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Until recently, built environments have been designed exclusively to meet the needs of neurotypical populations; however, there is increasing recognition of the need to make built environments more accommodating for neurodiverse populations, including autistic individuals. This scoping review aims to comprehensively explore and synthesise this literature on the internal built environment for autistic individuals providing recommendations for designers, policymakers and clinicians. Five electronic databases were searched, resulting in a total of 28 studies being reviewed. Recommendations are provided for design and construction, lighting, sound, aesthetics, temperature and air quality. While in its early stages, evidence demonstrating the impact that particular qualities of light, colour, sound and spatial planning have on the human sensorium is emerging. In turn, this new knowledge is informing design decisions that are progressing interior environments towards inclusivity. Understanding the positive and negative impacts of decisions made in the design of the built environment has the potential to facilitate the participation and inclusion of autistic individuals.

Children with autism spectrum disorder (ASD) display difficulties with response to joint attention in natural settings but often perform comparably to typically developing (TD) children in experimental studies of gaze following. Previous work comparing infants at elevated likelihood for ASD versus TD infants has manipulated aspects of the gaze cueing stimulus (e.g. eyes only versus head and eyes together), but the role the peripheral object being attended to is not known. In this study of infants at elevated likelihood of ASD (N = 97) and TD infants (N = 29), we manipulated whether or not a target object was present in the cued area. Performance was assessed at 10, 14, and 18 months, and diagnostic assessment was conducted at age 3 years. The results showed that although infants with later ASD followed gaze to the same extent as TD infants in all conditions, they displayed faster latencies back to the model's face when (and only when) a peripheral object was absent. These subtle atypicalities in the gaze behaviors directly after gaze following may implicate a different appreciation of the communicative situation in infants with later ASD, despite their ostensively typical gaze following ability.

Autistic individuals experience higher rates of externalising and internalising symptoms that may vary with environmental factors. However, there is limited research on variation across settings that may highlight common factors with globally generalisable effects. Data were taken from two cohorts: a multinational European sample (n = 764; 453 autistic; 311 non-autistic; 6–30 years), and a South African sample (n = 100 non-autistic; 3–11 years). An exploratory factor analysis aggregated clinical (Verbal Comprehension and Perceptual Index), adaptive traits (Vineland Adaptive Behaviour Scale) and socio-economic variables (parental employment and education, home and family characteristics) in each cohort separately. With regression, we investigated the effect of these factors and autistic traits on internalising and externalising scores (measured with the Strengths and Difficulties Questionnaire). Cohorts showed similar four-factor structures (Person Characteristics, Family System, Parental and Material Resources). The 'Family System' factor captured family size and maternal factors and was associated with lower internalising and externalising symptoms in both cohorts. In the European cohort, high autistic traits reduced this effect; the opposite was found in the South Africa cohort. Our exploratory findings from two separate analyses represent consistent evidence that Family System is associated with internalising and externalising symptoms, with a context-specific impact in persons with high autism traits. Autistic individuals are more likely than non-autistic individuals to experience a mental health condition in their lifetime, and this includes externalising and internalising symptoms. We know very little about how different environments and family conditions impact these symptoms for autistic individuals. Improving our understanding of these relationships is important so that we can identify individuals who may be in greater need of support. In this article, we seek to improve our understanding of how environmental and family conditions impact externalising and internalising symptoms in autistic and non-autistic people. To do this, we conducted analyses with two cohorts in very different settings – in Europe and South Africa – to ensure our findings are globally representative. We used advanced statistical methods to establish environmental and family conditions that were similar to each other, and which could be combined into specific 'factors'. We found that four similar 'factors' could be identified in the two cohorts. These were distinguished by personal characteristics and environmental conditions of individuals, and were named Person Characteristics, Family System, Parental and Material Resources. Interestingly, just 'Family System' was associated with internalising and externalising symptoms, and this was the same in both cohorts. We also found that having high traits of autism impacted this relationship between Family System and mental health conditions with opposite directions in the two settings. These results show that characteristics in the Family System are associated with internalising and externalising symptoms, and autistic persons are particularly impacted, reinforcing the notion that family stressors are important to consider when implementing policy and practice related to improving the mental health of autistic people. [ABSTRACT FROM AUTHOR]

Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) are two often co-occurring neurodevelopmental conditions. Nevertheless, there is limited research about symptom differences between ASD and ASD + ADHD groups. This study examined differences in social interaction and communication between children and adolescents with ASD and with ASD + ADHD. A total of 112 participants were identified from two clinical trials. Fifty-six children and adolescents with ASD aged 8–17 years were matched for age, gender and general intelligence quotient with fifty-six children and adolescents with ASD + ADHD. Group differences in scores on the Autism Diagnostic Observation Schedule were analysed. Our results showed that participants with ASD and with ASD + ADHD had similar profiles of social communication interaction challenges and restricted behaviour. However, items assessing gestures: Conventional, Instrumental or Informational Gestures and Empathic or Emotional gestures showed significant differences between the groups suggesting that the ASD + ADHD group used descriptive gestures to communicate to a greater extent than the ASD group. These findings suggest that children and adolescents in both groups have similar difficulties in social communication and interaction with observed differences in the use of gestures. Possible reasons and implications for the differences in the use of gestures are discussed. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum condition and attention-deficit/hyperactivity disorder (ADHD) are associated with a range of physical health conditions. The aim of this study was to examine the etiological components contributing to co-occurring physical health conditions in autism and ADHD. Methods: In this nationwide Child and Adolescent Twin Study in Sweden, we analyzed data from 10,347 twin pairs aged 9 and 12. Clinical diagnoses of autism, ADHD, and physical health conditions were identified through the Swedish National Patient Register. Subclinical phenotypes of autism and ADHD were defined by symptom thresholds on a standardized parent-interview, the Autism–Tics, ADHD, and Other Comorbidities inventory. Associations between physical health conditions and autism/ADHD phenotypes were examined using generalized estimating equations. Bivariate twin models were applied to estimate the extent to which genetic and environmental risk factors accounted for physical health comorbidities. Results: Similar patterns of association with physical health conditions were found in clinical and subclinical autism/ADHD, with odds ratios ranging from 1.31 for asthma in subclinical ADHD to 8.03 for epilepsy in clinical autism. The estimated genetic correlation (ra) with epilepsy was 0.50 for clinical autism and 0.35 for subclinical autism. In addition, a modest genetic correlation was estimated between clinical autism and constipation (ra = 0.31), functional diarrhea (ra = 0.27) as well as mixed gastrointestinal disorders (ra = 0.30). Genetic effects contributed 0.86 for mixed gastrointestinal disorders in clinical ADHD (ra = 0.21). Finally, subclinical ADHD shared genetic risk factors with epilepsy, constipation, and mixed gastrointestinal disorders (ra = 0.30, 0.17, and 0.17, respectively). Limitations: Importantly, since medical records from primary care were not included in the registry data used, we probably identified only more severe rather than the full range of physical health conditions. Furthermore, it needs to be considered that the higher prevalence of physical health conditions among autistic children and children with ADHD could be associated with the increased number of medical visits. Conclusions: Shared genetic effects contribute significantly to autism and ADHD phenotypes with the co-occurring physical health conditions across different organ systems, including epilepsy and gastrointestinal disorders. The shared genetic liability with co-occurring physical health conditions was present across different levels of autism and ADHD symptom severity. [ABSTRACT FROM AUTHOR]

Background: Reward processing has been proposed to underpin the atypical social feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social reward processing in ASD. Aims: Utilising a large sample, we aimed to assess reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD. Method: Functional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6–30.6 years of age) and 181 typically developing participants (7.6–30.8 years of age). Results: Across social and monetary reward anticipation, whole-brain analyses showed hypoactivation of the right ventral striatum in participants with ASD compared with typically developing participants. Further, region of interest analysis across both reward types yielded ASD-related hypoactivation in both the left and right ventral striatum. Across delivery of social and monetary reward, hyperactivation of the ventral striatum in individuals with ASD did not survive correction for multiple comparisons. Dimensional analyses of autism and attention-deficit hyperactivity disorder (ADHD) scores were not significant. In categorical analyses, post hoc comparisons showed that ASD effects were most pronounced in participants with ASD without co-occurring ADHD. Conclusions: Our results do not support current theories linking atypical social interaction in ASD to specific alterations in social reward processing. Instead, they point towards a generalised hypoactivity of ventral striatum in ASD during anticipation of both social and monetary rewards. We suggest this indicates attenuated reward seeking in ASD independent of social content and that elevated ADHD symptoms may attenuate altered reward seeking in ASD. [ABSTRACT FROM AUTHOR]

