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Autism and social anxiety (SA) share behavioral features like reduced eye contact, variable social attention, and differences in social interactions. However, the impact of the co-occurrence of these conditions (e.g., autism with co-occurring SA) on social attention remains unknown. Therefore, we evaluated whether the degree of SA characteristics in autistic youth modulated (e.g., amplified or lessened) a core hallmark feature of autism: social attention, or looking at faces. Fifty-four autistic and 35 non-autistic children and adolescents completed a gaze-contingent eye-tracking (ET) paradigm, in which faces dynamically expressed happy or fearful expressions contingent on participant eye contact. SA characteristics were assessed via standardized self- and parent-report measures. Social attention was measured by calculating the average percent looking time at the face and eye regions of each emotional expression. Autistic participants looked less at faces than non-autistic participants, and higher self-report SA was associated with less looking at eyes in both autistic and non-autistic participants. SA features affect social attention similarly in autistic and non-autistic youth, highlighting the importance of considering co-occurring psychiatric characteristics when assessing social attention and eye contact in autistic individuals., Competing Interests: Declarations Ethical Approval All study procedures were approved by the Institutional Review Board at the Yale University School of Medicine. Informed Consent Written informed consent was obtained from the legal guardians of all study participants. Competing Interests Cassandra J. Franke, Jason W. Griffin, Adam J. Naples, and Julie M. Wolf declare no potential conflicts of interest with respect to the research, authorship and/or publication of this article. James C. McPartland consults or has consulted with Customer Value Partners, Bridgebio, Determined Health, Apple, 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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Individuals with hoarding disorder (HD) have difficulty parting with personal possessions, which leads to the accumulation of excessive clutter. According to a proposed biphasic neurobiological model, HD is characterized by blunted central and peripheral nervous system activity at rest and during neutral (non-discarding) decisions, and exaggerated activity during decision-making about discarding personal possessions. Here, we compared the error-related negativity (ERN) and psychophysiological responses (skin conductance, heart rate and heart rate variability, and end tidal CO 2 ) during neutral and discarding-related decisions in 26 individuals with HD, 37 control participants with anxiety disorders, and 28 healthy control participants without psychiatric diagnoses. We also compared alpha asymmetry between the HD and control groups during a baseline resting phase. Participants completed a series of Go/No Go decision-making tasks, one involving choosing certain shapes (neutral task) and the other involving choosing images of newspapers to imaginally "discard" (discarding task). While all participants showed expected increased frontal negativity to commission of an error, contrary to hypotheses, there were no group differences in the ERN or any psychophysiological measures. Alpha asymmetry at rest also did not differ between groups. The findings suggest that the ERN and psychophysiological responses may not differ in individuals with HD during simulated discarding decisions relative to control participants, although the null results may be explained by methodological challenges in using Go/No Go tasks as discarding tasks. Future replication and extension of these results will be needed using ecologically valid discarding tasks., Competing Interests: Declaration of competing interest Dr. Levy has received grant funding from Hartford Hospital Medical Staff and the American Psychological Foundation. James C. McPartland consults with Customer Value Partners, Bridgebio, Determined Health, Apple 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. Dr. Tolin has received grant funding from Hartford Hospital Medical Staff; grant funding, material support, and consultant fees from Oui Therapeutics; consultant fees from Mindyra LLC; and royalties from Guilford Press, Oxford University Press, Cambridge University Press, John Wiley and Sons, Springer Publications, and New Harbinger Publications. Dr. Naples and Sarah Collett have no conflicts to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: KeepCalm is a digital mental health application, co-designed with community partners, that incorporates wearable biosensing with support for teams to address challenging behaviors and emotion dysregulation in children on the autism spectrum., Methods: We followed a user-centered design framework. Before app development, we conducted design workshops, needs assessment interviews, a systematic review, and created an Expert Advisory Board. Once we had a working prototype, we recruited 73 participants to test and help improve the app across five testing cycles., Results: Participants rated the app across testing cycles as highly acceptable, appropriate, feasible, and with good usability. Qualitative data indicated that KeepCalm helped teachers (a) be aware of students' previously unrealized triggers, especially for nonspeaking students; (b) prevent behavioral episodes; (c) communicate with parents about behaviors/strategies; and (d) equipped parents with knowledge of strategies to use at home. We learned that in order to make the app acceptable and appropriate we needed to make the app enjoyable/easy to use and to focus development on novel features that augment teachers' skills (e.g., behavioral pattern and stress detection). We also learned about the importance of maximizing feasibility, through in-person app training/support especially regarding the wearable devices, and the importance of having aides involved., Conclusion: Our findings have informed plans for wider-scale feasibility testing so that we may examine the determinants of implementation to inform adaptations and refinement, and gather preliminary efficacy data on KeepCalm's impact on reducing challenging behaviors and supporting emotion regulation in students on the autism spectrum., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The neural bases of autism are poorly understood at the molecular level, but evidence from animal models, genetics, post-mortem studies, and single-gene disorders implicate synaptopathology. Here, we use positron emission tomography (PET) to assess the density of synapses with synaptic vesicle glycoprotein 2A (SV2A) in autistic adults using 11 C-UCB-J. Twelve autistic (mean (SD) age 25 (4) years; six males), and twenty demographically matched non-autistic individuals (26 (3) years; eleven males) participated in a 11 C-UCB-J PET scan. Binding potential, BP ND , was the primary outcome measure and computed with the centrum semiovale as the reference region. Partial volume correction with Iterative Yang was applied to control for possible volumetric differences. Mixed-model statistics were calculated for between-group differences. Relationships to clinical characteristics were evaluated based on clinician ratings of autistic features. Whole cortex synaptic density was 17% lower in the autism group (p = 0.01). All brain regions in autism had lower 11 C-UCB-J BP ND compared to non-autistic participants. This effect was evident in all brain regions implicated in autism. Significant differences were observed across multiple individual regions, including the prefrontal cortex (-15%, p = 0.02), with differences most pronounced in gray matter (p < 0.0001). Synaptic density was significantly associated with clinical measures across the whole cortex (r = 0.67, p = 0.02) and multiple regions (rs = -0.58 to -0.82, ps = 0.05 to <0.01). The first in vivo investigation of synaptic density in autism with PET reveals pervasive and large-scale lower density in the cortex and across multiple brain areas. Synaptic density also correlated with clinical features, such that a greater number of autistic features were associated with lower synaptic density. These results indicate that brain-wide synaptic density may represent an as-yet-undiscovered molecular basis for the clinical phenotype of autism and associated pervasive alterations across a diversity of neural processes., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

