Low Risk For Autism Spectrum Disorder Research Articles

Cortical Source Analysis of the Face Sensitive N290 ERP Component in Infants at High Risk for Autism.

Appropriate head models for cortical source analysis were investigated and applied to source analyses examining the neural bases of the face-sensitive N290 event-related potential (ERP) component in infants at high risk for autism spectrum disorder (ASD). This included infant siblings of children with ASD (ASIBs) and infants with fragile X syndrome (FXS). First, alternative head models for use with ASIBs and FXS were investigated. Head models created from the infant’s own MRI were examined in relation to five head models based on average MRI templates. The results of the head model comparison identified group-specific (i.e., ASIB or FXS) head models created from a large collection of structural MRIs as the best substitution for the head model created from the participant’s own structural MRI. Second, the cortical source analysis was completed on N290 data collected from a previous study to investigate brain areas associated with face sensitive ERP responses. Participants’ own MRIs were used for head models when available, and the group-specific head model was used when the participants’ own MRIs were not available. The results provide evidence for unique patterns of neural activation during face processing across infants at high and low risk for ASD and across etiologically distinct high-risk groups. All infants demonstrated greater activation to faces than toys in brain areas most associated with specialized face processing. Infants with FXS displayed higher levels of activation to faces across all areas analyzed, while ASIBs show more muted levels of activation. Overall, the results of the current study demonstrate the importance of group-specific head models for accurate cortical source analysis in infants at high risk for ASD. This also allows for further research on early distinctions in brain function based on risk status.

Neuroimaging Techniques as Descriptive and Diagnostic Tools for Infants at Risk for Autism Spectrum Disorder: A Systematic Review.

Autism Spectrum Disorder (ASD) has traditionally been evaluated and diagnosed via behavioral assessments. However, increasing research suggests that neuroimaging as early as infancy can reliably identify structural and functional differences between autistic and non-autistic brains. The current review provides a systematic overview of imaging approaches used to identify differences between infants at familial risk and without risk and predictive biomarkers. Two primary themes emerged after reviewing the literature: (1) neuroimaging methods can be used to describe structural and functional differences between infants at risk and infants not at risk for ASD (descriptive), and (2) neuroimaging approaches can be used to predict ASD diagnosis among high-risk infants and developmental outcomes beyond infancy (predicting later diagnosis). Combined, the articles highlighted that several neuroimaging studies have identified a variety of neuroanatomical and neurological differences between infants at high and low risk for ASD, and among those who later receive an ASD diagnosis. Incorporating neuroimaging into ASD evaluations alongside traditional behavioral assessments can provide individuals with earlier diagnosis and earlier access to supportive resources.

Symptoms of Autism, Comorbid Mental Health Conditions and Challenging Behaviors among Toddlers with Down Syndrome at Low Risk for ASD-Characterization Using the BISCUIT-Parts 1-3.

Background: Autism spectrum disorder (ASD) may coexist with Down syndrome (DS). Most studies on this topic involve school-age children, adolescents, or adults with DS. This study looked at ASD symptoms, other mental health problems, and challenging behaviors in toddlers with DS at low risk of ASD. Methods: We used screening tools for autism in toddlers; BISCUIT–Parts 1–3 and Q-CHAT. We compared four groups of children aged 17–37 months: DS, ASD, Atypical Development (AD), and Typically Developing (TD). Results: Children with DS showed lower symptoms of ASD than children with ASD (without DS) and higher than TD children, except for repetitive behaviors/restricted interests. For comorbid mental health problems and difficult behaviors, children with DS scored lower than children with ASD. There were no differences between children with DS and TD children in this regard. Conclusions: The study results indicate that BISCUIT–Parts 1–3 are valid instruments to differentiate toddlers with DS from toddlers with ASD. However, they also show that toddlers with DS at low ASD risk are a very heterogeneous group when the ASD symptoms are considered. Autistic characteristics should be taken into account in supporting young children with this genetic condition.

Patterns of objectively measured motor activity among infants developing ASD and concerns for ADHD.

