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. Chakraborty S, Bhatia T, Antony N, Roy A, Shriharsh V, Sahay A, Brar JS, Iyengar S, Singh R, Nimgaonkar VL, Deshpande SN. Comparing the Indian Autism Screening Questionnaire (IASQ) and the Indian Scale for Assessment of Autism (ISAA) with the Childhood Autism Rating Scale-Second Edition (CARS2) in Indian settings. PLoS One;2022;17(9):e0273780.

The Indian Autism Screening Questionnaire (IASQ), derived from the Indian Scale for Assessment of Autism ISAA (the mandated tool for autism in India), is an autism screening instrument for use in the general population by minimally trained workers. While ISAA has 40 items with four anchor points, the IASQ is a 10-item questionnaire with yes/no answers. It was initially validated using the ISAA. During its development the ISAA was itself compared to the Childhood Autism Rating Scale version 1 (ISAA Manual). In the present study, we evaluated both the ISAA and the IASQ in relation to the Childhood Autism Rating Scale version 2 (CARS-2). METHODS: Participants were recruited from three settings: a referral clinic for neurodevelopmental conditions run by the Department of Paediatrics of a tertiary care teaching hospital (NDC OPD), the outpatient department of an institute for disability and rehabilitation (NIEPID), and from the community (CGOC). Persons between ages 3-18 were recruited following consent or assent (parent and child/adolescent). The IASQ was administered by a minimally trained administrator. It was followed by ISAA and the CARS-2 (in alternating order, by different evaluators blind to each other) (CARS2 SV (Standard Version) and CARS2 HF (High Functioning) as applicable). Sensitivity, specificity and area under the Receiver Operator Characteristics (ROC) curve were calculated for IASQ and CARS2, as well as for ISAA and CARS2. Concordance between CARS2 and ISAA was calculated using kappa coefficient. RESULTS: A total of 285 participants (NIEPD n = 124; NDC OPD, n = 4; CGOC n = 157) (a total of 70 with autism and 215 controls) participated. IASQ and CARS2 were administered on 285 participants, while IASQ and ISAA were administered on 264 participants. When IASQ was compared to CARS2, sensitivity was 97%, specificity 81%, PPV 63%, NPV 99% at cut off 1 while these values were 97%, 92%, 79% and 99% respectively at cut off 2. There was high concordance between CARS2 and ISAA (Kappa 0.907, p<0.0001). CONCLUSIONS: IASQ has satisfactory sensitivity, specificity and concordance when compared with CARS2; it can be used for screening children with autism in community. The ISAA also showed a high concordance with CARS2, as it had with the older version of CARS.

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4. Chawner S, Owen MJ. Autism: A model of neurodevelopmental diversity informed by genomics. Front Psychiatry;2022;13:981691.

Definitions of autism are constantly in flux and the validity and utility of diagnostic criteria remain hotly debated. The boundaries of autism are unclear and there is considerable heterogeneity within autistic individuals. Autistic individuals experience a range of co-occurring conditions notably including other childhood onset neurodevelopmental conditions such as intellectual disability, epilepsy and ADHD, but also other neuropsychiatric conditions. Recently, the neurodiversity movement has challenged the conception of autism as a medical syndrome defined by functional deficits. Whereas others have argued that autistic individuals with the highest support needs, including those with intellectual disability and limited functional communication, are better represented by a medical model. Genomic research indicates that, rather than being a circumscribed biological entity, autism can be understood in relation to two continua. On the one hand, it can be conceived as lying on a continuum of population variation in social and adaptive functioning traits, reflecting in large part the combination of multiple alleles of small effect. On the other, it can be viewed as lying on a broader neurodevelopmental continuum whereby rare genetic mutations and environmental risk factors impact the developing brain, resulting in a diverse spectrum of outcomes including childhood-onset neurodevelopmental conditions as well as adult-onset psychiatric conditions such as schizophrenia. This model helps us understand heterogeneity within autism and to reconcile the view that autism is a part of natural variability, as advocated by the neurodiversity movement, with the presence of co-occurring disabilities and impairments of function in some autistic individuals.

