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Early supports to enhance social development in children with autism are widely promoted. While oxytocin has a crucial role in mammalian social development, its potential role as a medication to enhance social development in humans remains unclear. We investigated the efficacy, tolerability, and safety of intranasal oxytocin in young children with autism using a double-blind, randomized, placebo-controlled, clinical trial, following a placebo lead-in phase. A total of 87 children (aged between 3 and 12 years) with autism received 16 International Units (IU) of oxytocin (n = 45) or placebo (n = 42) nasal spray, morning and night (32 IU per day) for twelve weeks, following a 3-week placebo lead-in phase. Overall, there was no effect of oxytocin treatment over time on the caregiver-rated Social Responsiveness Scale (SRS-2) (p = 0.686). However, a significant interaction with age (p = 0.028) showed that for younger children, aged 3–5 years, there was some indication of a treatment effect. Younger children who received oxytocin showed improvement on caregiver-rated social responsiveness ( SRS-2). There was no other evidence of benefit in the sample as a whole, or in the younger age group, on the clinician-rated Clinical Global Improvement Scale (CGI-S), or any secondary measure. Importantly, placebo effects in the lead-in phase were evident and there was support for washout of the placebo response in the randomised phase. Oxytocin was well tolerated, with more adverse side effects reported in the placebo group. This study suggests the need for further clinical trials to test the benefits of oxytocin treatment in younger populations with autism.Trial registration www.anzctr.org.au (ACTRN12617000441314).

Background and aims: New therapeutic options such as lisdexamfetamine and guanfacine have recently become available for the treatment of attention deficit hyperactivity disorder. We described contemporary patterns of attention deficit hyperactivity disorder medicine use among children, adolescents and adults in Australia. Methods: This population-based study used dispensing data for a 10% random sample of Australian residents between July 2012 and December 2020. We estimated the annual prevalence and incidence of attention deficit hyperactivity disorder medicines, second-line guanfacine use and examined concurrent medicine use of both stimulants and non-stimulants. We followed incident users for up to 5 years and analysed treatment persistence using a novel proportion of people covered method. Analyses were stratified by attention deficit hyperactivity disorder medicine, sex and age group; young children (0–5 years), children (6–12 years), adolescents (13–17 years), young adults (18–24 years) and adults (⩾25 years). Results: We observed a twofold increase in the overall prevalence of attention deficit hyperactivity disorder medicine use between 2013 and 2020, from 4.9 to 9.7 per 1000 persons. Incident use also increased across all age groups and both sexes, with the most pronounced increases among adolescent females (from 1.4 to 5.3 per 1000 persons). Stimulant treatment persistence after 5 years was highest among those initiating treatment as young children (64%) and children (69%) and lowest among those initiating treatment in adolescence (19%). Concurrent use of stimulants and non-stimulants was more common among males and younger age groups. Most children (87%) initiating guanfacine had prior dispensings of attention deficit hyperactivity disorder medicines. Conclusion: We observed increasing attention deficit hyperactivity disorder medicine use in Australia, especially among young females. Nevertheless, treatment rates remain lower than the estimated prevalence of attention deficit hyperactivity disorder across all subpopulations. Poor long-term treatment persistence in adolescence may warrant improved clinical monitoring of attention deficit hyperactivity disorder in patients transitioning from paediatric to adult care. Reassuringly, use of newly approved guanfacine appeared to be in accordance with guidelines among children.

Patients with depression and bipolar disorder have previously been shown to have impaired white matter (WM) integrity compared with healthy controls. This study aimed to investigate potential sex differences that may provide further insight into the pathophysiology of these highly debilitating mood disorders.Participants aged 17 to 30 years (168 with depression [60% females], 107 with bipolar disorder [74% females], and 61 controls [64% females]) completed clinical assessment, self-report measures, and a neuropsychological assessment battery. Participants also underwent magnetic resonance imaging from which diffusion tensor imaging data were collected among five fronto-limbic WM tracts: cingulum bundle (cingulate gyrus and hippocampus subsections), fornix, stria terminalis, and the uncinate fasciculus. Mean fractional anisotropy (FA) scores were compared between groups using analyses of variance with sex and diagnosis as fixed factors.Among the nine WM tracts analyzed, one revealed a significant interaction between sex and diagnosis, controlling for age. Male patients with bipolar disorder had significantly lower FA scores in the fornix compared with the other groups. Furthermore, partial correlations revealed a significant positive association between FA scores for the fornix and psychomotor speed.Our findings suggest that males with bipolar disorder may be at increased risk of disruptions in WM integrity, especially in the fornix, which is thought to be responsible for a range of cognitive functions. More broadly, our findings suggest that sex differences may exist in WM integrity and thereby alter our understanding of the pathophysiology of mood disorders.

Employment rates for autistic people are low, despite increasing employment-focused programmes. Given the reported complexities for autistic people in finding and keeping work and flourishing there, further exploration is needed to understand how best to help employers accommodate autistic employees.We assessed 88 employed autistic adults, without comorbid intellectual disability and examined whether self-reported disability and mental health symptoms were associated with two measures of vocational functioning: disability days off work and vocational disability.Nearly half (47%) reported at least one disability day absence in the previous month. Autism severity and IQ were not associated with either measure of vocational functioning. Greater disability and higher mental health symptoms were associated with both types of vocational functioning. However, the associations of anxiety and stress with both vocational outcomes were attenuated to null in a multivariable model. Disability (Clinicians and vocational support programmes addressing modifiable factors may need to focus on addressing mental health comorbidities, specifically depression rather than anxiety, or core features of autism to improve vocational outcomes for autistic people. Implications for RehabilitationIndividual-level interventions that reduce disablement, particularly in social areas, and depressive symptoms as a way of reducing days off work and improving workplace activities in autistic employees are recommended.Organisations can accommodate autistic employees by encouraging use of mental health programmes or looking at how the workplace environment can be adapted to limit social disability.