Background: Attenuated social attention is a key marker of autism spectrum disorder (ASD). Recent neuroimaging findings also emphasize an altered processing of sensory salience in ASD. The locus coeruleus–norepinephrine system (LC-NE) has been established as a modulator of this sensory salience processing (SSP). We tested the hypothesis that altered LC-NE functioning contributes to different SSP and results in diverging social attention in ASD. Methods: We analyzed the baseline eye-tracking data of the EU-AIMS Longitudinal European Autism Project (LEAP) for subgroups of autistic participants (n = 166, age = 6–30 years, IQ = 61–138, gender [female/male] = 41/125) or neurotypical development (TD; n = 166, age = 6–30 years, IQ = 63–138, gender [female/male] = 49/117) that were matched for demographic variables and data quality. Participants watched brief movie scenes (k = 85) depicting humans in social situations (human) or without humans (non-human). SSP was estimated by gazes on physical and motion salience and a corresponding pupillary response that indexes phasic activity of the LC-NE. Social attention is estimated by gazes on faces via manual areas of interest definition. SSP is compared between groups and related to social attention by linear mixed models that consider temporal dynamics within scenes. Models are controlled for comorbid psychopathology, gaze behavior, and luminance. Results: We found no group differences in gazes on salience, whereas pupillary responses were associated with altered gazes on physical and motion salience. In ASD compared to TD, we observed pupillary responses that were higher for non-human scenes and lower for human scenes. In ASD, we observed lower gazes on faces across the duration of the scenes. Crucially, this different social attention was influenced by gazes on physical salience and moderated by pupillary responses. Limitations: The naturalistic study design precluded experimental manipulations and stimulus control, while effect sizes were small to moderate. Covariate effects of age and IQ indicate that the findings differ between age and developmental subgroups. Conclusions: Pupillary responses as a proxy of LC-NE phasic activity during visual attention are suggested to modulate sensory salience processing and contribute to attenuated social attention in ASD. [ABSTRACT FROM AUTHOR]

Introduction: Facial emotion recognition (FER) requires the integration of multi-dimensional information across various brain regions. Autistic individuals commonly experience difficulties in FER, a phenomenon often attributed to differences in brain connectivity. The nature of task-induced functional brain networks could provide insight into the neuromechanisms underlying FER difficulties in autism, however, to date, these mechanisms remain poorly understood. Methods: In this study, the task induced functional brain networks of 19 autistic and 19 gender, age, and IQ matched non-autistic individuals were examined during a complex FER task. Electroencephalogram (EEG)-based functional brain networks were examined, including the investigation of differences in the time-varying whole-brain functional networks and the exploration of the task induced small-world properties. Results: The results showed statistically significant differences in the task-induced functional networks between autistic and non-autistic adults. Autistic adults compared to non-autistic adults showed a significant shift in the connectivity-based FER processing from the lower to the higher EEG frequency bands. Discussion: These findings may provide evidence at a neural level for the notion that autistic individuals have a preference for bottom-up lower-level processing, or alterations in top-down global processing, potentially contributing to the FER difficulties observed in this population. Results also suggest that functional brain networks in autism show significantly altered task-induced whole-brain small-world properties as compared to non-autistic individuals during complex FER. This study motivates further investigation of the underlying networks-basis of altered emotion processing in autism. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorder (autism) is a complex neurodevelopmental condition with pronounced behavioral, cognitive, and neural heterogeneities across individuals. Here, our goal was to characterize heterogeneity in autism by identifying patterns of neural diversity as reflected in BOLD fMRI in the way individuals with autism engage with a varied array of cognitive tasks. Methods: All analyses were based on the EU-AIMS/AIMS-2-TRIALS multisite Longitudinal European Autism Project (LEAP) with participants with autism (n = 282) and typically developing (TD) controls (n = 221) between 6 and 30 years of age. We employed a novel task potency approach which combines the unique aspects of both resting state fMRI and task-fMRI to quantify task-induced variations in the functional connectome. Normative modelling was used to map atypicality of features on an individual basis with respect to their distribution in neurotypical control participants. We applied robust out-of-sample canonical correlation analysis (CCA) to relate connectome data to behavioral data. Results: Deviation from the normative ranges of global functional connectivity was greater for individuals with autism compared to TD in each fMRI task paradigm (all tasks p < 0.001). The similarity across individuals of the deviation pattern was significantly increased in autistic relative to TD individuals (p < 0.002). The CCA identified significant and robust brain-behavior covariation between functional connectivity atypicality and autism-related behavioral features. Conclusions: Individuals with autism engage with tasks in a globally atypical way, but the particular spatial pattern of this atypicality is nevertheless similar across tasks. Atypicalities in the tasks originate mostly from prefrontal cortex and default mode network regions, but also speech and auditory networks. We show how sophisticated modeling methods such as task potency and normative modeling can be used toward unravelling complex heterogeneous conditions like autism. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental condition diagnosed in approximately 2% of children. Reliance on the emergence of clinically observable behavioral patterns only delays the mean age of diagnosis to approximately 4 years. However, neural pathways critical to language and social functions develop during infancy, and current diagnostic protocols miss the age when therapy would be most effective. We developed non-invasive ASD biomarkers using mass spectrometry analyses of elemental metabolism in single hair strands, coupled with machine learning. We undertook a national prospective study in Japan, where hair samples were collected at 1 month and clinical diagnosis was undertaken at 4 years. Next, we analyzed a national sample of Swedish twins and, in our third study, participants from a specialist ASD center in the US. In a blinded analysis, a predictive algorithm detected ASD risk as early as 1 month with 96.4% sensitivity, 75.4% specificity, and 81.4% accuracy (n = 486; 175 cases). These findings emphasize that the dynamics in elemental metabolism are systemically dysregulated in autism, and these signatures can be detected and leveraged in hair samples to predict the emergence of ASD as early as 1 month of age. [ABSTRACT FROM AUTHOR]