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5. Chhatbar K, Connelly J, Webb S, Kriaucionis S, Bird A. A critique of the hypothesis that CA repeats are primary targets of neuronal MeCP2. Life Sci Alliance;2022 (Dec);5(12)

The DNA-binding protein MeCP2 is reported to bind methylated cytosine in CG and CA motifs in genomic DNA, but it was recently proposed that arrays of tandemly repeated CA containing either methylated or hydroxymethylated cytosine are the primary targets for MeCP2 binding and function. Here we investigated the predictions of this hypothesis using a range of published datasets. We failed to detect enrichment of cytosine modification at genomic CA repeat arrays in mouse brain regions and found no evidence for preferential MeCP2 binding at CA repeats. Moreover, we did not observe a correlation between the CA repeat density near genes and their degree of transcriptional deregulation when MeCP2 was absent. Our results do not provide support for the hypothesis that CA repeats are key mediators of MeCP2 function. Instead, we found that CA repeats are subject to CAC methylation to a degree that is typical of the surrounding genome and contribute modestly to MeCP2-mediated modulation of gene expression in accordance with their content of this canonical target motif.

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6. Cho Y, Kim H. [A Predictive Model of Resilience in Mothers of Children with Developmental Disabilities]. J Korean Acad Nurs;2022 (Aug);52(4):407-420.

PURPOSE: This structural model study was constructed and verified a hypothetical model to examine the effects of parenting stress, social resources, family resources, and positive coping on resilience among mothers of children with developmental disabilities. METHODS: Data were collected using self-report structured questionnaires, from October 19 to October 30, 2018, with 214 mothers caring for children with developmental disabilities under the age of 20 years. RESULTS: In the fitness test results of the hypothesis model, with the fit index χ² (p) = 69.27 (< .001), and the normed fit indices (χ² = 1.87, GFI = .94, CFI = .97, NFI = .93, and TLI = .95, RMSEA = .06, SRMR = .06), this study satisfies the good fitness in standards. There are seven statistically significant paths among the 10 paths set in the hypothetical model. The explanatory power of parenting stress and social resources, which affects the family resources was 41.4%, the explanatory power of parenting stress, social resources, and family resources affecting the positive coping was 58.9%, and the explanatory power of parenting stress, social resources, family resources, and positive coping affecting resilience was 55.5%. CONCLUSION: Positive coping, family resources, and social resources of mothers of children with developmental disabilities directly affect their resilience, and parenting stress indirectly affects it. Therefore, to improve the resilience of mothers of children with developmental disabilities, it is necessary to develop a systematic nursing intervention that considers parenting stress, social resources, family resources, and positive coping.

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7. 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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8. Hewitt AS, Smith JG, Weintraub L. COVID-19 and Persons With Intellectual and Developmental Disabilities: Implications for Future Policy, Practice, and Research. Am J Intellect Dev Disabil;2022 (Jul 1);127(4):270-277.

The COVID-19 pandemic has been hard for everyone. For the estimated seven and a half million people in the United States who live with intellectual disability (Residential Information Systems Project, 2020), it has been very hard. Lives have been disrupted by lost jobs, lack of access to friends/family, and challenges finding enough staff to provide supports and needed healthcare. Studies have shown that people with IDD are at a much greater risk of getting COVID-19 and dying from it (Cuypers et al., 2020; Gleason et al., 2021; Kaye, 2021; Landes, Turk, & Ervin, 2020; Nygren & Lulinski, 2020). Without question, people with intellectual and developmental disabilities (IDD) struggled as the COVID-19 pandemic began and as it has continued. Too many were isolated from friends and family for far too long. Too many were lonely and bored. Too many have not received the support they have needed during the pandemic. Far too many were denied treatment and far too many have died. As a nation we must reflect on what has happened and listen to people with IDD and their families about their experiences. This commentary reflects on the implications of COVID-19 for research, policy, and practice through the lens of people with IDD.

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9. 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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10. Kim S, Oh H, Choi SH, Yoo YE, Noh YW, Cho Y, Im GH, Lee C, Oh Y, Yang E, Kim G, Chung WS, Kim H, Kang H, Bae Y, Kim SG, Kim E. Postnatal age-differential ASD-like transcriptomic, synaptic, and behavioral deficits in Myt1l-mutant mice. Cell Rep;2022 (Sep 20);40(12):111398.

