Interaction In Autism Spectrum Disorder Research Articles

Cohort-guided insights into gene-environment interactions in autism spectrum disorders.

Prospective birth cohorts offer unprecedented opportunities to investigate the pathogenesis of complex disorders such as autism, in which gene-environment interactions must be appreciated in a temporal context. This Perspective article considers the history of autism research, including missteps that reflected an incomplete understanding of the epidemiology of autistic spectrum disorders, the effects of advocacy and philanthropy on the trajectory of scientific inquiry, and the current and future roles of prospective birth cohort research in illuminating the pathology of these and other complex disorders wherein exposures during gestation might not manifest until later in life.

Cortico-Cerebellar neurodynamics during social interaction in Autism Spectrum Disorders

BackgroundExploring neural network dynamics during social interaction could help to identify biomarkers of Autism Spectrum Disorders (ASD). A cerebellar involvement in autism has long been suspected and recent methodological advances now enable studying cerebellar functioning in a naturalistic setting. Here, we investigated the electrophysiological activity of the cerebro-cerebellar network during real-time social interaction in ASD. We focused our analysis on theta oscillations (3–8 Hz), which have been associated with large-scale coordination of distant brain areas and might contribute to interoception, motor control, and social event anticipation, all skills known to be altered in ASD. MethodsWe combined the Human Dynamic Clamp, a paradigm for studying realistic social interactions using a virtual avatar, with high-density electroencephalography (HD-EEG). Using source reconstruction, we investigated power in the cortex and the cerebellum, along with coherence between the cerebellum and three cerebral-cortical areas, and compared our findings in a sample of participants with ASD (n = 107) and with typical development (TD) (n = 33). We developed an open-source pipeline to analyse neural dynamics at the source level from HD-EEG data. ResultsIndividuals with ASD showed a significant increase in theta band power over the cerebellum and the frontal and temporal cortices during social interaction compared to resting state, along with significant coherence increases between the cerebellum and the sensorimotor, frontal and parietal cortices. However, a phase-based connectivity measure did not support a strict activity increase in the cortico-cerebellar functional network. We did not find any significant differences between the ASD and the TD group. ConclusionsThis exploratory study uncovered increases in the theta band activity of participants with ASD during social interaction, pointing at the presence of neural interactions between the cerebellum and cerebral networks associated with social cognition. It also emphasizes the need for complementary functional connectivity measures to capture network-level alterations. Future work will focus on optimizing artifact correction to include more participants with TD and increase the statistical power of group-level contrasts.

A Role for Gene-Environment Interactions in Autism Spectrum Disorder Is Supported by Variants in Genes Regulating the Effects of Exposure to Xenobiotics.

Heritability estimates support the contribution of genetics and the environment to the etiology of Autism Spectrum Disorder (ASD), but a role for gene-environment interactions is insufficiently explored. Genes involved in detoxification pathways and physiological permeability barriers (e.g., blood-brain barrier, placenta and respiratory airways), which regulate the effects of exposure to xenobiotics during early stages of neurodevelopment when the immature brain is extremely vulnerable, may be particularly relevant in this context. Our objective was to identify genes involved in the regulation of xenobiotic detoxification or the function of physiological barriers (the XenoReg genes) presenting predicted damaging variants in subjects with ASD, and to understand their interaction patterns with ubiquitous xenobiotics previously implicated in this disorder. We defined a panel of 519 XenoReg genes through literature review and database queries. Large ASD datasets were inspected for in silico predicted damaging Single Nucleotide Variants (SNVs) (N = 2,674 subjects) or Copy Number Variants (CNVs) (N = 3,570 subjects) in XenoReg genes. We queried the Comparative Toxicogenomics Database (CTD) to identify interaction pairs between XenoReg genes and xenobiotics. The interrogation of ASD datasets for variants in the XenoReg gene panel identified 77 genes with high evidence for a role in ASD, according to pre-specified prioritization criteria. These include 47 genes encoding detoxification enzymes and 30 genes encoding proteins involved in physiological barrier function, among which 15 are previous reported candidates for ASD. The CTD query revealed 397 gene-environment interaction pairs between these XenoReg genes and 80% (48/60) of the analyzed xenobiotics. The top interacting genes and xenobiotics were, respectively, CYP1A2, ABCB1, ABCG2, GSTM1, and CYP2D6 and benzo-(a)-pyrene, valproic acid, bisphenol A, particulate matter, methylmercury, and perfluorinated compounds. Individuals carrying predicted damaging variants in high evidence XenoReg genes are likely to have less efficient detoxification systems or impaired physiological barriers. They can therefore be particularly susceptible to early life exposure to ubiquitous xenobiotics, which elicit neuropathological mechanisms in the immature brain, such as epigenetic changes, oxidative stress, neuroinflammation, hypoxic damage, and endocrine disruption. As exposure to environmental factors may be mitigated for individuals with risk variants, this work provides new perspectives to personalized prevention and health management policies for ASD.