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.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and repetitive behaviors. A diagnosis of ASD is provided by a clinician following cognitive and behavioral evaluations, but there is currently no biomarker associating these metrics with neurological changes. Our lab has previously found that g-ratio, the proportion of axon width to myelin diameter, and axonal conduction velocity, which is associated with the capacity of an axon to carry information, are both decreased in ASD individuals. By associating these differences with performance on cognitive and behavioral tests, we can evaluate which tests most reveal changes in the brain. Analyzing 273 participants (148 with ASD) ages 8-to-17 (49% female) through an NIH-sponsored Autism Centers of Excellence (ACE) network (Grant#: MH100028), we observe widespread associations between behavioral and cognitive evaluations of autism and between behavioral and microstructural metrics. Analyzing data from all participants, conduction velocity but not g-ratio was significantly associated with many behavioral metrics. However, this pattern was reversed when looking solely at ASD participants. This reversal may suggest that the mechanism underlying differences between autistic and non-autistic individuals may be distinct from the mechanism underlying ASD behavioral severity. Two additional machine learning cluster analyses applied to neuroimaging data reinforce the association between neuroimaging and behavioral metrics and suggest that age-related maturation of brain metrics may drive changes in ASD behavior. By associating neuroimaging metrics with ASD, it may be possible to measure and identify individuals at high risk of ASD before behavioral tests can detect them.

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.)

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.)

Autism spectrum disorder (autism) is a prevalent neurodevelopmental condition characterized by early emerging impairments in social behavior and communication. EEG represents a powerful and non-invasive tool for examining functional brain differences in autism. Recent EEG evidence suggests that greater intra-individual trial-to-trial variability across EEG responses in stimulus-related tasks may characterize brain differences in autism. Traditional analysis of EEG data largely focuses on mean trends of the trial-averaged data, where trial-level analysis is rarely performed due to low neural signal to noise ratio. We propose to use nonlinear (shape-invariant) mixed effects (NLME) models to study intra-individual inter-trial EEG response variability using trial-level EEG data. By providing more precise metrics of response variability, this approach could enrich our understanding of neural disparities in autism and potentially aid the identification of objective markers. The proposed multilevel NLME models quantify variability in the signal's interpretable and widely recognized features (e.g., latency and amplitude) while also regularizing estimation based on noisy trial-level data. Even though NLME models have been studied for more than three decades, existing methods cannot scale up to large data sets. We propose computationally feasible estimation and inference methods via the use of a novel minorization-maximization (MM) algorithm. Extensive simulations are conducted to show the efficacy of the proposed procedures. Applications to data from a large national consortium find that children with autism have larger intra-individual inter-trial variability in P1 latency in a visual evoked potential (VEP) task, compared to their neurotypical peers., (© 2024 John Wiley & Sons Ltd.)

One of the candidate genes related to language variability in individuals with Autism Spectrum Disorder (ASD) is the contactin-associated protein-like 2 gene (CNTNAP2), a member of the Neurexin family. However, due to the different assessment tools used, it is unknown whether the polymorphisms of the CNTNAP2 gene are linked to structural language skills or more general communication abilities. A total of 302 youth aged 7 to 18 years participated in the present study: 131 verbal youth with ASD (62 female), 130 typically developing (TD) youth (64 female), and 41 unaffected siblings (US) of youth with ASD (25 female). Blood samples were collected to obtain genomic DNA and processed by the Rutgers University Cell and Data Repository or using standard protocols (Gentra Puregene Blood DNA extraction kit; Qiagen). Language and verbal communication skills were screened with the Clinical Evaluation of Language Fundamental-4 (CELF-4) and Vineland-II Communication domain, subsequently. The results showed that the polymorphism of CNTNAP2 (SNP rs2710102) was related to structural language abilities, such that participants carrying the A-allele had lower language skills in comparison to the G-allele homozygotes. No relationship was found between the polymorphism of CNTNAP2 and more general communication abilities. Although the study revealed genetic mechanisms that are associated with CELF-4 measures but not Vineland-II in youth with ASD, follow-up studies are needed that will include measures of language and communication that are less correlated to each other as well as will include a group of minimally and/or non-verbal individuals with ASD., (© 2024 International Society for Autism Research and Wiley Periodicals LLC.)

