1. Alaerts K, Bernaerts S, Wenderoth N. Effects of single- and multiple-dose oxytocin treatment on amygdala low-frequency BOLD fluctuations and BOLD spectral dynamics in autism. Transl Psychiatry;2022 (Sep 20);12(1):393.

Prior neuroimaging clinical trials investigating the neural effects of intranasal administration of the neuropeptide oxytocin demonstrated a key role of the amygdala in oxytocin’s neuromodulatory effects. These studies mostly demonstrated the acute effects of single-dose administrations, examining task-dependent effects of oxytocin on brain activity elicited during explicit experimental tasks or stimuli presentations. The increased consideration of oxytocin as a potential ameliorating treatment in autism spectrum disorder (ASD) requires a better understanding of how multiple-dose oxytocin administration affects intrinsic, task-free, amygdala function. In this double-blind, randomized, placebo-controlled trial with between-subject design, 38 adult men with ASD underwent resting-state fMRI scanning before and after oxytocin or placebo treatment. Effects were assessed either after a single-dose administration, consisting of 24 international units, or after multiple-dose treatment, consisting of 4 weeks of once-daily nasal spray administrations. Compared to placebo, oxytocin induced a decrease in intrinsic resting-state BOLD signal amplitudes of the bilateral amygdala (fractional amplitudes of low-frequency fluctuations) and modulated cross-frequency interactions between adjacent BOLD frequency components. The right amygdala showed a pattern of reduced cross-frequency harmonicity, while the left amygdala showed a relative increase in harmonic cross-frequency interactions after oxytocin treatment. Notably, the direction and magnitude of BOLD spectral changes induced after a single-dose were qualitatively similar to treatment effects induced after multiple-dose treatment. Furthermore, the identified spectral changes in amygdalar BOLD amplitude and cross-frequency harmonicity were associated with improved feelings of tension, reflecting oxytocin’s anxiolytic, stress-reducing neuromodulatory role. The observed effects of oxytocin on amygdalar BOLD spectral characteristics and associated behaviors contribute to a deeper mechanistic understanding of the intrinsic, task-free neuromodulatory dynamics that underlie single- and multiple-dose oxytocin treatment in ASD. European Clinical Trial Registry (Eudract 2014-000586-45).

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2. Carey C, Singh N, Dunn JT, Sementa T, Mendez MA, Velthuis H, Pereira AC, Pretzsch CM, Horder J, Hader S, Lythgoe DJ, Rotaru DG, Gee A, Cash D, Veronese M, Murphy D, McAlonan G. From bench to bedside: The mGluR5 system in people with and without Autism Spectrum Disorder and animal model systems. Transl Psychiatry;2022 (Sep 20);12(1):395.

The metabotropic glutamate receptor 5 (mGluR5) is a key regulator of excitatory (E) glutamate and inhibitory (I) γ-amino butyric acid (GABA) signalling in the brain. Despite the close functional ties between mGluR5 and E/I signalling, no-one has directly examined the relationship between mGluR5 and glutamate or GABA in vivo in the human brain of autistic individuals. We measured [(18)F] FPEB ((18)F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile) binding in 15 adults (6 with Autism Spectrum Disorder) using two regions of interest, the left dorsomedial prefrontal cortex and a region primarily composed of left striatum and thalamus. These two regions were mapped out using MEGA-PRESS voxels and then superimposed on reconstructed PET images. This allowed for direct comparison between mGluR5, GABA + and Glx. To better understand the molecular underpinnings of our results we used an autoradiography study of mGluR5 in three mouse models associated with ASD: Cntnap2 knockout, Shank3 knockout, and 16p11.2 deletion. Autistic individuals had significantly higher [(18)F] FPEB binding (t (13) = -2.86, p = 0.047) in the left striatum/thalamus region of interest as compared to controls. Within this region, there was a strong negative correlation between GABA + and mGluR5 density across the entire cohort (Pearson’s correlation: r (14) = -0.763, p = 0.002). Cntnap2 KO mice had significantly higher mGlu5 receptor binding in the striatum (caudate-putamen) as compared to wild-type (WT) mice (n = 15, p = 0.03). There were no differences in mGluR5 binding for mice with the Shank3 knockout or 16p11.2 deletion. Given that Cntnap2 is associated with a specific striatal deficit of parvalbumin positive GABA interneurons and ‘autistic’ features, our findings suggest that an increase in mGluR5 in ASD may relate to GABAergic interneuron abnormalities.

