimuli (mean proportion, 0.51 [95% CI, 0.46-0.56]; P = .58). In contrast, the DD and TD groups demonstrated preference for the high-value social stimuli (DD mean proportion, 0.59 [95% CI, 0.54-0.64]; P = .001 and TD mean proportion, 0.57 [95% CI, 0.53-0.61]; P = .002) but not for the high-value nonsocial stimuli (DD mean proportion, 0.52 [95% CI, 0.44-0.59]; P = .64 and TD mean proportion, 0.50 [95% CI, 0.44-0.57]; P = .91). Controlling for age and nonverbal IQ, autism severity was positively correlated with enhanced learning in the nonsocial domain (r = 0.22; P = .03) and with poorer learning in the social domain (r = -0.26; P = .01)., Conclusions and Relevance: Increased attention to objects in preschoolers with ASD may be associated with enhanced VL in the nonsocial domain. When paired with poor VL in the social domain, enhanced value-driven attention to objects may play a formative role in the emergence of autism symptoms by altering attentional priorities and thus learning opportunities in affected children.

Biomarker development is currently a high priority in neurodevelopmental disorder research. For many types of biomarkers (particularly biomarkers of diagnosis), reliability over short periods is critically important. In the field of autism spectrum disorder (ASD), resting electroencephalography (EEG) power spectral densities (PSD) are well-studied for their potential as biomarkers. Classically, such data have been decomposed into pre-specified frequency bands (e.g., delta, theta, alpha, beta, and gamma). Recent technical advances, such as the Fitting Oscillations and One-Over-F (FOOOF) algorithm, allow for targeted characterization of the features that naturally emerge within an EEG PSD, permitting a more detailed characterization of the frequency band-agnostic shape of each individual's EEG PSD. Here, using two resting EEGs collected a median of 6 days apart from 22 children with ASD and 25 typically developing (TD) controls during the Feasibility Visit of the Autism Biomarkers Consortium for Clinical Trials, we estimate test-retest reliability based on the characterization of the PSD shape in two ways: (1) Using the FOOOF algorithm we estimate six parameters (offset, slope, number of peaks, and amplitude, center frequency and bandwidth of the largest alpha peak) that characterize the shape of the EEG PSD; and (2) using nonparametric functional data analyses, we decompose the shape of the EEG PSD into a reduced set of basis functions that characterize individual power spectrum shapes. We show that individuals exhibit idiosyncratic PSD signatures that are stable over recording sessions using both characterizations. Our data show that EEG activity from a brief 2-min recording provides an efficient window into characterizing brain activity at the single-subject level with desirable psychometric characteristics that persist across different analytical decomposition methods. This is a necessary step towards analytical validation of biomarkers based on the EEG PSD and provides insights into parameters of the PSD that offer short-term reliability (and thus promise as potential biomarkers of trait or diagnosis) vs. those that are more variable over the short term (and thus may index state or other rapidly dynamic measures of brain function). Future research should address the longer-term stability of the PSD, for purposes such as monitoring development or response to treatment., (Copyright © 2020 Levin, Naples, Scheffler, Webb, Shic, Sugar, Murias, Bernier, Chawarska, Dawson, Faja, Jeste, Nelson, McPartland and §cdilentürk.)

Clinical research in neurodevelopmental disorders remains reliant upon clinician and caregiver measures. Limitations of these approaches indicate a need for objective, quantitative, and reliable biomarkers to advance clinical research. Extant research suggests the potential utility of multiple candidate biomarkers; however, effective application of these markers in trials requires additional understanding of replicability, individual differences, and intra-individual stability over time. The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is a multi-site study designed to investigate a battery of electrophysiological (EEG) and eye-tracking (ET) indices as candidate biomarkers for autism spectrum disorder (ASD). The study complements published biomarker research through: inclusion of large, deeply phenotyped cohorts of children with ASD and typical development; a longitudinal design; a focus on well-evidenced candidate biomarkers harmonized with an independent sample; high levels of clinical, regulatory, technical, and statistical rigor; adoption of a governance structure incorporating diverse expertise in the ASD biomarker discovery and qualification process; prioritization of open science, including creation of a repository containing biomarker, clinical, and genetic data; and use of economical and scalable technologies that are applicable in developmental populations and those with special needs. The ABC-CT approach has yielded encouraging results, with one measure accepted into the FDA's Biomarker Qualification Program to date. Through these advances, the ABC-CT and other biomarker studies in progress hold promise to deliver novel tools to improve clinical trials research in ASD., (Copyright © 2020 McPartland, Bernier, Jeste, Dawson, Nelson, Chawarska, Earl, Faja, Johnson, Sikich, Brandt, Dziura, Rozenblit, Hellemann, Levin, Murias, Naples, Platt, Sabatos-DeVito, Shic, Senturk, Sugar, Webb and the Autism Biomarkers Consortium for Clinical Trials.)

