Ectodermal origins of the skin-brain axis: a novel model for the developing brain, inflammation, and neurodevelopmental conditions.

Early life development and its divergence is influenced by multiple genetic, neurological, and environmental factors. Atypical neurodevelopment, such as that observed in autism spectrum disorder, likely begins in early gestation during a period of entwined growth between the brain and epithelial barriers of the skin, gastrointestinal tract, and airway. This review coalesces epidemiological and neuroinflammatory evidence linking cutaneous atopic disease with both reduced skin barrier integrity and determinants of neurodivergence. We consider the shared developmental origin of epidermal and neural tissue with related genetic and environmental risk factors to evaluate potential pre- and postnatal modifiers of the skin-brain connection. Initial postnatal skin barrier integrity may provide a useful marker for both cortical integrity and meaningful subgroups of children showing early neurodevelopmental delays. It may also modify known risk factors to neurodevelopment, such as pathogen caused immune system activation. These novel insights of a skin-brain-neurodevelopment connection may advance detection and intervention opportunities.

Social impairments in autism spectrum disorder are related to maternal immune history profile.

Maternal immune activation has been highlighted as a factor that might increase the risk and severity of autism spectrum disorder (ASD) in children. Preclinical animal evidence shows that immune activation in mothers during pregnancy causes ASD-like behavioural traits in offspring. To this point, there has been no investigation of whether immune system activation in human mothers during pregnancy is associated with more severe symptoms in children with ASD. In this study, data from an existing ASD cohort (N=220) were analysed to investigate whether immune conditions in the mother were associated with greater severity of autism-related symptoms. Results showed that children whose mothers reported a history of immune activation (allergies and asthma) had significantly higher scores on the Social Responsiveness Scale (SRS; P=0.016), suggesting more severe social impairment symptoms in these children. This increasing severity of social impairment symptoms was further shown on the SRS cognition (P=0.007) and mannerisms (P=0.002) subscales. While immune history was associated with an increase in the severity of social impairment symptoms, history of autoimmune conditions in the mother did not have any effect in this cohort. To the best of our knowledge, this study is the first to show an association between immune activation history in the mother and increased ASD symptom severity in children with ASD. These findings support the idea of an immune system-mediated subtype in ASD, where the immune history of the mother may be an important factor.

Autism spectrum disorders: a meta-analysis of executive function.

Evidence of executive dysfunction in autism spectrum disorders (ASD) across development remains mixed and establishing its role is critical for guiding diagnosis and intervention. The primary objectives of this meta-analysis is to analyse executive function (EF) performance in ASD, the fractionation across EF subdomains, the clinical utility of EF measures and the influence of multiple moderators (for example, age, gender, diagnosis, measure characteristics). The Embase, Medline and PsychINFO databases were searched to identify peer-reviewed studies published since the inclusion of Autism in DSM-III (1980) up to end of June 2016 that compared EF in ASD with neurotypical controls. A random-effects model was used and moderators were tested using subgroup analysis. The primary outcome measure was Hedges' g effect size for EF and moderator factors. Clinical sensitivity was determined by the overlap percentage statistic (OL%). Results were reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A total of 235 studies comprising 14 081 participants were included (N, ASD=6816, Control=7265). A moderate overall effect size for reduced EF (Hedges' g=0.48, 95% confidence interval (CI) 0.43-0.53) was found with similar effect sizes across each domain. The majority of moderator comparisons were not significant although the overall effect of executive dysfunction has gradually reduced since the introduction of ASD. Only a small number of EF measures achieved clinical sensitivity. This study confirms a broad executive dysfunction in ASD that is relatively stable across development. The fractionation of executive dysfunction into individual subdomains was not supported, nor was diagnostic sensitivity. Development of feasible EF measures focussing on clinical sensitivity for diagnosis and treatment studies should be a priority.

A comprehensive systematic review and meta-analysis of pharmacological and dietary supplement interventions in paediatric autism: moderators of treatment response and recommendations for future research.