Children with autism spectrum disorder (ASD) display difficulties with response to joint attention in natural settings but often perform comparably to typically developing (TD) children in experimental studies of gaze following. Previous work comparing infants at elevated likelihood for ASD versus TD infants has manipulated aspects of the gaze cueing stimulus (e.g. eyes only versus head and eyes together), but the role the peripheral object being attended to is not known. In this study of infants at elevated likelihood of ASD (N = 97) and TD infants (N = 29), we manipulated whether or not a target object was present in the cued area. Performance was assessed at 10, 14, and 18 months, and diagnostic assessment was conducted at age 3 years. The results showed that although infants with later ASD followed gaze to the same extent as TD infants in all conditions, they displayed faster latencies back to the model's face when (and only when) a peripheral object was absent. These subtle atypicalities in the gaze behaviors directly after gaze following may implicate a different appreciation of the communicative situation in infants with later ASD, despite their ostensively typical gaze following ability. During the first year of life, infants start to align their attention with that of other people. This ability is called joint attention and facilitates social learning and language development. Although children with autism spectrum disorder (ASD) are known to engage less in joint attention compared to other children, several experimental studies have shown that they follow other's gaze (a requirement for visual joint attention) to the same extent as other children. In this study, infants' eye movements were measured at age 10, 14, and 18 months while watching another person look in a certain direction. A target object was either present or absent in the direction of the other person's gaze. Some of the infants were at elevated likelihood of ASD, due to having an older autistic sibling. At age 3 years, infants were assessed for a diagnosis of ASD. Results showed that infants who met diagnostic criteria at 3 years followed gaze to the same extent as other infants. However, they then looked back at the model faster than typically developing infants when no target object was present. When a target object was present, there was no difference between groups. These results may be in line with the view that directly after gaze following, infants with later ASD are less influenced by other people's gaze when processing the common attentional focus. The study adds to our understanding of both the similarities and differences in looking behaviors between infants who later receive an ASD diagnosis and other infants. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties in social communication, but also great heterogeneity. To offer individualized medicine approaches, we need to better target interventions by stratifying autistic people into subgroups with different biological profiles and/or prognoses. We sought to validate neural responses to faces as a potential stratification factor in ASD by measuring neural (electroencephalography) responses to faces (critical in social interaction) in N = 436 children and adults with and without ASD. The speed of early-stage face processing (N170 latency) was on average slower in ASD than in age-matched controls. In addition, N170 latency was associated with responses to faces in the fusiform gyrus, measured with functional magnetic resonance imaging, and polygenic scores for ASD. Within the ASD group, N170 latency predicted change in adaptive socialization skills over an 18-month follow-up period; data-driven clustering identified a subgroup with slower brain responses and poor social prognosis. Use of a distributional data-driven cutoff was associated with predicted improvements of power in simulated clinical trials targeting social functioning. Together, the data provide converging evidence for the utility of the N170 as a stratification factor to identify biologically and prognostically defined subgroups in ASD. Exploiting face processing in patients with ASD: The heterogeneity observed in patients with autism spectrum disorder (ASD) highlights the need for better patient stratification methods. Here, Mason et al. evaluated the use of the speed of early-stage face processing (N170 latency) for clinical stratification and prognosis in ASD and age-matched healthy individuals. N170 latency was slower in individuals with ASD and correlated with response to faces measured with fMRI and with polygenic risk score. Among participants with ASD, the N170 values stratified patients according to socialization prognosis and improved power in a simulated clinical trial. The results suggest that including N170 evaluation in clinical stratification might help the design and development of patient-specific therapies for ASD. [ABSTRACT FROM AUTHOR]

Background: Understanding the development of the neuronal circuitry underlying autism spectrum disorder (ASD) is critical to shed light into its etiology and for the development of treatment options. Resting state EEG provides a window into spontaneous local and long-range neuronal synchronization and has been investigated in many ASD studies, but results are inconsistent. Unbiased investigation in large and comprehensive samples focusing on replicability is needed. Methods: We quantified resting state EEG alpha peak metrics, power spectrum (PS, 2–32 Hz) and functional connectivity (FC) in 411 children, adolescents and adults (n = 212 ASD, n = 199 neurotypicals [NT], all with IQ > 75). We performed analyses in source-space using individual head models derived from the participants' MRIs. We tested for differences in mean and variance between the ASD and NT groups for both PS and FC using linear mixed effects models accounting for age, sex, IQ and site effects. Then, we used machine learning to assess whether a multivariate combination of EEG features could better separate ASD and NT participants. All analyses were embedded within a train-validation approach (70%–30% split). Results: In the training dataset, we found an interaction between age and group for the reactivity to eye opening (p =.042 uncorrected), and a significant but weak multivariate ASD vs. NT classification performance for PS and FC (sensitivity 0.52–0.62, specificity 0.59–0.73). None of these findings replicated significantly in the validation dataset, although the effect size in the validation dataset overlapped with the prediction interval from the training dataset. Limitations: The statistical power to detect weak effects—of the magnitude of those found in the training dataset—in the validation dataset is small, and we cannot fully conclude on the reproducibility of the training dataset's effects. Conclusions: This suggests that PS and FC values in ASD and NT have a strong overlap, and that differences between both groups (in both mean and variance) have, at best, a small effect size. Larger studies would be needed to investigate and replicate such potential effects. [ABSTRACT FROM AUTHOR]

Content validity describes the extent to which a measure represents, and is relevant to, the construct it aims to assess. The International Classification of Functioning, Disability and Health and derived Core/Code Sets (Sets) for autism, attention deficit-hyperactivity disorder, cerebral palsy and early developmental delay and disability are adequate to establish the content validity of measures aiming to assess functioning in young children with neurodevelopmental conditions (NDCs). This article aimed to assess the content validity of comprehensive assessments of functioning for young children with NDCs against these standards. Twenty-two common measures of functioning were evaluated for content validity against the International Classification of Functioning, Disability and Health at a domain level, with 10 measures analysed at the item-level and compared to the Sets relevant to young children with NDCs. Measures covered between 21% and 57% of the combined Set codes and 19% to 63% of codes from specific Sets. Much of this variation was between measures, with some variation due to differences between individual Sets. The percentages reflect that measures heavily focus on activities and participation areas, with environmental factors rarely assessed. These findings are useful for clinicians, policymakers, and researchers in identifying the most appropriate measures for assessing functioning in young children with neurodevelopmental conditions. Young children who have developmental delay, autism, or other neurodevelopmental conditions can have difficulties doing things in different areas of their life. What they can and cannot do is called their level of functioning. There are lots of assessment measures that aim to assess functioning. But, we are not sure if these measures assess all the things we need to know about these children's functioning. Other research has identified lists of items (codes) that need to be assessed to understand functioning for young children with different neurodevelopmental conditions fully. These lists include body functions (the things a child's body or brain can do), activities and participation (the activities and tasks a child does) and environmental factors (parts of the environment that can influence functioning). In this study, we looked at the items from these lists assessed by different functioning measures to see how they compared to what should be assessed. The measures that we looked at covered 21%–57% of all the codes and 19%–63% of the codes for lists specific to different conditions. Most of the measures focused on activity and participation codes, and they rarely assessed environmental factors. Knowing which codes and how much of the lists the measures assess can help researchers, clinicians and policymakers to choose measures that are more appropriate for young children with neurodevelopmental conditions. [ABSTRACT FROM AUTHOR]

Background: A significant proportion of variation in likelihood of neurodevelopmental conditions (NDCs) has been attributed to nonshared environmental (NSE) factors, although it remains unclear which NSE factors pose specific risks for certain NDCs. Methods: A monozygotic co-twin design was applied in a sample of 224 twins (mean age = 17.70 years, SD = 6.28) controlling for confounders such as genes and shared environment. Generalized estimating equation models were fitted, using perinatal and postnatal indications of NSEs as exposure, operationalized both as separate risk factors and as cumulative risk loads. Categorical and dimensional operationalizations of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), intellectual disability and other NDCs were used as outcomes. Results: Birth weight discordance was associated with dimensional autism and ADHD for the smaller twin, and medication during infancy was associated with dimensional autism. Among postnatal factors scarlet fever during early childhood was associated with lower IQ. Especially autism was associated with a greater cumulative perinatal or postnatal risk load. Limitations: When exploring the associations between each condition and specific NSEs the risk of being statistically underpowered increases. Hence, we limit the reported findings on specific indicators of NSEs to trait levels and present descriptive data for categorical NDCs. Conclusions: The findings support previous research by indicating an association between exposure to perinatal and postnatal risks and subsequent NDCs within twin pairs and suggest that autism may be especially linked to accumulative early environmental risks. The findings are potentially important for developmental outcomes prognoses and may inform targeted prevention and early interventions. [ABSTRACT FROM AUTHOR]

Previous research indicates elevated levels of clinically significant traits and symptoms of autism spectrum disorder and attention-deficit hyperactivity disorder (ADHD) in children with chronic pain, but associations with functioning and depression are yet unclear. The current study examined the relationships of autistic traits and ADHD symptoms with pain interference, depression, and health-related quality of life, as well as the mediating roles of insomnia and psychological inflexibility, in children with chronic pain (n = 146, 8–17 years, 102 girls) presenting at a tertiary pain clinic. Children completed measures of pain intensity, depression, pain interference, health-related quality of life, insomnia, and psychological inflexibility. Parents (n = 146, 111 mothers) completed measures to assess autistic traits and ADHD symptoms in their children. Children with clinically significant autistic traits and ADHD symptoms presented with significantly higher levels of depressive symptoms and pain interference, and significantly lower health-related quality of life, than did the other children. Autistic traits and ADHD symptoms contributed significantly to the prediction of pain interference and depressive symptoms, as well as health-related quality of life. Psychological inflexibility mediated the relationships between ADHD symptoms and autistic traits on the one hand and depression, pain interference, and health-related quality of life on the other, while insomnia mediated the relationships between ADHD symptoms and depression, pain interference, and health-related quality of life. All analyses were adjusted for demographics and pain intensity. Results suggest the utility of screening for neurodevelopmental disorders in children with chronic pain. Furthermore, the findings may indicate insomnia and skills related to psychological flexibility as potential treatment targets in interventions aiming at improving functioning and health-related quality of life in children with chronic pain and co-occurring symptoms of neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

