Investigating the development of the autonomic nervous system in infancy through pupillometry.

We aim to investigate early developmental trajectories of the autonomic nervous system (ANS) as indexed by the pupillary light reflex (PLR) in infants with (i.e. preterm birth, feeding difficulties, or siblings of children with autism spectrum disorder) and without (controls) increased likelihood for atypical ANS development. We used eye-tracking to capture the PLR in 216 infants in a longitudinal follow-up study spanning 5 to 24 months of age, and linear mixed models to investigate effects of age and group on three PLR parameters: baseline pupil diameter, latency to constriction and relative constriction amplitude. An increase with age was found in baseline pupil diameter (F(3,273.21) = 13.15, p < 0.001, [Formula: see text] = 0.13), latency to constriction (F(3,326.41) = 3.84, p = 0.010, [Formula: see text] = 0.03) and relative constriction amplitude(F(3,282.53) = 3.70, p = 0.012, [Formula: see text] = 0.04). Group differences were found for baseline pupil diameter (F(3,235.91) = 9.40, p < 0.001, [Formula: see text] = 0.11), with larger diameter in preterms and siblings than in controls, and for latency to constriction (F(3,237.10) = 3.48, p = 0.017, [Formula: see text] = 0.04), with preterms having a longer latency than controls. The results align with previous evidence, with development over time that could be explained by ANS maturation. To better understand the cause of the group differences, further research in a larger sample is necessary, combining pupillometry with other measures to further validate its value.

Conceptualization of quality of life in autistic individuals.

The present study examines to what extent two core characteristics of the quality of life (QoL) construct were incorporated in the field of autism: (1) its subjective nature; and (2) its multidimensionality. Therefore, we reviewed 174 articles examining QoL in individuals with autism. The review showed parents reporting a lower QoL compared with autistic individuals themselves, especially on internal domains. This may suggest different expectations about what a good QoL may entail. Such an underestimation of QoL by others is commonly observed in individuals with disabilities (the so-called 'disability paradox'). For the multidimensionality of the QoL construct, our findings suggest that the narrower (and more unidimensional) construct of health-related QoL is often measured instead of QoL. Additionally, a substantial proportion of items did not measure QoL, but they evaluated characteristics that may or may not have an impact on QoL. Researchers and clinicians should be aware that QoL domains are selected and operationalized differently by different instruments. QoL may benefit from an exclusive focus on subjective aspects, which can be measured alongside more normative, objective characteristics of individuals or their environment.

8p21.3 deletions are rare causes of non-syndromic autism spectrum disorder.

A de novo 0.95 Mb 8p21.3 deletion had been identified in an individual with non-syndromic autism spectrum disorder (ASD) through high-resolution copy number variant analysis. Subsequent screening of in-house and publicly available databases resulted in the identification of six additional individuals with 8p21.3 deletions. Through case-based reasoning, we conclude that 8p21.3 deletions are rare causes of non-syndromic neurodevelopmental and neuropsychiatric disorders. Based on literature data, we highlight six genes within the region of minimal overlap as potential ASD genes or genes for neuropsychiatric disorders: DMTN, EGR3, FGF17, LGI3, PHYHIP, and PPP3CC.

Ethics of returning children's individual research findings: from principles to practice.

Little ethical recommendations on returning children's individual research findings are available for researchers in behavioral sciences, especially when compared to genetic research. Anecdotic evidence suggests that since parents are often interested in their child's individual research findings, researchers tend to offer this information as a form of compensation for research participation. Despite good intentions, these practices are not without potential harmful consequences for children. We were confronted with these difficulties and with the paucity of available guidance on this topic, being involved in a longitudinal, infant development study, i.e. tracking infants at risk for autism (TIARA). First, we review current ethical recommendations and discuss their limitations in the light of the TIARA study. Second, we will suggest to revise these recommendations, by identifying and applying the relevant bioethical principles and concepts at hand. Third, as an example of practical implementation, the adopted 'return of research findings'-policy for the TIARA-study is presented. The principles and concepts we engage with are the ancillary care responsibilities of the researcher, non-maleficence and beneficence, the right to an open future of the child, and the avoidance of therapeutic misconception. Ultimately, we present the concrete return of research findings policy implemented in the TIARA-study. Here, we suggest restricting the systematic return of children's individual research findings to cases where findings are considered clinically significant and actionable for the child. We discuss the broader implications for designing and conducting research in behavioral sciences with children.