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3. Dong C, Zhao C, Chen X, Berry K, Wang J, Zhang F, Liao Y, Han R, Orgurek S, Xu L, Zhang L, Lin Y, Zhou W, Xin M, Lim DA, Campbell K, Nakafuku M, Waclaw RR, Lu QR. Conserved and distinct functions of the autism-related chromatin remodeler CHD8 in embryonic and adult forebrain neurogenesis. J Neurosci;2022 (Sep 20)

The chromatin remodeler CHD8 represents a high-confidence risk factor in autism, a multistage progressive neurological disorder, however the underlying stage-specific functions remain elusive. In this study, by analyzing Chd8 conditional knockout mice (male and female), we find that CHD8 controls cortical neural stem/progenitor cell (NSC) proliferation and survival in a stage-dependent manner. Strikingly, inducible genetic deletion reveals that CHD8 is required for the production and fitness of transit-amplifying intermediate progenitors (IPCs) essential for upper-layer neuron expansion in the embryonic cortex. p53 loss-of-function partially rescue apoptosis and neurogenesis defects in the Chd8-deficient brain. Further, transcriptomic and epigenomic profiling indicates that CHD8 regulates the chromatin accessibility landscape to activate neurogenesis-promoting factors including TBR2, a key regulator of IPC neurogenesis, while repressing DNA damage- and p53-induced apoptotic programs. In the adult brain, CHD8 depletion impairs forebrain neurogenesis by impeding IPC differentiation from NSCs in both subventricular and subgranular zones, however, unlike in embryos, it does not affect NSC proliferation and survival. Treatment with an FDA-approved antidepressant fluoxetine partially restores adult hippocampal neurogenesis in Chd8-ablated mice. Together, our multistage functional studies identify temporally-specific roles for CHD8 in developmental and adult neurogenesis, pointing to a potential strategy to enhance neurogenesis in the CHD8-deficient brain.SIGNIFICANCE STATEMENT:The role of the high-confidence autism gene CHD8 in neurogenesis remains incompletely understood. Here, we identify a stage-specific function of CHD8 in development of neural stem/progenitors (NSC) in developing and adult brains by conserved, yet spatiotemporally distinct, mechanisms. In embryonic cortex, CHD8 is critical for the proliferation, survival, and differentiation of both NSC and intermediate progenitors (IPC) during cortical neurogenesis. In adult brain, CHD8 is required for IPC generation but not the proliferation and survival of adult NSCs. Treatment with an FDA approved antidepressant fluoxetine partially rescues the adult neurogenesis defects in CHD8-mutants. Thus, our findings help resolve CHD8 functions throughout life during embryonic and adult neurogenesis, and point to a potential avenue to promote neurogenesis in CHD8 deficiency.

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4. Guo M, Li R, Wang Y, Ma S, Zhang Y, Li S, Zhang H, Liu Z, You C, Zheng H. Lactobacillus plantarum ST-III modulates abnormal behavior and gut microbiota in a mouse model of autism spectrum disorder. Physiol Behav;2022 (Sep 17):113965.

Probiotic treatment might improve autism spectrum disorder (ASD) behavior. In this study, we investigated the improvement effects of Lactobacillus plantarum ST-Ⅲ on a mouse model of ASD, which was constructed using triclosan. After two weeks of L. plantarum ST-III oral feeding, autism-like social deficits in male mouse models were ameliorated. L. plantarum ST-III also attenuated the self-grooming and freezing times of female mice. High-throughput sequencing revealed changes in the gut microbiota after L. plantarum ST-III intervention. In the female probiotic group, the abundance of beneficial Lachnospiraceae bacteria increased, whereas that of harmful Alistipes bacteria decreased. Correlation analysis showed that amelioration of abnormal behavior in a mouse model of ASD was related to the involvement of certain metabolic pathways. A reduction in the abundance of Alistipes was involved in stereotyped behavioral improvement. Thus, oral supplementation with L. plantarum ST-III can help improve social behavior in a male mouse model of ASD and contribute to more balanced intestinal homeostasis.