In inpatient psychiatric units, seclusion (isolation in a locked room) is recommended only as a last resort for serious aggression or agitation. In response to an increase in seclusion during 2015, an 8-bed child and adolescent inpatient unit implemented a suite of multidisciplinary interventions. This study examines changes in seclusion rates following intervention implementation and assesses whether specific patient factors were associated with seclusion rates before and after interventions.Multi-modal interventions, comprised of patient treatment plans, intake and handover meetings, staff supervision and debriefing sessions, were implemented from January 2016. We compared quarterly seclusion rates (episodes per 1000 patient days) across a thirteen-year period, from July 2008 to June 2021. Change in seclusion rates following intervention was evaluated using a segmented regression analysis. We examined whether patient factors were associated with seclusion rates, and whether the duration of seclusion episodes differed before and after interventions.There was a 100% reduction in seclusion rates in the 6 months following intervention implementation, from 28.4 episodes per 1000 patient days in July-September 2015, to 4.7 episodes in January-March 2016, reaching 0.0 episodes by April-June 2016. This reduction was maintained until April-June 2021. Most patients with seclusion events before and after intervention implementation had a neurodevelopmental disorder diagnosis and a minority of patients accounted for most seclusion events. There was a 65% reduction in the average duration of seclusion episodes following interventions, however this was not statistically significant.Due to a crisis in staff morale, interventions were implemented simultaneously, preventing an understanding of whether a single intervention accounted for change. While not addressed in the current study, assessing perceptions of staff, children and parents following intervention implementation may have elucidated barriers and facilitators to change.Multidisciplinary, patient-centered interventions may be effective for long-term reduction of seclusion rates in inpatient psychiatric units. These findings highlight patient factors associated with seclusion reduction which should be considered when implementing interventions.

Atypical sensory processing occurs in up to 97% of children on the autism spectrum. Children who are on the autism spectrum also commonly demonstrate challenging behaviors, and their caregivers report increased levels of strain in daily life. The aim of this study was to explore four sensory processing features; seeking, avoiding, sensitivity, and registration, and their relationships with maladaptive behaviors in children with autism, as well as with caregiver strain. Participants comprised 75 children with autism aged 7-12 years (M = 7.81). Caregivers completed three questionnaire measures examining child sensory processing, maladaptive behaviors, and perceptions of caregiver strain. We found avoiding significantly associated with irritability. Avoiding also displayed the strongest relationship with global caregiver strain. Avoiding and seeking were strongly related to hyperactivity/noncompliance (components of maladaptive behavior). A multiple regression was performed to explore how atypical sensory processing features and maladaptive behaviors together predicted caregiver strain. Together, maladaptive behaviors and sensory features accounted for 58% of the variance in total caregiver strain. The only significant individual predictor of total caregiver strain was sensory avoiding, which uniquely accounted for 5.76% of the variation. The findings suggest that atypical sensory processing is associated with overall caregiver strain, above that explained by maladaptive behaviors. Implications for targeted support for the benefit of the child, parents and family unit are discussed. LAY SUMMARY: Children who are on the autism spectrum often have differences in sensory processing. These children also tend to show challenging behaviors, and their caregivers can experience increased stress. This study looked at how sensory processing difficulties relate to such behaviors and caregiver stress. We found that both sensory processing and challenging behaviors were related to the amount of stress caregivers felt. This suggests that interventions may benefit from looking at sensory processing features when considering how to help reduce challenging behaviors and caregiver stress.

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.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.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.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; p0.001) and homesickness and anxiety r=0.426 (95% CI 0.369-0.479; p0.001). Age was not a significant moderator of homesickness severity. Consideration of effective interventions to address homesickness was limited.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.

Introduction: Changes in social behavior and emotion processing are common in frontotemporal dementia (FTD) and semantic dementia (SD), and less so in Alzheimer’s disease (AD). Recent research has investigated oxytocin as a potential treatment for these symptoms; however, whether plasma oxytocin is associated with social-emotional symptoms of dementia remains underexplored. Methods: Thirty behavioral-variant FTD (bvFTD), 28 SD, 39 AD, and 24 controls underwent blood sampling to measure oxytocin. Participants completed an emotion processing battery. Carers completed the Cambridge Behavioral Inventory and the Neuropsychiatric Inventory. Results: Patients with bvFTD were severely impaired in emotion processing and behavioral ratings, with milder impairment in SD and AD. No difference in plasma oxytocin was observed between groups (p = 0.632). No significant associations were found between oxytocin and social behavior or emotion processing (r values between −0.241 and 0.227, all p values >0.099). Conclusion: Our results indicate that plasma oxytocin is not reduced in dementia and is unrelated to social, emotional, and behavioral features. We noted high interindividual variability in our data; hence, future investigations should consider methodological influences such as serum versus saliva and diurnal variation on oxytocin function. These results demonstrate that current measurement measures of plasma oxytocin have limited utility in determining the role of oxytocin in FTD. Alternative oxytocin measures may prove more sensitive and should be considered when conducting clinical trials.

Routinely collected data help estimate the prevalence of autism spectrum disorder (ASD) in jurisdictions without active autism surveillance. We created a population-based cohort of 1,211,834 children born in 2002–2015 in New South Wales, Australia using data linkage. Children with ASD were identified in three datasets – disability services, hospital admissions, and ambulatory mental health data. The prevalence of ASD in the cohort was 1.3% by age 12 and prevalence at age 6 increased an average of 4.1% per year (95% Confidence Interval, 3.3%, 4.8%). Most children with ASD were identified in disability services data (87%), although data linkage identified 1,711 additional cases that were more likely female, older at first contact, and living in major cities and less disadvantaged areas.