How well are DSM-5 diagnostic criteria for ASD represented in standardized diagnostic instruments?

Five years after the publication of DSM-5 in 2013, three widely used diagnostic instruments have published algorithms designed to represent its (sub-)criteria for Autism Spectrum Disorder (ASD) in children and adolescents. This study aimed to: (1) establish the content validity of these three DSM-5-adapted algorithms, and (2) identify problems with the operationalization of DSM-5 diagnostic criteria in measurable and observable behaviors. Algorithm items of the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2), Developmental, Dimensional and Diagnostic Interview (3di) and Diagnostic Interview for Social and Communication Disorders-11th edition (DISCO-11) were mapped onto DSM-5 sub-criteria. The development and decision-making rules integrated in their algorithms were then compared with DSM-5. Results demonstrated significant variability in the number and nature of sub-criteria covered by the ADOS-2, 3di and DISCO-11. In addition to differences in the development of algorithms and cut-off scores, instruments also differed in the extent to which they follow DSM-5 decision-making rules for diagnostic classification. We conclude that such differences in interpretation of DSM-5 criteria provide a challenge for symptom operationalization which will be most effectively overcome by consensus, testing and reformulation.

Gaze-Contingent Display Changes as New Window on Analytical and Holistic Face Perception in Children With Autism Spectrum Disorder.

The strength of holistic face perception in children with autism spectrum disorder (ASD) was evaluated by applying the gaze-contingent mask and window technique to a face matching and discrimination task in 6- to 14-year-old children with (n = 36) and without ASD (n = 47), and by examining fixation patterns. Behavioral results suggested a slower and less efficient face processing in the ASD sample compared with the matched control group. Comparing the moving mask and window conditions revealed a reduced holistic face processing bias in the younger age group but not in the older sample. Preferential viewing patterns revealed both similarities and differences between both participant groups.

"Hold Me Tight So I Can Go It Alone": Developmental Themes for Young Adults With Autism Spectrum Disorder.

Although research shows that young adults with autism spectrum disorder (ASD) struggle with higher rates of depression, anxiety, and other co-occurring psychiatric disorders, their psychological development through emerging adulthood remains understudied. To explore relevant developmental themes for young adults with ASD while subscribing to a social-constructionist epistemology, we interviewed young adults with ASD and their mental health care professionals individually, and organized focus groups with their parents in a multiperspective design. Developmental themes were identified using interpretative phenomenological analysis. Despite a substantial body of research considering lack of social motivation, a central ASD characteristic, narratives were remarkably socially oriented. This article discusses the overarching themes of (a) searching for balance and negotiating ASD and (b) searching for suitable surroundings in different areas of life, as well as their implications for clinical practice.

Commentary: Conceptualising demand avoidance in an ASD context - a response to Osman Malik & Gillian Baird (2018).

Malik and Baird (this issue) have raised a number of important points drawing on our study of parent-reported dimensions of difficulty in children with features of extreme/'pathological' demand avoidance. In particular, they highlight the pressing need to understand why some children exhibit problematic demand avoidance, and identify factors that promote and maintain these behaviours. As Green et al. () note, children with ASD often show a strong reactivity to the environment. As such, stimuli, activities or interactions that present no problems for typically developing children may unexpectedly provoke extremes of affect. Both Green and colleagues (2018) and Malik & Baird (this issue) highlight a number of possible contributory factors, including sensory sensitivities, difficulty in predicting outcomes, need for sameness, poor tolerance of uncertainty, and fluctuations in autonomic arousal.