Cortico-Cerebellar Neurodynamics During Social Interaction in Autism Spectrum Disorder

Cortico-Cerebellar Neurodynamics During Social Interaction in Autism Spectrum Disorder

Using a STEM activity to improve social communication interactions in autism spectrum disorder

Social communication deficits associated with Autism Spectrum Disorder are often exacerbated during adolescence. Group based approaches are effective intervention techniques for facilitating improved social communication skills in people with ASD; however, science, technology, engineering, and math activities, while highly preferred areas of interest, are overlooked as a therapeutic tool. This study determines the effectiveness of peer collaborations using a STEM activity on social communication for adolescents with ASD. Using solarbotics kits, peer dyads worked together over the course of a 12-week period to construct a functioning robot. Measures of social communication were collected prior to the initiation of the intervention, during the intervention, and after the intervention. Results indicated that the collaborative peer intervention using a STEM focused approach facilitated non-verbal and pragmatic improvements.

Early developmental changes in visual social engagement in infant rhesus monkeys

Impairments in social interaction in Autism Spectrum Disorder (ASD) differ greatly across individuals and vary throughout an individual’s lifetime. Yet, an important marker of ASD in infancy is deviations in social-visual engagement, such as the reliably detectable early deviations in attention to the eyes or to biological movement (Klin et al., 2015). Given the critical nature of these early developmental periods, understanding its neurobehavioral underpinnings by means of a nonhuman primate model will be instrumental to understanding the pathophysiology of ASD. Like humans, rhesus macaques 1) develop in rich and complex social behaviors, 2) progressively develop social skills throughout infancy, and 3) have high similarities with humans in brain anatomy and cognitive functions (Machado and Bachevalier, 2003). In this study, male infant rhesus macaques living with their mothers in complex social groups were eye-tracked longitudinally from birth to 6 months while viewing full-faced videos of unfamiliar rhesus monkeys differing in age and sex. The results indicated a critical period for the refinement of social skills around 4–8 weeks of age in rhesus macaques. Specifically, infant monkeys’ fixation to the eyes shows an inflection in developmental trajectory, increasing from birth to 8 weeks, decreasing slowly to a trough between 14–18 weeks, before increasing again. These results parallel the developmental trajectory of social visual engagement published in human infants (Jones & Klin, 2013) and suggest the presence of a switch in the critical networks supporting these early developing social skills that is highly conserved between rhesus macaque and human infant development.

Gut-Amygdala Interactions in Autism Spectrum Disorders: Developmental Roles via regulating Mitochondria, Exosomes, Immunity and microRNAs.