Myelin transcription factor 1 like (Myt1l), a zinc-finger transcription factor, promotes neuronal differentiation and is implicated in autism spectrum disorder (ASD) and intellectual disability. However, it remains unclear whether Myt1l promotes neuronal differentiation in vivo and its deficiency in mice leads to disease-related phenotypes. Here, we report that Myt1l-heterozygous mutant (Myt1l-HT) mice display postnatal age-differential ASD-related phenotypes: newborn Myt1l-HT mice, with strong Myt1l expression, show ASD-like transcriptomic changes involving decreased synaptic gene expression and prefrontal excitatory synaptic transmission and altered righting reflex. Juvenile Myt1l-HT mice, with markedly decreased Myt1l expression, display reverse ASD-like transcriptomes, increased prefrontal excitatory transmission, and largely normal behaviors. Adult Myt1l-HT mice show ASD-like transcriptomes involving astrocytic and microglial gene upregulation, increased prefrontal inhibitory transmission, and behavioral deficits. Therefore, Myt1l haploinsufficiency leads to ASD-related phenotypes in newborn mice, which are temporarily normalized in juveniles but re-appear in adults, pointing to continuing phenotypic changes long after a marked decrease of Myt1l expression in juveniles.

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11. Lee J, Gao M, Lee C. Gendered racial disparities in health of parents with children with developmental disabilities. Front Psychol;2022;13:926655.

BACKGROUND: There is little information on (1) how adverse experiences in early life are associated with the risk of having a child with health problems and (2) whether the health of racial and gender minority groups would be particularly compromised if they have developmentally disabled (DD) children. OBJECTIVE: By integrating life-course perspectives and the intersectionality framework, we examine (1) the extent to which parents’ early-life adversities (ELAs) are associated with having children with DD or other health issues and (2) whether the association between having DD children and parental (physical and mental) health varies across race-gender groups after accounting for ELAs. METHODS: Using data from Black and White parents from the Midlife in the US Study (n = 7,425; 18% Black), we employed (1) multinomial logistic regression models to investigate the degree to which ELAs are associated with parenting types (having a child with DD, a child with recent illness, or a child without these health issues) and (2) multiple regression models with a three-way interaction term to investigate whether the gender-parenting type association differs by race. RESULTS: With more adversities, the probability of having children with health issues increases for all race-gender groups, but most dramatically for Black women. Having DD children is associated with more chronic illnesses and functional limitations for women than men, with the largest burden for Black women, yet neither gender nor racial differences in depressive symptoms. Our results highlight that while raising children with DD takes a toll on the health of all parents, the strain might be larger for Black mothers. CONCLUSION: The adverse effects of parenting a child with DD is more pronounced for Black women than for other race-gender groups indicating opportunities to promote community-based programs for these parents.

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12. Liu H, Ding L, Qu G, Guo X, Liang M, Ma S, Sun Y. Particulate matter exposure during pregnancy and infancy and risks of autism spectrum disorder in children: A systematic review and meta-analysis. Sci Total Environ;2022 (Sep 20):158830.

PURPOSE: This meta-analysis aimed to clarify the relationship between particulate matter (PM) and autism spectrum disorder (ASD) in detail. METHODS: A systematic literature search was performed using eight databases before April 9, 2022. The estimated effects were combined separately according to the PM type. Subgroup analyses were conducted in terms of the study design type, study location, exposure window, birth year, and sex. RESULTS: PM(2.5) was associated with an increased risk of ASD, while PM(10) was not. PMc, PM(1), and diesel particulate matter (DPM) were also associated with an increased risk of ASD. Specifically, a 10 μg/m(3) increase in PM(2.5) was associated with a 1.337-fold increased risk of ASD in children, and a 10 μg/m(3) increase in PMc and PM(1) may increase the risk of ASD by 1.062 and 3.643 times, respectively. PM(2.5) exposure may increase the risk of ASD in boys. Exposure to PMc might increase the risk of ASD in children born after the year 2000. The combined results of different PM differed between studies with continuous and non-continuous data for different study design type, study location, and birth year. The sensitive window for PM(2.5) exposure to increase the risk of ASD may be from the first, second, and third trimesters to the first year of the postnatal period. Exposure to PMc during pregnancy was significantly associated with ASD. CONCLUSION: Exposure to PM(2.5) may increase the risk of ASD in boys. Exposure to PM(2.5) during the first, second, and third trimesters and postnatally increased the risk of ASD.

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13. London E, Jure R, Gaspar P, Puelles L, Kulesza RJ. Editorial: The role of the brainstem and cerebellum in autism and related neurodevelopmental disorders (DD). Front Integr Neurosci;2022;16:957003.

