Amygdala subnuclei development in adolescents with autism spectrum disorder: Association with social communication and repetitive behaviors

Introduction: The amygdala subnuclei regulate emotional processing and are widely implicated in social cognitive impairments often seen in children with autism spectrum disorder (ASD). Dysregulated amygdala development has been reported in young children with ASD; less is known about amygdala maturation in later adolescence, a sensitive window for social skill development. Methods: The macrostructural development of the amygdala subnuclei was assessed at two time points in a longitudinal magnetic resonance imaging (MRI) study of adolescents with ASD (n = 23) and typically-developing adolescents (n = 15). In adolescents with ASD, amygdala subnuclei growth was assessed in relation to ASD symptomatology based on standardized diagnostic assessments. Participants were scanned with MRI at median age of 12 years and returned for a second scan at a median age of 15 years. The volumes of nine amygdala subnuclei were extracted using an automatic segmentation algorithm. Results: When examining the longitudinal data acquired across two time points, adolescents with ASD had larger basolateral amygdala (BLA) nuclei volumes compared to typically developing adolescents (B = 46.8, p = 0.04). When examining ASD symptomatology in relation to the growth of the amygdala subnuclei, reciprocal social interaction scores on the ADI-R were positively associated with increased growth of the BLA nuclei (B = 8.3, p \u3c 0.001). Growth in the medial nucleus negatively predicted the communication (B = −46.9, p = 0.02) and social (B = −47.7, p \u3c 0.001) domains on the ADOS-G. Growth in the right cortical nucleus (B = 26.14, p = 0.02) positively predicted ADOS-G social scores. Central nucleus maturation (B = 29.9, p = 0.02) was associated with the repetitive behaviors domain on the ADOS-G. Conclusions: Larger BLA volumes in adolescents with ASD may reflect underlying alterations in cellular density previously reported in post-mortem studies. Furthermore, findings demonstrate an association between regional growth in amygdala subnuclei volumes and ASD symptomatology. Improved understanding of the developmental trajectories of the amygdala subnuclei may aid in identifying key windows for interventions, particularly for social communication, in adolescents with ASD

Variable phenotype expression in a family segregating microdeletions of the NRXN1 and MBD5 autism spectrum disorder susceptibility genes

Autism spectrum disorder is a developmental condition of early childhood onset, which impacts socio-communicative functioning and is principally genetic in etiology. Currently, more than 50 genomic loci are deemed to be associated with susceptibility to autism spectrum disorder, showing de novo and inherited unbalanced copy number variants and smaller insertions and deletions (indels), more complex structural variants, as well as single-nucleotide variants deemed of pathological significance. However, the phenotypes associated with many of these genes are variable, and penetrance is largely unelaborated in clinical descriptions. This case report describes a family harboring two copy number variant microdeletions, which affect regions of NRXN1 and MBD5 - each well-established in association with risk of autism spectrum disorder and other neurodevelopmental disorders. Although each copy number variant would likely be categorized as pathologically significant, both genomic alterations are transmitted in this family from an unaffected father to the proband, and shared by an unaffected sibling. This family case illustrates the importance of recognizing that phenotype can vary among exon overlapping variants of the same gene, and the need to evaluate penetrance of such variants in order to properly inform on risks

Exploring sensory phenotypes in autism spectrum disorder

Background: Atypical reactions to the sensory environment are often reported in autistic individuals, with a high degree of variability across the sensory modalities. These sensory differences have been shown to promote challenging behaviours and distress in autistic individuals and are predictive of other functions including motor, social, and cognitive abilities. Preliminary research suggests that specific sensory differences may cluster together within individuals creating discrete sensory phenotypes. However, the manner in which these sensory differences cluster, and whether the resulting phenotypes are associated with specific cognitive and social challenges is unclear. Methods: Short sensory profile data from 599 autistic children and adults between the ages of 1 and 21 years were subjected to a K-means cluster analysis. Analysis of variances compared age, adaptive behaviour, and traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder across the resultant clusters. Results: A five-cluster model was found to minimize error variance and produce five sensory phenotypes: (1) sensory adaptive, (2) generalized sensory differences, (3) taste and smell sensitivity, (4) under-responsive and sensation seeking, and (5) movement difficulties with low energy. Age, adaptive behaviour, and traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder were found to differ significantly across the five phenotypes. Limitations: The results were based on parent-report measures of sensory processing, adaptive behaviour, traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder, which may limit the generalizability of the findings. Further, not all measures are standardized, or psychometrically validated with an autism population. Autistic individuals with an intellectual disability were underrepresented in this sample. Further, as these data were obtained from established records from a large provincial database, not all measures were completed for all individuals. Conclusions: These findings suggest that sensory difficulties in autistic individuals can be clustered into sensory phenotypes, and that these phenotypes are associated with behavioural differences. Given the large degree of heterogeneity in sensory difficulties seen in the autistic population, these sensory phenotypes represent an effective way to parse that heterogeneity and create phenotypes that may aid in the development of effective treatments and interventions for sensory difficulties