Autism Spectrum Disorders (ASD) have long been conceived as developmental disorder. A growing body of data highlights a role for alterations in the gut in the pathoetiology and/or pathophysiology of ASD. Recent work shows alterations in the gut microbiome to have a significant impact on amygdala development in infancy, suggesting that the alterations in the gut microbiome may act to modulate not only amygdala development but how the amygdala modulates the development of the frontal cortex and other brain regions. This article reviews wide bodies of data pertaining to the developmental roles of the maternal and foetal gut and immune systems in the regulation of offspring brain development. A number of processes seem to be important in mediating how genetic, epigenetic and environmental factors interact in early development to regulate such gut-mediated changes in the amygdala, wider brain functioning and inter-area connectivity, including via regulation of microRNA (miR)-451, 14-3-3 proteins, cytochrome P450 (CYP)1B1 and the melatonergic pathways. As well as a decrease in the activity of monoamine oxidase, heightened levels of in miR-451 and CYP1B1, coupled to decreased 14-3-3 act to inhibit the synthesis of N-acetylserotonin and melatonin, contributing to the hyperserotonemia that is often evident in ASD, with consequences for mitochondria functioning and the content of released exosomes. These same factors are likely to play a role in regulating placental changes that underpin the association of ASD with preeclampsia and other perinatal risk factors, including exposure to heavy metals and air pollutants. Such alterations in placental and gut processes act to change the amygdala-driven biological underpinnings of affect-cognitive and affect-sensory interactions in the brain. Such a perspective readily incorporates previously disparate bodies of data in ASD, including the role of the mu-opioid receptor, dopamine signaling and dopamine receptors, as well as the changes occurring to oxytocin and taurine levels. This has a number of treatment implications, the most readily applicable being the utilization of sodium butyrate and melatonin.

A novel concept of immunological and allergy interactions in autism spectrum disorders: Molecular, anti-inflammatory effect of osthole

BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder defined by Diagnosis and Statistic Manual 5 (DSM-5) as persistent social interaction and communication deficient across multiple contexts. Various immunological findings have been reported in children with ASD, and co-existing allergic problems have been recorded in children diagnosed with ASD. Osthole, the effective component of Chinese traditional medicine, is reported to have anti-inflammatory effects. This study assessed the anti-inflammatory effect of osthole on the histamine-induced inflammatory responses in PBMC cells. MethodsPeripheral blood mononuclear cells (PBMC's) from children with: (1) ASD group with co-existing allergies/asthma (n = 29); (2) ASD group without allergy/asthma (n = 29); (3) Allergy group (n = 30) and from typically developing age-matched control subjects (n = 28) were stimulated with either histamine, FXF, osthole or mixture of this substances. mRNA COX-2 gene expression, COX-2 production and inhibitory effect of tested substances on COX-2 were assessed after stimulation. ResultsChildren with ASD may show either an innate proinflammatory response or increased activity of COX-2 which could display more impaired behavioral profile than children with non-inflamed. This study indicated that COX-2 may be involved in pathogenesis of ASD and/or allergy, and osthole could be used to decrease the effects of COX-2 in inflammation and ASD development. High incidence of allergy in ASD patients may indicate immune dysregulation that could be of relevance to the pathophysiology, symptomatology or neuroimmunology of ASD. ConclusionsThis study shows that fexofenadine (FXF – antihistamine drug) and osthole exhibit selective COX-2 enzyme inhibitory activity. The selective COX-2 activity of osthole may explain further the anti-inflammatory properties of osthole in relieving congestion in allergic rhinitis, and as distinctive effects between FXF and osthole were observed, individual antihistamines may have different modes of action via the COX enzyme system.

Inferring power and dominance from dyadic nonverbal interactions in autism spectrum disorder.

Research studies to date have revealed conflicting results with respect to the processing of nonverbal cues from social interactions in autism spectrum disorder (ASD). Therefore, the aim of the present study was to investigate the contribution of two important factors for the perception of dyadic social interactions, namely (a) the movement contingency and (b) the spatial context. To this end, 26 adult participants with ASD and 26 age-, sex-, and IQ-matched typically developed control participants observed animations presenting nonverbal interactions between two human virtual characters enacting power relationships. We manipulated (a) movement contingency by exchanging one of the two original agents with an agent from another dyad and (b) spatial context by changing agents' spatial orientation to a back-to-back position. Participants were asked to rate dominance and submissiveness of these agents. Results showed that the movement contingency manipulation affected accuracy and consistency of power perception and that the spatial context manipulation slowed down reaction times comparably in both groups. With regard to group differences, individuals with ASD were found to judge power relationships slower compared to control participants, potentially suggesting a more explicit processing style in ASD. Furthermore, the spatial context manipulation slowed down the reaction times more in the contingent compared to the non-contingent conditions only in the ASD group. These findings contribute to the ongoing debate whether individuals with ASD have difficulties in understanding nonverbal cues in a dyadic context by suggesting that they do so in more subtle ways than previously investigated. Autism Res 2019, 12: 505-516 © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study shows that the ability and speed of judging who is dominant in a social interaction depends on two factors: (a) whether their movements are matched and (b) whether they are facing each other or not. This is similarly the case for participants with and without autism. Interestingly, however, individuals with autism seem to judge generally slower, suggesting a more explicit processing style. The two factors seem to interact, suggesting that nonverbal processing difficulties are subtler than previously thought.