Background: Impaired attention to faces of interactive partners is a marker for autism spectrum disorder (ASD) in early childhood. However, it is unclear whether children with ASD avoid faces or find them less salient and whether the phenomenon is linked with the presence of eye contact or speech., Methods: We investigated the impacts of speech (SP) and direct gaze (DG) on attention to faces in 22-month-old toddlers with ASD (n = 50) and typically developing controls (TD, n = 47) using the Selective Social Attention 2.0 (SSA 2.0) task. The task consisted of four conditions where the presence (+) and absence (-) of DG and SP were systematically manipulated. The severity of autism symptoms, and verbal and nonverbal skills were characterized concurrently with eye tracking at 22.4 (SD = 3.2) months and prospectively at 39.8 (SD = 4.3) months., Results: Toddlers with ASD looked less than TD toddlers at face and mouth regions only when the actress was speaking (direct gaze absence with speech, DG-SP+: d = 0.99, p < .001 for face, d = 0.98, p < .001 for mouth regions; direct gaze present with speech, DG+SP+, d = 1.47, p < .001 for face, d = 1.01, p < .001 for mouth regions). Toddlers with ASD looked less at the eye region only when both gaze and speech cues were present (d = 0.46, p = .03). Salience of the combined DG and SP cues was associated concurrently and prospectively with the severity of autism symptoms, and the association remained significant after controlling for verbal and nonverbal levels., Conclusions: The study links poor attention to faces with limited salience of audiovisual speech and provides no support for the face avoidance hypothesis in the early stages of ASD. These results are consequential for research on early discriminant and predictive biomarkers as well as identification of novel treatment targets., (© 2019 Association for Child and Adolescent Mental Health.)

The objective of the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is to evaluate a set of lab-based behavioral video tracking (VT), electroencephalography (EEG), and eye tracking (ET) measures for use in clinical trials with children with autism spectrum disorder (ASD). Within the larger organizational structure of the ABC-CT, the Data Acquisition and Analytic Core (DAAC) oversees the standardization of VT, EEG, and ET data acquisition, data processing, and data analysis. This includes designing and documenting data acquisition and analytic protocols and manuals; facilitating site training in acquisition; data acquisition quality control (QC); derivation and validation of dependent variables (DVs); and analytic deliverables including preparation of data for submission to the National Database for Autism Research (NDAR). To oversee consistent application of scientific standards and methodological rigor for data acquisition, processing, and analytics, we developed standard operating procedures that reflect the logistical needs of multi-site research, and the need for well-articulated, transparent processes that can be implemented in future clinical trials. This report details the methodology of the ABC-CT related to acquisition and QC in our Feasibility and Main Study phases. Based on our acquisition metrics from a preplanned interim analysis, we report high levels of acquisition success utilizing VT, EEG, and ET experiments in a relatively large sample of children with ASD and typical development (TD), with data acquired across multiple sites and use of a manualized training and acquisition protocol., (Copyright © 2020 Webb, Shic, Murias, Sugar, Naples, Barney, Borland, Hellemann, Johnson, Kim, Levin, Sabatos-DeVito, Santhosh, Senturk, Dziura, Bernier, Chawarska, Dawson, Faja, Jeste, McPartland and the Autism Biomarkers Consortium for Clinical Trials.)

Importance: Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with different genetic etiologies. Prospective examination of familial-risk infants informs understanding of developmental trajectories preceding ASD diagnosis, potentially improving early detection., Objective: To compare outcomes and trajectories associated with varying familial risk for ASD across the first 3 years of life., Design, Setting, and Participants: This longitudinal, prospective cohort study used data from 11 sites in the Baby Siblings Research Consortium database. Data were collected between 2003 and 2015. Infants who were younger siblings of children with ASD were followed up for 3 years. Analyses were conducted in April 2018. Of the initial 1008 infants from the database, 573 were removed owing to missing necessary data, diagnostic discrepancies, or only having 1 older sibling., Exposures: Number of siblings with ASD., Main Outcomes and Measures: Outcomes included ASD symptoms, cognitive abilities, and adaptive skills. Diagnosis (ASD or no ASD) was given at 36-month outcome. The no-ASD group was classified as atypical (developmental delays and/or social-communication concerns) or typical for some analyses. Generalized linear mixed models examined developmental trajectories by ASD outcome and familial-risk group., Results: In the 435 analyzed participants (age range at outcome, 32-43 months; 246 male [57%]), 355 (82%) were from single-incidence families (1 sibling with ASD and ≥1 sibling without ASD) and 80 (18%) were from multiplex families (≥2 siblings with ASD). There were no significant group differences in major demographics. Children from multiplex families were more likely than those from single-incidence families to be classified as having ASD (29 of 80 [36%] vs 57 of 355 [16%]; 95% CI, 9%-31%; P < .001) and less likely as typical (26 of 80 [33%] vs 201 of 355 [57%]; 95% CI, -36% to -13%; P < .001), with similar rates of atypical classifications (25 of 80 [31%] vs 97 of 355 [27%]; 95% CI, -7% to 15%; P = .49). There were no differences in ASD symptoms between multiplex and single-incidence groups after controlling for ASD outcome (95% CI, -0.02 to 0.20; P = .18). During infancy, differences in cognitive and adaptive abilities were observed based on ASD outcome in the single-incidence group only. At 36 months, the multiplex/no-ASD group had lower cognitive abilities than the single-incidence/no-ASD group (95% CI, -11.89 to -2.20; P = .02), and the multiplex group had lower adaptive abilities than individuals in the single-incidence group after controlling for ASD outcome (95% CI, -9.01 to -1.48; P = .02)., Conclusions and Relevance: Infants with a multiplex family history of ASD should be monitored early and often and referred for early intervention at the first sign of concern. Direct examination of genetic contributions to neurodevelopmental phenotypes in infants with familial risk for ASD is needed.