Challenging behavior, such as aggression, is highly prevalent in children and adolescents on the autism spectrum and can have a devastating impact. Previous reviews of challenging behavior interventions did not include interventions targeting emotion dysregulation, a common cause of challenging behavior. We reviewed emotion dysregulation and challenging behavior interventions for preschoolers to adolescents to determine which evidence-based strategies have the most empirical support for reducing/preventing emotion dysregulation/challenging behavior. We reviewed 95 studies, including 29 group and 66 single case designs. We excluded non-behavioral/psychosocial interventions and those targeting internalizing symptoms only. We applied a coding system to identify discrete strategies based on autism practice guidelines with the addition of strategies common in childhood mental health disorders, and an evidence grading system. Strategies with the highest quality evidence (multiple randomized controlled trials with low bias risk) were Parent-Implemented Intervention, Emotion Regulation Training, Reinforcement, Visual Supports, Cognitive Behavioral/Instructional Strategies and Antecedent-Based Interventions. Regarding outcomes, most studies included challenging behavior measures, while few included emotion dysregulation measures. This review highlights the importance of teaching emotion regulation skills explicitly, positively reinforcing replacement/alternative behaviors, using visuals and metacognition, addressing stressors proactively, and involving parents. It also calls for more rigorously designed studies and for including emotion dysregulation as an outcome/mediator in future trials., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Individuals with autism spectrum disorder (ASD) engage in less physical activity than typically-developing peers. This can result in serious negative consequences for individual well-being and may contribute to the physical, behavioral, and emotional challenges associated with ASD. This study explored the potential benefits of trainer-led, individualized, physical fitness sessions specialized for ASD. Eleven individuals (ages 7-24 years) with ASD were assessed at baseline and following 15 fitness sessions. Participants demonstrated improvements in core and lower-body strength and reductions in restricted and repetitive patterns of behavior, along with non-significant but marked reductions in issues with daytime sleepiness. Results suggest the merit of specialized fitness programs and emphasize the need for larger and more rigorous research studies on this topic., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Most children with Autism Spectrum Disorder (ASD) have co-occurring language impairments and some of these autism-specific language difficulties are also present in their non-autistic first-degree relatives. One of the possible neural mechanisms associated with variability in language functioning is alterations in cortical gamma-band oscillations, hypothesized to be related to neural excitation and inhibition balance., Methods: We used a high-density 128-channel electroencephalography (EEG) to register brain response to speech stimuli in a large sex-balanced sample of participants: 125 youth with ASD, 121 typically developing (TD) youth, and 40 unaffected siblings (US) of youth with ASD. Language skills were assessed with Clinical Evaluation of Language Fundamentals., Results: First, during speech processing, we identified significantly elevated gamma power in ASD participants compared to TD controls. Second, across all youth, higher gamma power was associated with lower language skills. Finally, the US group demonstrated an intermediate profile in both language and gamma power, with nonverbal IQ mediating the relationship between gamma power and language skills., Limitations: We only focused on one of the possible neural contributors to variability in language functioning. Also, the US group consisted of a smaller number of participants in comparison to the ASD or TD groups. Finally, due to the timing issue in EEG system we have provided only non-phase-locked analysis., Conclusions: Autistic youth showed elevated gamma power, suggesting higher excitation in the brain in response to speech stimuli and elevated gamma power was related to lower language skills. The US group showed an intermediate pattern of gamma activity, suggesting that the broader autism phenotype extends to neural profiles., (© 2024. The Author(s).)

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

Purpose: Visual face recognition-the ability to encode, discriminate, and recognize the faces of others-is fundamentally supported by eye movements and is a common source of difficulty for autistic individuals. We aimed to evaluate how visual processing strategies (i.e., eye movement patterns) directly support encoding and recognition of faces in autistic and neurotypical (NT) individuals., Methods: We used a hidden Markov modeling approach to evaluate the spatiotemporal dynamics of eye movements in autistic (n = 15) and neurotypical (NT) adolescents (n = 17) during a face identity recognition task., Results: We discovered distinct eye movement patterns among all participants, which included a focused and exploratory strategy. When evaluating change in visual processing strategy across encoding and recognition phases, autistic individuals did not shift their eye movement patterns like their NT peers, who shifted to a more exploratory visual processing strategy during recognition., Conclusion: These findings suggest that autistic individuals do not modulate their visual processing strategy across encoding and recognition of faces, which may be an indicator of less efficient face processing., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Social difficulties during interactions with others are central to autism spectrum disorder (ASD). Understanding the links between these social difficulties and their underlying neural processes is a primary aim focused on improved diagnosis and treatment. In keeping with this goal, we have developed a multivariate classification method based on neural data acquired by functional near infrared spectroscopy, fNIRS, during live eye-to-eye contact with adults who were either typically developed (TD) or individuals with ASD. The ASD diagnosis was based on the gold-standard Autism Diagnostic Observation Schedule (ADOS) which also provides an index of symptom severity. Using a nested cross-validation method, a support vector machine (SVM) was trained to discriminate between ASD and TD groups based on the neural responses during eye-to-eye contact. ADOS scores were not applied in the classification training. To test the hypothesis that SVM identifies neural activity patterns related to one of the neural mechanisms underlying the behavioral symptoms of ASD, we determined the correlation coefficient between the SVM scores and the individual ADOS scores. Consistent with the hypothesis, the correlation between observed and predicted ADOS scores was 0.72 (p < 0.002). Findings suggest that multivariate classification methods combined with the live interaction paradigm of eye-to-eye contact provide a promising approach to link neural processes and social difficulties in individuals with ASD., (© 2024. The Author(s).)