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5. Kalb LG, DiBella F, Jang YS, Fueyo M, Mahajan R, Vasa RA. Mental Health Crisis Screening in Youth with Autism Spectrum Disorder. J Clin Child Adolesc Psychol;2022 (Sep 21):1-9.

OBJECTIVE: While a growing body of evidence suggests youth with autism are at increased risk of experiencing a mental health crisis, no study has screened for crises in an outpatient setting. The current study fills this gap by examining a) the feasibility and utility of conducting routine crisis screenings; b) the psychometrics of a brief crisis screener (the Mental Health Crisis Assessment Scale-Revised; MCAS-R); and, c) the prevalence of and types of behaviors associated with crises. METHOD: This study was conducted at two different outpatient mental health clinics. Screenings were conducted using the MCAS-R, a 23-item parent report measure. A total of 406 youth with autism (76% Male; 72% White; M = 11.2y; SD = 3.5y), evenly divided across clinics, were screened. Seven clinicians conducted a clinical visit, which incorporated the results of the MCAS-R, to determine whether the child was in crisis. RESULTS: Eighty percent of youth were successfully screened, suggesting crisis screening is feasible. Most parents (73%) felt the MCAS-R helped communicate concerns with the clinician; few (<6%) felt the survey was too long or upsetting. All clinicians (100%) indicated that the MCAS-R was very helpful in facilitating communication and identifying/mitigating safety concerns; although, 33% reported screenings "sometimes" interrupted clinical flow. The MCAS-R strongly aligned with clinician ratings (88% correctly classified). Twenty percent of youth met the cutoff for crisis; aggression and self-injurious behaviors were the most common reasons for crises. CONCLUSION: This study suggests that outpatient crisis screening via the MCAS-R is feasible, accurate, and well received by parents and clinicians. ABBREVIATIONS: ASD: Autism Spectrum Disorder; MCAS-R: Mental Health Assessment Crisis Scale-Revised; DSM-5: Diagnostic and Statistical Manual, 5(th) Edition; ADOS-2: Autism Diagnostic Observation Schedule, Second Edition; ROC: Receiver Operating Curve.

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6. Kim KN, Sohn JH, Cho SJ, Seo HY, Kim S, Hong YC. Effects of short-term exposure to air pollution on hospital admissions for autism spectrum disorder in Korean school-aged children: a nationwide time-series study. BMJ Open;2022 (Sep 20);12(9):e058286.

OBJECTIVES: This study explored the effects of short-term exposure to air pollution on hospital admissions for autism spectrum disorder (ASD), a proxy for symptom aggravation, among Korean children aged 5-14 years. DESIGN: Time-series study. SETTING, PARTICIPANTS AND OUTCOME MEASURES: We used data from the National Health Insurance Service (2011-2015). Daily concentrations of fine particulate matter (PM(2.5)), nitrogen dioxide (NO(2)) and ozone (O(3)) levels in each region were used as exposures. ASD cases were defined based on a principal admission diagnosis of the claims data. We applied distributed lag non-linear models and a generalised difference-in-differences method to the quasi-Poisson models to estimate the causal effects of air pollution for up to 6 days. We also performed weighted quantile sum regression analyses to assess the combined effects of air pollution mixtures. RESULTS: PM(2.5) levels at lag day 1, NO(2) levels at lag day 5 and O(3) levels at lag day 4 increased the risks of hospital admissions for ASD (relative risk (RR)=1.17, 95% CI 1.10 to 1.25 for PM(2.5); RR=1.09, 95% CI 1.01 to 1.18 for NO(2) and RR=1.03, 95% CI 1.00 to 1.06 for O(3)). The mean daily count of hospital admissions for ASD was 8.5, and it would be 7.3, 7.8 and 8.3 when the PM(2.5) levels would be decreased by 10.0 µg/m(3), NO(2) by 10 ppb and O(3) by 10 ppb, respectively. The weighted quantile sum index, constructed from PM(2.5), NO(2) and O(3) levels, was associated with a higher risk of hospital admissions for ASD (RR 1.29, 95% CI 1.14 to 1.46), where NO(2) was found to contribute to the effects most (the weight of 0.80). CONCLUSIONS: These results emphasise that reduction of air pollution exposure should be considered for ASD symptom management, with important implications for the quality of life and economic costs.