BACKGROUND: Autism spectrum disorders (ASDs) are pervasive and multifactorial neurodevelopmental conditions, characterized by impairments in social communication and interaction, and restricted, repetitive patterns of behaviour, interests or activities. Treatment options to ameliorate symptoms of ASDs are limited. Heterogeneity complicates the quest for personalized medicine in this population. Our aim was to investigate if there are baseline characteristics of patients that moderate response or trial design features that impede the identification of efficacious interventions for ASDs. METHOD: Literature searches of EMBASE, MEDLINE and PsycINFO identified 43 studies for qualitative assessment of baseline characterization of participants and 37 studies for quantitative analysis of moderators of treatment response. Criteria included blinded randomized controlled trials (RCTs) in paediatric ASD, with at least 10 participants per arm or 20 overall, of oral treatments, including pharmacological interventions and dietary supplements. RESULTS: Random-effects meta-analysis of 1997 participants (81% male) identified three moderators associated with an increase in treatment response: trials located in Europe and the Middle-East; outcome measures designated primary status; and the type of outcome measure. Inconsistent reporting of baseline symptom severity and intellectual functioning prevented analysis of these variables. Qualitative synthesis of baseline characteristics identified at least 31 variables, with only age and gender reported in all trials. Biological markers were included in six RCTs. CONCLUSIONS: Few trials reported adequate baseline characteristics to permit detailed analysis of response to treatment. Consideration of geographical location, baseline severity and intellectual function is required to ensure generalizability of results. The use of biological markers and correlates in ASD trials remains in its infancy. There is great need to improve the application of baseline characterization and incorporation of biological markers and correlates to permit selection of participants into homogeneous subgroups and to inform response to treatment in ASD.

The promise and pitfalls of intranasally administering psychopharmacological agents for the treatment of psychiatric disorders.

Accumulating research demonstrates the potential of intranasal delivery of psychopharmacological agents to treat a range of psychiatric disorders and symptoms. It is believed that intranasal administration offers both direct and indirect pathways to deliver psychopharmacological agents to the central nervous system. This administration route provides a unique opportunity to repurpose both old drugs for new uses and improve currently approved drugs that are indicated for other administration routes. Despite this promise, however, the physiology of intranasal delivery and related assumptions behind the bypassing of the blood brain barrier is seldom considered in detail in clinical trials and translational research. In this review, we describe the current state of the art in intranasal psychopharmacological agent delivery research and current challenges using this administration route, and discuss important aspects of nose-to-brain delivery that may improve the efficacy of these new therapies in future research. We also highlight current gaps in the literature and suggest how research can directly examine the assumptions of nose-to-brain delivery of psychopharmacological agents in humans.

The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial.

Interventions for autism are limited. The synthetic hormone oxytocin may provide a potential treatment to improve core social and behavioral difficulties in autism, but its efficacy has yet to be evaluated in young children who potentially may benefit to a greater extent. We investigated the efficacy, tolerability and safety of oxytocin treatment in young children with autism using a double-blind, randomized, placebo-controlled, crossover, clinical trial. Thirty-one children with autism received 12 International Units (IU) of oxytocin and placebo nasal spray morning and night (24 IU per day) for 5 weeks, with a 4-week washout period between each treatment. Compared with placebo, oxytocin led to significant improvements on the primary outcome of caregiver-rated social responsiveness. Overall, nasal spray was well tolerated, and the most common reported adverse events were thirst, urination and constipation. This study is the first clinical trial to support the potential of oxytocin as an early intervention for young children with autism to help improve social interaction deficits.

Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis.

The role of non-diagnostic features in the pathophysiology of autism spectrum disorders (ASDs) is unclear. Increasing evidence suggests immune system alterations in ASD may be implicated in the severity of behavioral impairment and other developmental outcomes. The primary objective of this meta-analysis was to investigate if there is a characteristic abnormal cytokine profile in ASD compared with healthy controls (HCs). We identified relevant studies following a search of MEDLINE, EMBASE, PsycINFO, Web of Knowledge and Scopus. A meta-analysis was performed on studies comparing plasma and serum concentrations of cytokines in unmedicated participants with ASD and HCs. Results were reported according to PRISMA statement. Seventeen studies with a total sample size of 743 participants with ASD and 592 HC were included in the analysis. Nineteen cytokines were assessed. Concentrations of interleukin (IL)-1beta (P<0.001), IL-6 (P=0.03), IL-8 (P=0.04), interferon-gamma (P=0.02), eotaxin (P=0.01) and monocyte chemotactic protein-1 (P<0.05) were significantly higher in the participants with ASD compared with the HC group, while concentrations of transforming growth factor-ß1 were significantly lower (P<0.001). There were no significant differences between ASD participants and controls for the other 12 cytokines analyzed. The findings of our meta-analysis identified significantly altered concentrations of cytokines in ASD compared to HCs, strengthening evidence of an abnormal cytokine profile in ASD where inflammatory signals dominate.