Executive functioning and local-global visual processing: candidate endophenotypes for autism spectrum disorder?

BACKGROUND: Heterogeneity within autism spectrum disorder (ASD) hampers insight in the etiology and stimulates the search for endophenotypes. Endophenotypes should meet several criteria, the most important being the association with ASD and the higher occurrence rate in unaffected ASD relatives than in the general population. We evaluated these criteria for executive functioning (EF) and local-global (L-G) visual processing. METHODS: By administering an extensive cognitive battery which increases the validity of the measures, we examined which of the cognitive anomalies shown by ASD probands also occur in their unaffected relatives (n = 113) compared to typically developing (TD) controls (n = 100). Microarrays were performed, so we could exclude relatives from probands with a de novo mutation in a known ASD susceptibility copy number variant, thus increasing the probability that genetic risk variants are shared by the ASD relatives. An overview of studies investigating EF and L-G processing in ASD relatives was also provided. RESULTS: For EF, ASD relatives - like ASD probands - showed impairments in response inhibition, cognitive flexibility and generativity (specifically, ideational fluency), and EF impairments in daily life. For L-G visual processing, the ASD relatives showed no anomalies on the tasks, but they reported more attention to detail in daily life. Group differences were similar for siblings and for parents of ASD probands, and yielded larger effect sizes in a multiplex subsample. The group effect sizes for the comparison between ASD probands and TD individuals were generally larger than those of the ASD relatives compared to TD individuals. CONCLUSIONS: Impaired cognitive flexibility, ideational fluency and response inhibition are strong candidate endophenotypes for ASD. They could help to delineate etiologically more homogeneous subgroups, which is clinically important to allow assigning ASD probands to different, more targeted, interventions.

Visuoperceptual processing in children with neurofibromatosis type 1: True deficit or artefact?

Impairments in visuoperceptual processing have long been considered a hallmark deficit of individuals with Neurofibromatosis type 1 (NF1). However, it is unclear which specific visuoperceptual subprocesses are impaired and whether impairments on these tasks really result from visuoperceptual impairments or rather from confounding factors like Executive Functioning (EF) impairments, lower intelligence (IQ) and/or co-occurring symptoms of Autism Spectrum Disorder (ASD). To answer these questions, we administered four visuoperceptual tasks and two control tasks in 39 children with NF1, 52 typically developing children and 52 children with ASD (8-18 years), all matched for age and gender. Furthermore, EF, IQ, and symptoms of ASD were assessed. Children with NF1 displayed intact visual form discrimination and intact information integration along the dorsal visual pathway. Moreover, their reduced performance on a task requiring integration of information along the ventral visual stream and their more detail-oriented processing style appeared to result from confounding EF impairments and not from visuoperceptual impairments per se. The co-occurring ASD symptoms and lower IQ of the children with NF1 did not impact substantially upon their visuoperceptual performance. These findings point to the large impact of EF impairments on the performance of visuoperceptual task and suggest that individuals with NF1 show intact visual form discrimination, intact visual integration, and typical visual processing style when potential confounding factors are controlled for. This may have large repercussions for the interpretation of other findings on visuoperceptual processing in individuals with NF1. © 2017 Wiley Periodicals, Inc.

Executive functioning deficits in children with neurofibromatosis type 1: The influence of intellectual and social functioning.

The aim of this study was to provide a broad picture of Executive Functioning (EF) in NF1 children, while taking into account their lower average IQ and increased Autism Spectrum Disorder (ASD) symptoms. This was done by administering an extended battery of tasks and questionnaires, designed to reduce task impurity, that measures five EF domains (inhibition, cognitive flexibility, working memory, generativity and planning) in a laboratory setting and in daily life. Data are presented for 42 age- and gender-matched NF1, 52 typically developing, and 52 ASD children (8-18 years). Our results indicated that although EF is highly influenced by IQ and severity of ASD symptoms, EF deficits seem to be a core feature of NF1 and not merely a secondary effect of a lower IQ and/or increased ASD symptoms. However, additional research is needed to confirm these findings.