Despite long wait times, public paediatric developmental assessment services remain crucial for the assessment of vulnerable children, particularly those from disadvantaged backgrounds. Assessment represents a critical opportunity to guide the placement of supports to improve functioning and developmental trajectories. There is, however, a lack of research examining how multi-disciplinary assessment services conduct assessments, synthesise results and provide reports to families. This study retrospectively examined 85 reports provided to caregivers at a multi-disciplinary developmental assessment service. Reports were evaluated for whether they (1) addressed caregiver perceived needs, (2) used available data to provide appropriate information about child needs, (3) provided recommendations that were actionable and specific to needs, (4) had appropriate readability levels and (5) followed existing autism assessment guidelines. Findings showed clinicians were more focused on autism diagnostic needs while caregivers were more focused on multiple transdiagnostic needs. Recommendations provided in the reports that were related to autism diagnoses were specific and actionable, but reports rarely addressed transdiagnostic needs or comorbidities (e.g. cognitive impairments, mental health). For instance, only 13% of reports contained recommendations for conditions other than autism spectrum disorder, despite 61% of the population receiving two or more diagnoses. Reports largely followed autism assessment guidelines, but the language used was more complex for families than what is typically recommended. Recommendations for future practice are provided to improve the quality of reports and to better meet the needs of children and families attending developmental assessment services. Lay abstract Despite long wait times, public paediatric developmental assessment services remain crucial for assessment of children. Assessment is a critical opportunity to guide the placement of supports to improve outcomes. There is little research examining how clinical assessment services conduct their assessments, present results and write reports to families. This study examined 85 reports provided to caregivers at a developmental assessment service. Reports were evaluated for whether they (1) addressed caregiver perceived needs, (2) used available data to provide appropriate information about child needs, (3) provided recommendations that were actionable and specific to needs, (4) had appropriate readability levels and (5) followed existing autism assessment guidelines. Findings showed clinicians were more focused on autism diagnostic needs while caregivers were more focused on non-diagnostic needs. Recommendations related to autism diagnoses were actionable, but they rarely addressed comorbidities such as cognitive impairments or mental health. For instance, only 13% of reports contained recommendations for conditions other than autism spectrum disorder, despite 61% of the population receiving two or more diagnoses. Reports largely followed autism assessment guidelines, but the language used was more complex for families than recommended. Recommendations for future practice are provided so that consideration may be given to how to improve the quality and effectiveness of reports for families attending services.

There is significant interest in the possible influence of chronotype on clinical states in young people with emerging mental disorders. We apply a dynamic approach (bivariate latent change score modelling) to examine the possible prospective influence of chronotype on depressive and hypo/manic symptoms in a youth cohort with predominantly depressive, bipolar, and psychotic disorders (N = 118; 14–30-years), who completed a baseline and follow-up assessment of these constructs (mean interval = 1.8-years). Our primary hypotheses were that greater baseline eveningness would predict increases in depressive but not hypo/manic symptoms. We found moderate to strong autoregressive effects for chronotype (β = -0.447 to −0.448, p < 0.001), depressive (β = -0.650, p < 0.001) and hypo/manic symptoms (β = -0.819, p < 0.001). Against our predictions, baseline chronotypes did not predict change in depressive (β = -0.016, p = 0.810) or hypo/manic symptoms (β = 0.077, p = 0.104). Similarly, the change in chronotype did not correlate with the change in depressive symptoms (β = -0.096, p = 0.295) nor did the change in chronotype and the change in hypo/manic symptoms (β = -0.166, p = 0.070). These data suggest that chronotypes may have low utility for predicting future hypo/manic and depressive symptoms in the short term, or that more frequent assessments over longer periods are needed to observe these associations. Future studies should test whether other circadian phenotypes (e.g. sleep-wake variability) are better indicators of illness course.

Objective To identify trajectories of social and occupational functioning in young people during the two years after presenting for early intervention mental health care; to identify demographic and clinical factors that influence these trajectories. Design Longitudinal, observational study of young people presenting for mental health care. Setting Two primary care-based early intervention mental health services at the Brain and Mind Centre (University of Sydney), 1 June 2008 - 31 July 2018. Participants 1510 people aged 12-25 years who had presented with anxiety, mood, or psychotic disorders, for whom two years' follow-up data were available for analysis. Main outcome measures Latent class trajectories of social and occupational functioning based on growth mixture modelling of Social and Occupational Assessment Scale (SOFAS) scores. Results We identified four trajectories of functioning during the first two years of care: deteriorating and volatile (733 participants, 49%); persistent impairment (237, 16%); stable good functioning (291, 19%); and improving, but late recurrence (249, 16%). The less favourable trajectories (deteriorating and volatile; persistent impairment) were associated with physical comorbidity, not being in education, employment, or training, having substance-related disorders, having been hospitalised, and having a childhood onset mental disorder, psychosis-like experiences, or a history of self-harm or suicidality. Conclusions Two in three young people with emerging mental disorders did not experience meaningful improvement in social and occupational functioning during two years of early intervention care. Most functional trajectories were also quite volatile, indicating the need for dynamic service models that emphasise multidisciplinary interventions and measurement-based care.