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7. Lee JYS, Whittingham K, Mitchell AE. Childhood experiences of being parented, adult attachment, psychological inflexibility, social engagement, and mental health of autistic adults. Res Dev Disabil;2022 (Sep 21);130:104343.

BACKGROUND: Autistic adults have an increased risk of poor mental health. Although parental care and overprotection in childhood influence later attachment and mental health in the general adult population, this has not been investigated in the autistic population. Likewise, the roles of psychological inflexibility and social engagement in influencing mental health outcomes for autistic adults have yet to be examined. AIMS: To examine if retrospectively recalled childhood experiences of parental care and overprotection, as well as current adult attachment, psychological inflexibility and social engagement are associated with mental health in autistic adulthood. Further, to examine mediators of the association between parental care and overprotection and mental health in autistic adults. METHODS AND PROCEDURES: A community-recruited convenience sample of 126 Australian autistic adults completed an online survey assessing childhood experiences of parental care and overprotection and current adult attachment, psychological inflexibility, social engagement, and mental health. OUTCOMES AND RESULTS: Linear regressions showed that psychological inflexibility was the strongest predictor of depression, anxiety, and stress, followed by attachment anxiety (depression, anxiety) and attachment avoidance (anxiety, stress). Mediation analyses revealed that psychological inflexibility and attachment anxiety mediated the associations between parental care and overprotection and mental health outcomes in autistic adulthood. CONCLUSIONS AND IMPLICATIONS: Psychological inflexibility and adult attachment (anxious and avoidant attachment) are important to understanding mental health of autistic adults. Psychological inflexibility and attachment anxiety mediate associations between recalled childhood experiences of parental care and overprotection and mental health in autistic adulthood.

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8. Licari MK, Alvares GA, Reynolds JE, Uljaveric M. Motor impairment should be a « Specifier » for autism spectrum disorder. Autism Res;2022 (Sep 21)

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9. Maleki M, Noorimotlagh Z, Mirzaee SA, Jaafarzadeh N, Martinez SS, Rahim F, Kaffashian M. An updated systematic review on the maternal exposure to environmental pesticides and invoved mechanisms of autism spectrum disorder (ASD) progression risk in children. Rev Environ Health;2022 (Sep 21)

Autism spectrum disorder (ASD) increased dramatically over the past 25 years because of genetic and environmental factors. This systematic review (SR) aimed to determine the association between maternal exposure during pregnancy to environmental pesticides and other associations with the risk of ASD progression in children. PubMed (MEDLINE), Scopus (Elsevier) and the Institute for Scientific Information (ISI) Web of Science were searched using appropriate keywords up to March 2021. Twenty-four studies met the inclusion/exclusion criteria and were selected. Most studies reported that ASD increases the risk of offspring after prenatal exposure to environmental pesticides in pregnant mother’s residences, against offspring of women from the same region without this exposure. The main potential mechanisms inducing ASD progressions are ROS and prostaglandin E2 synthesis, AChE inhibition, voltage-gated sodium channel disruption, and GABA inhibition. According to the included studies, the highest rates of ASD diagnosis increased relative to organophosphates, and the application of the most common pesticides near residences might enhance the prevalence of ASD.

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10. Memisevic H, Djipa A. Content Analysis of Abstracts Published in Autism Journals in 2021: The year in Review. J Autism Dev Disord;2022 (Sep 20):1-7.