A psychometric investigation of health-related quality of life measures for paediatric neurodevelopment assessment: Reliability and concurrent validity of the PEDS-QL, CHU-9D, and the EQ-5D-Y.

There is a need for tools that can provide a brief assessment of functioning for children with neurodevelopmental conditions, including health-related quality of life (HR-QoL). This study evaluated the psychometric properties of three commonly used and well known HR-QoL measures in a cohort of children presenting to clinical developmental assessment services. The most common diagnoses received in these assessment services were autism spectrum disorders. Findings showed good internal consistency for the PedsQL and the CHU-9D, but not the EQ-5D-Y. This research also found that the CHU-9D, EQ-5D-Y, and PedsQL correlated with relevant functioning domains assessed by the VABS-III. Overall, the measures showed that children with neurodevelopmental conditions experienced poor HR-QoL. The majority of children (>86%) met cut-off criteria for significant health concerns on the PedsQL. On the EQ-5D-Y and CHU-9D, they showed reduced HR-QoL particularly on domains relating to school and homework, being able to join in activities, looking after self, and doing usual activities. This study supports the use of the CHU-9D and PedsQL in this population to assess and potentially track HR-QoL in a broad neurodevelopment paediatric population.

Eczema and related atopic diseases are associated with increased symptom severity in children with autism spectrum disorder.

Growing evidence indicates that autism spectrum disorder (ASD) has diverse genetic, neurological, and environmental factors that contribute to its neurodevelopmental course. Interestingly, childhood ASD is often accompanied by skin disorders, such as eczema, and other related atopic manifestations. This link may be due to the shared embryonic origin of epidermal and neural tissue. Accordingly, we consider the potential influence of a skin-brain co-vulnerability and ensuing atopic cascade on ASD symptomatology by investigating whether atopic disorders (asthma, allergies, eczema and hay fever) are associated with increased symptom severity in children with ASD. Overall, 45 atopic and 93 non-atopic children with ASD were assessed using the ADOS-2 on scores of total, social and non-social symptoms. Differences in ASD symptom severity were further evaluated as a function of atopic disease type. Atopic children displayed greater symptom severity overall and in the social domain, relative to non-atopic participants. Atopic children were 2.4 times more likely to experience overall impairments classified within the ADOS-2 highest-level severity bracket and 2.7 times more likely to show social difficulties in this range. Moreover, those reporting comorbid eczema displayed increased symptom severity relative to both their non-atopic peers and those reporting asthma and allergies. Taken together, findings indicate that atopic disorders, and particularly comorbid eczema, are associated with increases in ASD symptom severity. Findings provide grounds for future investigations into this link between childhood skin diseases and ASD symptom severity to advance our understanding of neurodevelopment and to develop targeted assessment and intervention opportunities.

An evaluation of homesickness in children: A systematic review and meta-analysis.

OBJECTIVE: To provide a systematic review and meta-analysis of the quantitative literature on homesickness in children, including how it is assessed and relationship to other negative states. STUDY SELECTION AND SYNTHESIS: A literature search was conducted using Medline, PsychINFO and Scopus databases. Studies were included if they assessed homesickness in children under eighteen years of age and were published in peer reviewed journals in the English language between 1990 and December 2020. A total of 176 studies were screened for relevance and 17 met the inclusion criteria for the systematic review with five studies included in the meta-analysis. MAIN OUTCOMES AND MEASURES: The primary outcome measure was homesickness severity, and it was examined in relation to measures of depression and anxiety. The literature in relation to known risk and protective factors was also reviewed. RESULTS: Homesickness was reported in the majority of children who were separated from their home. It was associated with negative emotional states. A total of seventeen studies were included in the quantitative review. The meta-analysis showed a significant relationship between homesickness and depression r=0.431 (95% CI 0.344-0.510; p<0.001) and homesickness and anxiety r=0.426 (95% CI 0.369-0.479; p<0.001). Age was not a significant moderator of homesickness severity. Consideration of effective interventions to address homesickness was limited. CONCLUSIONS AND RELEVANCE: Homesickness significantly impacts children's well-being regardless of age and is associated with overall distress, depression and anxiety. Future studies are required to examine homesickness interventions and supports to improve well-being in children.

A transdiagnostic examination of anxiety and stress on executive function outcomes in disorders with social impairment.