Heightened motor activity is a hallmark of attention-deficit/hyperactivity disorder (ADHD), yet high activity levels are also often reported in young children with autism spectrum disorder (ASD). It is currently unclear whether increased motor activity represents a distinct versus shared early predictor of ASD and ADHD; no prior studies have directly examined this prospectively. We investigated differences in longitudinal patterns of objectively measured motor activity during early development. Participants included 113 infants at high and low risk for ASD or ADHD. Continuous motion-based activity was recorded using tri-axial accelerometers at 12, 18, 24, and 36 months of age. At 36 months, participants were categorized into one of three outcome groups: ASD (n = 19), ADHD Concerns (n = 17), and Typically Developing (TD; n = 77). Group differences in trajectories of motor activity were examined in structured and semistructured contexts. Associations with behaviors relevant to ASD, ADHD, and general development were also examined. In both structured and semistructured contexts, both the ASD and ADHD Concerns groups exhibited heightened activity relative to the TD group by 18 months; the ASD group exhibited higher activity than the ADHD Concerns group at 24-36 months in the structured context only. Attention/behavior regulation, nonverbal, and verbal development-but not social engagement-were differentially associated with objectively measured activity by outcome group across contexts. Overactivity may be a shared, rather than distinct, precursor of atypical development in infants/toddlers developing ASD and concerns for ADHD, emerging as early as 18 months. Group differences in overactivity may be context-specific and associated with different underlying mechanisms.

Sleep Onset Problems and Subcortical Development in Infants Later Diagnosed With Autism Spectrum Disorder.

Sleep patterns in children with autism spectrum disorder (ASD) appear to diverge from typical development in the second or third year of life. Little is known, however, about the occurrence of sleep problems in infants who later develop ASD and possible effects on early brain development. In a longitudinal neuroimaging study of infants at familial high or low risk for ASD, parent-reported sleep onset problems were examined in relation to subcortical brain volumes in the first 2 years of life. A total of 432 infants were included across three study groups: infants at high risk who developed ASD (N=71), infants at high risk who did not develop ASD (N=234), and infants at low risk (N=127). Sleep onset problem scores (derived from an infant temperament measure) were evaluated in relation to longitudinal high-resolution T1 and T2 structural imaging data acquired at 6, 12, and 24 months of age. Sleep onset problems were more common at 6-12 months among infants who later developed ASD. Infant sleep onset problems were related to hippocampal volume trajectories from 6 to 24 months only for infants at high risk who developed ASD. Brain-sleep relationships were specific to the hippocampus; no significant relationships were found with volume trajectories of other subcortical structures examined (the amygdala, caudate, globus pallidus, putamen, and thalamus). These findings provide initial evidence that sleep onset problems in the first year of life precede ASD diagnosis and are associated with altered neurodevelopmental trajectories in infants at high familial risk who go on to develop ASD. If replicated, these findings could provide new insights into a potential role of sleep difficulties in the development of ASD.

Development of neural responses to hearing their own name in infants at low and high risk for autism spectrum disorder

The own name is a salient stimulus, used by others to initiate social interaction. Typically developing infants orient towards the sound of their own name and exhibit enhanced event-related potentials (ERP) at 5 months. The lack of orientation to the own name is considered to be one of the earliest signs of autism spectrum disorder (ASD). In this study, we investigated ERPs to hearing the own name in infants at high and low risk for ASD, at 10 and 14 months. We hypothesized that low-risk infants would exhibit enhanced frontal ERP responses to their own name compared to an unfamiliar name, while high-risk infants were expected to show attenuation or absence of this difference in their ERP responses. In contrast to expectations, we did not find enhanced ERPs to own name in the low-risk group. However, the high-risk group exhibited attenuated frontal positive-going activity to their own name compared to an unfamiliar name and compared to the low-risk group, at the age of 14 months. These results suggest that infants at high risk for ASD start to process their own name differently shortly after one year of age, a period when frontal brain development is happening at a fast rate.