There has been a heightened awareness of an increased risk of suicidality among individuals with autism spectrum disorder (ASD) due to high rates of suicidal ideation (SI) in this population (11-66%). The current study investigated the rate of parent-endorsed SI and associated clinical features in 48 youths with ASD (Age; M: 12.97 years, SD: 2.33). SI was endorsed in 18.75% of participants. Youth with SI exhibited significantly higher levels of affective problems, externalizing problems, feelings of humiliation and rejection, and symptoms related to perfectionism. Results indicate that co-occurring mental health problems are associated with suicidal ideation and provide relevant targets for psychotherapeutic intervention. This preliminary study in a modest sample suggests the value of further research in larger samples to replicate and generalize these findings., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In youth broadly, EEG frontal alpha asymmetry (FAA) associates with affective style and vulnerability to psychopathology, with relatively stronger right activity predicting risk for internalizing and externalizing behaviors. In autistic youth, FAA has been related to ASD diagnostic features and to internalizing symptoms. Among our large, rigorously characterized, sex-balanced participant group, we attempted to replicate findings suggestive of altered FAA in youth with an ASD diagnosis, examining group differences and impact of sex assigned at birth. Second, we examined relations between FAA and behavioral variables (ASD features, internalizing, and externalizing) within autistic youth, examining effects by sex. Third, we explored whether the relation between FAA, autism features, and mental health was informed by maternal depression history. In our sample, FAA did not differ by diagnosis, age, or sex. However, youth with ASD had lower total frontal alpha power than youth without ASD. For autistic females, FAA and bilateral frontal alpha power correlated with social communication features, but not with internalizing or externalizing symptoms. For autistic males, EEG markers correlated with social communication features, and with externalizing behaviors. Exploratory analyses by sex revealed further associations between youth FAA, behavioral indices, and maternal depression history. In summary, findings suggest that individual differences in FAA may correspond to social-emotional and mental health behaviors, with different patterns of association for females and males with ASD. Longitudinal consideration of individual differences across levels of analysis (e.g., biomarkers, family factors, and environmental influences) will be essential to parsing out models of risk and resilience among autistic youth., (© 2023 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.)

Electroencephalographic peak alpha frequency (PAF) is a marker of neural maturation that increases with age throughout childhood. Distinct maturation of PAF is observed in children with autism spectrum disorder such that PAF does not increase with age and is instead positively associated with cognitive ability. The current study clarifies and extends previous findings by characterizing the effects of age and cognitive ability on PAF between diagnostic groups in a sample of children and adolescents with and without autism spectrum disorder. Resting EEG data and behavioral measures were collected from 45 autistic children and 34 neurotypical controls aged 8 to 18 years. Utilizing generalized additive models to account for nonlinear relations, we examined differences in the joint effect of age and nonverbal IQ by diagnosis as well as bivariate relations between age, nonverbal IQ, and PAF across diagnostic groups. Age was positively associated with PAF among neurotypical children but not among autistic children. In contrast, nonverbal IQ but not age was positively associated with PAF among autistic children. Models accounting for nonlinear relations revealed different developmental trajectories as a function of age and cognitive ability based on diagnostic status. Results align with prior evidence indicating that typical age-related increases in PAF are absent in autistic children and that PAF instead increases with cognitive ability in these children. Findings suggest the potential of PAF to index distinct trajectories of neural maturation in autistic children., (© 2023 International Society for Autism Research and Wiley Periodicals LLC.)

Importance: Face processing is foundational to human social cognition, is central to the hallmark features of autism spectrum disorder (ASD), and shapes neural systems and social behavior. Highly efficient and specialized, the face processing system is sensitive to inversion, demonstrated by reduced accuracy in recognition and altered neural response to inverted faces. Understanding at which mechanistic level the autistic face processing system may be particularly different, as measured by the face inversion effect, will improve overall understanding of brain functioning in autism., Objective: To synthesize data from the extant literature to determine differences of the face processing system in ASD, as measured by the face inversion effect, across multiple mechanistic levels., Data Sources: Systematic searches were conducted in the MEDLINE, Embase, Web of Science, and PubMed databases from inception to August 11, 2022., Study Selection: Original research that reported performance-based measures of face recognition to upright and inverted faces in ASD and neurotypical samples were included for quantitative synthesis. All studies were screened by at least 2 reviewers., Data Extraction and Synthesis: This systematic review and meta-analysis was conducted according to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Multiple effect sizes were extracted from studies to maximize information gain and statistical precision and used a random-effects, multilevel modeling framework to account for statistical dependencies within study samples., Main Outcomes and Measures: Effect sizes were calculated as a standardized mean change score between ASD and neurotypical samples (ie, Hedges g). The primary outcome measure was performance difference between upright and inverted faces during face recognition tasks. Measurement modality, psychological construct, recognition demand, sample age, sample sex distribution, and study quality assessment scores were assessed as moderators., Results: Of 1768 screened articles, 122 effect sizes from 38 empirical articles representing data from 1764 individual participants (899 ASD individuals and 865 neurotypical individuals) were included in the meta-analysis. Overall, face recognition performance differences between upright and inverted faces were reduced in autistic individuals compared with neurotypical individuals (g = -0.41; SE = 0.11; 95% credible interval [CrI], -0.63 to -0.18). However, there was considerable heterogeneity among effect sizes, which were explored with moderator analysis. The attenuated face inversion effect in autistic individuals was more prominent in emotion compared with identity recognition (b = 0.46; SE = 0.26; 95% CrI, -0.08 to 0.95) and in behavioral compared with electrophysiological measures (b = 0.23; SE = 0.24; 95% CrI, -0.25 to 0.70)., Conclusions and Relevance: This study found that on average, face recognition in autism is less impacted by inversion. These findings suggest less specialization or expertise of the face processing system in autism, particularly in recognizing emotion from faces as measured in behavioral paradigms.

