Context Autism is considered the most heritable of neurodevelopmental disorders, mainly because of the large difference in concordance rates between monozygotic and dizygotic twins. Objective To provide rigorous quantitative estimates of genetic heritability of autism and the effects of shared environment. Design, Setting, and Participants Twin pairs with at least 1 twin with an autism spectrum disorder (ASD) born between 1987 and 2004were identified through the California Department of Developmental Services. Main Outcome Measures Structured diagnostic assessments (Autism Diagnostic Interview–Revised and Autism Diagnostic Observation Schedule) were completed on 192 twin pairs. Concordance rates were calculated and parametric models were fitted for 2 definitions, 1 narrow (strict autism) and 1 broad (ASD). Results For strict autism, probandwise concordance for male twins was 0.58 for 40 monozygotic pairs (95% confidence interval [CI], 0.42–0.74) and 0.21 for 31 dizygotic pairs (95% CI, 0.09–0.43); for female twins, the concordance was 0.60 for 7 monozygotic pairs (95% CI, 0.28–0.90) and 0.27 for 10 dizygotic pairs (95% CI, 0.09–0.69). For ASD, the probandwise concordance for male twins was 0.77 for 45 monozygotic pairs (95% CI, 0.65–0.86) and 0.31 for 45 dizygotic pairs (95% CI, 0.16–0.46); for female twins, the concordance was 0.50 for 9 monozygotic pairs (95% CI, 0.16–0.84) and 0.36 for 13 dizygotic pairs (95% CI, 0.11–0.60). A large proportion of the variance in liability can be explained by shared environmental factors (55%; 95% CI, 9%–81% for autism and 58%; 95% CI, 30%–80% for ASD) in addition to moderate genetic heritability (37%; 95% CI, 8%–84% for autism and 38%; 95% CI, 14%–67% for ASD). Conclusion Susceptibility to ASD has moderate genetic heritability and a substantial shared twin environmental component.

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Summary Autism spectrum disorder (ASD), a neurodevelopmental disorder affecting nearly 1 in 88 children, is thought to result from aberrant brain connectivity. Remarkably, there have been no systematic attempts to characterize whole-brain connectivity in children with ASD. Here, we use neuroimaging to show there are more instances of greater functional connectivity in the brains of children with ASD compared with typically developing children. Hyper-connectivity in ASD was observed at the whole-brain and subsystems level, across long- and short-range connections, and was associated with higher levels of fluctuations in regional brain signals. Brain hyper-connectivity predicted symptom severity in ASD such that children with greater functional connectivity exhibited more severe social deficits. We replicated these findings in two additional independent cohorts, demonstrating again that at earlier ages, the brain in ASD is largely functionally hyper-connected in ways that contribute to social dysfunction. Our findings provide novel insights into brain mechanisms underlying childhood autism.

Background The default mode network (DMN), a brain system anchored in the posteromedial cortex, has been identified as under-connected in adults with autism spectrum disorder (ASD). However, to date there have been no attempts to characterize this network and its involvement in mediating social deficits in children with ASD. Furthermore, the functionally heterogeneous profile of the posteromedial cortex raises questions regarding how altered connectivity manifests in specific functional modules within this brain region in children with ASD. Methods Here we use resting-state fMRI and an anatomically informed approach to investigate the functional connectivity of the DMN in 20 children with ASD and 19 age-, gender-, and IQ-matched typically developing children. We utilize multivariate regression analyses to test whether altered patterns of connectivity are predictive of social impairment severity. Results Compared to TD children, children with ASD demonstrated hyper-connectivity of the posterior cingulate and retrosplenial cortices with predominately medial and anterolateral temporal cortex. In contrast, the precuneus in ASD children demonstrated hypo-connectivity with visual cortex, basal ganglia, and locally within the posteromedial cortex. Aberrant posterior cingulate cortex hyper-connectivity was linked with severity of social impairments in ASD, whereas precuneus hypo-connectivity was unrelated to social deficits. Consistent with previous work in healthy adults, we observe a functionally heterogeneous profile of connectivity within the posteromedial cortex in both TD and ASD children. Conclusions This work links hyper-connectivity of DMN-related circuits to the core social deficits in young children with ASD and highlights fundamental aspects of posteromedial cortex heterogeneity.

Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.A utism spectrum disorder (ASD) is a brain disorder of early childhood onset. ASD is characterized by core social communication impairments as well as restricted, repetitive behaviors, which jeopardize the development of appropriate social skills and the maintenance of social relationships (1). Despite being one of the most devastating childhood disorders in terms of prevalence [1 in 68 US children (2)] and societal cost [$236 billion expended annually in the United States (3)], ASD pathophysiology remains poorly understood. Consequently, there are no approved medications that enhance social abilities in individuals with ASD.

The neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate social functioning in animals and humans. Initial clinical research suggests that dysregulated plasma OXT concentrations and/or OXTR SNPs may be biomarkers of social impairments in autism spectrum disorder (ASD). We do not know, however, whether OXT dysregulation is unique to ASD or whether OXT biology influences social functioning more generally, thus contributing to, but not causing, ASD phenotypes. To distinguish between these possibilities, we tested in a child ASD cohort, which included unaffected siblings and unrelated neurotypical controls (ages 3-12 y; n = 193), whether plasma OXT concentrations and OXTR SNPs (i) interact to produce ASD phenotypes, (ii) exert differential phenotypic effects in ASD vs. non-ASD children, or (iii) have similar phenotypic effects independent of disease status. In the largest cohort tested to date, we found no evidence to support the OXT deficit hypothesis of ASD. Rather, OXT concentrations strongly and positively predicted theory of mind and social communication performance in all groups. Furthermore, OXT concentrations showed significant heritability between ASD-discordant siblings (h 2 = 85.5%); a heritability estimate on par with that of height in humans. Finally, carriers of the "G" allele of rs53576 showed impaired affect recognition performance and carriers of the "A" allele of rs2254298 exhibited greater global social impairments in all groups. These findings indicate that OXT biology is not uniquely associated with ASD, but instead exerts independent, additive, and highly heritable influences on individual differences in human social functioning, including the severe social impairments which characterize ASD. T he neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate affiliative motivation, social bonding, and social recognition in animals (1, 2). Preclinical research likewise has shown that individual differences in OXT biology (e.g., OXT concentrations, OXTR distribution in key brain regions) are associated with individual differences in social functioning (3-6). At the extreme, experimental manipulations that diminish OXT peptide and/or receptor signaling produce a variety of social deficits in animal models (7,8).Translation of this animal research to neurotypical populations has confirmed that OXT administration enhances social functioning in humans (9, 10). Individual differences in endogenous OXT concentrations are also positively correlated with social behavior measures (11, 12), such that lower OXT concentrations are frequently associated with diminished social functioning even within neurotypical cohorts. This research has led to the hypothesis that abnormalities in OXT peptide biology may be directly related to social impairments observed in clinical populations, particularly in people with autism spectrum disorder (ASD), who exhibit core deficits in social interactions and preferences, eye contact, facial recognition, empathy, and social communication.Several studies have begun to exp...

The aim of this study was to examine the relationship between emotion dysregulation and the core features of Autism Spectrum Disorder (ASD), which include social/communication deficits, restricted/repetitive behaviors, and sensory abnormalities. An 18-item Emotion Dysregulation Index was developed on the basis of expert ratings of the Child Behavior Checklist. Compared to typically developing controls, children and adolescents with ASD showed more emotion dysregulation and had significantly greater symptom severity on all scales. Within ASD participants, emotion dysregulation was related to all core features of the disorder, but the strongest association was with repetitive behaviors. These findings may facilitate the development of more effective therapeutic strategies targeting emotion dysregulation in order to optimize longterm outcomes for individuals with ASD.

This is the first randomized controlled trial of group-delivered PRT and one of the largest experimental investigations of the PRT model to date. The findings suggest that specific instruction in PRT results in greater skill acquisition for both parents and children, especially in functional and adaptive communication skills. Further research in PRT is warranted to replicate the observed results and address other core ASD symptoms.