A Phase II Randomized Clinical Trial of the Safety and Efficacy of Intravenous Umbilical Cord Blood Infusion for Treatment of Children with Autism Spectrum Disorder.

OBJECTIVE: To evaluate whether umbilical cord blood (CB) infusion is safe and associated with improved social and communication abilities in children with autism spectrum disorder (ASD). STUDY DESIGN: This prospective, randomized, placebo-controlled, double-blind study included 180 children with ASD, aged 2-7 years, who received a single intravenous autologous (n = 56) or allogeneic (n = 63) CB infusion vs placebo (n = 61) and were evaluated at 6 months postinfusion. RESULTS: CB infusion was safe and well tolerated. Analysis of the entire sample showed no evidence that CB was associated with improvements in the primary outcome, social communication (Vineland Adaptive Behavior Scales-3 [VABS-3] Socialization Domain), or the secondary outcomes, autism symptoms (Pervasive Developmental Disorder Behavior Inventory) and vocabulary (Expressive One-Word Picture Vocabulary Test). There was also no overall evidence of differential effects by type of CB infused. In a subanalysis of children without intellectual disability (ID), allogeneic, but not autologous, CB was associated with improvement in a larger percentage of children on the clinician-rated Clinical Global Impression-Improvement scale, but the OR for improvement was not significant. Children without ID treated with CB showed significant improvements in communication skills (VABS-3 Communication Domain), and exploratory measures including attention to toys and sustained attention (eye-tracking) and increased alpha and beta electroencephalographic power. CONCLUSIONS: Overall, a single infusion of CB was not associated with improved socialization skills or reduced autism symptoms. More research is warranted to determine whether CB infusion is an effective treatment for some children with ASD.

Associations between executive function and attention abilities and language and social communication skills in young autistic children.

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.

Attention Allocation During Exploration of Visual Arrays in ASD: Results from the ABC-CT Feasibility Study.

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.

The Autism Biomarkers Consortium for Clinical Trials: Initial Evaluation of a Battery of Candidate EEG Biomarkers.

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.

The Selective Social Attention task in children with autism spectrum disorder: Results from the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) feasibility study.

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.

Shorter average look durations to dynamic social stimuli are associated with higher levels of autism symptoms in young autistic children.

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.

Identifying Age Based Maturation in the ERP Response to Faces in Children With Autism: Implications for Developing Biomarkers for Use in Clinical Trials.

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.

The autism biomarkers consortium for clinical trials: evaluation of a battery of candidate eye-tracking biomarkers for use in autism clinical trials.

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.

Developmental change in the ERP responses to familiar faces in toddlers with autism spectrum disorders versus typical development.

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.

Distance from Typical Scan Path When Viewing Complex Stimuli in Children with Autism Spectrum Disorder and its Association with Behavior.

Eye-tracking is often used to study attention in children with autism spectrum disorder (ASD). Previous research has identified multiple atypical patterns of attention in children with ASD based on areas-of-interest analysis. Fewer studies have investigated gaze path, a measure which is dependent on the dynamic content of the stimulus presented. Here, rather than looking at proportions of looking time to areas of interest, we calculated mean fixations frame-by-frame in a group of typically developing children (36 to 72 months) and determined the distance from those typical fixations for 155 children with ASD (27-95 months). Findings revealed that distance from the typical scan path among the children with ASD was associated with lower communication abilities and greater ASD symptomatology.

Long-term follow-up of children with in utero exposure to sulfonylurea medications.

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.

Relative Average Look Duration and its Association with Neurophysiological Activity in Young Children with Autism Spectrum Disorder.

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.

Day-to-Day Test-Retest Reliability of EEG Profiles in Children With Autism Spectrum Disorder and Typical Development.

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

The Autism Biomarkers Consortium for Clinical Trials (ABC-CT): Scientific Context, Study Design, and Progress Toward Biomarker Qualification.

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

An investigation of the relationship between fMRI and ERP source localized measurements of brain activity during face processing.

Brain activity patterns during face processing have been extensively explored with functional magnetic resonance imaging (fMRI) and event-related potentials (ERPs). ERP source localization adds a spatial dimension to the ERP time series recordings, which allows for a more direct comparison and integration with fMRI findings. The goals for this study were (1) to compare the spatial descriptions of neuronal activity during face processing obtained with fMRI and ERP source localization using low-resolution electromagnetic tomography (LORETA), and (2) to use the combined information from source localization and fMRI to explore how the temporal sequence of brain activity during face processing is summarized in fMRI activation maps. fMRI and high-density ERP data were acquired in separate sessions for 17 healthy adult males for a face and object processing task. LORETA statistical maps for the comparison of viewing faces and viewing houses were coregistered and compared to fMRI statistical maps for the same conditions. The spatial locations of face processing-sensitive activity measured by fMRI and LORETA were found to overlap in a number of areas including the bilateral fusiform gyri, the right superior, middle and inferior temporal gyri, and the bilateral precuneus. Both the fMRI and LORETA solutions additionally demonstrated activity in regions that did not overlap. fMRI and LORETA statistical maps of face processing-sensitive brain activity were found to converge spatially primarily at LORETA solution latencies that were within 18 ms of the N170 latency. The combination of data from these techniques suggested that electrical brain activity at the latency of the N170 is highly represented in fMRI statistical maps.

Electrophysiological Correlates of Response Time Variability During a Sustained Attention Task.

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.

On Target Shift in Adversarial Domain Adaptation.

Discrepancy between training and testing domains is a fundamental problem in the generalization of machine learning techniques. Recently, several approaches have been proposed to learn domain invariant feature representations through adversarial deep learning. However, label shift, where the percentage of data in each class is different between domains, has received less attention. Label shift naturally arises in many contexts, especially in behavioral studies where the behaviors are freely chosen. In this work, we propose a method called Domain Adversarial nets for Target Shift (DATS) to address label shift while learning a domain invariant representation. This is accomplished by using distribution matching to estimate label proportions in a blind test set. We extend this framework to handle multiple domains by developing a scheme to upweight source domains most similar to the target domain. Empirical results show that this framework performs well under large label shift in synthetic and real experiments, demonstrating the practical importance.

Methodological considerations in the use of Noldus EthoVision XT video tracking of children with autism in multi-site studies.

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.

Biomarker Acquisition and Quality Control for Multi-Site Studies: The Autism Biomarkers Consortium for Clinical Trials.

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

The role of face familiarity in eye tracking of faces by individuals with autism spectrum disorders.

It has been shown that individuals with autism spectrum disorders (ASD) demonstrate normal activation in the fusiform gyrus when viewing familiar, but not unfamiliar faces. The current study utilized eye tracking to investigate patterns of attention underlying familiar versus unfamiliar face processing in ASD. Eye movements of 18 typically developing participants and 17 individuals with ASD were recorded while passively viewing three face categories: unfamiliar non-repeating faces, a repeating highly familiar face, and a repeating previously unfamiliar face. Results suggest that individuals with ASD do not exhibit more normative gaze patterns when viewing familiar faces. A second task assessed facial recognition accuracy and response time for familiar and novel faces. The groups did not differ on accuracy or reaction times.