Autism (ASD) and schizophrenia spectrum disorders (SCZ) are neurodevelopmental conditions with overlapping and interrelated symptoms. A network analysis approach that represents clinical conditions as a set of "nodes" (symptoms) connected by "edges" (relations among symptoms) was used to compare symptom organization in the two conditions. Gaussian graphical models were estimated using Bayesian methods to model separate symptom networks for adults with confirmed ASD or SCZ diagnoses. Though overall symptom organization differed by diagnostic group, both symptom networks demonstrated high centrality of social communication difficulties. Autism-relevant restricted and repetitive behaviors and schizophrenia-related cognitive-perceptual symptoms were uniquely central to the ASD and SCZ networks, respectively. Results offer recommendations to improve differential diagnosis and highlight potential treatment targets in ASD and SCZ., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.)

Visual exploration paradigms involving object arrays have been used to examine salience of social stimuli such as faces in ASD. Recent work suggests performance on these paradigms may associate with clinical features of ASD. We evaluate metrics from a visual exploration paradigm in 4-to-11-year-old children with ASD (n = 23; 18 males) and typical development (TD; n = 23; 13 males). Presented with arrays containing faces and nonsocial stimuli, children with ASD looked less at (p = 0.002) and showed fewer fixations to (p = 0.022) faces than TD children, and spent less time looking at each object on average (p = 0.004). Attention to the screen and faces correlated positively with social and cognitive skills in the ASD group (ps < .05). This work furthers our understanding of objective measures of visual exploration in ASD and its potential for quantifying features of ASD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: As much as 80% of children on the autism spectrum exhibit challenging behaviors (ie, behaviors dangerous to the self or others, behaviors that interfere with learning and development, and behaviors that interfere with socialization) that can have a devastating impact on personal and family well-being, contribute to teacher burnout, and even require hospitalization. Evidence-based practices to reduce these behaviors emphasize identifying triggers (events or antecedents that lead to challenging behaviors); however, parents and teachers often report that challenging behaviors surface with little warning. Exciting recent advances in biometric sensing and mobile computing technology allow the measurement of momentary emotion dysregulation using physiological indexes., Objective: We present the framework and protocol for a pilot trial that will test a mobile digital mental health app, the KeepCalm app. School-based approaches to managing challenging behaviors in children on the autism spectrum are limited by 3 key factors: children on the autism spectrum often have difficulties in communicating their emotions; it is challenging to implement evidence-based, personalized strategies for individual children in group settings; and it is difficult for teachers to track which strategies are successful for each child. KeepCalm aims to address those barriers by communicating children's stress to their teachers using physiological signaling (emotion dysregulation detection), supporting the implementation of emotion regulation strategies via smartphone pop-up notifications of top strategies for each child according to their behavior (emotion regulation strategy implementation), and easing the task of tracking outcomes by providing the child's educational team with a tool to track the most effective emotion regulation strategies for that child based on physiological stress reduction data (emotion regulation strategy evaluation)., Methods: We will test KeepCalm with 20 educational teams of students on the autism spectrum with challenging behaviors (no exclusion based on IQ or speaking ability) in a pilot randomized waitlist-controlled field trial over a 3-month period. We will examine the usability, acceptability, feasibility, and appropriateness of KeepCalm as primary outcomes. Secondary preliminary efficacy outcomes include clinical decision support success, false positives or false negatives of stress alerts, and the reduction of challenging behaviors and emotion dysregulation. We will also examine technical outcomes, including the number of artifacts and the proportion of time children are engaged in high physical movement based on accelerometry data; test the feasibility of our recruitment strategies; and test the response rate and sensitivity to change of our measures, in preparation for a future fully powered large-scale randomized controlled trial., Results: The pilot trial will begin by September 2023., Conclusions: Results will provide key data about important aspects of implementing KeepCalm in preschools and elementary schools and will provide preliminary data about its efficacy to reduce challenging behaviors and support emotion regulation in children on the autism spectrum., Trial Registration: ClinicalTrials.gov NCT05277194; https://www.clinicaltrials.gov/ct2/show/NCT05277194., International Registered Report Identifier (irrid): PRR1-10.2196/45852., (©Emma H Palermo, Amanda V Young, Sky Deswert, Alyssa Brown, Miranda Goldberg, Evan Sultanik, Jessica Tan, Carla A Mazefsky, Lauren Brookman-Frazee, James C McPartland, Matthew S Goodwin, Jeffrey Pennington, Steven C Marcus, Rinad S Beidas, David S Mandell, Heather J Nuske. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 26.06.2023.)

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.)