Parents’ experiences from participating in an infant sibling study of autism spectrum disorder

BackgroundProspective longitudinal studies of infant siblings of children with autism spectrum disorder (ASD) play an important role in advancing our knowledge about early developmental pathways in ASD. Despite this clear benefit, currently little is known about potential risks or disadvantages for participating families. As a first step in addressing this issue, we asked parents about their experiences from participating in an infant sibling study. MethodEighty-eight families responded to a questionnaire examining parents’ experiences from participating in an infant sibling study. The questions assessed parents’ satisfaction with the study, the child’s perceived satisfaction, and the parents’ motivation for participating. The study included parents of two groups, (1) infants with an older sibling diagnosed with ASD (HR, high risk, n = 43) and (2) infants with no familial history of ASD (LR, low risk, n = 21). ResultsThe results indicated that parents are generally positive about study participation and few disadvantages were reported. This pattern was mirrored when splitting parents’ responses into the two groups. There was no indication for group differences between parents of infants at high risk and low risk for ASD. ConclusionOur findings present a first step into understanding parents’ experiences from participating in an infant sibling study. Most parents were satisfied with participation in the study and only few disadvantages were reported. Our results have implications for ethical discussions about benefits and risks regarding infant sibling studies in various fields.

M15 - SPECTRUM OF COMMON AND RARE MUTATIONS CONTRIBUTING TO AUTISM RISK IN FAMILIES

Background Autism Spectrum Disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication and repetitive behavior. ASD-associated variants range from changes to a Single Base Pair (SNPs), to the loss or gain of multiple base pairs (Copy Number Variants, CNVs). In addition, ASD-associated variants can be either inherited or de-novo, and either common, with a small increase to risk, or rare, with a strong causal effect. Identifying a set of individuals with greater phenotypic homogeneity may help us reduce genetic heterogeneity, and pinpoint mutations that give us greater insight into the genetic roots of the entire autism spectrum. Under this hypothesis, the Perelman School of Medicine at the University of Pennsylvania established ASPE, the Asperger Syndrome/Autism Spectrum (AS/ASD) Program of Excellence, in 2017, to significantly improve the understanding of the genetic causes of AS/ASD. A major focus of ASPE will be on the NRXN1 gene, which codes for the protein neurexin 1 and has been associated with Autism Spectrum Disorder and other psychiatric and neurodevelopmental disorders. Methods The team will compare the genomes of individuals with and without mutations in the NRXN1 gene and individuals with AS and their family members who may or may not have been diagnosed with AS. We hypothesized that risk for ASD is the result of a cumulative effect of common, small effect variants with additional strong contributions to risk arising from rare, severe effect mutations in genes such as NRXN1. As an initial exploration of this hypothesis, we utilized publically available genotype and exome sequence data (Autism Genetic Resource Exchange, Simons Simplex Collection) and summary statistics from a recent autism GWAS (Psychiatric Genomics Consortium: ASD) to generate polygenic risk scores for all individuals within a family, and establish the contribution of common variants to ASD risk. In addition, we identified rare damaging mutations (both SNPs and CNVs) in genes previously associated with ASD, including NRXN1. Results Common polygenic risk for ASD varies between families with an ASD proband, with some families carrying high risk for ASD, and others carrying low risk. Risk scores in the ASD probands are significantly higher than unaffected family members. We identified several families with low risk for ASD that carry a mutation in NRXN1, suggesting that some individuals will develop ASD as a result of common variation, whereas others with low common polygenic risk may develop ASD as a result of a severe effect variant. Discussion Overall, our findings show that it is necessary to explore the mutational spectrum of variants in families by including both common and rare SNPs and CNVs, to fully capture the genetic basis of risk for ASD.

Vocalization Rate and Consonant Production in Toddlers at High and Low Risk for Autism.

Previous work has documented lower vocalization rate and consonant acquisition delays in toddlers with autism spectrum disorder (ASD). We investigated differences in these variables at 12, 18, and 24 months in toddlers at high and low risk for ASD. Vocalization rate and number of different consonants were obtained from speech samples from a prospective study of infant siblings of children with ASD. Three groups were compared: 18 toddlers at low risk for ASD (low-risk control), 18 high-risk siblings without ASD (HRA-), and 10 high-risk siblings with ASD (HRA+). All groups' mean language scores were within the normal range. HRA+ toddlers showed consistently lower vocalization rate; vocalization rate did not predict number of different consonants at 12 months for HRA+. HRA-, not HRA+, toddlers had the smallest number of different consonants and produced significantly fewer different consonants than predicted by their vocalization rate at 12 months. Consonant-acquisition trajectories differed between groups, with HRA- showing the greatest increase from 12 to 18 months. Lower vocalization rate was not associated with reduced number of different consonants in these toddlers. Between-groups differences in developmental trajectories are discussed in the context of the social feedback loop and differential ability to benefit from adult feedback between groups.

