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

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).

Social and joint attention during shared book reading in young autistic children: a potential marker for social development.

BACKGROUND: Atypical patterns of social engagement and joint attention behaviors are diagnostic criteria for people with autism spectrum disorder. Experimental tasks using eye-tracking methodologies have, however, shown inconsistent results. The development of tasks with greater ecological validity and relevance for developmentally appropriate social milestones has been identified as important for the field. METHODS: We developed a novel, dynamic eye-tracking task emulating a shared book reading (SBR) scenario. Four SBR videos of an adult reader engaging with the viewer while reading a children's picture book and including sequenced bids for joint attention were developed. Participants included 90 children (N = 56 autistic children, N = 34 neurotypical children; aged 3-12). Social attention was also measured in a live free play task between participants and an experimenter. RESULTS: Compared to neurotypical children, autistic children displayed reduced attention to socially salient stimuli including the reader's face and picture book across SBR videos and during joint attention bids specifically. In contrast, they showed increased attention to nonsalient background stimuli compared to their neurotypical peers. These attention patterns in autistic children were associated with reduced verbal and nonverbal cognitive skills and increased symptoms associated with autism. Interestingly, positive correlations in the frequency of eye gaze between SBR and free play suggested a potential predictive value for social attention in live social interactions. CONCLUSIONS: Findings highlight the utility of SBR eye-tracking tasks in understanding underlying divergences in social engagement and joint attention between autistic and neurotypical children. This commonly practiced early childhood activity may provide insights into the relationship between social engagement and learning to reveal how such attentional patterns might influence broader developmental and educational outcomes.

Statistical Validation of An Automated Method for Calculating Time Domain Heart Rate Variability on The QT Dataset.

Heart rate variability measures calculated from electrocardiography recordings reflect social competence. Clinical assessments of social skills have found that reduced heart rate variability is related to differences in the development of social skills in children and increase the risk of mental disorders. Limited by widespread manual signal processing and R-peak detection in current clinical assessments, most literature reports only short-term baseline studies, with fewer studies reporting social interaction settings with prolonged recording. There is an urgent need for an automated physiological signal processing toolbox to detect R-peaks and perform heart rate variability measurements in social settings. This paper proposes a modified automated Neurokit2 toolbox with signal processing procedures similar to the MindWare software that requires manual inspection of R-peak locations. We calculate time domain heart rate variability metrics from the publicly available QT database by PhysioNet collected at resting states and under stress tests, mimicking social interaction stress scenarios. Statistical analysis conveys that heart rate variability metrics calculation applying both signal processing approaches using the Neurokit2 toolbox are statistically equivalent in comparison to the hand-labelled R-peaks from the QT database (n= 10 in the normal sinus rhythm group, and n= 6 in the ST Change group). Such validation results are crucial for the adoption of automated toolboxes for heart rate variability measures in social interaction assessments, where more movement and mood changes of participants are expected.Clinical Relevance- This contributes to the body of evidence of the reliability of the Neurokit2 toolbox for automatic cleaning of prolonged cardiac electrophysiological signals and calculation of heart rate variability in time-domain characterization in social interaction stress assessment.

Burden of paediatric hospitalisations to the health care system, child and family: a systematic review of Australian studies (1990-2022).