Executive functioning in autism spectrum disorders: influence of task and sample characteristics and relation to symptom severity.

Impaired executive functioning (EF) has been proposed to underlie symptoms of autism spectrum disorders (ASD). However, insight in the EF profile of ASD individuals is hampered due to task impurity and inconsistent findings. To elucidate these inconsistencies, we investigated the influence of task and sample characteristics on EF in ASD, with an extended test battery designed to reduce task impurity. Additionally, we studied the relation between EF and ASD symptoms. EF (inhibition, cognitive flexibility, generativity, working memory and planning) was measured in open-ended versus structured assessment situations, while controlling for possible confounding EF and non-EF variables. The performance of 50 individuals with ASD was compared with that of 50 age, gender and IQ matched typically developing (TD) individuals. The effects of group (ASD versus TD), age (children versus adolescents) and gender were examined, as well as the correlation between age, IQ, ASD symptoms and EF. Individuals with ASD showed impairments in all EF domains, but deficits were more pronounced in open-ended compared to structured settings. Group differences did not depend on gender and only occasionally on participants' age. This suggests that inconsistencies between studies largely result from differences in task characteristics and less from differences in the investigated sample features. However, age and IQ strongly correlated with EF, indicating that group differences in these factors should be controlled for when studying EF. Finally, EF correlated with both social and non-social ASD symptoms, but further research is needed to clarify the nature of this relationship.

Measuring quantitative autism traits in families: informant effect or intergenerational transmission?

Autism spectrum disorders (ASD) have a high degree of heritability, but there is still much debate about specific causal genes and pathways. To gain insight into patterns of transmission, research has focused on the relatedness of quantitative autism traits (QAT) between family members, mostly using questionnaires. Yet, different kinds of bias may influence research results. In this paper, we focus on possible informant effects and, taking these into account, on possible intergenerational transmission of QAT. This study used multiple informant data retrieved via the Social Responsiveness Scale from 170 families with at least one member with ASD. Using intraclass correlations (ICCs) and mixed model analyses, we investigated inter-informant agreement and differences between parent and teacher reports on children and between self- and other-reports on adults. Using structural equation modelling (SEM), we investigated the relatedness of QAT between family members in ASD families. Parent-teacher agreement about social responsiveness was poor, especially for children with ASD, though agreement between parents was moderate to strong for affected and unaffected children. Agreement between self- and other-report in adult men was good, but only moderate in women. Agreement did not differ between adults with and without ASD. While accounting for informant effects, our SEM results corroborated the assortative mating theory and the intergenerational transmission of QAT from both fathers and mothers to their offspring.

Prevalence of Autism Spectrum Disorder symptoms in children with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic condition. While considerable work has focused on cognitive functioning, several research groups also observed difficulties in social functioning as a prominent feature of NF1. These problems and the possible link between NF1 and Autism Spectrum Disorder (ASD) have become increasingly important in recent NF1 literature. The aim of the current study was to assess ASD characteristics in a hospital-based NF1 pediatric population (n = 82) using the standardized Children Social Behavior Questionnaire (CSBQ) and Social Responsiveness Scale (SRS) to account for the prevalence, severity, and nature of social problems. In a parallel study, comprehensive ASD assessment was performed in a subgroup of NF1 children with a strong suspicion of ASD (n = 31). Results indicate that NF1 children have more social problems than typical controls, more frequently reported above 8 years. The SRS shows that 63% is at risk of ASD symptoms. According to item analyses, most problems were observed on items measuring orientation in, understanding of and being tuned onto a social situation (CSBQ) and social cognition and communication (SRS). In the parallel study, 27 NF1 children were diagnosed with ASD. These children have a distinct phenotype compared to a heterogeneous ASD group, with pronounced social-communicative impairments and fewer restrictive/repetitive behaviors. This study provides a better understanding of social problems in NF1 and the phenotypical overlap with ASD symptomatology. Despite their willingness to engage with others, NF1 children with or without ASD encounter various difficulties in their social-communicative life.