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14. 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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15. Muscatello RA, Rafatjoo E, Mirpuri KK, Kim A, Vandekar S, Corbett BA. Salivary testosterone in male and female youth with and without autism spectrum disorder: considerations of development, sex, and diagnosis. Mol Autism;2022 (Sep 19);13(1):37.

BACKGROUND: Puberty is characterized by significant physical, hormonal, and psychological changes, which may be especially challenging for individuals with autism spectrum disorder (ASD). Although the etiology of ASD remains uncertain, studies suggest imbalances in hormones, such as testosterone, may modulate the autism phenotype. While differences in fetal and postnatal testosterone have been reported, there is limited literature regarding testosterone variations during adolescence in ASD. We investigated morning salivary testosterone levels in youth with ASD and typical development (TD) to explore hypothesized differences, expecting elevated hormonal levels in ASD compared to TD. METHODS: Youth with ASD (n = 140) and TD (n = 104), ages 10 to 13 years, were enrolled as part of a longitudinal study on pubertal development. Pubertal stage was determined by gold standard physical examination, and salivary testosterone was collected in the morning immediately upon waking and 30 min after waking and averaged across 3 days. Diagnostic (ASD/TD) and sex (male/female) differences, as well as interactions with age and puberty, were examined using robust linear mixed effect models. RESULTS: Youth with ASD showed significantly elevated testosterone concentrations compared to same-age TD peers. After the inclusion of natural cubic splines to account for nonlinearity in age, a significant age-by-sex interaction emerged with distinct developmental slopes for males and females. At younger ages, females had higher testosterone, until about 11.5 years of age, when levels began to plateau, while male testosterone concentrations continued to rapidly increase and surpass females. As expected, more advanced pubertal development was associated with elevated testosterone. In contrast, no significant effect of parent-reported social communication symptoms was observed. LIMITATIONS: Limitations include an unequal sex distribution, non-representative sample (e.g., cognition and race/ethnicity), and inability to examine afternoon/evening testosterone due to detection limits. CONCLUSIONS: Testosterone may play a unique role in the presentation of ASD, especially during periods of dynamic hormonal changes including puberty. Inherent developmental (age, puberty) and sex-based (male, female) factors play a more prominent role in changes in testosterone levels during adolescence. Even so, future research is warranted to determine the differential expression and impact of exposure to excess testosterone during the pubertal transition for youth with ASD.

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16. Nasrallah O, Alzeer S. Measuring Some Oxidative Stress Biomarkers in Autistic Syrian Children and Their Siblings: A Case-Control Study. Biomark Insights;2022;17:11772719221123913.

OBJECTIVE: Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder whose cause remains unknown. Oxidative stress is one of the possible causes of many disorders, including neurological ones. This study aims to measure some oxidative stress biomarkers (Malondialdehyde « MDA, » Advanced Oxidation Protein Product « AOPP, » Glutathione « GSH ») within Syrian children with ASD. METHODS: MDA, AOPP & GSH were measured in the plasma of a total of 60 children. The ages of the children ranged from 1 to 13 years old. Thirty children had ASD and were compared with 30 controls that don’t have ASD. Fifteen of the controls were siblings of an ASD child, while the remaining 15 had no relations with ASD. RESULTS: MDA and AOPP plasma levels were higher in ASD children compared with non-related controls (P = .0001). However, there were no significant differences between MDA and AOPP plasma levels in ASD children in comparison with related controls (P > .05). Alternatively, GSH plasma levels were lower in ASD children compared with both related and non-related controls (P = .0001). CONCLUSION: Further studies are needed to investigate more regarding the diagnostic use of oxidative stress biomarkers, and the therapeutic use of antioxidants in children affected with the autism spectrum disorder.

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17. Pokorski EA, LeJeune LM. A Systematic Review of Maintenance Measurement in Early Childhood Autism Spectrum Disorder Research. Am J Intellect Dev Disabil;2022 (Jul 1);127(4):313-327.