Eye tracking (ET) experiments commonly record the continuous trajectory of a subject's gaze on a two-dimensional screen throughout repeated presentations of stimuli (referred to as trials). Even though the continuous path of gaze is recorded during each trial, commonly derived outcomes for analysis collapse the data into simple summaries, such as looking times in regions of interest, latency to looking at stimuli, number of stimuli viewed, number of fixations or fixation length. In order to retain information in trial time, we utilize functional data analysis (FDA) for the first time in literature in the analysis of ET data. More specifically, novel functional outcomes for ET data, referred to as viewing profiles, are introduced that capture the common gazing trends across trial time which are lost in traditional data summaries. Mean and variation of the proposed functional outcomes across subjects are then modeled using functional principal components analysis. Applications to data from a visual exploration paradigm conducted by the Autism Biomarkers Consortium for Clinical Trials showcase the novel insights gained from the proposed FDA approach, including significant group differences between children diagnosed with autism and their typically developing peers in their consistency of looking at faces early on in trial time., Competing Interests: 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. 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. Dawson has stock interests in Neuvana, Inc. Dawson has the following patent No. 10,912,801 and patent applications: 62,757,234, 25,628,402, and 62,757,226. 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. Shic consults for Roche Pharmaceutical Company, Janssen Research and Development, BlackThorn Therapeutics, and BioStream Technologies.

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.

Autism spectrum disorder (ASD) and schizophrenia spectrum disorders (SZ) are characterized by difficulty with social cognition and atypical reception of facial communication - a key area in the Research Domain Criteria framework. To identify areas of overlap and dissociation between ASD and SZ, we review studies of event-related potentials (ERP) to faces across ASD and SZ populations, focusing on ERPs implicated in social perception: P100, N170, N250, and P300. There were many inconsistent findings across studies; however, replication was strongest for delayed N170 latency in ASD and attenuated N170 amplitude in SZ. These results highlight the challenges of replicating research findings in heterogeneous clinical populations and the need for transdiagnostic research that continuously quantifies behavior and neural activity across neurodevelopmental disorders., Competing Interests: CONFLICT-OF-INTEREST STATEMENT The authors declare that they have no conflict of interest.

Autism Spectrum Disorder (ASD) is a developmental condition characterized by social and communication differences. Recent research suggests ASD affects 1-in-44 children in the United States. ASD is diagnosed more commonly in males, though it is unclear whether this diagnostic disparity is a result of a biological predisposition or limitations in diagnostic tools, or both. One hypothesis centers on the 'female protective effect,' which is the theory that females are biologically more resistant to the autism phenotype than males. In this examination, phenotypic data were acquired and combined from four leading research institutions and subjected to multivariate linear discriminant analysis. A linear discriminant model was trained on the training set and then deployed on the test set to predict group membership. Multivariate analyses of variance were performed to confirm the significance of the overall analysis, and individual analyses of variance were performed to confirm the significance of each of the resulting linear discriminant axes. Two discriminant dimensions were identified between the groups: a dimension separating groups by the diagnosis of ASD (LD1: 87% of variance explained); and a dimension reflective of a diagnosis-by-sex interaction (LD2: 11% of variance explained). The strongest discriminant coefficients for the first discriminant axis divided the sample in domains with known differences between ASD and comparison groups, such as social difficulties and restricted repetitive behavior. The discriminant coefficients for the second discriminant axis reveal a more nuanced disparity between boys with ASD and girls with ASD, including executive functioning and high-order behavioral domains as the dominant discriminators. These results indicate that phenotypic differences between males and females with and without ASD are identifiable using parent report measures, which could be utilized to provide additional specificity to the diagnosis of ASD in female patients, potentially leading to more targeted clinical strategies and therapeutic interventions. The study helps to isolate a phenotypic basis for future empirical work on the female protective effect using neuroimaging, EEG, and genomic methodologies., Competing Interests: The 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 Jacokes, Jack, Sullivan, Aylward, Bookheimer, Dapretto, Bernier, Geschwind, Sukhodolsky, McPartland, Webb, Torgerson, Eilbott, Kenworthy, Pelphrey, Van Horn and The GENDAAR Consortium.)

