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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.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.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.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.

Prior eye-tracking studies involving autistic individuals have focused on total looking time or proportion of looking time to key regions of interest. These studies have not examined another important feature, the ability to sustain attention to stimuli. In particular, the ability to sustain attention to a dynamic social stimulus might reflect more advanced self-regulatory skills that may enhance engagement with and comprehension of social information. In a sample of 155 autistic children (2–8 years of age), we examined children’s average look duration while they viewed a complex, dynamic stimulus containing both social and nonsocial elements. After accounting for children’s age and intelligence quotient, we found that shorter average look duration was associated with increased autism spectrum disorder severity across multiple clinical measures. To calculate average look duration, we divided the length of total looking time in seconds by the total number of uninterrupted looks to the video media. Thus, the ability to sustain attention while viewing complex dynamic information could be important for comprehending dynamic social information. Lay Abstract Many studies of autism look at the differences in how autistic research participants look at certain types of images. These studies often focus on where research participants are looking within the image, but that does not tell us everything about how much they are paying attention. It could be useful to know more about how well autistic research participants can focus on an image with people in it, because those who can look at images of people for longer duration without stopping may be able to easily learn other skills that help them to interact with people. We measured how long autistic research participants watched the video without breaking their attention. The video sometimes had a person speaking, and at other times had toys moving and making sounds. We measured the typical amount of time autistic research participants could look at the video before they looked away. We found that research participants with more severe autism tended to look at the video for shorter amounts of time. The ability to focus without stopping may be related to social skills in autistic people.

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.

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.

Although it has been found that autistic children exhibit delays in executive function abilities and atypical patterns of attention, less is known about the relationship between executive function and attention abilities and social and language skills in early childhood. In this study, 180 autistic children, age 2–8 years, participated in a study examining the relationship between executive function abilities, measured by the Behavior Rating Inventory of Executive Function, and assessments of sustained attention measured via eye-tracking and several language and social communication measures. Results revealed that children with higher caregiver-reported executive function skills, specifically, working memory and planning/organization abilities, demonstrated higher levels of caregiver-reported receptive-expressive social communication abilities measured via the Pervasive Developmental Disorder Behavior Inventory. Higher executive function abilities across all domains were associated with lower levels of social pragmatic problems. Children who were able to sustain their attention for a longer duration demonstrated higher expressive language abilities. These results suggest that executive function and attention skills may play an important role in multiple domains of functioning in autistic children. It will be useful to determine whether therapies that seek to improve executive function skills in autistic individuals also positively influence their social/communication and language abilities. Lay Abstract Executive functioning describes a set of cognitive processes that affect thinking and behavior. Past research has shown that autistic individuals often have delays in the acquisition of executive function abilities. Our study explored how differences in executive function and attention abilities relate to social abilities and communication/language in 180 young autistic children. Data were gathered via caregiver report (questionnaires/interviews) and an assessment of vocabulary skills. The ability to sustain attention to a dynamic video was measured via eye tracking. We found that children with higher levels of executive function skills demonstrated lower levels of social pragmatic problems, a measure of having difficulties in social contexts. Furthermore, children who were able to sustain their attention longer to the video displayed higher levels of expressive language. Our results emphasize the importance of executive function and attention skills across multiple areas of functioning in autistic children, in particular those that involve language and social communication.

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.

Using eye tracking, a rich body of literature has identified atypical attention to dynamic social stimuli in children with autism. What is less clear is what constitutes typical gaze as this is highly dependent on stimulus content. Instead of looking at proportions of looking time to predefined areas of interested, here we calculate mean fixations frame-by-frame in a group of typically developing children. We then determined the distance from that typical fixation point for 155 children with autism frame-by-frame. Distance from the typical scan path was assessed in relation to clinical measures of adaptive skills and autism symptomatology. Findings revealed that less typical scan paths among children with autism were associated with lower communication abilities and greater autism symptomatology.