Autistic adults report concerns with social skills and unemployment. Despite anxiety and difficulty with executive cognitive skills being associated with autism, no studies to date have investigated relationships between anxiety or executive cognition with social and work functioning. This study aimed to investigate the associations between perceived social anxiety, perceived and objective executive function, and perceived social and work functioning in a sample of autistic people. A total of 62 participants completed self-report questionnaires of social anxiety (via the Liebowitz Social Anxiety Scale), mental health (via the Depression Anxiety Stress Scale), executive cognition (via the Behaviour Rating Inventory of Executive Function) and perceived social and work functioning (the Work and Social Adjustment Scale), and a smaller subset ( n = 36–40) completed performance-based executive function tasks (Trail Making Task and Rapid Visual Processing Task). Participants who reported having more social anxiety and more difficulty with executive cognition also perceived themselves as having poorer social and work functioning. Performance-based executive function was not related to social or work functioning. Our results suggest that perceived social anxiety and executive cognition are both areas that have potential to be targeted to investigate whether they improve social and vocational outcomes for autistic people. Lay abstract Many autistic adults have trouble in social situations and at work. Researchers do not know exactly why autistic people might find it difficult in these environments, and no studies to date have looked the way anxiety or other cognitive processes might affect autistic peoples’ ability to socialise and succeed in getting and keeping jobs. Anxiety (how much you worry) and difficulty with getting stuff done or switching attention (known as executive function) can be concerns for autistic people and may contribute to social and work difficulties. This study looked at the relationships between the way autistic people perceived their anxiety and executive functioning and their ability to socialise and work. Sixty-two autistic participants completed questionnaires related to their ability to socialise and work, their social anxiety and their executive function. We found that participants who thought that they had poorer ability to work also found themselves to have more difficulties with executive function and they were more socially anxious. Our results showed that how autistic participants perceived their social anxiety and executive function were important in their perception of their social skills and work ability. This study supports the idea that anxiety and executive function could be targeted in interventions to support autistic people and their social and work outcomes.

An ongoing need exists for innovation in service delivery to ensure that mental health services deliver high-quality treatment and prevention in the population. This Special Article proposes the adoption of “staged care” as a population health–oriented service delivery model for packages of specialized services delivered largely in ambulatory care settings for individuals with common affective disorders. Staged care integrates measures of clinical need alongside clinical stage and personal choice to select hierarchically arranged service packages for individuals. Packages then vary according to the intensity, duration, and mix of treatment options. This Special Article describes five levels of care in staged care: self- or family-directed monitoring and management, low-intensity services, moderate-intensity services, high-intensity services, and acute and specialist community mental health services. The care environment, treatment team, and length of treatment are also described, and provisional criteria are specified for assigning individuals to different care levels on the basis of current clinical need and clinical stage. Staged care is presented as a model that guides treatment selection and health service delivery to ensure that the high-quality care aims of “right care first time” and prevention are achieved and optimal use of available resources is considered.

Reduced social attention is characteristic of Autism Spectrum Disorder (ASD). It has been suggested to result from an early onset and excessive influence of circumscribed interests (CIs) on gaze behaviour, compared to typically developing (TYP) individuals. To date, these findings have been mixed. The current eye-tracking study utilised a visual preference paradigm to investigate the influence of CI versus non-CI objects on attention patterns in children with ASD (aged 3–12 years, n = 37) and their age-matched TYP peers (n = 30). Compared to TYP, social and object attention was reduced in the ASD group irrespective of the presence of CIs. Results suggest a reduced role for CIs and extend recent evidence of atypical attention patterns across social and non-social domains in ASD.

The current pilot study aimed to investigate the benefit of imagery rescripting (IR) as an adjunct to Group Cognitive Behavioural Therapy (GCBT) for SAD, given recent research suggesting that IR is beneficial in the treatment of social anxiety disorder (SAD). Fifteen participants with SAD completed eight sessions of GCBT and two additional individual sessions of IR to address negative meanings embedded in memories of traumatic social experiences. As expected, participants reported significant reductions in fear of negative evaluation and identification of negative core beliefs as valid/accurate over the course of the two session IR intervention. Moreover, IR yielded significant improvements in negative affect and maladaptive appraisals associated with self-imagery and aversive memories, as well as depressive symptoms. However, unexpectedly, IR did not yield significant additive reductions in social anxiety symptoms over and above GCBT. Results indicate that IR appears to be a beneficial adjunct to GCBT, and lack of improvement in social anxiety symptoms across IR sessions may be due to methodological limitations. Outcomes suggest that IR may also benefit patients with comorbid depression, given high rates of comorbid unipolar depression for people with SAD, presenting an exciting area for further investigation. Taken together, findings suggest that IR may be a valuable adjunct to GCBT for SAD, especially among patients with comorbid unipolar depression. However, further research including a follow up period is indicated.

Difficulties in adaptive functioning are common in autism spectrum disorder (ASD) and contribute to negative outcomes across the lifespan. Research indicates that cognitive ability is related to degree of adaptive functioning impairments, particularly in young children with ASD. However, the extent to which other factors, such as socioeconomic status (SES) and ASD symptom severity, predict impairments in adaptive functioning remains unclear. The goal of this study was to determine the extent to which SES, ASD symptom severity, and cognitive ability contribute to variability in domain-specific and global components of adaptive functioning in preschool-aged children with ASD. Participants were 99 preschool-aged children (2-6 years) with ASD who attended a tertiary diagnostic service. Results demonstrate that cognitive ability accounted for a significant proportion of variance in domain-specific and global components of adaptive functioning, with higher cognitive ability predicting better adaptive functioning. Results also demonstrate that SES accounted for some variability in domain-specific communication skills and global adaptive functioning when compared to basic demographic factors alone (age and gender). By contrast, ASD symptom severity did not predict variability in domain-specific or global components of adaptive functioning. These findings provide support for a relationship between cognitive ability and adaptive functioning in preschool-aged children with ASD and help to explain specific contributions of verbal and nonverbal ability to adaptive functioning; from this, we can better understand which children are likely to show the greatest degree of impairments across components of adaptive functioning early in development. LAY SUMMARY: People with autism often have difficulties with everyday communication, daily living, and social skills, which are also called adaptive functioning skills. This study investigated factors that might be related to these difficulties in preschoolers with autism. We found that better cognitive ability, but not autism symptoms, were associated with better adaptive functioning. This suggests that interventions for young children with autism should take into account cognitive ability to better understand which children are likely to have difficulties with adaptive functioning.