While neurodevelopmental disorders (NDDs) are highly heritable, several environmental risk factors have also been suggested. However, the role of familial confounding is unclear. To shed more light on this, we reviewed the evidence from twin and sibling studies. A systematic review was performed on case control and cohort studies including a twin or sibling within-pair comparison of neurodevelopmental outcomes, with environmental exposures until the sixth birthday. From 7,315 screened abstracts, 140 eligible articles were identified. After adjustment for familial confounding advanced paternal age, low birth weight, birth defects, and perinatal hypoxia and respiratory stress were associated with autism spectrum disorder (ASD), and low birth weight, gestational age and family income were associated with attention-deficit/hyperactivity disorder (ADHD), categorically and dimensionally. Several previously suspected factors, including pregnancy-related factors, were deemed due to familial confounding. Most studies were conducted in North America and Scandinavia, pointing to a global research bias. Moreover, most studies focused on ASD and ADHD. This genetically informed review showed evidence for a range of environmental factors of potential casual significance in NDDs, but also points to a critical need of more genetically informed studies of good quality in the quest of the environmental causes of NDDs. [ABSTRACT FROM AUTHOR]

No robust biomarkers have yet been identified for autism spectrum disorder (ASD) or autistic traits. Familial factors likely influence biomarkers such as protein concentrations. Comparing twins with ASD or high autistic traits to the less affected co‐twin allows estimating the impact of familial confounding. We measured 203 proteins in cerebrospinal fluid (n = 86) and serum (n = 127) in twins (mean age 14.2 years, 44.9% females) enriched for ASD and other neurodevelopmental conditions. Autistic traits were assessed by using the parent‐report version of the Social Responsiveness Scale‐2. In cerebrospinal fluid, autistic traits correlated negatively with three proteins and positively with one. In serum, autistic traits correlated positively with 15 and negatively with one. Also in serum, six were positively—and one negatively—associated with ASD. A pathway analysis of these proteins revealed immune system enrichment. In within twin pair analyses, autistic traits were associated with serum B‐cell activating factor (BAFF) only, whereas Cystatin B (CSTB) remained significantly associated with ASD. These associations did not remain significant when only considering monozygotic twins. For the remainder, the within‐pair analysis indicated familial confounding, including shared environment and genes, influencing both autism and protein levels. Our findings indicate proteins involved in immunity as putative biomarkers of autistic traits and ASD with partial genetic confounding. Although some results are in line with previous studies in general, further studies are needed for replication. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder is associated with sensory processing alterations, such as sensory hyper- and hypo-responsiveness. Twin studies are scarce in this field, but they are necessary in order to disentangle the genetic and environmental contributions to this association. Furthermore, it is unclear how different neurodevelopmental/psychiatric conditions contribute to altering sensory processing. We investigated the association between autistic traits/autism spectrum disorder diagnosis and sensory processing alterations in twins (N = 269), using the adult/adolescent sensory profile, which differentiates four sub-domains: Low Registration, Sensation Seeking, Sensory Sensitivity, and Sensation Avoiding. While the associations between autistic traits and Low Registration and Sensation Avoiding persisted within monozygotic (genetically identical) twins, Sensory Sensitivity was only associated with autistic traits within dizygotic twins. In multivariate analyses with different neurodevelopmental/psychiatric diagnoses as predictor variables, autism spectrum disorder and attention deficit hyperactivity disorder were the strongest predictors for two adult/adolescent sensory profile sub-domains each. The results suggest that the association between autistic traits and Sensory Sensitivity is influenced by genetics while non-shared environmental factors influence the associations between autistic traits and Low Registration and Sensation Avoiding. They further indicate that altered sensory processing is not specific to autism spectrum disorder, while autism spectrum disorder is a strong predictor of certain sensory processing alterations, even when controlling for other (comorbid) neurodevelopmental/psychiatric conditions. Individuals diagnosed with autism often describe that they process sensory information differently from others, and many experience sensory issues as problematic. For instance, an increased sensitivity to smells or sounds can make participating in social settings challenging. While sensory issues are now part of the diagnostic criteria for autism, they also co-occur with other psychiatric diagnoses such as attention deficit hyperactivity disorder and anxiety disorders. It is unclear to what extent the relationship between autism and alterations in sensory processing are due to genetics or environment. In addition, more research is needed on how autism, as compared to other diagnoses, is associated with sensory issues. Using a twin study, we found that genetic factors influenced self-reported reactivity to sensory stimuli in autism while environmental factors influenced other sensory issues (e.g. difficulties in detecting or differentiating sensory input). Hence, sensory hyper-reactivity might be an early onset core feature of autism, while other domains of alterations in sensory processing might develop later, influenced by the environment. Moreover, autism was more strongly associated with sensory issues related to increased sensitivity/reactivity as compared to other psychiatric diagnoses. However, attention deficit hyperactivity disorder was more strongly related to deficits in detecting/differentiating sensory stimuli and with an increased drive to seek sensory input. Our results indicate that sensory issues are not specific to autism, but that some aspects of altered sensory processing are more relevant for autism than for other diagnoses. [ABSTRACT FROM AUTHOR]

Theory of mind (ToM), or the ability to attribute mental states to oneself and others, is a core element of social cognition (SC). Even though its importance for social functioning in general, and neurodevelopmental disorders (NDDs), in particular, is well established, the links between ToM and other cognitive functions are not. Especially the familial underpinnings of such links remain unclear. Using a co-twin control design, we examined N = 311 twins (mean age M = 17.19 years, 47% females) diagnosed with autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), other NDDs, or typically developing individuals. We used the Reading the Mind in the Eyes Test to operationalize ToM, the Fragmented Pictures Test for central coherence (CC), the Tower Test for executive functioning (EF), and the general ability index in the Wechsler Intelligence Scales for IQ. In the linear regressions, weak CC and a lower IQ were associated with a reduced ToM ability across pairs. Female sex and higher age were robustly associated with increased ToM ability, whereas EF was not associated with ToM. In the within-pair analyses, where unmeasured familial confounders are implicitly adjusted, the associations between ToM and other cognitive functions, were attenuated and the association with CC was non-significant. The result suggests that familial factors shared by the twins, such as genetic and shared environment, influence the association between CC, IQ, and ToM. Future studies need to include a larger sample of monozygotic twins, who are genetically identical, in order to draw more firm conclusions regarding the influence of familial factors, and to differentiate between shared environmental and genetic effects on the associations between cognitive functions. [ABSTRACT FROM AUTHOR]

Social-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here, we developed a phenotypic stratification model that makes highly accurate (97–99%) out-of-sample SC = RRB, SC > RRB, and RRB > SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset (n = 509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show replicable differences within some networks compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC > RRB and visual association circuitry in SC = RRB. The SC = RRB subtype show hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these networks show a differential enrichment pattern with known autism-associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share many commonalities, but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry. Natasha Bertelsen et al. develop a computational model to categorize patients with autism spectrum disorder (ASD) into distinct subgroups, based on social-communicative or restricted repetitive behaviors. By integrating publicly available neuroimaging and genetic data, they report neural and molecular signatures in two of these subgroups, altogether highlighting subtle differences in neural circuitry and genomic networks that could underlie phenotypic differences among ASD patients. [ABSTRACT FROM AUTHOR]

