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.

Cortical glutamate, Glx, and total N-acetylaspartate: potential biomarkers of repetitive transcranial magnetic stimulation treatment response and outcomes in major depression.

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for individuals with major depressive disorder (MDD) who have not improved with standard therapies. However, only 30-45% of patients respond to rTMS. Predicting response to rTMS will benefit both patients and providers in terms of prescribing and targeting treatment for maximum efficacy and directing resources, as individuals with lower likelihood of response could be redirected to more suitable treatment alternatives. In this exploratory study, our goal was to use proton magnetic resonance spectroscopy to examine how glutamate (Glu), Glx, and total N-acetylaspartate (tNAA) predict post-rTMS changes in overall MDD severity and symptoms, and treatment response. Metabolites were measured in a right dorsal anterior cingulate cortex voxel prior to a standard course of 10 Hz rTMS to the left DLPFC in 25 individuals with MDD. MDD severity and symptoms were evaluated via the Inventory of Depression Symptomatology Self-Report (IDS-SR). rTMS response was defined as ≥50% change in full-scale IDS-SR scores post treatment. Percent change in IDS-SR symptom domains were evaluated using principal component analysis and established subscales. Generalized linear and logistic regression models were used to evaluate the relationship between baseline Glu, Glx, and tNAA and outcomes while controlling for age and sex. Participants with baseline Glu and Glx levels in the lower range had greater percent change in full scale IDS-SR scores post-treatment (p < 0.001), as did tNAA (p = 0.007). Low glutamatergic metabolite levels also predicted greater percent change in mood/cognition symptoms (p ≤ 0.001). Low-range Glu, Glx, and tNAA were associated with greater improvement on the immuno-metabolic subscale (p ≤ 0.003). Baseline Glu predicted rTMS responder status (p = 0.025) and had an area under the receiving operating characteristic curve of 0.81 (p = 0.009), demonstrating excellent discriminative ability. Baseline Glu, Glx, and tNAA significantly predicted MDD improvement after rTMS; preliminary evidence also demonstrates metabolite association with symptom subdomain improvement post-rTMS. This work provides feasibility for a personalized medicine approach to rTMS treatment selection, with individuals with Glu levels in the lower range potentially being the best candidates.

Changes in brain metabolite levels across childhood.

Metabolites play important roles in brain development and their levels change rapidly in the prenatal period and during infancy. Metabolite levels are thought to stabilize during childhood, but the development of neurochemistry across early-middle childhood remains understudied. We examined the developmental changes of key metabolites (total N-acetylaspartate, tNAA; total choline, tCho; total creatine, tCr; glutamate+glutamine, Glx; and myo-inositol, mI) using short echo-time magnetic resonance spectroscopy (MRS) in the anterior cingulate cortex (ACC) and the left temporo-parietal cortex (LTP) using a mixed cross-sectional/longitudinal design in children aged 2-11 years (ACC: N = 101 children, 112 observations; LTP: N = 95 children, 318 observations). We found that tNAA increased with age in both regions, while tCho decreased with age in both regions. tCr increased with age in the LTP only. Glx did not show linear age effects in either region, but a follow-up analysis in participants with ≥3 datapoints in the LTP revealed a quadratic effect of age following an inverted U-shape. These substantial changes in neurochemistry throughout childhood likely underlie various processes of structural and functional brain development.

Changes in Brain GABA and Glutamate and Improvements in Physical Functioning Following Intensive Pain Rehabilitation in Youth With Chronic Pain.

Intensive interdisciplinary pain treatments (IIPT) have been developed to treat youth with unmanaged chronic pain and functional disability. Dysregulation of metabolites gamma-aminobutyric acid (GABA) and glutamate are thought to play a role in the chronification of pain due to imbalances in inhibition and excitation in adults. Using magnetic resonance spectroscopy (MRS), we investigated the effect of IIPT on GABA and Glx (glutamate + glutamine) in 2 pain-related brain regions: the left posterior insula (LPI) and the anterior cingulate cortex (ACC). Data were collected in 23 youth (mean age = 16.09 ± 1.40, 19 female) at entry and discharge from a hospital-based outpatient IIPT. GABA and Glx were measured using GABA-edited MEGA-PRESS and analyzed using Gannet. Physical measures including a 6-minute walk test were recorded, and patients completed the PLAYSelf Physical Literacy Questionnaire, PROMIS Pain Interference Questionnaire, and Functional Disability Inventory. LPI GABA (P < .05) significantly decreased, but not ACC GABA (P > .05), following IIPT. There were no significant Glx changes (P > .05). The decrease in LPI GABA was associated with increased distance in the 6-minute walk test (P < .001). IIPT may decrease GABAergic inhibitory tone within the LPI, thereby promoting plasticity and contributing to improvements in physical outcomes with IIPT. PERSPECTIVE: Regional GABA changes are associated with a reduction in pain interference and improvement in physical function in youth following intensive pain rehabilitation. GABA may serve as a possible biomarker for IIPT; and may also further aid in the development of IIPT, and other treatments for chronic pain in youth.