BACKGROUND: Paediatric hospital length of stay (LoS) is often used as a benchmark for resource use of hospitalisations. Previous studies have mostly focused on LoS of admissions for specific conditions or medical specialties. We aimed to conduct an evaluation of LoS of all paediatric hospitalisations exploring the frequency and characteristics; and associated childhood conditions. METHODS: This population-based cross-sectional study included all hospital admissions in children aged 7 days represented 2.8% of total admissions, they accounted for 27% of total bed days. Children aged 1–4 years had the highest proportion of admissions (35%), with a majority lasting ≤7 days, whereas 45.6% of admissions ≥22 days were for children aged ≥12 years. Respiratory conditions, diseases of the digestive system and traumatic injuries were the most common reasons for hospitalization. LoS >7 days were more common in children from most disadvantaged backgrounds, residing further from hospital and those aged ≥12 years with mental health conditions. INTERPRETATION: The majority of paediatric hospitalizations are for short stay and require programs that target acute conditions that can be managed in primary care. Interventions such as care coordination, tailored models of care and enhanced outpatient/community treatment programs for high-risk groups will help reduce extended LoS and improving child health and well-being. FUNDING: 10.13039/501100000925Australian National Health and Medical Research Council.

GABA is the primary inhibitory neurotransmitter in the brain, and is essential to the balance of cortical excitation and inhibition. Reductions in GABA are proposed to result in an overly excitatory cortex that may cause, or contribute to, symptoms of autism spectrum disorder (ASD). This study employed a cross-sectional design to explore GABA+ differences in ASD and the impact of age, comparing 4-12 year olds with ASD (N = 24) to typically developing children (N = 35). GABA+ concentration was measured using edited magnetic resonance spectroscopy in the left parietal lobe. This study used a mixed model to investigate group differences between children with ASD and typically developing children. There was a significant difference in GABA+ levels between the groups, a significant effect of age and interaction between age and diagnostic group. The ASD group showed an association between GABA+ and age, with GABA+ levels gradually increasing with age (r = 0.59, p = 0.003). Typically developing children did not show age-related change in GABA+ concentration (r = 0.09, p = 0.60). By the age of 9, children with ASD showed GABA+ levels that were comparable to their typically developing peers. This study suggests that children with ASD have initially lower levels of GABA+ in the left parietal lobe compared to typically developing children, and that these initially lower levels of GABA+ increase with age in ASD within this region. It is suggested that this developmental shift of GABA+ levels within the left parietal lobe provides a possible explanation for the previously found reductions in childhood that does not persist in adults. LAY SUMMARY: This study measured levels of GABA in the left parietal lobe using magnetic resonance spectroscopy in children with ASD and typically developing children. GABA levels were initially lower in the ASD group, and increased with age, while GABA did not change with age in the typically developing group. This suggests that alterations in GABA signaling may be associated with ASD in childhood. Autism Res 2021, 14: 859-872. © 2021 International Society for Autism Research, Wiley Periodicals LLC.

The aim of this study was to examine potential synergistic effects between maternal autoimmune disease and early childhood infections and their association with autism spectrum disorder (ASD) in offspring. Both exposures have been associated with increased risk of ASD in previous studies, but potential synergistic effects remain underexplored. We conducted a population-based cohort study of singleton children born at term gestation (37-41 weeks) in New South Wales, Australia from January 2002 to December 2008. Maternal autoimmune diagnoses and childhood infections before age 2 years were identified from linked maternal and child hospital admissions, and ASD diagnoses by age 9 years were identified from linked disability services data. Multivariable logistic regression assessed the association between each exposure and ASD and additive interaction between exposures, controlling for potential confounders. A total of 18,451 children exposed to maternal autoimmune disease were propensity score matched (1:2) to 36,902 unexposed children. Any maternal autoimmune disease (adjusted odds ratio (aOR) 1.25, 95% confidence interval (CI) 1.07-1.47) and any childhood infection before age 2 years (aOR 1.38, 95% CI 1.15-1.67) were each associated with ASD. However, there was no evidence of additive interaction between the two exposures (relative excess risk due to interaction [RERI] 0.128, 95% CI -0.418-0.675) resulting in increased odds of ASD in offspring. Future studies could examine potential interactions between other sources of maternal immune activation and childhood infection and impact on ASD and other neurodevelopmental disorders.

UNSTRUCTURED Recent years have seen remarkable progress in our scientific understanding of early childhood social, emotional, and cognitive development, as well as our capacity to widely disseminate health information using digital technologies. Together, these scientific and technological advances offer exciting opportunities to deliver high-quality information about early childhood development (ECD) to parents and families globally, which may ultimately lead to greater knowledge and confidence among parents and better outcomes among children (particularly in lower-and-middle income countries). With these potential benefits in mind, we set out to design, develop, implement, and evaluate a new parenting app – “Thrive by Five” – that will be available in 30 countries, providing caregivers and families with evidence-based and culturally appropriate information about ECD, accompanied by sets of “collective actions” that go beyond mere “tips” for parenting practices. Here, we describe this ongoing global project and discuss the components of our scientific framework for developing and prototyping the app’s content. Specifically, we describe: (1) five domains used to organise the content and goals of the app’s information and associated practices; (2) five neurobiological systems that are relevant to ECD and can be “targeted” behaviourally to potentially influence social, emotional, and cognitive development; (3) our anthropological and cultural framework to learn about local contexts and appreciate decolonisation perspectives; and (4) our approach to tailor the app’s content to local contexts, involving collaboration with in-country partner organisations and local and international subject-matter experts in ECD, education, medicine, psychology, and anthropology, among others. Finally, we provide examples of content that has been incorporated in Thrive by Five’s global launch in Indonesia.