BACKGROUND: Executive function (EF) difficulties characterise a number of psychiatric conditions and EF impairment may be a predisposing factor and/or consequence of anxiety and stress. The aim of the study was to examine EF factors in a mixed clinical cohort (Autism Spectrum Disorder and Social Anxiety Disorder) characterised by social impairment and investigate the influence of trait anxiety and state-based depression, anxiety and stress. METHODS: In Study 1, a factor analysis identified EF and non-EF latent factor structures (N=205). In Study 2, (N=137) multiple regression analyses investigated the association between trait anxiety and state based depression, anxiety and stress, on EF and non-EF cognitive domains and on the two composite indices of the Behavioural Rating Inventory of Executive Function (BRIEF). RESULTS: Trait anxiety was associated with better performance on neuropsychological measures of EF while state-based stress was associated with lower EF performance. A dissociation was observed between trait anxiety and state stress on the two behavioural indices of the BRIEF. Depression, anxiety and stress did not predict performance on non-EF cognitive domains. LIMITATIONS: The cross-sectional design precludes cause-effect conclusions, further only self-report measures of affect were utilised and our performance measures of EF did not include a working memory test. CONCLUSIONS: The results demonstrate that trait anxiety and state-based stress influence EF processes across disorders with social impairment. The transdiagnostic efficacy of this finding can facilitate remediation strategies, it may also contribute to individuals with Autism Spectrum Disorder gaining better access to mental health services.

Autism, early psychosis, and social anxiety disorder: understanding the role of social cognition and its relationship to disability in young adults with disorders characterized by social impairments.

Impairments in social cognition are believed contribute to disability, particularly for disorders characterized by difficulties in social interaction. There has been little transdiagnostic investigation of this across social cognition domains in young adults. A total of 199 young adults diagnosed with autism spectrum disorder (ASD; N = 53), early psychosis (EP; N = 51), and social anxiety disorder (SAD; N = 64) were compared against neurotypical controls (NT; N = 31) on a battery of lower and higher-order and self-report social cognition measures. For both ASD and EP, participants showed impaired performance on all lower-order emotion recognition tasks and one higher-order social cognition test. Self-reports of empathy were reduced in all clinical groups and particularly in ASD. For SAD, despite showing no objective social cognition impairment, self-reported empathy was reduced to the same level as EP. Discriminant analysis revealed that self-reported empathy and lower-order emotion recognition tests provide best capacity to differentiate groups. Regressions predicting disability revealed depression as the strongest predictor across all disability measures. Empathy provided additional predictive value for social disability and social interaction anxiety. Overall, results support a similar social-cognitive development profile across ASD and EP. While self-reported empathy differentiated between groups, discrepancy between objective social cognition test performance and self-reported empathy in the SAD group suggests probable threat-related self-monitoring report biases that likely further influence all group outcomes. As depression and empathy were the most important predictors of disability, regardless of diagnostic group, research is required to explore targeted interventions for difficulties in these domains to reduce disability.

Predictors of placebo response in pharmacological and dietary supplement treatment trials in pediatric autism spectrum disorder: a meta-analysis.

Large placebo responses in many clinical trials limit our capacity to identify effective therapeutics. Although it is often assumed that core behaviors in children with autism spectrum disorders (ASDs) rarely remit spontaneously, there has been limited investigation of the size of the placebo response in relevant clinical trials. These trials also rely on caregiver and clinical observer reports as outcome measures. The objectives of this meta-analysis are to identify the pooled placebo response and the predictors of placebo response in pharmacological and dietary supplement treatment trials for participants with a diagnosis of ASD. Randomized controlled trials (RCTs) in pediatric ASD, conducted between 1980 and August 2014, were identified through a search of Medline, EMBASE, Web of Science, Cochrane Database of Systematic Reviews and clinicaltrials.gov. RCTs of at least 14 days duration, comparing the treatment response for an oral active agent and placebo using at least one of the common outcome measures, were included. Analysis of 25 data sets (1315 participants) revealed a moderate effect size for overall placebo response (Hedges' g=0.45, 95% confidence interval (0.34-0.56), P<0.001). Five factors were associated with an increase in response to placebo, namely: an increased response to the active intervention; outcome ratings by clinicians (as compared with caregivers); trials of pharmacological and adjunctive interventions; and trials located in Iran. There is a clear need for the identification of objective measures of change in clinical trials for ASD, such as evaluation of biological activity or markers, and for consideration of how best to deal with placebo response effects in trial design and analyses.