Attention-deficit/hyperactivity disorder (ADHD) has been associated with increased risk for physical comorbidity. This study used a twin cohort to investigate the association between physical diseases and phenotypic variations of ADHD. A twin cohort enriched for ADHD and other neurodevelopmental conditions were analysed. The Attention Problems subscale of the Child Behavior Checklist/Adult Behavior Checklist (CBCL/ABCL-AP) was used to measure the participants' severity of ADHD symptoms. Physical health issues were obtained with a validated questionnaire and were tested in relation to ADHD symptom severity in a co-twin control model. Neurological problems were significantly associated with a diagnosis of ADHD. A conditional model for the analysis of within-twin pair effects revealed an inverse association between digestive problems and the severity of ADHD symptoms, after adjusting for co-existing autism spectrum disorder and ADHD medications. Our findings suggest that individuals with ADHD are susceptible to neurological problems, why a thorough neurological check-up is indicated in clinical practice for this population. In addition, health conditions of digestive system could be considered as a non-shared environmental factor for behavioral phenotypes in ADHD. It supports the possible role of gut-brain axis in the underpinnings of ADHD symptoms, at least for a subgroup of individuals with certain genetic predisposition. [ABSTRACT FROM AUTHOR]

While previous research has investigated neuroradiological findings in autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), the entire range of neurodevelopmental disorders (NDDs) has not yet been well-studied using magnetic resonance imaging (MRI). Considering the overlap among NDDs and simultaneous development of the brain and face, guided by molecular signaling, we examined the relationship of actionable and incidental (non-actionable) MRI findings and NDD diagnoses together with facial morphological variants and genetic copy number variants (CNVs). A cross-sectional study was conducted with a twin cohort 8–36 years of age (57% monozygotic, 40% dizygotic), including 372 subjects (46% with NDDs; 47% female) imaged by MRI, 280 with data for facial morphological variants, and 183 for CNVs. Fifty-one percent of participants had MRI findings. Males had a statistically significantly higher percentage of MRI findings (57.7%) compared with females (43.8%, p = 0.03). Twin zygosity was not statistically significantly correlated with incidence or severity of specific MRI findings. No statistically significant association was found between MRI findings and any NDD diagnosis or facial morphological variants; however, MRI findings were statistically significantly associated with the number of CNVs (OR 1.20, 95% CI 1.00–1.44, p = 0.05, adjusted OR for sex 1.24, 95% CI 1.03–1.50, p = 0.02). When combining the presence of MRI findings, facial morphological variants, and CNVs, statistically significant relationships were found with ASD and ADHD diagnoses (p = 0.0006 and p = 0.002, respectively). The results of this study demonstrate that the ability to identify NDDs from combined radiology, morphology, and CNV assessments may be possible. Additionally, twins do not appear to be at increased risk for neuroradiological variants. [ABSTRACT FROM AUTHOR]

This study used a twin cohort to investigate the association of autism spectrum disorder (ASD) and autistic traits with somatic health. A total of 344 twins (172 pairs; mean age 15.56 ± 5.62 years) enriched for ASD and other neurodevelopmental conditions were examined. Medical history and current physical problems were collected with a validated questionnaire to determine twin's somatic health. The Social Responsiveness Scale (SRS-2) was used to measure the participant's severity of autistic traits. Identified somatic health issues with significant within-twin pair differences were tested in relation to both ASD diagnosis and autistic traits in a co-twin control model. Twins with ASD exhibited more neurological and immunological health problems compared to those without ASD (p = 0.005 and p = 0.004, respectively). The intra-pair differences of neurological conditions and SRS-2 score were significantly correlated in monozygotic twins differing for autism traits (r = 0.40, p = 0.001), while the correlation was not found for immunological problems. In addition, a conditional model for analysis of within-twin pair effects revealed an association between neurological problems and clinical ASD diagnosis (Odds ratio per neurological problem 3.15, p = 0.02), as well as autistic traits (β = 10.44, p = 0.006), after adjusting for possible effects of co-existing attention deficit hyperactivity disorder and general intellectual abilities. Our findings suggest that neurological problems are associated with autism, and that non-shared environmental factors contribute to the overlap for both clinical ASD and autistic traits. Further population-based twin studies are warranted to validate our results and examine in detailed the shared genetic and environmental contributions of neurological problems and ASD. [ABSTRACT FROM AUTHOR]

Background: Synesthesia is a sensory phenomenon where certain domain-specific stimuli trigger additional sensations of e.g. color or texture. The condition occurs in about 4% of the general population, but is overrepresented in individuals with Autism Spectrum Disorder (ASD), where it might also be associated with the presence of prodigious talents. Case presentation: Here we describe the case of a young transsexual man with Asperger Syndrome, synesthesia and a prodigious talent for foreign language acquisition. In our case, not only letters, numbers, spoken words, music, noises, weekdays and months lead to highly consistent, vivid color sensations but also his own and others' emotions, geometric shapes, any mathematical symbol, and letters from an unfamiliar alphabet (Hebrew). These color associations seem to aid categorization, differentiation and storage of information and might thereby contribute to the young man's language acquisition ability. We investigated the young man's structural brain connectivity in comparison to adults with or without ASD, applying global fiber tracking to diffusion-weighted Magnetic Resonance Imaging (MRI) data. The case presented with increased connectivity, especially between regions involved in visual and emotion processing, memory, and higher order associative binding regions. An electroencephalography experiment investigating synesthetic color and shape sensations while listening to music showed a negligible occipital alpha suppression, indicating that these internally generated synesthetic sensations derive from a different brain mechanism than when processing external visual information. Conclusions: Taken together, this case study endorses the notion of a link between synesthesia, prodigious talent and autism, adding to the currently still sparse literature in this field. It provides new insights into the possible manifestations of synesthesia in individuals with ASD and its potential contribution to prodigious talents in people with an otherwise unexceptional cognitive profile. Additionally, this case impressively illustrates how synesthesia can be a key element not only of sensory perception but also social and emotional processing and contributes to existing evidence of increased brain connectivity in association with synesthesia. [ABSTRACT FROM AUTHOR]