Early interaction in autism spectrum disorder: Mothers' and children's behaviours during joint engagement.

More knowledge about the interaction between young children with autism spectrum disorder and their parents is one way to improve intervention. This study aims to investigate the behaviours of mothers and children with autism spectrum disorder during joint engagement, with a focus on pacing or rate (i.e., incidences per minute) of their behaviours when being in this state. Video recordings of 10min of free-play between 58 children (2-4years) diagnosed with childhood autism and their mothers were used to examine rate of mothers' and children's behaviours (i.e., toy introduction, toy expansion, positive affect, and language) during joint engagement, the association between rate of mothers and children's behaviours, the relation between rate of mothers' behaviours and time in joint engagement, and how child factors might be associated with the latter. Mothers(m) and children(c) showed similar rate of positive affect (Mm =0.6/Mc =0.5) and toy expansion (Mm =0.7/Mc =0.7) per minute, whereas mothers talked almost three times more than their children (Mm =10.2/Mc =3.8). In contrast, mothers introduced fewer toys compared to the children (Mm =0.7/Mc =1.2). Rate of mothers' toy introduction, toy expansion, and positive affect was inversely related to time in joint engagement (Regression coefficient=-70.7 to -48.5, p=.006 to .024). Rates of mothers' and children's behaviours were associated (Spearman rank order coefficient=.53 to .29, p<.001 to .03), but neither rate of children's behaviours nor mental age was associated with the observed relation between rate of these maternal behaviours and time in joint engagement. Time in joint engagement was related to rate of mothers' behaviours and children's mental age but not to rate of children's behaviours in this study. Thus, intervention teaching parents of young children with autism strategies designed to increase time in joint engagement may be vital. The complex nature of the interaction between mother and child behaviours in promoting joint engagement warrants further elucidation.

Simulating interaction: Using gaze-contingent eye-tracking to measure the reward value of social signals in toddlers with and without autism

Several accounts have been proposed to explain difficulties with social interaction in autism spectrum disorder (ASD), amongst which atypical social orienting, decreased social motivation or difficulties with understanding the regularities driving social interaction. This study uses gaze-contingent eye-tracking to tease apart these accounts by measuring reward related behaviours in response to different social videos. Toddlers at high or low familial risk for ASD took part in this study at age 2 and were categorised at age 3 as low risk controls (LR), high-risk with no ASD diagnosis (HR-no ASD), or with a diagnosis of ASD (HR-ASD). When the on-demand social interaction was predictable, all groups, including the HR-ASD group, looked longer and smiled more towards a person greeting them compared to a mechanical Toy (Condition 1) and also smiled more towards a communicative over a non-communicative person (Condition 2). However, all groups, except the HR-ASD group, selectively oriented towards a person addressing the child in different ways over an invariant social interaction (Condition 3). These findings suggest that social interaction is intrinsically rewarding for individuals with ASD, but the extent to which it is sought may be modulated by the specific variability of naturalistic social interaction.