Association of CDH11 with non-syndromic ASD.

We report a sporadic patient with Autism Spectrum Disorder (ASD), mild intellectual disability and attention deficit hyperactivity disorder (ADHD) with a de novo partial deletion of CADHERIN 11 (CDH11). The deletion is associated with one of the breakpoints of a de novo complex chromosomal rearrangement 46,XY,t(3;16;5)(q29;q22;q15)inv4(p14;q21)ins(4;5)(q21;q14.3q15). Cadherins are cell adhesion molecules involved in synaptic plasticity. Since genetic evidence points towards a role for cadherins in ASD, we studied the possible contribution of CDH11 to ASD. A case-control association study for 14 SNP variants in 519 ASD cases and 1,192 controls showed significant overrepresentation of rs7187376C/C genotypes in the patient group [P = 0.0049 (Chi-square = 7.90 1 df) and O.R. 3.88 C.I. = 1.403-10.733]. There was no association for C/T versus T/T [P = 0.6772 (Chi-square = 0.17 1 df)] nor was there association at the allelic level [P = 0.4373 (Chi-square = 0.6 1 df)]. In addition to the association of common variants in CDH11 with ASD, we studied the possible contribution of rare variants by sequencing CDH11 in 247 patients, and found three novel variants in the coding region of CDH1, of which two variants were unlikely to be causal. Targeted CNV screening in these 247 patients did not reveal copy number variation in CDH11. In conclusion, the data provide evidence for the involvement of CDH11 in ASD which is consistent with the association of other cadherins with ASD and neuropsychiatric diseases.

Short report: Recommendations for education, clinical practice, research, and policy on promoting well-being in autistic youth and adults through a positive focus on sexuality and gender diversity.

LAY ABSTRACT: In this article, we propose recommendations on what we can do to promote that autistic people can enjoy their sexuality and gender identity, because that contributes to overall well-being.First, we briefly summarize the existing research on sexuality and gender diversity in autistic individuals.Next, we propose recommendations for how to promote sexual and gender diversity-related health and well-being. Based on what is known about sexuality, gender diversity, and relationships in autistic adolescents and adults, we convened an international group of autistic and non-autistic researchers, advocates, parents, and professionals to develop recommendations to promote sexual and gender health in autistic people.The resulting recommendations were checked through an online survey distributed to autistic people across the world. The online participants endorsed the importance of eight final recommendations related to:1. Providing education and information on sexuality, relationships, and gender diversity to autistic individuals and their families;2. Improving expertise in and accessibility to healthcare for sexuality, relationships, and gender-related questions, with specific attention to prevention of and support after sexual victimization; and3. Meaningfully including the autism community in future research that addresses well-being relating to sexuality, relationships, and gender diversity.These community-driven recommendations aim to promote sexual health and well-being in autistic individuals internationally.

Autism spectrum disorders in children with functional defecation disorders.

OBJECTIVE: To prospectively assess the prevalence of autism spectrum disorder (ASD) symptoms in children presenting with functional defecation disorders. STUDY DESIGN: Children (age 4-12 years) with functional constipation or functional non-retentive fecal incontinence according to the Rome III criteria referred to a specialized outpatient clinic were included. Parents completed 2 validated ASD screening questionnaires about their child; the Social Responsiveness Scale (SRS) and the Social Communication Questionnaire-Lifetime (SCQ-L). A total SRS score of ≥ 51 is a strong indicator for the presence of ASD. On the SCQ-L, a score of ≥ 15 is suggestive for ASD. RESULTS: In total, 242 patients (130 males, median age 7.9 years) were included. Of these, 91% were diagnosed with functional constipation and 9% with functional non-retentive fecal incontinence. Thirteen children (5.4%) had previously been diagnosed with ASD. Twenty-six children (11%) had both SRS and SCQ-L scores at or above cutoff points, strongly suggestive for the presence of ASD. Solely high SRS were present in 42 children (17%), whereas two children (1%) only had high SCQ-L scores. Altogether, 29% had ASD symptoms, indicated by SRS and/or SCQ-L scores at or above the cutoff values. These children were older than children without ASD symptoms and presented with a longer duration of symptoms. CONCLUSIONS: A substantial number of children (29%) presenting with a functional defecation disorder at a tertiary hospital has concomitant ASD symptoms. Clinicians should be aware of ASD symptoms in children with functional defecation disorders.