Single case research designs (SCRDs) are integral to identifying evidence-based practices (EBPs) for young children with autism spectrum disorder (ASD); however, the field lacks guidance on measuring response maintenance within SCRDs. We identified 103 studies in which researchers used SCRD to investigate the maintenance of behavioral intervention outcomes for children with ASD ages 0-5. Findings include: (a) maintenance conditions across most EBP categories, (b) limited within-case replication of maintenance assessment, (c) inconsistent use of maintenance terminology, (d) varying frequencies of maintenance assessment, and (e) wide range in latency to first and last maintenance probe. Results indicate a pressing need for the regular inclusion of maintenance conditions in behavioral research to increase our understanding of programming for and assessing maintenance.

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18. Ridley E, Arnott B, Riby DM, Burt DM, Hanley M, Leekam SR. The Quality of Everyday Eye Contact in Williams Syndrome: Insights From Cross-Syndrome Comparisons. Am J Intellect Dev Disabil;2022 (Jul 1);127(4):293-312.

Past research shows that individuals with Williams syndrome (WS) have heightened and prolonged eye contact. Using parent report measures, we examined not only the presence of eye contact but also its qualitative features. Study 1 included individuals with WS (n = 22, ages 6.0-36.3). Study 2 included children with different neurodevelopmental (ND) conditions (WS, autism spectrum condition, fragile X syndrome, attention-deficit/hyperactivity disorder) and children with neurotypical development (NT; n = 262, ages 4.0-17.11). Unusual eye contact features, including staring, were found in approximately half of the WS samples. However, other features such as brief glances were frequently found in WS and in all ND conditions, but not NT. Future research in ND conditions should focus on qualitative as well as quantitative features of eye contact.

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19. Scharrenberg R, Richter M, Johanns O, Meka DP, Rücker T, Murtaza N, Lindenmaier Z, Ellegood J, Naumann A, Zhao B, Schwanke B, Sedlacik J, Fiehler J, Hanganu-Opatz IL, Lerch JP, Singh KK, de Anda FC. TAOK2 rescues autism-linked developmental deficits in a 16p11.2 microdeletion mouse model. Mol Psychiatry;2022 (Sep 19)

The precise development of the neocortex is a prerequisite for higher cognitive and associative functions. Despite numerous advances that have been made in understanding neuronal differentiation and cortex development, our knowledge regarding the impact of specific genes associated with neurodevelopmental disorders on these processes is still limited. Here, we show that Taok2, which is encoded in humans within the autism spectrum disorder (ASD) susceptibility locus 16p11.2, is essential for neuronal migration. Overexpression of de novo mutations or rare variants from ASD patients disrupts neuronal migration in an isoform-specific manner. The mutated TAOK2α variants but not the TAOK2β variants impaired neuronal migration. Moreover, the TAOK2α isoform colocalizes with microtubules. Consequently, neurons lacking Taok2 have unstable microtubules with reduced levels of acetylated tubulin and phosphorylated JNK1. Mice lacking Taok2 develop gross cortical and cortex layering abnormalities. Moreover, acute Taok2 downregulation or Taok2 knockout delayed the migration of upper-layer cortical neurons in mice, and the expression of a constitutively active form of JNK1 rescued these neuronal migration defects. Finally, we report that the brains of the Taok2 KO and 16p11.2 del Het mouse models show striking anatomical similarities and that the heterozygous 16p11.2 microdeletion mouse model displayed reduced levels of phosphorylated JNK1 and neuronal migration deficits, which were ameliorated upon the introduction of TAOK2α in cortical neurons and in the developing cortex of those mice. These results delineate the critical role of TAOK2 in cortical development and its contribution to neurodevelopmental disorders, including ASD.

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20. Shen Y, Li N, Sun S, Dong L, Wang Y, Chang L, Zhang X, Wang F. Non-invasive, targeted, and non-viral ultrasound-mediated brain-derived neurotrophic factor plasmid delivery for treatment of autism in a rat model. Front Neurosci;2022;16:986571.