Mostly worse, occasionally better: impact of COVID-19 pandemic on the mental health of Canadian children and adolescents

This large cross-sectional study examined the impact of COVID-19 emergency measures on child/adolescent mental health for children/adolescents with and without pre-existing psychiatric diagnoses. Using adapted measures from the CRISIS questionnaire, parents of children aged 6–18 (N = 1013; 56% male; 62% pre-existing psychiatric diagnosis) and self-reporting children/adolescents aged 10–18 (N = 385) indicated changes in mental health across six domains: depression, anxiety, irritability, attention, hyperactivity, and obsessions/compulsions. Changes in anxiety, irritability, and hyperactivity were calculated for children aged 2–5 years using the Strengths and Difficulties Questionnaire. COVID-19 exposure, compliance with emergency measures, COVID-19 economic concerns, and stress from social isolation were measured with the CRISIS questionnaire. Prevalence of change in mental health status was estimated for each domain; multinomial logistic regression was used to determine variables associated with mental health status change in each domain. Depending on the age group, 67–70% of children/adolescents experienced deterioration in at least one mental health domain; however, 19–31% of children/adolescents experienced improvement in at least one domain. Children/adolescents without and with psychiatric diagnoses tended to experience deterioration during the first wave of COVID-19. Rates of deterioration were higher in those with a pre-exiting diagnosis. The rate of deterioration was variable across different age groups and pre-existing psychiatric diagnostic groups: depression 37–56%, anxiety 31–50%, irritability 40–66%, attention 40–56%, hyperactivity 23–56%, obsessions/compulsions 13–30%. Greater stress from social isolation was associated with deterioration in all mental health domains (all ORs 11.12–55.24). The impact of pre-existing psychiatric diagnosis was heterogenous, associated with deterioration in depression, irritability, hyperactivity, obsession/compulsions for some children (ORs 1.96–2.23) but also with improvement in depression, anxiety, and irritability for other children (ORs 2.13–3.12). Economic concerns were associated with improvement in anxiety, attention, and obsessions/compulsions (ORs 3.97–5.57). Children/adolescents with and without pre-existing psychiatric diagnoses reported deterioration. Deterioration was associated with increased stress from social isolation. Enhancing social interactions for children/adolescents will be an important mitigation strategy for current and future COVID-19 waves

Linking jet emission and X-ray properties in the peculiar neutron star X-ray binary Circinus X-1

We present the results of simultaneous X-ray and radio observations of the peculiar Z-type neutron star X-ray binary Cir X-1, observed with the Rossi X-ray timing explorer satellite and the Australia Telescope Compact Array in 2000 October and 2002 December. We identify typical Z source behaviour in the power density spectra as well as characteristic Z patterns drawn in an X-ray hardness-intensity diagram. Power spectra typical of bright atoll sources have also been identified at orbital phases after the periastron passage, while orbital phases before the periastron passage are characterized by power spectra that are typical neither of Z nor of atoll sources. We investigate the coupling between the X-ray and the radio properties, focusing on three orbital phases when an enhancement of the radio flux density has been detected, to test the link between the inflow (X-ray) and the outflow (radio jet) to/from the compact object. In two out of three cases we associate the presence of the radio jet to a spectral transition in the X-rays, although the transition does not precede the radio flare, as detected in other Z sources. An analogous behaviour has recently been found in the black hole candidate GX 339-4. In the third case, the radio light curve shows a similar shape to the X-ray light curve. We discuss our results in the context of jet models, considering also black hole candidates.Comment: Accepted for publication in MNRA

Oxytocin Receptor Polymorphisms are Differentially Associated with Social Abilities across Neurodevelopmental Disorders

Oxytocin is a pituitary neuropeptide that affects social behaviour. Single nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR) have been shown to explain some variability in social abilities in control populations. Whether these variants similarly contribute to the severity of social deficits experienced by children with neurodevelopmental disorders is unclear. Social abilities were assessed in a group of children with autism spectrum disorder (ASD, n = 341) or attention deficit hyperactivity disorder (ADHD, n = 276) using two established social measures. Scores were compared by OXTR genotype (rs53576, rs237887, rs13316193, rs2254298). Unexpectedly, the two most frequently studied OXTR SNPs in the general population (rs53576 and rs2254298) were associated with an increased severity of social deficits in ASD (p \u3c 0.0001 and p = 0.0005), yet fewer social deficits in ADHD (p = 0.007 and p \u3c 0.0001). We conclude that these genetic modifier alleles are not inherently risk-conferring with respect to their impact on social abilities; molecular investigations are greatly needed

Amygdala subnuclei volumes and anxiety behaviors in children and adolescents with autism spectrum disorder, attention deficit hyperactivity disorder, and obsessive–compulsive disorder