Decreased heart rate variability (HRV) is considered a common marker of autonomic dysfunction that contributes to poor health outcomes. While some studies have suggested that children with autism spectrum disorder (ASD) show reduced HRV, research is yet to consider whether this may be associated with medication use and symptom severity. This study examined the relationship between resting state HRV, medication use and symptom severity in children diagnosed with ASD. Children with ASD (N = 86), aged between 3 and 12 years (M = 8.09), were compared to 44 neurotypical children of similar age (M = 7.15). Laboratory assessment of HRV involved 5 min of non-invasive baseline electrocardiogram assessments while participants viewed an age-appropriate non-verbal animated video. Time-domain and frequency-domain HRV measures were analyzed. ASD symptom severity was assessed using the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) and Social Responsiveness Scale (SRS-2). Results indicated that children with ASD exhibited reduced resting HRV relative to neurotypical children. Subsequent analyses within the ASD group suggested that this group difference was greater in children who were taking psychotropic medication (N = 36). Our data also provides tentative evidence of a relationship between HRV and social impairment symptoms in children with ASD, with more severe repetitive behaviors (as measured by the ADOS-2) associated with decreased resting HRV. Overall, these findings suggest that HRV may be atypical in children with ASD and suggest the importance of exploring HRV as a risk factor for cardiovascular health in this group. LAY SUMMARY: Cardiac activity, such as heart rate variability (HRV), can provide insight into the autonomic nervous system. This study reports on the association between resting-state HRV and autonomic nervous system activity in young children with autism spectrum disorder (ASD) compared to neurotypical children. These results may help us understand what underlies autonomic nervous system dysfunction and the potential pathophysiological mechanisms leading to increased cardiovascular risk in ASD.

BackgroundPredictors of new-onset bipolar disorder (BD) or psychotic disorder (PD) have been proposed on the basis of retrospective or prospective studies of ‘at-risk’ cohorts. Few studies have compared concurrently or longitudinally factors associated with the onset of BD or PDs in youth presenting to early intervention services. We aimed to identify clinical predictors of the onset of full-threshold (FT) BD or PD in this population.MethodMulti-state Markov modelling was used to assess the relationships between baseline characteristics and the likelihood of the onset of FT BD or PD in youth (aged 12–30) presenting to mental health services.ResultsOf 2330 individuals assessed longitudinally, 4.3% (n = 100) met criteria for new-onset FT BD and 2.2% (n = 51) met criteria for a new-onset FT PD. The emergence of FT BD was associated with older age, lower social and occupational functioning, mania-like experiences (MLE), suicide attempts, reduced incidence of physical illness, childhood-onset depression, and childhood-onset anxiety. The emergence of a PD was associated with older age, male sex, psychosis-like experiences (PLE), suicide attempts, stimulant use, and childhood-onset depression.ConclusionsIdentifying risk factors for the onset of either BD or PDs in young people presenting to early intervention services is assisted not only by the increased focus on MLE and PLE, but also by recognising the predictive significance of poorer social function, childhood-onset anxiety and mood disorders, and suicide attempts prior to the time of entry to services. Secondary prevention may be enhanced by greater attention to those risk factors that are modifiable or shared by both illness trajectories.

Epidemiological and animal research shows that maternal immune activation increases the risk of autism spectrum disorders (ASD) in offspring. Emerging evidence suggests that maternal immune conditions may play a role in the phenotypic expression of neurodevelopmental difficulties in children with ASD and this may be moderated by offspring sex. This study aimed to investigate whether maternal immune conditions were associated with increased severity of adverse neurodevelopmental outcomes in children with ASD. Maternal immune conditions were examined as predictors of ASD severity, behavioural and emotional well-being, and cognitive functioning in a cohort of 363 children with ASD (n = 363; 252 males, 111 females; median age 3.07 [interquartile range 2.64–3.36 years]). We also explored whether these outcomes varied between male and female children. Results showed that maternal asthma was the most common immune condition reported in mothers of children with ASD. A history of maternal immune conditions (p = 0.009) was more common in male children with ASD, compared to female children. Maternal immune conditions were associated with increased behavioural and emotional problems in male and female children. By contrast, maternal immune conditions were not associated with decreased cognitive function. The findings demonstrate that MIA may influence the expression of symptoms in children with ASD and outcomes may vary between males and females.

BackgroundEmerging research suggests that maternal immune activation (MIA) may be associated with an increased risk of adverse neurodevelopmental and mental health outcomes in offspring. Using data from the Raine Study, we investigated whether MIA during pregnancy was associated with increased behavioral and emotional problems in offspring longitudinally across development.MethodsMothers (Generation 1; N = 1905) were classified into the following categories: AAAE (Asthma/Allergy/Atopy/Eczema; N = 1267); infection (during pregnancy; N = 1082); no AAAE or infection (N = 301). The Child Behavior Checklist (CBCL) was administered for offspring at ages 5, 8, 10, 14, and 17. Generalized estimating equations were used to investigate the effect of maternal immune status on CBCL scores.ResultsAAAE conditions were associated with significant increases in CBCL Total (β 2.49; CI 1.98–3.00), Externalizing (β 1.54; CI 1.05–2.03), and Internalizing (β 2.28; CI 1.80–2.76) scores. Infection conditions were also associated with increased Total (β 1.27; CI 0.77–1.78), Externalizing (β 1.18; CI 0.70–1.66), and Internalizing (β 0.76; CI 0.28–1.24) scores. Exposure to more than one AAAE and/or infection condition was associated with a greater elevation in CBCL scores than single exposures in males and females. Females showed greater increases on the Internalizing scale from MIA, while males showed similar increases on both Internalizing and Externalizing scales.ConclusionsMIA was associated with increased behavioral and emotional problems in offspring throughout childhood and adolescence. This highlights the need to understand the relationship between MIA, fetal development, and long-term outcomes, with the potential to advance early identification and intervention strategies.