Diagnosing autism spectrum disorder: who will get a DSM-5 diagnosis?

BACKGROUND: Introduction of proposed criteria for DSM-5 Autism Spectrum Disorder (ASD) has raised concerns that some individuals currently meeting diagnostic criteria for Pervasive Developmental Disorder (PDD; DSM-IV-TR/ICD-10) will not qualify for a diagnosis under the proposed changes. To date, reports of sensitivity and specificity of the new criteria have been inconsistent across studies. No study has yet considered how changes at the 'sub domain' level might affect overall sensitivity and specificity, and few have included individuals of different ages and ability levels. METHODS: A set of DSM-5 ASD algorithms were developed using items from the Diagnostic Interview for Social and Communication Disorders (DISCO). The number of items required for each DSM-5 subdomain was defined either according to criteria specified by DSM-5 (Initial Algorithm), a statistical approach (Youden J Algorithm), or to minimise the number of false positives while maximising sensitivity (Modified Algorithm). The algorithms were designed, tested and compared in two independent samples (Sample 1, N = 82; Sample 2, N = 115), while sensitivity was assessed across age and ability levels in an additional dataset of individuals with an ICD-10 PDD diagnosis (Sample 3, N = 190). RESULTS: Sensitivity was highest in the Initial Algorithm, which had the poorest specificity. Although Youden J had excellent specificity, sensitivity was significantly lower than in the Modified Algorithm, which had both good sensitivity and specificity. Relaxing the domain A rules improved sensitivity of the Youden J Algorithm, but it remained less sensitive than the Modified Algorithm. Moreover, this was the only algorithm with variable sensitivity across age. All versions of the algorithm performed well across ability level. CONCLUSIONS: This study demonstrates that good levels of both sensitivity and specificity can be achieved for a diagnostic algorithm adhering to the DSM-5 criteria that is suitable across age and ability level.

Is there a common neuroanatomical substrate of language deficit between autism spectrum disorder and specific language impairment?

Discussion of an overlap between specific language impairment (SLI) and autism spectrum disorder (ASD) is on going. The most intriguing overlap between both phenotypes is the similarity in the observed language deficits described in SLI and a subgroup of ASD with co-occurring linguistic impairment, ASD-LI. Examining whether a similar neuroanatomical substrate underlies this phenotypical linguistic overlap, we studied the white matter microstructural properties of the superior longitudinal fascicle (SLF) of 19 ASD-LI adolescents (mean age 13.8 ± 1.6 years) and 21 age-matched controls and compared them with 13 SLI children (mean age 10.1 ± 0.4 years) and 12 age-matched controls. A linguistic profile assessment and a diffusion tensor imaging analysis of the SLF were performed. Linguistic testing revealed a mixed receptive-expressive disorder profile in both groups, confirming their overlap at phenotypical level. At neuroanatomical level, no significant differences in mean SLF fractional anisotropy (FA) and mean SLF apparent diffusion coefficient values between ASD-LI participants and controls were seen. By contrast, the mean SLF FA was significantly reduced in the SLI children as compared with their controls. The observation of structural SLF disturbances in SLI but not in ASD-LI suggests the existence of a different neuroanatomical substrate for the language deficits in both disorders.