Young children with autism spectrum disorder (ASD) look less toward faces compared to their non-ASD peers, limiting access to social learning. Currently, no technologies directly target these core social attention difficulties. This study examines the feasibility of automated gaze modification training for improving attention to faces in 3-year-olds with ASD. Using free-viewing data from typically developing (TD) controls (n = 41), we implemented gaze-contingent adaptive cueing to redirect children with ASD toward normative looking patterns during viewing of videos of an actress. Children with ASD were randomly assigned to either (a) an adaptive Cue condition (Cue, n = 16) or (b) a No-Cue condition (No-Cue, n = 19). Performance was examined at baseline, during training, and post-training, and contrasted with TD controls (n = 23). Proportion of time looking at the screen (%Screen) and at actresses' faces (%Face) was analyzed. At Pre-Training, Cue and No-Cue groups did not differ in %Face (P > 0.1). At Post-Training, the Cue group had higher %Face than the No-Cue group (P = 0.015). In the No-Cue group %Face decreased Pre- to Post-Training; no decline was observed in the Cue group. These results suggest gaze-contingent training effectively mitigated decreases of attention toward the face of onscreen social characters in ASD. Additionally, larger training effects were observed in children with lower nonverbal ability, suggesting a gaze-contingent approach may be particularly relevant for children with greater cognitive impairment. This work represents development toward new social attention therapeutic systems that could augment current behavioral interventions. Autism Res 2020, 13: 61-73. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In this study, we leverage a new technology that combines eye tracking and automatic computer programs to help very young children with ASD look at social information in a more prototypical way. In a randomized controlled trial, we show that the use of this technology prevents the diminishing attention toward social information normally seen in children with ASD over the course of a single experimental session. This work represents development toward new social attention therapeutic systems that could augment current behavioral interventions., (© 2019 International Society for Autism Research, Wiley Periodicals, Inc.)

Animal models of autism spectrum disorders (ASD) contribute to understanding of the role of genetics and the biological mechanisms underlying behavioral phenotypes and inform the development of potential treatments. Translational biomarkers are needed that can both validate these models and facilitate behavioral testing paradigms for ASD in humans. Automated video tracking of movement patterns and positions recorded from overhead cameras is routinely applied in behavioral paradigms designed to elicit core behavioral manifestations of ASD in rodent models. In humans, laboratory-based observations are a common semi-naturalistic context for assessing a variety of behaviors relevant to ASD such as social engagement, play, and attention. We present information learned and suggest guidelines for designing, recording, acquiring, and evaluating video tracking data of human movement patterns based on our experience in a multi-site video tracking study of children with ASD in the context of a parent-child, laboratory-based play interaction., (Copyright © 2019. Published by Elsevier B.V.)

Research has identified early appearing differences in gross and fine motor abilities in infants at heightened risk (HR) for autism spectrum disorder (ASD) because they are the younger siblings of children with ASD, and it suggests that such differences may be especially apparent among those HR infants themselves eventually diagnosed with ASD. The present study examined overall and item-level performance on the gross (GM) and fine motor (FM) subscales of the Mullen Scales of Early Learning (MSEL) administered at 6 months to a large, geographically diverse sample of HR infants with varying developmental outcomes (ASD, elevated ADOS without ASD, low ADOS without ASD) and to infants with low ASD risk (low risk [LR]). We also explored whether motor abilities assessed at 6 months predicted ASD symptom severity at 36 months. FM (but not GM) performance distinguished all 3 HR groups from LR infants with the weakest performance observed in the HR-Elevated ADOS children, who exhibited multiple differences from both LR and other HR infants in both gross and fine motor skills. Finally, 6-month FM (but not GM) scores significant predicted 36-month ADOS severity scores in the HR group; but no evidence was found of specific early appearing motor signs associated with a later ASD diagnosis. Vulnerabilities in infants' fine and gross motor skills may have significant consequences for later development not only in the motor domain but in other domains. (PsycINFO Database Record (c) 2019 APA, all rights reserved).