Neurocognitive impairment is commonly associated with functional disability in established depressive, bipolar and psychotic disorders. However, little is known about the longer-term functional implications of these impairments in early phase transdiagnostic cohorts. We aimed to examine associations between neurocognition and functioning at baseline and over time. We used mixed effects models to investigate associations between neurocognitive test scores and longitudinal social and occupational functioning (“Social and Occupational Functioning Assessment Scale”) at 1–7 timepoints over five-years in 767 individuals accessing youth mental health services. Analyses were adjusted for age, sex, premorbid IQ, and symptom severity. Lower baseline functioning was associated with male sex (coefficient −3.78, 95% CI −5.22 to −2.34 p

Recent years have seen remarkable progress in our scientific understanding of early childhood social, emotional, and cognitive development, as well as our capacity to widely disseminate health information by using digital technologies. Together, these scientific and technological advances offer exciting opportunities to deliver high-quality information about early childhood development (ECD) to parents and families globally, which may ultimately lead to greater knowledge and confidence among parents and better outcomes among children (particularly in lower- and middle-income countries). With these potential benefits in mind, we set out to design, develop, implement, and evaluate a new parenting app—Thrive by Five—that will be available in 30 countries. The app will provide caregivers and families with evidence-based and culturally appropriate information about ECD, accompanied by sets of collective actions that go beyond mere tips for parenting practices. Herein, we describe this ongoing global project and discuss the components of our scientific framework for developing and prototyping the app’s content. Specifically, we describe (1) 5 domains that are used to organize the content and goals of the app’s information and associated practices; (2) 5 neurobiological systems that are relevant to ECD and can be behaviorally targeted to potentially influence social, emotional, and cognitive development; (3) our anthropological and cultural framework for learning about local contexts and appreciating decolonization perspectives; and (4) our approach to tailoring the app’s content to local contexts, which involves collaboration with in-country partner organizations and local and international subject matter experts in ECD, education, medicine, psychology, and anthropology, among others. Finally, we provide examples of the content that was incorporated in Thrive by Five when it launched globally.

ObjectivesEarly developmental assessment is crucial for effective support and intervention. This study examined factors that contribute to (a) older child age when caregivers first became concerned about their child’s development and (b) older child age at the point of entry into developmental and diagnostic assessment. We also quantified how factors contributed to risk of children not receiving an assessment by 5 years and considered the acceptability of electronic data capture for families.DesignThis cross-sectional study collected information about caregiver developmental concerns, family history and child characteristics.SettingChildren and families entered a large, publicly funded hospital-based paediatric developmental assessment service.ParticipantsConsecutively enrolled children (N=916) aged 6 months to 17 years with neurodevelopmental concerns and their caregivers.Main outcomes and measuresA developmental history questionnaire completed by caregivers.ResultsThe average age that caregivers identified developmental concerns was 3.0 years of age but the average age of a receiving a developmental assessment was 6.6 years. Only 46.4% of children received a diagnostic assessment by 5 years of age, even though 88.0% of caregivers were concerned about their child’s development by that age. Parental age, relationship status, education level, prior use of support services and being from a culturally and linguistically diverse background contributed to age at identification of concern, age at diagnostic assessment and the likelihood of receiving a diagnostic assessment by 5 years. Electronic data capture had high acceptability, with 88.2% of caregivers reporting a preference for electronic completion of questionnaires.ConclusionsThe study shows a substantial delay in diagnostic assessments that leaves most vulnerable children without an assessment by school age and highlights contributors to delays. These delays highlight the complexity of delivering early intervention and support policies that rely on swift and appropriate developmental assessment to vulnerable families.

Early life social experiences shape neural pathways in infants to develop lifelong social skills. This review presents the first unified circuit-based model of social learning that can be applied to early life social development, drawing together unique human developmental milestones, sensitive learning periods, and behavioral and neural scaffolds. Circuit domains for social learning are identified governing Activation, Integration, Discrimination, Response and Reward (AIDRR) to sculpt and drive human social learning. This unified model can be used to identify social delays earlier in development. We propose social impairments observed in Autism Spectrum Disorder are underpinned by early mistimed sensitive periods in brain development and alterations in amygdala development to disrupt the AIDRR circuits. This model directs how interventions can target neural circuits for social development and be applied early in life. To illustrate, the role of oxytocin and its use as an intervention is explored. The AIDRR model shifts focus away from delivering broad treatments based only on diagnostic classifications, to specifying and targeting the relevant circuits, at the right time of development, to optimize social learning.

Background Deficient extinction learning and threat adaptation in the ventromedial prefrontal cortex (vmPFC)-amygdala circuitry strongly impede the efficacy of exposure-based interventions in anxiety disorders. Recent animal models suggest a regulatory role of the renin-angiotensin system in both these processes. Against this background, the present randomized placebo-controlled pharmacologic functional magnetic resonance imaging experiment aimed at determining the extinction enhancing potential of the angiotensin II type 1 receptor antagonist losartan (LT) in humans. Methods Seventy healthy male subjects underwent Pavlovian threat conditioning and received single-dose LT (50 mg) or placebo administration before extinction. Psychophysiological threat reactivity (skin conductance response) and neural activity during extinction served as primary outcomes. Psychophysiological interaction, voxelwise mediation, and novel multivariate pattern classification analyses were used to determine the underlying neural mechanisms. Results LT significantly accelerated the decline of the psychophysiological threat response during within-session extinction learning. On the neural level, the acceleration was accompanied and critically mediated by threat-specific enhancement of vmPFC activation. Furthermore, LT enhanced vmPFC-basolateral amygdala coupling and attenuated the neural threat expression, particularly in the vmPFC, during early extinction. Conclusions Overall the results indicate that LT facilitates within-session threat memory extinction by augmenting threat-specific encoding in the vmPFC and its regulatory control over the amygdala. The findings document a pivotal role of angiotensin regulation of extinction learning in humans and suggest that adjunct LT administration has the potential to facilitate the efficacy of exposure-based interventions in anxiety disorders.