A female advantage in social cognition (SoC) might contribute to women's underrepresentation in autism spectrum disorder (ASD). The latter could be underpinned by sex differences in social brain structure. This study investigated the relationship between structural social brain networks and SoC in females and males in relation to ASD and autistic traits in twins. We used a co-twin design in 77 twin pairs (39 female) aged 12.5 to 31.0 years. Twin pairs were discordant or concordant for ASD or autistic traits, discordant or concordant for other neurodevelopmental disorders or concordant for neurotypical development. They underwent structural magnetic resonance imaging and were assessed for SoC using the naturalistic Movie for the Assessment of Social Cognition. Autistic traits predicted reduced SoC capacities predominantly in male twins, despite a comparable extent of autistic traits in each sex, although the association between SoC and autistic traits did not differ significantly between the sexes. Consistently, within-pair associations between SoC and social brain structure revealed that lower SoC ability was associated with increased cortical thickness of several brain regions, particularly in males. Our findings confirm the notion that sex differences in SoC in association with ASD are underpinned by sex differences in brain structure. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition with key deficits in social functioning. It is widely assumed that the biological underpinnings of social impairment are neurofunctional alterations in the "social brain," a neural circuitry involved in inferring the mental state of a social partner. However, previous evidence comes from small-scale studies and findings have been mixed. We therefore carried out the to-date largest study on neural correlates of mentalizing in ASD. Methods: As part of the Longitudinal European Autism Project, we performed functional magnetic resonance imaging at six European sites in a large, well-powered, and deeply phenotyped sample of individuals with ASD (N = 205) and typically developing (TD) individuals (N = 189) aged 6 to 30 years. We presented an animated shapes task to assess and comprehensively characterize social brain activation during mentalizing. We tested for effects of age, diagnosis, and their association with symptom measures, including a continuous measure of autistic traits. Results: We observed robust effects of task. Within the ASD sample, autistic traits were moderately associated with functional activation in one of the key regions of the social brain, the dorsomedial prefrontal cortex. However, there were no significant effects of diagnosis on task performance and no effects of age and diagnosis on social brain responses. Besides a lack of mean group differences, our data provide no evidence for meaningful differences in the distribution of brain response measures. Extensive control analyses suggest that the lack of case-control differences was not due to a variety of potential confounders. Conclusions: Contrary to prior reports, this large-scale study does not support the assumption that altered social brain activation during mentalizing forms a common neural marker of ASD, at least with the paradigm we employed. Yet, autistic individuals show socio-behavioral deficits. Our work therefore highlights the need to interrogate social brain function with other brain measures, such as connectivity and network-based approaches, using other paradigms, or applying complementary analysis approaches to assess individual differences in this heterogeneous condition. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorder (ASD) evolves from an interplay between genetic and environmental factors during prenatal development. Since identifying maternal biomarkers associated with ASD risk in offspring during early pregnancy might result in new strategies for intervention, we investigated maternal metabolic biomarkers in relation to occurrence of ASD in offspring using both univariate logistic regression and multivariate network analysis. Methods: Serum samples from 100 women with an offspring diagnosed with ASD and 100 matched control women with typically developing offspring were collected at week 14 of pregnancy. Concentrations of 62 metabolic biomarkers were determined, including amino acids, vitamins (A, B, D, E, and K), and biomarkers related to folate (vitamin B9) metabolism, lifestyle factors, as well as C-reactive protein (CRP), the kynurenine-tryptophan ratio (KTR), and neopterin as markers of inflammation and immune activation. Results: We found weak evidence for a positive association between higher maternal serum concentrations of folate and increased occurrence of ASD (OR per 1 SD increase: 1.70, 95% CI 1.22–2.37, FDR adjusted P = 0.07). Multivariate network analysis confirmed expected internal biochemical relations between the biomarkers. Neither inflammation markers nor vitamin D3 levels, all hypothesized to be involved in ASD etiology, displayed associations with ASD occurrence in the offspring. Conclusions: Our findings suggest that high maternal serum folate status during early pregnancy may be associated with the occurrence of ASD in offspring. No inference about physiological mechanisms behind this observation can be made at the present time because blood folate levels may have complex relations with nutritional intake, the cellular folate status and status of other B-vitamins. Therefore, further investigations, which may clarify the potential role and mechanisms of maternal blood folate status in ASD risk and the interplay with other potential risk factors, in larger materials are warranted. [ABSTRACT FROM AUTHOR]

Background: Wearable technology (WT) to measure and support social and non-social functioning in Autism Spectrum Disorder (ASD) has been a growing interest of researchers over the past decade. There is however limited understanding of the WTs currently available for autistic individuals, and how they measure functioning in this population. Objective: This scoping review explored the use of WTs for measuring and supporting abilities, disabilities and functional skills in autistic youth. Method: Four electronic databases were searched to identify literature investigating the use of WT in autistic youth, resulting in a total of 33 studies being reviewed. Descriptive and content analysis was conducted, with studies subsequently mapped to the ASD International Classification of Functioning, Disability and Health Core-sets and the ICF Child and Youth Version (ICF-CY). Results: Studies were predominately pilot studies for novel devices. WTs measured a range of physiological and behavioural functions to objectively measure stereotypical motor movements, social function, communication, and emotion regulation in autistic youth in the context of a range of environments and activities. Conclusions: While this review raises promising prospects for the use of WTs for autistic youth, the current evidence is limited and requires further investigation. [ABSTRACT FROM AUTHOR]

Background: Females with autism spectrum disorder have been reported to exhibit fewer and less severe restricted and repetitive behaviors and interests compared to males. This difference might indicate sex-specific alterations of brain networks involved in autism symptom domains, especially within cortico-striatal and sensory integration networks. This study used a well-controlled twin design to examine sex differences in brain anatomy in relation to repetitive behaviors. Methods: In 75 twin pairs (n = 150, 62 females, 88 males) enriched for autism spectrum disorder (n = 32), and other neurodevelopmental disorders (n = 32), we explored the association of restricted and repetitive behaviors and interests—operationalized by the Autism Diagnostic Interview-Revised (C domain) and the Social Responsiveness Scale-2 (Restricted Interests and Repetitive Behavior subscale)—with cortical volume, surface area and thickness of neocortical, sub-cortical, and cerebellar networks. Results: Co-twin control analyses revealed within-pair associations between RRBI symptoms and increased thickness of the right intraparietal sulcus and reduced volume of the right orbital gyrus in females only, even though the mean number of RRBIs did not differ between the sexes. In a sub-sample of ASD-discordant pairs, increased thickness in association with RRBIs was found exclusively in females in the orbitofrontal regions, superior frontal gyrus, and intraparietal sulcus, while in males RRBIs tended to be associated with increased volume of the bilateral pallidum. Limitations: However, due to a small sample size and the small difference in RRBI symptoms within pairs, the results of this exploratory study need to be interpreted with caution. Conclusions: Our findings suggest that structural alterations of fronto-parietal networks in association with RRBIs are found mostly in females, while striatal networks are more affected in males. These results endorse the importance of investigating sex differences in the neurobiology of autism symptoms, and indicate different etiological pathways underlying restricted and repetitive behaviors and interests in females and males. [ABSTRACT FROM AUTHOR]

Background: It has been suggested that parents of children with autism spectrum disorder (ASD) curtail their reproduction, a phenomenon known as reproductive stoppage. To investigate the presence of reproductive stoppage, we followed the reproduction in mothers of children with or without an ASD diagnosis using Swedish population-based registries. Methods: We followed all families with first child born in 1987 or later. In total 2,521,103 children, nested within 1,270,017 mothers, were included. Exposure was presence of ASD diagnosis in earlier born siblings, and outcome was considered as (1) inter-pregnancy interval and (2) number of subsequent children. Results: Analyses of inter-pregnancy intervals showed that the association differed across birth orders, with a lower rate of second children when first child had ASD diagnosis, but an increased rate of third and higher birth orders in families where a previous child had an ASD diagnosis. When all birth orders were simultaneously considered, families with a child with an ASD diagnosis were less likely to have another child (hazard ratio (HR), 0.79; 95% confidence interval [95% CI], 0.78–0.80). However, when adjusted for birth order, the association was close to null (HR, 0.97; 95% CI, 0.96–0.99), and after additional adjustments (maternal age, birth period, sex, paternal age, and maternal education), the association disappeared (HR, 1.00; 95% CI, 0.99–1.02). In analyses of subsequent children, after adjustment for covariates, families with an ASD diagnosis had 4% more subsequent children (rate ratio, 1.04; 95% CI, 1.03–1.05). Limitations: The study was undertaken in a country with largely tax-funded healthcare; results may not generalize to other societies. Following the current dominating umbrella concept of ASD, we did not differentiate between the ASD sub-diagnoses; it is possible that reproductive patterns can be dependent on ASD subtypes and the severity and composition of ASD phenotypes and comorbidities. Conclusions: This study does not support a universal reproductive stoppage effect in ASD families, when birth order and other factors are considered. Therefore, proper attention to birth order and other factors may alleviate potential bias in familial aggregation studies of ASD. [ABSTRACT FROM AUTHOR]

Alterations in social cognition are hypothesized to underlie social communication challenges in autism spectrum disorder. However, the etiologic underpinnings driving this association, as well as the impact of other psychiatric conditions on the association, remain unclear. Using a co-twin control design, we examined n = 308 twins (mean age = 16.63; 46% females) with autism spectrum disorder, attention-deficit/hyperactivity disorder, affective disorders, or typical development using the Reading the Mind in the Eyes Test to operationalize social cognition ability. Clinical diagnosis of autism spectrum disorder, as well as the extent of quantitative autistic traits, as measured by parental reports using the Social Responsiveness Scale-2, predicted fewer expected responses on the Reading the Mind in the Eyes Test across the pairs. The association remained when adjusting for other diagnoses and IQ. In addition, male sex, lower age, and lower IQ predicted poorer performance on the Reading the Mind in the Eyes Test. The associations between autism and social cognition ability were lost within pairs in both the full sample and the monozygotic subsample. We conclude that the association between autism and social cognition across the sample highlights the importance of social cognition alterations in autism spectrum disorder when compared with other conditions. The attenuation of the association in the within-pair models indicate familial confounding, such as genes and shared environment, influencing both autism and social cognition. [ABSTRACT FROM AUTHOR]