Background Offspring born to mothers with gestational diabetes mellitus (GDM) are more likely to have negative neurodevelopmental health outcomes, early obesity, type 2 diabetes, and metabolic syndrome in childhood, adolescence, and adulthood. Standard of care management for GDM and type 2 diabetes mellitus during pregnancy is insulin, but oral sulfonylurea use is increasing, and these medications cross the placenta. Literature on treatment with sulfonylureas for maternal GDM has focused on maternal glycemic control and neonatal outcomes. Studies that have evaluated the long‐term outcomes of children exposed to sulfonylureas in utero are limited. Objective This study evaluated anthropometric and neurodevelopmental outcomes of 55 children (ages 5–10) born to mothers with diabetes during pregnancy treated with sulfonylurea or insulin. Methods and Results A group of 25 sulfonylurea‐exposed and 30 insulin‐exposed participants were age‐ and sex‐matched between groups. No significant differences were identified in z‐scores for body mass index (BMI), waist circumference, skinfold measurements, and body fat or rates of overweight/obese BMI between groups. On performance‐based cognitive assessment, the sulfonylurea‐exposed group had significantly lower scores on inhibition (p = 0.043). Conclusion In summary, children with in utero sulfonylurea exposure had similar physical measurements compared to children with insulin exposure and lower performance on a measure of executive function (inhibition), which is associated with adverse health outcomes.

Outcome data in children exposed to glyburide for maternal treatment of gestational diabetes mellitus (GDM) is lacking. Insulin is the standard of care for GDM medical management, yet glyburide use is increasing and this medication crosses the placenta. The study objective was to evaluate physical and neurodevelopmental outcomes of 5-10 year old children born to GDM mothers treated with glyburide or insulin. Children had anthropometric measures including body composition with air displacement plethysmography, and underwent a neurodevelopmental assessment with performance-based tests to evaluate executive functions of working memory and inhibition. Analysis included paired t-tests, chi-square test, and multivariate analysis of variance (MANOVA). Participants, n=51, 25 glyburide-exposed, 26 insulin-exposed were age and sex-matched between groups. Mean age was 7.7 years and 45% were female. Ethnicity and maternal education differed between groups: glyburide-exposed were primarily Hispanic (80%) and had lower maternal education level compared to insulin-exposed (50% Hispanic). Anthropometric means were: BMI 18.8 kg/m2 (sd 5.1), BMI%ile 67.7% (32.3), waist circumference z-score 0.6 (1.1), body fat 21.9% (11.6), triceps z-score 0.8 (1.2), subscapular z-score 1.1 (1.1), sum of 3 skinfolds, triceps, subscapular, iliac crest 39.3 mm (26.0), systolic bp 101 (10.1), diastolic bp 63 (8.2). Among participants, 17.6% had an overweight BMI and 23.5% had an obese BMI. No significant differences were identified in these measures or rates of overweight/obese BMI between groups. A MANOVA with maternal education as a covariate showed that the glyburide-exposed group had significantly lower scores on a visual-spatial working memory test compared to the insulin-exposed group (p=0.03). No differences were observed on an inhibition test. In summary, children with intrauterine glyburide exposure had reduced spatial working memory yet similar physical measurements compared to children with insulin exposure. Disclosure M.S. Rodenstein: None. M.E. Bianco: None. M. Ramchal: None. R.L. Silton: None. M. Murias: None. J.L. Josefson: None. Funding Evergreen Invitational and Institute for Innovations in Developmental Sciences

Autism Spectrum Disorder (ASD) is characterized by early attentional differences that often precede the hallmark symptoms of social communication impairments. Development of novel measures of attentional behaviors may lead to earlier identification of children at risk for ASD. In this work, we first introduce a behavioral measure, Relative Average Look Duration (RALD), indicating attentional preference to different stimuli, such as social versus nonsocial stimuli; and then study its association with neurophysiological activity. We show that (1) ASD and typically developing (TD) children differ in both (absolute) Average Look Duration (ALD) and RALD to stimuli during an EEG experiment, with the most pronounced differences in looking at social stimuli; and (2) associations between looking behaviors and neurophysiological activity, as measured by EEG, are different for children with ASD versus TD. Even when ASD children show attentional engagement to social content, our results suggest that their underlying brain activity is different than TD children. This study therefore introduces a new measure of social/nonsocial attentional preference in ASD and demonstrates the value of incorporating attentional variables measured simultaneously with EEG into the analysis pipeline.

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 autism spectrum disorder (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.

Biomarker development is currently a high priority in neurodevelopmental disorder research. For many types of biomarkers (particularly biomarkers of diagnosis), reliability over short time 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 within visit test-retest reliability based on 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 two-minute recording provides an efficient window into understanding 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) versus 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 longer-term stability of the PSD, for purposes such as monitoring development or response to treatment.