Background Children with neurodevelopmental disorders share common phenotypes, support needs and comorbidities. Such overlap suggests the value of transdiagnostic assessment pathways that contribute to knowledge about research and clinical needs of these children and their families. Despite this, large transdiagnostic data collection networks for neurodevelopmental disorders are not well developed. This paper describes the development of a nationally supported transdiagnostic clinical and research assessment protocol across Australia. The vision is to establish a harmonised network for data collection and collaboration that promotes transdiagnostic clinical practice and research. Methods Clinicians, researchers and community groups across Australia were consulted using surveys and national summits to identify assessment instruments and unmet needs. A national research committee was formed and, using a consensus approach, selected assessment instruments according to pre‐determined criteria to form a harmonised transdiagnostic assessment protocol. Results Identified assessment instruments were clustered into domains of transdiagnostic assessment needs, which included child functioning/quality of life, child mental health, caregiver mental health, and family background information. From this, the research committee identified a core set of nine measures and an extended set of 14 measures that capture these domains with potential for further modifications as recommended by clinicians, researchers and community members. Conclusion The protocol proposed here was established through a strong partnership between clinicians, researchers and the community. It will enable (i) consensus driven transdiagnostic clinical assessments for children with neurodevelopmental disorders, and (ii) research studies that will inform large transdiagnostic datasets across neurodevelopmental disorders and that can be used to inform research and policy beyond narrow diagnostic groups. The long‐term vision is to use this framework to facilitate collaboration across clinics to enable large‐scale data collection and research. Ultimately, the transdiagnostic assessment data can be used to inform practice and improve the lives of children with neurodevelopmental disorders and their families.

This chapter provides an overview of the oxytocinergic system and its role in social behavior. We first consider the relationship between oxytocin and social behavior in neurotypical individuals, focusing on studies that have looked at effects of intranasal oxytocin treatment, as well as research investigating the genetic and epigenetic mechanisms associated with individual differences in social behavior. We then outline the proposed role of the oxytocinergic system in autism spectrum disorder and Williams syndrome, two neurodevelopmental disorders where a dysfunctional oxytocinergic system is thought to lead to difficulties in social behavior. Given the contrasting social phenotypes of these disorders, they provide an intriguing comparison through which we can better understand the role of the oxytocinergic system in social behavior. Finally, we consider how future research can best harness the potential of oxytocin, both by addressing measurement and administration issues inherent in many studies, and by developing our understanding of the oxytocinergic system so we are better able to identify the people who are likely to benefit from oxytocin treatment, and intervene at the right time.

This chapter provides an overview of the oxytocinergic system and its role in social behavior. We first consider the relationship between oxytocin and social behavior in neurotypical individuals, focusing on studies that have looked at effects of intranasal oxytocin treatment, as well as research investigating the genetic and epigenetic mechanisms associated with individual differences in social behavior. We then outline the proposed role of the oxytocinergic system in autism spectrum disorder and Williams syndrome, two neurodevelopmental disorders where a dysfunctional oxytocinergic system is thought to lead to difficulties in social behavior. Given the contrasting social phenotypes of these disorders, they provide an intriguing comparison through which we can better understand the role of the oxytocinergic system in social behavior. Finally, we consider how future research can best harness the potential of oxytocin, both by addressing measurement and administration issues inherent in many studies, and by developing our understanding of the oxytocinergic system so we are better able to identify the people who are likely to benefit from oxytocin treatment, and intervene at the right time.

IntroductionAttention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder which affects 5% of children globally. In Australia, it is estimated that 4.1% of children and adolescents have ADHD. While research has examined the treatment and outcomes of children with ADHD attending public mental health services during their time in the public system in Australia, it is not known what treatment they received before and after these treatment episodes, which will provide a more complete understanding of these children’s treatment journey.Methods and analysisWe will link clinical data from cohorts of children and adolescents treated in the public child and youth mental health and/or child development services in Brisbane, Melbourne and Sydney to the Medicare Benefits Schedule (MBS), Pharmaceutical Benefits Scheme (PBS) and National Death Index. MBS data will demonstrate the treatment journey with respect to clinicians seen, and treatment episodes from the public health service data sets will be examined to assess if the type and intensity of treatment are related to treatment outcomes. PBS data will reveal all psychotropic medications prescribed, allowing an examination of not just ADHD medications, but also other psychotropics which may indicate co-occurring conditions (eg, anxiety and mood disorders). Statistical analyses will include descriptive statistics to describe the rates of specific medications and clinician specialties seen. Linear and logistic regression will be used to model how treatment and sociodemographic variables relate to routinely collected outcome measures in the public health system while controlling for covarying factors.Ethics and disseminationThis study has been approved by the following institutional ethics committees: (1) Children’s Health Queensland Hospital and Health Service (HREC/21/QCHQ/76260), (2) The University of Queensland (2021/HE002143) and (3) The Australian Institute of Health and Welfare (EO2021/4/1300). Findings will be disseminated through peer-reviewed journals, conferences, professional associations and to public mental health services that treat ADHD.