Designing an App for Parents and Caregivers to Promote Cognitive and Socioemotional Development and Well-being Among Children Aged 0 to 5 Years in Diverse Cultural Settings: Scientific Framework.

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.

Consistency of frontal cortex metabolites quantified by magnetic resonance spectroscopy within overlapping small and large voxels.

Single voxel magnetic resonance spectroscopy (MRS) quantifies metabolites within a specified volume of interest. MRS voxels are constrained to rectangular prism shapes. Therefore, they must define a small voxel contained within the anatomy of interest or include not of interest neighbouring tissue. When studying cortical regions without clearly demarcated boundaries, e.g. the dorsolateral prefrontal cortex (DLPFC), it is unclear how representative a larger voxel is of a smaller volume within it. To determine if a large voxel is representative of a small voxel placed within it, this study quantified total N-Acetylaspartate (tNAA), choline, glutamate, Glx (glutamate and glutamine combined), myo-inositol, and creatine in two overlapping MRS voxels in the DLPFC, a large (30×30x30 mm) and small (15×15x15 mm) voxel. Signal-to-noise ratio (SNR) and tissue type factors were specifically investigated. With water-referencing, only myo-inositol was significantly correlated between the two voxels, while all metabolites showed significant correlations with creatine-referencing. SNR had a minimal effect on the correspondence between voxels, while tissue type showed substantial influence. This study demonstrates substantial variability of metabolite estimates within the DLPFC. It suggests that when small anatomical structures are of interest, it may be valuable to spend additional acquisition time to obtain specific, localized data.

Hippocampal Neuronal Integrity and Functional Connectivity Within the Default Mode Network in Mild Cognitive Impairment: A Multimodal Investigation.

Background: In older people with mild cognitive impairment (MCI), the relationship between early changes in functional connectivity and in vivo changes in key neurometabolites is not known. Two established correlates of MCI diagnosis are decreased N-acetylaspartate (NAA) in the hippocampus, indicative of decreased neuronal integrity, and changes in the default mode network (DMN) functional network. If and how these measures interrelate is yet to be established, and such understanding may provide insight into the processes underpinning observed cognitive decline. Objectives: To determine the relationship between NAA levels in the left hippocampus and functional connectivity within the DMN in an aging cohort. Methods: In a sample of 51 participants with MCI and 30 controls, hippocampal NAA was determined using magnetic resonance spectroscopy, and DMN connectivity was quantified using resting-state functional MRI. The association between hippocampal NAA and the DMN functional connectivity was tested within the MCI group and separately within the control group. Results: In the DMN, we showed a significant inverse association between functional connectivity and hippocampal NAA in 20 specific brain connections for patients with MCI. This was despite no evidence of any associations in the healthy control group or group differences in either of these measures alone. Conclusions: This study suggests that decreased neuronal integrity in the hippocampus is associated with functional change within the DMN for those with MCI, in contrast to healthy older adults. These results highlight the potential of multimodal investigations to better understand the processes associated with cognitive decline. Impact statement This study measured activity within the default mode network (DMN) and quantified N-acetylaspartate (NAA), a measure of neuronal integrity, within the hippocampus in participants with mild cognitive impairment (MCI) and healthy controls. In participants with MCI, NAA levels were inversely associated with connectivity between specific regions of the DMN, a relationship not evident in healthy controls. This association was present even in the absence of group differences in DMN connectivity or NAA levels. This research illustrates the possibility of using multiple magnetic resonance modalities for more sensitive measures of early cognitive decline to identify and intervene earlier.

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).

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.

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.

Investigating white matter structure in social anxiety disorder using fixel-based analysis.