Hundreds of penetrant risk loci have been identified across different neurodevelopmental disorders (NDDs), and these often involve rare (<1% frequency) copy number variations (CNVs), which can involve one or more genes. Monozygotic (MZ) twin pairs are long thought to share 100% of their genomic information. However, genetic differences in the form of postzygotic somatic variants have been reported recently both in typically developing (TD) and in clinically discordant MZ pairs. We sought to investigate the contribution of rare CNVs in 100 twin pairs enriched for NDD phenotypes with a particular focus on postzygotic CNVs in MZ pairs discordant for autism spectrum disorder (ASD) using the Illumina Infinium PsychArray. In our sample, no postzygotic de novo CNVs were found in 55 MZ twin pairs, including the 13 pairs discordant for ASD. We did detect a higher rate of CNVs overlapping genes involved in disorders of the nervous system, such as a rare deletion affecting HNRNPU, in MZ pairs discordant and concordant for ASD in comparison with TD pairs (p = .02). Our results are in concordance with earlier findings that postzygotic de novo CNV events are typically rare in genomic DNA derived from saliva or blood, and suggests that the discordance of NDDs in our sample of twins is not explained by discordant CNVs. Still, studies investigating postzygotic variation in MZ discordant twins using DNA from different tissues and single cells and higher resolution genomics are needed in the future. [ABSTRACT FROM AUTHOR]

Summary: Background: Associations between parental asthma and prenatal exposure to asthma medications with offspring autism spectrum disorder (ASD) have been reported. However, the associations might be confounded by unmeasured (genetic and shared environmental) familial factors. Objective: We investigated the association between (a) maternal/paternal asthma and offspring ASD, and (b) prenatal exposures to β2‐agonists, other asthma medications and offspring ASD using cases and controls selected from the population as well as biological relatives with different degrees of relatedness. Methods: We included all children (N = 1 579 263) born in Sweden 1992‐2007. A nested case‐control design was used to compare 22 894 ASD cases identified from the National Patient Register to (a) 228 940 age‐, county‐ and sex‐matched controls randomly selected from the population, (b) their eligible full‐siblings (n = 1267), (c) half‐siblings (n = 1323), (d) full‐cousins (n = 11 477) and (e) half‐cousins (n = 3337). Conditional logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for ASD in children differentially exposed to parental asthma or prenatal asthma medications. Results: Maternal asthma was associated with increased risk of offspring ASD (OR 1.43, 95% CI 1.38‐1.49); there was a weaker association for paternal asthma (OR 1.17, 95% CI 1.11‐1.23). The risk of offspring ASD in mothers with asthma showed similar estimates when adjusting for shared familial factors among paternal half‐siblings (OR 1.20, 95% CI 0.80‐1.81), full‐cousins (OR 1.28, 95% CI 1.16‐1.41) and half‐cousins (OR 1.30, 95% CI 1.10‐1.54), albeit with wider confidence intervals. Prenatal exposure to asthma medications among subjects whose mothers had asthma was not associated with subsequent ASD. Conclusions and Clinical Relevance: In this large observational study, parental asthma was associated with slightly elevated risk of ASD in offspring. More specifically, the increased risk by maternal asthma did not seem to be confounded by familial factors. There was no evidence of an association between asthma medications during pregnancy and offspring ASD. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental condition of heterogeneous etiology. While it is widely recognized that genetic and environmental factors and their interactions contribute to autism phenotypes, their precise causal mechanisms remain poorly understood. This article reviews our current understanding of environmental risk factors of ASD and their presumed adverse physiological mechanisms. It comprehensively maps the significance of parental age, teratogenic compounds, perinatal risks, medication, smoking and alcohol use, nutrition, vaccination, toxic exposures, as well as the role of extreme psychosocial factors. Further, we consider the role of potential protective factors such as folate and fatty acid intake. Evidence indicates an increased offspring vulnerability to ASD through advanced maternal and paternal age, valproate intake, toxic chemical exposure, maternal diabetes, enhanced steroidogenic activity, immune activation, and possibly altered zinc-copper cycles and treatment with selective serotonin reuptake inhibitors. Epidemiological studies demonstrate no evidence for vaccination posing an autism risk. It is concluded that future research needs to consider categorical autism, broader autism phenotypes, as well as autistic traits, and examine more homogenous autism variants by subgroup stratification. Our understanding of autism etiology could be advanced by research aimed at disentangling the causal and non-causal environmental effects, both founding and moderating, and gene-environment interplay using twin studies, longitudinal and experimental designs. The specificity of many environmental risks for ASD remains unknown and control of multiple confounders has been limited. Further understanding of the critical windows of neurodevelopmental vulnerability and investigating the fit of multiple hit and cumulative risk models are likely promising approaches in enhancing the understanding of role of environmental factors in the etiology of ASD. [ABSTRACT FROM AUTHOR]

Education is effective in improving outcomes in autism spectrum disorder (ASD). While peer mentoring has demonstrated preliminary promise in supporting university students with ASD, the effective mechanisms remain unclear. The aims of this study were to explore the required contexts, mechanisms and outcomes of peer mentoring for university students with ASD. Semi‐structured interviews based on a Realist Evaluation framework were conducted with 23 peer mentors and 24 university students with ASD. Thematic analysis identified three context themes: 'environmental conditions', 'university course demands' and 'aspects of ASD'; four mechanism themes: 'mentor', 'communication and social interaction', 'problem solving' and 'training and supervision'; and five outcome themes: 'identifying personal strengths', 'increased autonomy', 'achieving goals', 'relationships' and 'positive mentor outcomes'. Standard peer mentoring approaches can be enhanced to meet the needs of students with ASD by including training for mentors on ASD, and approaches that support mentees' social interaction and communication needs. [ABSTRACT FROM AUTHOR]

In typical development, infants often alternate their gaze between their interaction partners and interesting stimuli, increasing the probability of joint attention toward surrounding objects and creating opportunities for communication and learning. Children with Autism Spectrum Disorder (ASD) have been found to engage less in behaviors that can initiate joint attention compared to typically developing children, but the role of such atypicalities in the development of ASD during infancy is not fully understood. Here, using eye tracking technology in a live setting, we show that 10-month-olds at high familial risk for ASD engage less in alternating gaze during interaction with an adult compared to low risk infants. These differences could not be explained by low general social preference or slow visual disengagement, as the groups performed similarly in these respects. We also found that less alternating gaze at 10 months was associated with more social ASD symptoms and less showing and pointing at 18 months. These relations were similar in both the high risk and the low risk groups, and remained when controlling for general social preference and disengagement latencies. This study shows that atypicalities in alternating gaze in infants at high risk for ASD emerge already during the first 10 months of life - a finding with theoretical as well as potential practical implications. [ABSTRACT FROM AUTHOR]

There are no alterations in GABAA receptor availability in adults with autism spectrum disorder or in commonly used rodent models of the condition. A window into the ASD brain: A leading hypothesis for autism spectrum disorder (ASD) is that this condition is associated with an imbalance between excitatory glutamate and inhibitory GABA neurotransmission in the brain. To investigate one aspect of GABA signaling, Horder et al. measured the availability of the GABAA receptor in adults with ASD using positron emission tomography. No differences were found compared to control subjects without ASD in two studies performed at different clinical centers. GABAA receptor availability was also normal in three different mouse models of ASD. However, adults with ASD did display altered performance on a GABA-sensitive perceptual task, suggesting that although GABAA receptor density seemed to be normal, GABA signaling pathways could be impaired. Preliminary studies have suggested that γ-aminobutyric acid type A (GABAA) receptors, and potentially the GABAA α5 subtype, are deficient in autism spectrum disorder (ASD). However, prior studies have been confounded by the effects of medications, and these studies did not compare findings across different species. We measured both total GABAA and GABAA α5 receptor availability in two positron emission tomography imaging studies. We used the tracer [11C]flumazenil in 15 adults with ASD and in 15 control individuals without ASD and the tracer [11C]Ro15-4513 in 12 adults with ASD and in 16 control individuals without ASD. All participants were free of medications. We also performed autoradiography, using the same tracers, in three mouse models of ASD: the Cntnap2 knockout mouse, the Shank3 knockout mouse, and mice carrying a 16p11.2 deletion. We found no differences in GABAA receptor or GABAA α5 subunit availability in any brain region of adults with ASD compared to those without ASD. There were no differences in GABAA receptor or GABAA α5 subunit availability in any of the three mouse models. However, adults with ASD did display altered performance on a GABA-sensitive perceptual task. Our data suggest that GABAA receptor availability may be normal in adults with ASD, although GABA signaling may be functionally impaired. [ABSTRACT FROM AUTHOR]