Reluctance to make eye contact during natural interactions is a central diagnostic criterion for autism spectrum disorder (ASD). However, the underlying neural correlates for eye contacts in ASD are unknown, and diagnostic biomarkers are active areas of investigation. Here, neuroimaging, eye-tracking, and pupillometry data were acquired simultaneously using two-person functional near-infrared spectroscopy (fNIRS) during live "in-person" eye-to-eye contact and eye-gaze at a video face for typically-developed (TD) and participants with ASD to identify the neural correlates of live eye-to-eye contact in both groups. Comparisons between ASD and TD showed decreased right dorsal-parietal activity and increased right ventral temporal-parietal activity for ASD during live eye-to-eye contact (p≤0.05, FDR-corrected) and reduced cross-brain coherence consistent with atypical neural systems for live eye contact. Hypoactivity of right dorsal-parietal regions during eye contact in ASD was further associated with gold standard measures of social performance by the correlation of neural responses and individual measures of: ADOS-2, Autism Diagnostic Observation Schedule, 2nd Edition (r = -0.76, -0.92 and -0.77); and SRS-2, Social Responsiveness Scale, Second Edition (r = -0.58). The findings indicate that as categorized social ability decreases, neural responses to real eye-contact in the right dorsal parietal region also decrease consistent with a neural correlate for social characteristics in ASD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Hirsch et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Deficits in establishing and maintaining eye-contact are early and persistent vulnerabilities of autism spectrum disorder (ASD), and the neural bases of these deficits remain elusive. A promising hypothesis is that social features of autism may reflect difficulties in making predictions about the social world under conditions of uncertainty. However, no research in ASD has examined how predictability impacts the neural processing of eye-contact in naturalistic interpersonal interactions., Method: We used eye tracking to facilitate an interactive social simulation wherein onscreen faces would establish eye-contact when the participant looked at them. In Experiment One, receipt of eye-contact was unpredictable; in Experiment Two, receipt of eye-contact was predictable. Neural response to eye-contact was measured via the N170 and P300 event-related potentials (ERPs). Experiment One included 23 ASD and 46 typically developing (TD) adult participants. Experiment Two included 25 ASD and 43 TD adult participants., Results: When receipt of eye-contact was unpredictable, individuals with ASD showed increased N170 and increased, but non-specific, P300 responses. The magnitude of the N170 responses correlated with measures of sensory and anxiety symptomology, such that increased response to eye-contact was associated with increased symptomology. However, when receipt of eye-contact was predictable, individuals with ASD, relative to controls, exhibited slower N170s and no differences in the amplitude of N170 or P300., Limitations: Our ASD sample was composed of adults with IQ > 70 and included only four autistic women. Thus, further research is needed to evaluate how these results generalize across the spectrum of age, sex, and cognitive ability. Additionally, as analyses were exploratory, some findings failed to survive false-discovery rate adjustment., Conclusions: Neural response to eye-contact in ASD ranged from attenuated to hypersensitive depending on the predictability of the social context. These findings suggest that the vulnerabilities in eye-contact during social interactions in ASD may arise from differences in anticipation and expectation of eye-contact in addition to the perception of gaze alone., (© 2022. The Author(s).)

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.)

Electroencephalography experiments produce region-referenced functional data representing brain signals in the time or the frequency domain collected across the scalp. The data typically also have a multilevel structure with high-dimensional observations collected across multiple experimental conditions or visits. Common analysis approaches reduce the data complexity by collapsing the functional and regional dimensions, where event-related potential (ERP) features or band power are targeted in a pre-specified scalp region. This practice can fail to portray more comprehensive differences in the entire ERP signal or the power spectral density (PSD) across the scalp. Building on the weak separability of the high-dimensional covariance process, the proposed multilevel hybrid principal components analysis (M-HPCA) utilizes dimension reduction tools from both vector and functional principal components analysis to decompose the total variation into between- and within-subject variance. The resulting model components are estimated in a mixed effects modeling framework via a computationally efficient minorization-maximization algorithm coupled with bootstrap. The diverse array of applications of M-HPCA is showcased with two studies of individuals with autism. While ERP responses to match vs mismatch conditions are compared in an audio odd-ball paradigm in the first study, short-term reliability of the PSD across visits is compared in the second. Finite sample properties of the proposed methodology are studied in extensive simulations., (© 2022 John Wiley & Sons Ltd.)

Social behaviour is an essential component of human life and deficits in social function are seen across multiple psychiatric conditions with high morbidity. However, there are currently no FDA-approved treatments for social dysfunction. Since social cognition and behaviour rely on multiple signalling processes acting in concert across various neural networks, treatments aimed at social function may inherently require a combinatorial approach. Here, we describe the social neurobiology of the oxytocin and endocannabinoid signalling systems as well as translational evidence for their use in treating symptoms in the social domain. We leverage this systems neurobiology to propose a network-based framework that involves pharmacology, psychotherapy, non-invasive brain stimulation and social skills training to combinatorially target trans-diagnostic social impairment. Lastly, we discuss the combined use of oxytocin and endocannabinoids within our proposed framework as an illustrative strategy to treat specific aspects of social function. Using this framework provides a roadmap for actionable treatment strategies for neuropsychiatric social impairment. This article is part of the theme issue 'Interplays between oxytocin and other neuromodulators in shaping complex social behaviours'.

Autistic individuals experience significantly higher rates of sleep problems compared to the general population, which negatively impacts various aspects of daytime functioning. The strength of associations across domains of functioning has not yet been summarized across studies. The present meta-analysis examined the strength of associations between sleep problems and various domains of daytime functioning in autistic individuals. Searches were conducted in EMBASE, PubMed, Web of Science, and Google Scholar through May 2020. Inclusion criteria were: an index of sleep disturbance in individuals diagnosed with autism spectrum disorder (ASD); data collected prior to any sleep-related intervention; statistical data indicating relations between sleep problems and outcomes relevant to behavior, cognition, and physical or mental health. Exclusion criteria were: statistics characterizing the relationship between sleep disturbance and outcome variables that partialled out covariates; studies examining correlations between different measures of sleep disturbance. Participants totaled 15,074 from 49 published articles and 51 samples, yielding 209 effect sizes. Sleep problems were significantly associated with more clinical symptomatology and worse daytime functioning. Subgroup analyses demonstrated that sleep problems were most strongly associated with internalizing and externalizing symptoms and executive functioning, followed by core autism symptoms, family factors, and adaptive functioning. Findings highlight the far-reaching consequences of sleep problems on daytime functioning for autistic individuals and support the continued prioritization of sleep as a target for intervention through integrated care models to improve wellbeing. LAY SUMMARY: Autistic individuals experience higher rates of sleep problems, such as difficulty falling asleep and staying asleep, compared to the general population. We quantitatively summarized the literature about how sleep problems are related to different aspects of daytime functioning to identify areas that may be most affected by sleep. Sleep problems were related to all areas assessed, with the strongest associations for mood and anxiety symptoms. We recommend prioritizing sleep health in autistic individuals to improve wellbeing and quality of life., (© 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.)