Epigenetic Understanding of Gene-Environment Interaction in Autism Spectrum Disorder

AbstractThe number of children with autism spectrum disorder (ASD) has increased in many countries over the past 10 years. Genetic studies have revealed that ASD is caused by mutations in the genes coding proteins related to neuronal function. However, such genetic abnormalities cannot underlie the increase in this disorder since mutations do not accumulate among children in the short-term. Epigenetics is a mechanism that is involved in gene regulation not by changing DNA sequence (mutations) but by changing the chemical modifications of DNA and histone proteins. Current studies suggest that mental stress and other forms of environmental stress in early life alter the epigenetic status of genes and change the neuronal gene function, resulting in persistent behavioral abnormalities. Therefore, it can be speculated that the current increase in the prevalence of ASD is partially caused by epigenetic changes in the brains of children induced by some recent socio-environmental conditions. However, epigenetic changes are reversible. Indeed, it has been demonstrated that some drugs for mental disorders reverse the altered epigenetic state and recover the expression of neuronal genes. It has also been demonstrated that offering an appropriate nurturing environment in early life reverses the altered epigenetic state and recovers the neurological gene function in mouse models of ASD. Therefore, from the epigenetic point of view, early medical and educational interventions may be important for children with ASD.

Tumor necrosis factor-alpha expression in peripheral blood mononuclear cells correlates with early childhood social interaction in autism spectrum disorder

Autism spectrum disorder is a neurodevelopmental disorder characterized by impaired social interaction, poor communication skills, and repetitive/restrictive behaviors. Elevated blood levels of pro-inflammatory cytokines have been reported in subjects with autism spectrum disorder. On the other hand, early childhood adverse experience also increases blood levels of these cytokines. Since social experience of children with autism spectrum disorder is generally unlike to typically developing children, we hypothesized that social interaction during childhood contribute to pro-inflammatory cytokine expression in subjects with autism spectrum disorder. We compared revised Autism Diagnostic Interview scores and expression levels of pro-inflammatory cytokines in peripheral blood mononuclear cells of subjects with autism spectrum disorder (n = 30). The score of domain A on the revised Autism Diagnostic Interview, indicating social interaction impairment in early childhood, was negatively correlated with tumor necrosis factor-α mRNA expression level in peripheral blood mononuclear cells but not interleukin-1β or -6. Consistently, tumor necrosis factor-α mRNA expression was markedly low in subjects with autism spectrum disorder compared to typically developing children who presumably experienced the regular levels of social interaction. These findings suggest that the low blood levels of tumor necrosis factor-α mRNA in subjects with autism spectrum disorder might be due to impaired social interaction in early childhood.

Gut to brain interaction in Autism Spectrum Disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters.

BackgroundA high prevalence of a variety of gastrointestinal (GI) symptoms is frequently reported in patients with Autism Spectrum Disorders (ASD). The GI disturbances in ASD might be linked to gut dysbiosis representing the observable phenotype of a “gut-brain axis” disruption. The exploitation of strategies which can restore normal gut microbiota and reduce the gut production and absorption of toxins, such as probiotics addition/supplementation in a diet, may represent a non-pharmacological option in the treatment of GI disturbances in ASD. The aim of this randomized controlled trial is to determine the effects of supplementation with a probiotic mixture (Vivomixx®) in ASD children not only on specific GI symptoms, but also on the core deficits of the disorder, on cognitive and language development, and on brain function and connectivity. An ancillary aim is to evaluate possible effects of probiotic supplementation on urinary concentrations of phthalates (chemical pollutants) which have been previously linked to ASD.MethodsA group of 100 preschoolers with ASD will be classified as belonging to a GI group or to a Non-GI (NGI) group on the basis of a symptom severity index specific to GI disorders. In order to obtain four arms, subjects belonging to the two groups (GI and NGI) will be blind randomized 1:1 to regular diet with probiotics or with placebo for 6 months. All participants will be assessed at baseline, after three months and after six months from baseline in order to evaluate the possible changes in: (1) GI symptoms; (2) autism symptoms severity; (3) affective and behavioral comorbid symptoms; (4) plasmatic, urinary and fecal biomarkers related to abnormal intestinal function; (5) neurophysiological patterns.DiscussionThe effects of treatments with probiotics on children with ASD need to be evaluated through rigorous controlled trials. Examining the impact of probiotics not only on clinical but also on neurophysiological patterns, the current trial sets out to provide new insights into the gut-brain connection in ASD patients. Moreover, results could add information to the relationship between phthalates levels, clinical features and neurophysiological patterns in ASD.Trial registrationClinicalTrials.gov Identifier: NCT02708901. Retrospectively registered: March 4, 2016.