Social anxiety disorder (SAD) is one of the most common mental health disorders in youth, defined by a persistent and intense fear of negative evaluation by others. Recent research has examined its neurological underpinnings, including structural connectivity changes in the brain. This has been examined through measurement of the white matter (WM) structure of fibre pathways. Previous studies have shown inconsistent results. This study attempts to resolve these inconsistencies by utilising a recently proposed, advanced method for diffusion MRI analysis, known as fixel based analysis (FBA). This technique enables examination of WM macro- and micro-structure with measures of fibre density (FD), fibre bundle cross-section (FC) and fibre density-cross-section (FDC). This study evidenced increased FDC in a region of the right superior longitudinal fasciculus (SLF) from a whole brain FBA, along with increased FC and FDC from an analysis restricted to a-priori tracts of interest, in regions of the right inferior longitudinal fasciculus (R-ILF). The average FDC of the left uncinate fasciculus (L-UF) was also increased. To examine the relationship between WM structure and severity of symptoms, these FBA metrics were correlated with Leibowitz Social Anxiety Scale (LSAS) scores. From the tract-restricted analysis an inverse correlation between FC and LSAS scores was found in the R-ILF. The average FC of the R-ILF was also inversely correlated with symptom severity. By utilising a more sensitive and fibre-specific method of analysis than previous studies, these findings highlight innovative outcomes relating to white matter in numerous fibre tracts.

Intermittent Theta-Burst Stimulation Transcranial Magnetic Stimulation Increases GABA in the Medial Prefrontal Cortex: A Preliminary Sham-Controlled Magnetic Resonance Spectroscopy Study in Acute Bipolar Depression.

Background: Magnetic resonance spectroscopy (MRS) has been used to identify gamma-aminobutyric acid (GABA) alterations in mood disorders, particularly in the medial prefrontal cortex (mPFC) where decreased concentrations have been associated with anhedonia. In major depressive disorder (MDD), prior work suggests that repetitive transcranial magnetic stimulation (rTMS) increases mPFC GABA concentrations proportional to antidepressant response. To our knowledge, this has not been examined in acute bipolar depression. Methods: As part of a multicentre 4-week randomized, double-blind, sham-controlled trial using intermittent theta-burst stimulation (iTBS) of the left dorsolateral prefrontal cortex (DLPFC) in individuals with acute bipolar depression, we quantified mPFC GABA and Glx (glutamate+glutamine) concentrations using a 3T MRS scan at baseline and after the intervention. Depressive symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale-17 (HRDS-17), and anhedonia was measured using the Snaith-Hamilton Pleasure Scale (SHAPS). Results: The trial was terminated for futility and magnetic resonance spectroscopy data was acquired for 18 participants. At baseline, there were no associations between GABA or Glx concentrations and anhedonia, however GABA was negative correlated with depressive symptom severity on the HRDS-17. Compared to the sham-iTBS group, participants receiving active-iTBS had a significant increase in mPFC GABA concentrations. This was unrelated to antidepressant outcomes or improvements in anhedonia. Conclusion: Our data suggests that iTBS targeting the DLPFC is associated with physiological changes in the mPFC. In acute bipolar depression, our preliminary data suggests that mPFC GABA is dissociated from antidepressant iTBS treatment outcomes and anhedonia.

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.

Obesity and Oxidative Stress in Older Adults At Risk for Dementia: A Magnetic Resonance Spectroscopy Study.

OBJECTIVE: This study aimed to investigate the relationship between obesity and oxidative stress in older adults at risk for dementia. It also aimed to explore the influence of physical activity on the relationship between obesity and oxidative stress in this at risk cohort. METHODS: Older adults at risk for dementia underwent comprehensive medical, neuropsychological, and psychiatric assessment. At risk was defined as participants with subjective or mild cognitive impairment. Glutathione was assessed by magnetic resonance spectroscopy in the left hippocampus and the anterior and posterior cingulate cortex. Body mass index (BMI) was calculated and classified as healthy (BMI <25 kg/m2) or overweight/obese (BMI ≥25 kg/m2). RESULTS: Sixty-five older adults (mean age=66.2 y) were included for analysis. The overweight/obese group had significantly greater glutathione in the hippocampus compared with the healthy weight group (t=-2.76, P=0.008). No significant difference in glutathione was observed between groups in the anterior or posterior cingulate. In the overweight/obese group, a higher BMI was associated with a diabetes diagnosis and lower total time engaging in physical activity (r=-0.36, P=0.025), however, glutathione did not correlate with activity levels across groups. CONCLUSION: This study demonstrates that changes in in vivo markers of oxidative stress are present in overweight/obese older adults at risk for dementia. Future research should explore the relationship with diabetes and the longitudinal relationship between BMI and oxidative stress, and response to therapeutic interventions.