Background: Paediatric hospitalisations represent a significant cost to the health system and cause significant burden to children and their families. Understanding trends in hospitalisation costs can assist with health planning and support strategies across stakeholders. The objective of this systematic review is to examine the trends in costs and burden of paediatric hospitalisations in Australia to help inform policy and promote the well-being of children and their families. Methods: Electronic data sources (Embase, Medline, Web of Science, PSYCH-Info, CINAHL and Scopus) were searched from 1990 until December 2022. Any quantitative or qualitative studies conducted in Australian tertiary hospitals were included in the review. Eligible studies were those that included paediatric (<18 years) hospitalisations and reported on economic and/or non-economic costs for the child, family unit and/or health system. Study quality and risk of bias for each study were assessed with the Joanna Briggs Critical Appraisal Tools. We present a summary of the findings of the hospitalisation burden across major diagnostic admission categories and for the child and family unit. The systematic review was registered with Prospero (ID: CRD42021276202). Findings: The review summarises a total of 88 studies published between 1990 and December 2022. Overall, the studies identified that paediatric hospitalisations incur significant financial costs, which have not shown significant reductions over time. In-patient direct hospital costs varied depending on the type of treatment and diagnostic condition. The costs per-case were found to range from just below AUD$2000 to AUD$20,000 or more. The financial burden on the family unit included loss of productivity, transport and travel costs. Some studies reported estimates of these costs upward of AUD$500 per day. Studies evaluating 'hospital in the home' options identified significant benefits in reducing hospitalisations and costs without compromising care. Interpretation: Increasing focus on alternative models of care may help alleviate the significant costs associated with paediatric hospitalisation. Funding: This research was supported by Hospitals United for Sick Kids (formerly Curing Homesickness).

The Feasibility of Magnetic Resonance Imaging in a Non-Selective Comprehensive Clinical Trial in Pediatric Autism Spectrum Disorder.

There is an increasing interest in using magnetic resonance imaging (MRI) as a tool for precision medicine in autism spectrum disorder (ASD). This study investigated the feasibility of MRI scanning in a large comprehensive, inclusive and test heavy clinical trial for children (aged 3-12 years) with ASD, without functioning constraints for participation. Of the 71 participants enrolled who consented to the MRI, 24 participants (38%) successfully completed an MRI scan at baseline along with other assessments. This scanning followed a familiarization procedure at two preceding visits. At post-treatment, 21 participants successfully completed the MRI scan. This study highlights the challenge of completing MRI assessments in ASD populations when conducted as one of a number of tests in a clinical trial.

Atypical sensory processing features in children with autism, and their relationships with maladaptive behaviors and caregiver strain.

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.

Age-related parietal GABA alterations in children with autism spectrum disorder.

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.

Heart Rate Variability in Children With Autism Spectrum Disorder and Associations With Medication and Symptom Severity.

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.

Reduced heart rate variability in adults with autism spectrum disorder.

A growing body of research has suggested heart rate variability (HRV) may be reduced in autism spectrum disorder (ASD) in comparison to neurotypical cohorts. While there have been several studies investigating HRV in children diagnosed with ASD, few studies have been conducted in adults. The objective of the current study was to investigate autonomic nervous system activity as assessed by HRV in adults diagnosed with ASD. We hypothesized that adults with ASD would show a reduction in HRV compared to neurotypical participants. Participants diagnosed with ASD (n = 55) were recruited from the Autism Clinic for Translational Research at the Brain and Mind Centre (University of Sydney) between 2013 and 2017. Neurotypical participants were recruited from advertisements and online media. Resting state heart rate was measured for 5 min while participants sat in an upright position. Results showed there was an overall significant difference in resting-state HRV between adults diagnosed with ASD compared to the neurotypical control group. Logarithmically transformed high frequency (HF) and root mean square of successive differences were particularly decreased in the ASD group, suggesting lower parasympathetic activity. The use of psychotropic medications and comorbidities were associated with reductions in low frequency of HRV. Our data suggest an overall dysregulation in resting autonomic activity in adults with ASD. This may represent an important physiological mechanism leading to potential cardiovascular risk in ASD, which warrants further investigation. Autism Res 2019, 12: 922-930. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: ASD is commonly associated with a range of physical and mental health comorbidities. Autonomic disruptions underlying reductions in heart rate variability (HRV) have been linked to a range of mental and physical health conditions. We assessed resting-state HRV in adults diagnosed with ASD in comparison to healthy individuals. Our results showed reduced heart rate variability in people diagnosed with ASD compared to adults without ASD. These findings implicate a role for autonomic activity as a potentially modifiable risk factor for ASD.