Peer-mediated theatrical engagement for improving reciprocal social interaction in autism spectrum disorder.

The hallmark characteristic of autism spectrum disorder (ASD) is poor reciprocal social communication. Interventions designed to improve this core deficit are critically needed. Social skills interventions such as direct training, peer mediation, and video modeling have contributed to improvements in various social skills in children with ASD. This paper reviews existing social competence interventions available for children with ASD while highlighting hypothesized critical components for advancing, maintaining, and generalizing skills, which include (1) peer mediation, (2) active learning, and (3) implementation in supportive, natural contexts. As a framework for these approaches, this conceptual paper describes SENSE Theatre, a novel intervention that combines trained peers that facilitate the performance-based theatrical treatment delivered in a supportive, community-based environment. A review of previous research shows early feasibility, setting the stage for more rigorous studies to aid in developing a standardized intervention package.

Psychosocial treatments for individuals with autism spectrum disorder across the lifespan: new developments and underlying mechanisms.

Researchers have studied many interventions to address the core impairment in social interactions in autism spectrum disorder. We reviewed the social skills intervention literature over the past two years (2012-2014). Social skills intervention studies have increased by 35% over our previous review of 2010-2012. Nearly equal numbers of studies reported results using single subject research designs (n = 29) and group designs (n = 25). Consistent with our previous review, many studies focused on joint attention/joint engagement for young children and interventions addressing peer interactions for older children. Advancements in this review period included more replications of intervention models, longitudinal outcomes, and a focus on minimally verbal children. Notably absent are social interventions for adults, and interventions addressing school-based inclusion. In addition to these target areas, future studies should isolate active ingredients of social interventions, include broader participant representation, and further examine the relation between neural development and behavioral outcomes.

Atypical Social Judgment and Sensitivity to Perceptual Cues in Autism Spectrum Disorders.

Evaluation of faces is an important dimension of social relationships. A degraded sensitivity to facial perceptual cues might contribute to atypical social interactions in autism spectrum disorder (ASD). The current study investigated whether face based social judgment is atypical in ASD and if so, whether it could be related to a degraded sensitivity to facial perceptual cues. Individuals with ASD (n=33) and IQ- and age-matched controls (n=38) were enrolled in this study. Watching a series of photographic or synthetic faces, they had to judge them for "kindness". In synthetic stimuli, the amount of perceptual cues available could be either large or small. We observed that social judgment was atypical in the ASD group on photographic stimuli, but, contrarily to the prediction based on the degraded sensitivity hypothesis, analyses on synthetic stimuli found a similar performance and a similar effect of the amount of perceptual cues in both groups. Further studies on perceptual differences between photographs and synthetic pictures of faces might help understand atypical social judgment in ASD.

Oxytocin improves behavioural and neural deficits in inferring others' social emotions in autism.