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8-17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Eye tracking (ET) is a powerful methodology for studying attentional processes through quantification of eye movements. The precision, usability, and cost-effectiveness of ET render it a promising platform for developing biomarkers for use in clinical trials for autism spectrum disorder (ASD)., Methods: The autism biomarkers consortium for clinical trials conducted a multisite, observational study of 6-11-year-old children with ASD (n = 280) and typical development (TD, n = 119). The ET battery included: Activity Monitoring, Social Interactive, Static Social Scenes, Biological Motion Preference, and Pupillary Light Reflex tasks. A priori, gaze to faces in Activity Monitoring, Social Interactive, and Static Social Scenes tasks were aggregated into an Oculomotor Index of Gaze to Human Faces (OMI) as the primary outcome measure. This work reports on fundamental biomarker properties (data acquisition rates, construct validity, six-week stability, group discrimination, and clinical relationships) derived from these assays that serve as a base for subsequent development of clinical trial biomarker applications., Results: All tasks exhibited excellent acquisition rates, met expectations for construct validity, had moderate or high six-week stabilities, and highlighted subsets of the ASD group with distinct biomarker performance. Within ASD, higher OMI was associated with increased memory for faces, decreased autism symptom severity, and higher verbal IQ and pragmatic communication skills., Limitations: No specific interventions were administered in this study, limiting information about how ET biomarkers track or predict outcomes in response to treatment. This study did not consider co-occurrence of psychiatric conditions nor specificity in comparison with non-ASD special populations, therefore limiting our understanding of the applicability of outcomes to specific clinical contexts-of-use. Research-grade protocols and equipment were used; further studies are needed to explore deployment in less standardized contexts., Conclusions: All ET tasks met expectations regarding biomarker properties, with strongest performance for tasks associated with attention to human faces and weakest performance associated with biological motion preference. Based on these data, the OMI has been accepted to the FDA's Biomarker Qualification program, providing a path for advancing efforts to develop biomarkers for use in clinical trials., (© 2022. The Author(s).)

Impairments in theory of mind (ToM) - long considered common among individuals with autism spectrum disorder (ASD) - are in fact highly heterogeneous across this population. While such heterogeneity should be reflected in differential recruitment of neural mechanisms during ToM reasoning, no research has yet uncovered a mechanism that explains these individual differences. In this study, 78 (48 ASD) adolescents viewed ToM vignettes and made mental state inferences about characters' behavior while participant electrophysiology was concurrently recorded. Two candidate event-related potentials (ERPs) - the Late Positive Complex (LPC) and the Late Slow Wave (LSW) - were successfully elicited. LPC scores correlated positively with ToM accuracy and negatively with ASD symptom severity. Notably, the LPC partially mediated the relationship between ASD symptoms and ToM accuracy, suggesting this ERP component, thought to represent cognitive metarepresentation, may help explain differences in ToM performance in some individuals with ASD.

Objective : Despite the frequent occurrence of depressive symptoms in children and adolescents with autism spectrum disorder (ASD), few studies have investigated the relationship between depressive symptoms and adaptive functioning. The present study explored the impact of depressive symptoms on different domains of adaptive functioning in children and adolescents with ASD. Methods : Depressive symptoms and adaptive functioning were analyzed in 62 children and adolescents with ASD (20 females) and 36 children and adolescents (15 females) with typical development between 5 and 18 years of age. Results : After controlling for IQ, age and sex, higher depressive symptoms predicted lower functioning in the social domain among children and adolescents with ASD. Depressive symptoms did not significantly predict communication or daily living skills. Conclusions : These findings highlight the relevance of depression in social adaptive function in ASD and emphasize the importance of assessing depressive symptomatology when evaluating social skills and planning treatment for children and adolescents with ASD.

Aggressive behaviors are common among youth with autism spectrum disorder (ASD) and correlate with pervasive social-emotional difficulties. Communication skill is an important correlate of disruptive behavior in typical development, and clarification of links between communication and aggression in ASD may inform intervention methods. We investigate child/family factors and communication in relation to aggression among 145 individuals with ASD (65 female; ages 8-17 years). Overall, more severe aggression was associated with younger age, lower family income, and difficulties with communication skills. However, this pattern of results was driven by males, and aggression was unrelated to child or family characteristics for females. Future work should incorporate these predictors in conjunction with broader contextual factors to understand aggressive behavior in females with ASD., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

During the last 40 years, neuroscience has become one of the most central and most productive approaches to investigating autism. In this commentary, we assemble a group of established investigators and trainees to review key advances and anticipated developments in neuroscience research across five modalities most commonly employed in autism research: magnetic resonance imaging, functional near infrared spectroscopy, positron emission tomography, electroencephalography, and transcranial magnetic stimulation. Broadly, neuroscience research has provided important insights into brain systems involved in autism but not yet mechanistic understanding. Methodological advancements are expected to proffer deeper understanding of neural circuitry associated with function and dysfunction during the next 40 years., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)