Alterations in the structural maturation of the amygdala subnuclei volumes are associated with anxiety behaviors in adults and children with neurodevelopmental and associated disorders. This study investigated the relationship between amygdala subnuclei volumes and anxiety in 233 children and adolescents (mean age = 11.02 years; standard deviation = 3.17) with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and children with obsessive compulsive disorder (OCD), as well as typically developing (TD) children. Parents completed the Child Behavior Checklist (CBCL), and the children underwent structural MRI at 3 T. FreeSurfer software was used to automatically segment the amygdala subnuclei. A general linear model revealed that children and adolescents with ASD, ADHD, and OCD had higher anxiety scores compared to TD children (p \u3c.001). A subsequent interaction analysis revealed that children with ASD (B = 0.09, p \u3c.0001) and children with OCD (B = 0.1, p \u3c.0001) who had high anxiety had larger right central nuclei volumes compared with TD children. Similar results were obtained for the right anterior amygdaloid area. Amygdala subnuclei volumes may be key to identifying children with neurodevelopmental disorders or those with OCD who are at high risk for anxiety. Findings may inform the development of targeted behavioral interventions to address anxiety behaviors and to assess the downstream effects of such interventions

The Serotonin Transporter Promoter Polymorphism and Childhood Positive and Negative Emotionality

Association studies of the serotonin transporter promoter polymorphism (5-HTTLPR) and negative emotionality (NE) are inconclusive. However, emerging evidence suggests that the association between this polymorphism and NE may be influenced by levels of another temperament trait, positive emotionality (PE). Therefore, this study examined whether the association between the 5-HTTLPR and NE was moderated by PE. A community sample of 413 three-year-old children completed a standardized battery of laboratory tasks designed to tap temperamental emotionality. Children were also genotyped for the 5-HTTLPR. No direct association between 5-HTTLPR genotype and NE was found. However, the interaction of child PE and NE predicted 5-HTTLPR genotype. Furthermore, children with a short allele who were also low in PE had significantly greater NE than children without a short allele or children with high PE. Our findings suggest that the short allele of the 5-HTTLPR is associated with NE only in the context of low PE. Inconsistent links between NE and this gene in previous research may stem from the failure to consider other temperament traits that moderate associations. © 2010 American Psychological Association

The serotonin transporter linked polymorphic region and brain-derived neurotrophic factor valine to methionine at position 66 polymorphisms and maternal history of depression: Associations with cognitive vulnerability to depression in childhood

Preliminary work indicates that cognitive vulnerability to depression may be associated with variants of the serotonin transporter promoter polymorphism (5-HTTLPR) and the valine to methionine at position 66 (val66met) polymorphism of the brain-derived neurotrophic factor (BDNF) gene; however, existing reports come from small samples. The present study sought to replicate and extend this research in a sample of 375 community-dwelling children and their parents. Following a negative mood induction, children completed a self-referent encoding task tapping memory for positive and negative self-descriptive traits. Consistent with previous work, we found that children with at least one short variant of the 5-HTTLPR had enhanced memory for negative self-descriptive traits. The BDNF val66met polymorphism had no main effect but was moderated by maternal depression, such that children with a BDNF methionine allele had a heightened memory for negative self-descriptive traits when mothers had experienced depression during children\u27s lifetimes; in contrast, children with a methionine allele had low recall of negative traits when mothers had no depression history. The findings provide further support for the notion that the 5-HTTLPR is associated with cognitive markers of depression vulnerability and that the BDNF methionine allele moderates children\u27s sensitivity to contextual factors. Copyright © Cambridge University Press 2013

Vulnerability pathways to mental health outcomes in children and parents during COVID-19

We examined pathways from pre-existing psychosocial and economic vulnerability to mental health difficulties and stress in families during the COVID-19 pandemic. Data from two time points from a multi-cohort study initiated during the COVID-19 pandemic were used. Parents of children 6–18 years completed questionnaires on pre-COVID-19 socioeconomic and demographic factors in addition to material deprivation and stress due to COVID-19 restrictions, mental health, and family functioning. Youth 10 years and older also completed their own measures of mental health and stress. Using structural equation modelling, pathways from pre-existing vulnerability to material deprivation and stress due to COVID-19 restrictions, mental health, and family functioning, including reciprocal pathways, were estimated. Pre-existing psychosocial and economic vulnerability predicted higher material deprivation due to COVID-19 restrictions which in turn was associated with parent and child stress due to restrictions and mental health difficulties. The reciprocal effects between increased child and parent stress and greater mental health difficulties at Time 1 and 2 were significant. Reciprocal effects between parent and child mental health were also significant. Finally, family functioning at Time 2 was negatively impacted by child and parent mental health and stress due to COVID-19 restrictions at Time 1. Psychosocial and economic vulnerability is a risk factor for material deprivation during COVID-19, increasing the risk of mental health difficulties and stress, and their reciprocal effects over time within families. Implications for prevention policy and parent and child mental health services are discussed