Acquisition of voice onset time in toddlers at high and low risk for autism spectrum disorder.

Although language delay is common in autism spectrum disorder (ASD), research is equivocal on whether speech development is affected. We used acoustic methods to investigate the existence of sub-perceptual differences in the speech of toddlers who developed ASD. Development of the distinction between b and p was prospectively tracked in 22 toddlers at low risk for ASD (LRC), 22 at high risk for ASD without ASD (HRA-), and 11 at high risk for ASD who were diagnosed with ASD at 36 months (HRA+). Voice onset time (VOT), the main acoustic difference between b and p, was measured from spontaneously produced words at 18, 24, and 36 months. Number of words, number of tokens (instances) of syllable-initial b and p produced, error rates, language scores, and motor ability were also assessed. All groups' mean language scores were within the average range or slightly higher. No between-group differences were found in number of words, b's, p's, or errors produced; or in mean or standard deviation of VOT. Binary logistic regression showed that only diagnostic status, not language score, motor ability, number of words, number of b's and p's, or number of errors significantly predicted whether a toddler produced acoustically distinct b and p populations at 36 months. HRA+ toddlers were significantly less likely to produce acoustically distinct b's and p's at 36 months, which may indicate that the HRA+ group may be using different strategies to produce this distinction. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 1269-1279. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Performance of Motor Sequences in Children at Heightened vs. Low Risk for ASD: A Longitudinal Study from 18 to 36 Months of Age.

Recent research shows that motor difficulties are a prominent component of the behavioral profile of autism spectrum disorder (ASD) and are also apparent from early in development in infants who have an older sibling with ASD (High Risk; HR). Delays have been reported for HR infants who do and who do not receive an eventual diagnosis of ASD. A growing body of prospective studies has focused on the emergence of early motor skills primarily during the first year of life. To date, however, relatively little work has examined motor skills in the second and third years. Thus, the present research was designed to investigate motor performance in object transport tasks longitudinally in HR and LR (Low Risk) children between the ages of 18 and 36 months. Participants (15 HR children and 14 LR children) were observed at 18, 24, and 36 months. Children completed two motor tasks, the Ball Task and the Block Task, each of which included two conditions that varied in terms of the precision demands of the goal action. Kinematic data were acquired via two magneto inertial sensors worn on each wrist. In the Block Task, HR children reached more slowly (i.e., mean acceleration was lower) compared to LR children. This finding is in line with growing evidence of early delays in fine motor skills in HR children and suggests that vulnerabilities in motor performance may persist into the preschool years in children at risk for ASD.

The Effect of Parenting Style on Social Smiling in Infants at High and Low Risk for ASD.

This study examined how parenting style at 9months predicts growth in infant social engagement (i.e., social smiling) between 9 and 18months during a free-play interaction in infants at high (HR-infants) and low (LR-infants) familial risk for autism spectrum disorder (ASD). Results indicated that across all infants, higher levels of maternal responsiveness were concurrently associated with higher levels of social smiling, while higher levels of maternal directiveness predicted slower growth in social smiling. When accounting for maternal directiveness, which was higher in mothers of HR-infants, HR-infants exhibited greater growth in social smiling than LR-infants. Overall, each parenting style appears to make a unique contribution to the development of social engagement in infants at high- and low-risk for ASD.

Eye-tracking measurements of language processing: developmental differences in children at high risk for ASD.

To explore how being at high risk for autism spectrum disorder (ASD), based on having an older sibling diagnosed with ASD, affects word comprehension and language processing speed, 18-, 24- and 36-month-old children, at high and low risk for ASD were tested in a cross- sectional study, on an eye gaze measure of receptive language that measured how accurately and rapidly the children looked at named target images. There were no significant differences between the high risk ASD group and the low risk control group of 18- and 24-month-olds. However, 36-month-olds in the high risk for ASD group performed significantly worse on the accuracy measure, but not on the speed measure. We propose that the language processing efficiency of the high risk group is not compromised, but other vocabulary acquisition factors might have lead to the high risk 36-month-olds to comprehend significantly fewer nouns on our measure.