PURPOSE: Ever since Leo Kanner first described autism in 1943, the research in this field has grown immensely. In 2021 alone, 5837 SCOPUS indexed documents were published with a title that contained the words: « autism », « autistic », or « ASD ». The purpose of this study was to examine the most common topics of autism research in 2021 and present a geographical contribution to this research. METHODS: We performed a content analysis of 1102 abstracts from the articles published in 11 Autism journals in 2021. The following journals, indexed by the SCOPUS database, were included: Autism, Autism Research, Molecular Autism, Journal of Autism and Developmental Disorders, Research in Autism Spectrum Disorders, Focus on Autism and Other Developmental Disabilities, Education and Training in Autism and Developmental Disabilities, Review Journal of Autism and Developmental Disorders, Advances in Autism, Autism and Developmental Language Impairments, and Autism in Adulthood. RESULTS: According to the analysis, the main research topics were: mental health, social communication, social skills, quality of life, parenting stress, ADHD, Covid-19, self-efficacy, special education, and theory of mind. In relation to geographic distribution, most studies came from the USA, followed by the UK, Australia, and Canada. CONCLUSION: Research topics were aligned with the priorities set by stakeholders in autism, most notably persons with autism themselves and their family members. There is a big gap in research production between developed countries and developing countries.

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11. Norris LA, Rabner JC, Storch EA, Wood JJ, Kerns C, Lewin AB, Small BJ, Kendall PC. Idiographic Coping Outcomes in Youth with Autism Spectrum Disorder and Co-Occurring Anxiety: Results from the TAASD Study. J Autism Dev Disord;2022 (Sep 21)

Versions of cognitive behavioral therapy (Coping Cat, CC; Behavioral Interventions for Anxiety in Children with Autism, BIACA) have shown efficacy in treating anxiety among youth with autism spectrum disorder. Measures of efficacy have been primarily nomothetic symptom severity assessments. The current study examined idiographic coping outcomes in the Treatment of Anxiety in Autism Spectrum Disorder study (N = 167). Longitudinal changes in coping with situations individualized to youth fears (Coping Questionnaire) were examined across CC, BIACA and treatment as usual (TAU) in a series of multilevel models. CC and BIACA produced significantly greater improvements than TAU in caregiver-reported coping. Youth report did not reflect significant differences. Results show the efficacy of CC and BIACA in improving idiographic caregiver-, but not youth-, reported youth coping.

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12. Rixon L, Hastings RP, Kovshoff H, Bailey T. Short Report: Outcomes for siblings associated with sub-groups of autistic children with intellectual disability identified by latent profile analysis. Res Dev Disabil;2022 (Sep 17);130:104337.

BACKGROUND: Recent research suggests that having a brother or sister with autism may contribute to increased positive or negative emotional or psychological impact on siblings. AIMS: To use a novel multidimensional data analysis method to further understand outcomes for siblings of autistic children. METHODS AND PROCEDURES: 318 siblings of children with a recorded autism diagnosis and an intellectual disability were included for latent profile analysis. Five variables (DBC disruptive and anxiety; VABS II communication, daily living, and socialization skills) were used to identify sub-groups of autistic children. Primary carers reported on sibling relationship quality (items from the Sibling Relationship Questionnaire warmth/closeness and conflict scales), and siblings’ behavioral and emotional problems. OUTCOMES AND RESULTS: The profile groups differed in their levels of ID coupled with disruptive behavior, emotional problems and adaptive skills. Profiles included a severe ID, low behavior and emotional problems and low adaptive skills group; a group with mild ID coupled with high adaptive skills and low emotional and behavioral problems; and a mild ID group with high emotional and behavioral problems. Conflict in the sibling relationship differed across the profile groups (F (4304) = 15.13, p < .001). CONCLUSIONS AND IMPLICATIONS: Siblings of autistic children with the highest support needs were reported to have the lowest conflict in their relationships. Conversely, siblings of the autistic children with the highest levels of externalizing behaviors and anxiety were reported to have the highest levels of conflict in the sibling relationship.

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13. Salleh NS, Tang LY, Jayanath S, Lim Abdullah K. An Explorative Study of Affiliate Stigma, Resilience, and Quality of Life Among Parents of Children with Autism Spectrum Disorder (ASD). J Multidiscip Healthc;2022;15:2053-2066.