Recent studies have suggested oxytocin's therapeutic effects on deficits in social communication and interaction in autism spectrum disorder through improvement of emotion recognition with direct emotional cues, such as facial expression and voice prosody. Although difficulty in understanding of others' social emotions and beliefs under conditions without direct emotional cues also plays an important role in autism spectrum disorder, no study has examined the potential effect of oxytocin on this difficulty. Here, we sequentially conducted both a case-control study and a clinical trial to investigate the potential effects of oxytocin on this difficulty at behavioural and neural levels measured using functional magnetic resonance imaging during a psychological task. This task was modified from the Sally-Anne Task, a well-known first-order false belief task. The task was optimized for investigation of the abilities to infer another person's social emotions and beliefs distinctively so as to test the hypothesis that oxytocin improves deficit in inferring others' social emotions rather than beliefs, under conditions without direct emotional cues. In the case-control study, 17 males with autism spectrum disorder showed significant behavioural deficits in inferring others' social emotions (P = 0.018) but not in inferring others' beliefs (P = 0.064) compared with 17 typically developing demographically-matched male participants. They also showed significantly less activity in the right anterior insula and posterior superior temporal sulcus during inferring others' social emotions, and in the dorsomedial prefrontal cortex during inferring others' beliefs compared with the typically developing participants (P < 0.001 and cluster size > 10 voxels). Then, to investigate potential effects of oxytocin on these behavioural and neural deficits, we conducted a double-blind placebo-controlled crossover within-subject trial for single-dose intranasal administration of 24 IU oxytocin in an independent group of 20 males with autism spectrum disorder. Behaviourally, oxytocin significantly increased the correct rate in inferring others' social emotions (P = 0.043, one-tail). At the neural level, the peptide significantly enhanced the originally-diminished brain activity in the right anterior insula during inferring others' social emotions (P = 0.004), but not in the dorsomedial prefrontal cortex during inferring others' beliefs (P = 0.858). The present findings suggest that oxytocin enhances the ability to understand others' social emotions that have also required second-order false belief rather than first-order false beliefs under conditions without direct emotional cues in autism spectrum disorder at both the behaviour and neural levels.

Gene × Environment interactions in autism spectrum disorders: role of epigenetic mechanisms.

Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model. However, despite advances in epidemiological, molecular and clinical genetics, the genetic risk factors remain difficult to identify, with the exception of a few chromosomal disorders and several single gene disorders associated with an increased risk for autism. Furthermore, several studies suggest a role of environmental factors in autism spectrum disorders (ASD). First, arguments for a genetic contribution to autism, based on updated family and twin studies, are examined. Second, a review of possible prenatal, perinatal, and postnatal environmental risk factors for ASD are presented. Then, the hypotheses are discussed concerning the underlying mechanisms related to a role of environmental factors in the development of ASD in association with genetic factors. In particular, epigenetics as a candidate biological mechanism for gene × environment interactions is considered and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed. Furthermore, the example of in utero exposure to valproate provides a good illustration of epigenetic mechanisms involved in ASD and innovative therapeutic strategies. Epigenetic remodeling by environmental factors opens new perspectives for a better understanding, prevention, and early therapeutic intervention of ASD.

The Roots of Autism and ADHD Twin Study in Sweden (RATSS).

Neurodevelopmental disorders affect a substantial minority of the general population. Their origins are still largely unknown, but a complex interplay of genetic and environmental factors causing disturbances of the central nervous system's maturation and a variety of higher cognitive skills is presumed. Only limited research of rather small sample size and narrow scope has been conducted in neurodevelopmental disorders using a twin-differences design. The Roots of Autism and ADHD Twin Study in Sweden (RATSS) is an ongoing project targeting monozygotic twins discordant for categorical or dimensional autistic and inattentive/hyperactive-impulsive phenotypes as well as other neurodevelopmental disorders, and typically developing twin controls. Included pairs are 9 years of age or older, and comprehensively assessed for psychopathology, medical history, neuropsychology, and dysmorphology, as well as structural, functional, and molecular brain imaging. Specimens are collected for induced pluripotent (iPS) and neuroepithelial stem cells, genetic, gut bacteria, protein-/monoamine, and electron microscopy analyses. RATSS's objective is to generate a launch pad for novel surveys to understand the complexity of genotype-environment-phenotype interactions in autism spectrum disorder and attention-deficit hyperactivity disorder (ADHD). By October 2013, RATSS had collected data from 55 twin pairs, among them 10 monozygotic pairs discordant for autism spectrum disorder, seven for ADHD, and four for other neurodevelopmental disorders. This article describes the design, recruitment, data collection, measures, collected pairs' characteristics, as well as ongoing and planned analyses in RATSS. Potential gains of the study comprise the identification of environmentally mediated biomarkers, the emergence of candidates for drug development, translational modeling, and new leads for prevention of incapacitating outcomes.