Executive Function in Autism Spectrum Disorder: History, Theoretical Models, Empirical Findings, and Potential as an Endophenotype.

This review presents an outline of executive function (EF) and its application to autism spectrum disorder (ASD). The development of the EF construct, theoretical models of EF, and limitations in the study of EF are outlined. The potential of EF as a cognitive endophenotype for ASD is reviewed, and the Research Domain Criteria (RDoC) framework is discussed for researching EF in ASD given the multifaceted factors that influence EF performance. A number of executive-focused cognitive models have been proposed to explain the symptom clusters observed in ASD. Empirical studies suggest a broad impairment in EF, although there is significant inter-individual variability in EF performance. The observed heterogeneity of EF performance is considered a limiting factor in establishing EF as a cognitive endophenotype in ASD. We propose, however, that this variability in EF performance presents an opportunity for subtyping within the spectrum that can contribute to targeted diagnostic and intervention strategies. Enhanced understanding of the neurobiological basis that underpins EF performance, such as the excitation/inhibition hypothesis, will likely be important. Application of the RDoC framework could provide clarity on the nature of EF impairment in ASD with potential for greater understanding of, and improved interventions for, this disorder.

Circuits for social learning: A unified model and application to Autism Spectrum Disorder.

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.

A Review of the Safety, Efficacy and Mechanisms of Delivery of Nasal Oxytocin in Children: Therapeutic Potential for Autism and Prader-Willi Syndrome, and Recommendations for Future Research.

In this article, we conduct a comprehensive review of existing evidence for the safety and therapeutic potential of intranasal oxytocin in pediatric populations. Unique considerations for dosing and delivery of oxytocin to the nasal passageway in pediatric populations and methods to promote adherence are reviewed. Intranasal oxytocin has been administered to 261 children in three open-label studies and eight randomized controlled trials. To date, the only published results in pediatric populations have focused on autism spectrum disorder (ASD) and Prader-Willi syndrome (PWS). Results regarding efficacy for improving social impairment in ASD are equivocal, partially due to mixed methodological designs, dosing regimens, and outcome measures. At present, there is no randomized controlled evidence that oxytocin provides benefit to individuals with PWS. There is no clear evidence of a link between oxytocin administration and any specific adverse event. Adverse events have been assessed using medical interviews, open reports, checklists, and physiological assessments. Adverse events reports have been largely classified as mild (n = 93), with few moderate (n = 9) or severe (n = 3) events reported. There were 35 additional adverse events reported, without severity ratings. Severe events, hyperactivity and irritability, occurred at first administration in both placebo and oxytocin groups, and subsided subsequent to discontinuation. We note that adverse event monitoring is inconsistent and often lacking, and reporting of its relationship to the study drug is poor. Only one study reported adherence data to suggest high adherence. Recommendations are then provided for the delivery of nasal sprays to the nasal passageway, monitoring, and reporting of efficacy, safety, and adherence for oxytocin nasal spray trials in pediatric populations.

An Overview of Autism Spectrum Disorder, Heterogeneity and Treatment Options.

Since the documented observations of Kanner in 1943, there has been great debate about the diagnoses, the sub-types, and the diagnostic threshold that relates to what is now known as autism spectrum disorder (ASD). Reflecting this complicated history, there has been continual refinement from DSM-III with 'Infantile Autism' to the current DSM-V diagnosis. The disorder is now widely accepted as a complex, pervasive, heterogeneous condition with multiple etiologies, sub-types, and developmental trajectories. Diagnosis remains based on observation of atypical behaviors, with criteria of persistent deficits in social communication and restricted and repetitive patterns of behavior. This review provides a broad overview of the history, prevalence, etiology, clinical presentation, and heterogeneity of ASD. Factors contributing to heterogeneity, including genetic variability, comorbidity, and gender are reviewed. We then explore current evidence-based pharmacological and behavioral treatments for ASD and highlight the complexities of conducting clinical trials that evaluate therapeutic efficacy in ASD populations. Finally, we discuss the potential of a new wave of research examining objective biomarkers to facilitate the evaluation of sub-typing, diagnosis, and treatment response in ASD.