PURPOSE: Children diagnosed with ASD usually have impaired social functions, exhibit repetitive, stereotyped and self-stimulatory behaviors, which make them prone to be stigmatized by the public. However, stigma not only affects those with stigmatization characteristics such as children with ASD but also tends to include other people related to them including parents. This is called affiliate stigma. However, affiliate stigma is unlikely to occur if public awareness is high. Considering that awareness of ASD is still comparatively low in this region and that, as a review of the literature showed, there have been limited studies on stigma and ASD conducted in South-East Asia, particularly in Malaysia, this study is of great significance, especially in the context of the East and other developing countries. The aim of this study was to explore parents’ experiences of caring and perceptions of affiliate stigma, resilience and quality of life (QoL) when caring for a child with ASD. METHODS: This paper is part of the sequential explanatory mixed-methods study in which, after a cross-sectional study of 144 parents, a qualitative approach was used to explore parents’ experiences of caring and their perceptions of affiliate stigma, resilience, and QoL. Participants were recruited when they were accompanying their children to therapy at two tertiary public hospitals in one of the north-eastern states of Malaysia. Eleven parents of children with ASD aged 2-12 years participated. Qualitative data analysis followed Braun and Clarke’s methodology of thematic analysis. RESULTS: Four themes were identified: the meaning of QoL, ASD and life adjustment, perceived stigma, and resilience. CONCLUSION: This is the first Southeast Asian study on parent-perceived affiliate stigma, resilience, and QoL in the context of ASD. These findings can inform healthcare personnel and policymakers into day-to-day parenting realities and therefore an effort to coordinate support services across all disciplines could be made to improve outcomes for both parents and children.

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14. Tonge BJ, Brereton AV. World Autism Awareness Day: Reflections on the Indian context. Indian J Med Res;2022 (Mar&Apr);155(3&4):329-332.

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15. Velkey AJ, Koon CH, Danstrom IA, Wiens KM. Female zebrafish (Danio rerio) demonstrate stronger preference for established shoals over newly-formed shoals in the three-tank open-swim preference test. PLoS One;2022;17(9):e0265703.

Zebrafish (Danio rerio) share a considerable amount of biological similarity with mammals, including identical or homologous gene expression pathways, neurotransmitters, hormones, and cellular receptors. Zebrafish also display complex social behaviors like shoaling and schooling, making them an attractive model for investigating normal social behavior as well as exploring impaired social function conditions such as autism spectrum disorders. Newly-formed and established shoals exhibit distinct behavior patterns and inter-member interactions that can convey the group’s social stability. We used a three-chamber open-swim preference test to determine whether individual zebrafish show a preference for an established shoal over a newly-formed shoal. Results indicated that both sexes maintained greater proximity to arena zones nearest to the established shoal stimulus. In addition, we report the novel application of Shannon entropy to discover sex differences in systematicity of responses not revealed by unit-based measurements; male subjects spent more time investigating between the two shoals than female subjects. This novel technique using established versus newly-formed shoals can be used in future studies testing transgenics and pharmacological treatments that mimic autism spectrum disorder and other disorders that affect social interaction.

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16. Yu YT, Lin CH, Li HJ, Tsai CH, Chen KL. Different mediators of applied theory-of-mind competence in children with autism spectrum disorder. Res Dev Disabil;2022 (Sep 18);130:104335.

BACKGROUND: Children with autistic spectrum disorder (ASD) with mild and moderate symptom levels have significant differences in applied theory of mind (ToM) competence. However, their mediators of applied ToM competence have not been documented. AIMS: This study aimed to identify the mediators of applied ToM competence in these two clinically distinct groups. METHODS: A total of 163 children with ASD aged 3-12 years old (88 and 75 children respectively in the mild and moderate groups) and their caregivers participated in this study. Data of children’s verbal comprehension, explicit ToM knowledge and applied ToM competence were collected and then analyzed using mediation analysis. RESULTS: The results of mediation analysis showed that verbal comprehension (95% confidence interval [CI] of indirect effect: 0.02 – 0.19) and explicit ToM knowledge (95% CI of indirect effect: 0.01 – 0.07) were the mediators of applied ToM competence in children with mild and those with moderate symptoms, respectively. CONCLUSIONS AND IMPLICATIONS: Our findings demonstrate that the mediators of applied ToM competence differ by symptom level in children with ASD. Applied ToM competence and the mediators should be assessed for designing tailored and effective intervention plans for these children according to their symptom level.

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