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Europe is diverse in terms of economy, cultures, socio-demography, and languages. A crucial aspect of psychiatric research is the availability of standardized screening, diagnostic, and characterization instruments. We fine-mapped the accessibility of 14 clinical scales and cognitive tests for the assessment of early childhood Autism Spectrum Disorder (ASD; e.g., ADOS, ADI-R, SCQ, SRS, CHAT, MESL) within 21 European countries. These tools are essential for internationally competitive early ASD detection research. We identified a considerable variation not only in the availability, but also psychometric standardization, and formal distribution of the instruments between the countries, privileging English speaking, high-income, and highly populated European countries. Absence of country-specific standardization was a problem across many countries, independent of income and size. Findings demonstrate, on a concrete level, the challenges in creating equal early ASD identification research opportunities in Europe, and the need for increased funding for instrument development and validation. We discuss the reasons, implications, and consequences of this inequity and ways of reducing it. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental condition affecting around 1% of the population. We previously discovered that infant siblings of children with ASD had stronger pupillary light reflexes compared to low-risk infants, a result which contrasts sharply with the weak pupillary light reflex typically seen in both children and adults with ASD. Here, we show that on average the relative constriction of the pupillary light reflex is larger in 9-10-month-old high risk infant siblings who receive an ASD diagnosis at 36 months, compared both to those who do not and to low-risk controls. We also found that the magnitude of the pupillary light reflex in infancy is associated with symptom severity at follow-up. This study indicates an important role of sensory atypicalities in the etiology of ASD, and suggests that pupillometry, if further developed and refined, could facilitate risk assessment in infants. [ABSTRACT FROM AUTHOR]

Introduction: The purpose of this study was to explore the viewpoints of parents of young people with Autism Spectrum Disorder (ASD) in relation to their child’s transition to adulthood. Methods: Data were collected during four structured focus groups with 19 parents of young people with ASD with average to high intellectual capacities. Condensed meaning units were identified and checked during focus groups, and were subsequently linked to the International Classification of Functioning, Disability and Health (ICF). Results: Three major themes emerged: to be understood, to understand the world and to succeed. The ICF domains of activity and participation and environmental factors emerged as having the greatest potential to influence transition outcomes. Conclusions: Policies and services should focus on strengths to maximise participation in higher education, employment and independent living amongst young people with ASD. Interventions targeting environmental factors could be effective in improving participation in adult life. Person-centred and individualised approaches could further complement this approach supporting the transition to adulthood for people with ASD, ultimately improving outcomes in adulthood. [ABSTRACT FROM AUTHOR]

Impaired facial affect recognition (FAR) is observed in schizophrenia and autism spectrum disorder (ASD) and has been linked to amygdala and fusiform gyrus dysfunction. ASD patient's impairments seem to be more pronounced during implicit rather than explicit FAR, whereas for schizophrenia data are inconsistent. However, there are no studies comparing both patient groups in an identical design. The aim of this three-group study was to identify (i) whether FAR alterations are equally present in both groups, (ii) whether they are present rather during implicit or explicit FAR, (iii) and whether they are conveyed by similar or disorder-specific neural mechanisms. Using fMRI, we investigated neural activation during explicit and implicit negative and neutral FAR in 33 young-adult individuals with ASD, 20 subjects with paranoid-schizophrenia and 25 IQ- and gender-matched controls individuals. Differences in activation patterns between each clinical group and controls, respectively were found exclusively for implicit FAR in amygdala and fusiform gyrus. In addition, the ASD group additionally showed reduced activations in medial prefrontal cortex (PFC), bilateral dorso-lateral PFC, ventro-lateral PFC, posterior-superior temporal sulcus and left temporo-parietal junction. Although subjects with ASD showed more widespread altered activation patterns, a direct comparison between both patient groups did not show disorder-specific deficits in neither patient group. In summary, our findings are consistent with a common neural deficit during implicit negative facial affect recognition in schizophrenia and autism spectrum disorders. [ABSTRACT FROM AUTHOR]

Background: Minor physical anomalies (MPAs) are subtle anatomical deviations in one's appearance and may suggest altered embryogenesis. MPAs have been shown to be more common in neurodevelopmental disorders (NDDs) compared with typical development. Still, further studies are needed on MPAs in NDDs, especially using twins to adjust for confounding familial factors. Methods: Clinical assessments were conducted on 116 twins (61 NDD, 55 controls) from 51 monozygotic and 7 dizygotic pairs to examine MPAs and their association with DSM-5 defined NDDs. Additionally, the relationship between the number of MPAs within twins by zygosity was investigated. Results: Within the cohort sample, a specific association was found between MPAs and autism spectrum disorder (ASD) diagnosis (crude odds ratio = 1.29, p = .047; adjusted odds ratios = 1.26-1.33, adjusted p values = .032-.073) and autistic traits (crude ß = 3.02, p = .002; adjusted ß = 2.28, p = .019), but not NDDs in general or ADHD, nor within-pairs. Identified MPAs in ASD included overweight, hypermobility, pes planus, straight eyebrows, vision impairment, arachnodactyly/long toes, long eyelashes, and microtia. The number of MPAs within all monozygotic pairs was highly correlated (r = .88, p < .001). Conclusion: MPAs are more frequent in participants with ASD and may be influenced by genetics. The value of MPAs for (early) detection should be further explored, as they might index individuals at increased risk for ASD in particular. [ABSTRACT FROM AUTHOR]

Background: The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multidisciplinary observational study on biomarkers for autism spectrum disorder (ASD). The current paper describes the clinical characteristics of the LEAP cohort and examines age, sex and IQ differences in ASD core symptoms and common co-occurring psychiatric symptoms. A companion paper describes the overall design and experimental protocol and outlines the strategy to identify stratification biomarkers. Methods: From six research centres in four European countries, we recruited 437 children and adults with ASD and 300 controls between the ages of 6 and 30 years with IQs varying between 50 and 148. We conducted in-depth clinical characterisation including a wide range of observational, interview and questionnaire measures of the ASD phenotype, as well as co-occurring psychiatric symptoms. Results: The cohort showed heterogeneity in ASD symptom presentation, with only minimal to moderate site differences on core clinical and cognitive measures. On both parent-report interview and questionnaire measures, ASD symptom severity was lower in adults compared to children and adolescents. The precise pattern of differences varied across measures, but there was some evidence of both lower social symptoms and lower repetitive behaviour severity in adults. Males had higher ASD symptom scores than females on clinician-rated and parent interview diagnostic measures but not on parent-reported dimensional measures of ASD symptoms. In contrast, self-reported ASD symptom severity was higher in adults compared to adolescents, and in adult females compared to males. Higher scores on ASD symptom measures were moderately associated with lower IQ. Both inattentive and hyperactive/impulsive ADHD symptoms were lower in adults than in children and adolescents, and males with ASD had higher levels of inattentive and hyperactive/impulsive ADHD symptoms than females. Conclusions: The established phenotypic heterogeneity in ASD is well captured in the LEAP cohort. Variation both in core ASD symptom severity and in commonly co-occurring psychiatric symptoms were systematically associated with sex, age and IQ. The pattern of ASD symptom differences with age and sex also varied by whether these were clinician ratings or parent- or self-reported which has important implications for establishing stratification biomarkers and for their potential use as outcome measures in clinical trials. [ABSTRACT FROM AUTHOR]