Individuals with Attention Deficit Hyperactivity Disorder (ADHD) tend to perform cognitive tasks with greater Response Time Variability (RTV). Greater RTV in ADHD may be due to inefficient functional connectivity of the brain during information processing. This study aimed to investigate the relationship between brain connectivity, RTV, and levels of ADHD symptoms. Twenty-eight children aged 9–12 years and 49 adolescents aged 15–18 years performed the Sustained Attention to Response Task (SART) while EEG was recorded. The participants’ levels of ADHD symptoms were measured using self- and parent-rated questionnaires. The ex-Gaussian analysis and The Fast Fourier Transform were used to measure multiple aspects of RTV. Functional connectivity between 64 electrodes was computed during task performance, and global efficiency and modularity were calculated, reflecting integration and segregation of the brain, respectively. There was a positive association between multiple RTV measures and the level of ADHD symptoms, where participants with higher levels of ADHD symptoms showed greater RTV, except for sigma from the ex-Gaussian analysis. More efficient brain network activity, measured by global efficiency, was associated with reduced RTV. Children showed greater RTV and less efficient brain network activity compared with the adolescents. These findings support the view that stable responses are achieved with more integrated (and efficient) brain connectivity.

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.

Social communication impairments are a core feature of autism spectrum disorder (ASD), and this class of symptoms is a target for treatments for the disorder. Measures of social attention, assessed via eye-gaze tracking (EGT), have been proposed as an early efficacy biomarker for clinical trials targeting social communication skills. EGT measures have been shown to differentiate children with ASD from typical children; however, there is less known about their relationships with social communication outcome measures that are typically used in ASD clinical trials. In the present study, an EGT task involving viewing a videotape of an actor making bids for a child's attention was evaluated in 25 children with ASD aged 24-72 months. Children's attention to the actor during the dyadic bid condition measured via EGT was found to be strongly associated with five well-validated caregiver-reported outcome measures that are commonly used to assess social communication in clinical trials. These results highlight the convergent validity of EGT measures of social attention in relation to caregiver-reported clinical measures. EGT holds promise as a non-invasive, quantitative, and objective biomarker that is associated with social communication abilities in children with ASD. Autism Res 2018, 11: 166-174. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.Eye-gaze tracking (EGT), an automated tool that tracks eye-gaze patterns, might help measure outcomes in clinical trials investigating interventions to treat autism spectrum disorders. In this study, an EGT task was evaluated in children with ASD, who watched a video with an actor talking directly to them. Patterns of eye-gaze were associated with caregiver-reported measures of social communication that are used in clinical trials. We show EGT may be a promising objective tool measuring outcomes.

It has been suggested that atypical amygdala function contributes to the social impairments characteristic of autism spectrum disorders (ASDs). Previous research has demonstrated that adolescents and adults with ASD generate normal response during a fear-potentiated startle paradigm, suggesting this aspect of amygdala function is intact and may not account for the social dysfunction associated with the condition. The amygdala also plays a crucial role in the expression of anxiety and may contribute to high rates of reported anxiety in individuals with ASD. The present study partially replicates prior work by examining the fear-potentiated startle response in adolescents with ASD, and extends this to investigate the relationship between startle response and anxiety. Eyeblink magnitude and latency (electromyographic activity; EMG) were collected from 20 adolescents with ASD and 19 typically developing (TD) age-matched adolescents during a fear-potentiated startle paradigm. Parent report and self-report of anxiety and additional psychiatric symptoms were collected. Parental reports indicated higher rates of associated psychopathology in adolescents with ASD compared with TD adolescents. Consistent with previous results, both groups showed normal potentiated startle response, and no group differences in EMG were found. Symptoms of anxiety and level of social impairment were unrelated to startle response. These findings held for all levels of anxiety, suggesting that within the context of the fear-potentiated startle paradigm, amygdala response is not associated with degree of atypical social or emotional functioning in ASD.

Individuals with autism spectrum disorder (ASD) show differences in face processing abilities from early in development. To examine whether these differences reflect an atypical versus delayed developmental trajectory, neural responses to familiar and unfamiliar faces in twenty-four 18- to 47-month-old children with ASD were compared with responses of thirty-two 12- to 30-month-old typically developing children. Results of 2 experiments revealed that neural responses to faces in children with ASD resembled those observed in younger typically developing children, suggesting delayed development. Electrophysiological responses to faces were also related to parent report of adaptive social behaviors for both children with ASD and typical development. Slower development of the face processing system in ASD may be related to reduced self-directed "expected" experience with faces in early development.