Autism has clinical manifestations such as social interaction disorder, speech and intellectual development disorder, narrow interest range, and stereotyped and repetitive behavior, all of which bring considerable economic and mental burden to society and families, and represent a public health problem requiring urgent attention. Brain-derived neurotrophic factor (BDNF) plays an important role in supporting survival, differentiation, growth, and synapse formation of neurons and participates in the plasticity of nerves. However, it is difficult for BDNF to penetrate the blood-brain barrier (BBB) due to its large molecular weight. Low-frequency focused ultrasound (FUS) combined with microbubbles (MBs) has been demonstrated to be a promising method for opening the BBB non-invasively, transiently, and locally. Here, we studied the therapeutic effect of FUS combined with BDNF plasmid-loaded cationic microbubbles (BDNFp-CMBs) in a rat model of autism. BDNF-CMBs were prepared and the transfection efficiency of FUS combined with BDNF-CMBs was tested in vitro. A rat model of autism was established from the juvenile male offspring of Sprague-Dawley (SD) pregnant rats treated with sodium valproate (VPA) solution through intraperitoneal injection. The autism rats were randomized into three groups: the VPA group, which received no treatment, the BDNFp group, which was treated by injection of BDNFp, and the FUS + BDNFp-CMBs group, which was administered FUS combined with BDNFp-CMBs. Age-matched normal rats served as the control group (Con). Following treatment, stereotyped, exploratory, and social-behavioral tests were performed on the animals in each group. The rat brains were then collected for subsequent histological examination, and the changes in synaptic structures in the prefrontal cortex (PFC) were detected under transmission electron microscopy. The results showed that the constructed BDNFp could be loaded onto CMBs with high loading efficiency. The BDNFp-CMBs prepared in this study showed good stability in vivo. FUS combined BDNFp-CMBs could effectively and non-invasively open the BBB of rats. The stereotyped, exploratory, and social behaviors of the FUS + BDNFp-CMBs group were significantly improved. Compared to the VPA group, the abnormality of neuronal morphology and number in the PFC of the FUS + BDNFp-CMBs was alleviated to a certain extent and was accompanied by restoration of the damaged synapses in the encephalic region. Our work demonstrates the positive therapeutic effect of BDNF delivered by FUS non-invasively across the BBB into the PFC in a rat model of autism, offering a potential strategy for treating autism.

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21. Verma A, Priyank H, Viswanath B, Bhagat JK, Purbay S, V M, Shivakumar S. Assessment of Parental Perceptions of Socio-Psychological Factors, Unmet Dental Needs, and Barriers to Utilise Oral Health Care in Autistic Children. Cureus;2022 (Aug);14(8):e27950.

INTRODUCTION: Parents’ participation is crucial in the dental health intervention of children with autism spectrum disorder (ASD). Parenting children with ASD is extremely stressful and challenging. Parents and other caregivers have a responsibility to care for and raise children with ASD. Parental perception of the condition, situational adaptation, and attitude towards the issue are significant indicators of how they will respond and eventually adapt to it. METHODOLOGY: A comparative, descriptive study was done on parents of 154 autistic children and 235 normal children. An 11-variable questionnaire eliciting various details of socio-psychological factors affecting the utilisation of oral health care was designed and validated. The questionnaire also included parameters regarding barriers to accessing dental services. The dental caries and oral hygiene status of all children were examined using the Basic Oral Health Survey 2013 proforma. Chi-square and independent t-tests were applied to find significant differences between the groups. RESULTS: A greater number of male children (61.0%) were observed among autistic children. Parental perception regarding socio-psychological concerns with raising an autistic child showed significant differences for all variables between the groups except for assistance in the child’s task with 90.2% as against 55% of the parents with non-autistic children. Parents of autistic children were more receptive to the idea of focus group discussion. Decayed teeth were significantly found to be higher in autistic cohorts (2.554 ± 1.616 versus 1.779 ± 1.841). Oral hygiene status was also statistically significant amongst autism-affected children than those who were not at p =0.000. CONCLUSION: The present study explored various socio-psychological factors of parental perception of autistic children. A better outcome can be suggested when parents gained awareness regarding various strategies and treatment options available for their child’s oral health. Furthermore, dental health can be improved by bringing in certain environmental modifications in which the autistic child is groomed.

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22. Ye C, Chen QY, Ma XQ, Lv P, Yang HL, Tian D, Zhao ZL, Lin JQ, Cui N, Li HL, Qin H. [Long-term outcomes of 328 patients with of autism spectrum disorder after fecal microbiota transplantation]. Zhonghua Wei Chang Wai Ke Za Zhi;2022 (Sep 25);25(9):798-803.

Objective: To evaluate the efficacy and safety of fecal microbiota transplantation (FMT) in the treatment of autism spectrum disorder (ASD). Methods: A longitudinal study was conducted. Clinical data from ASD patients with gastrointestinal symptoms and who underwent FMT in the Tenth People’s Hospital affiliated to Tongji University or Jinling Hospital between May 2012 to May 2021 were retrospectively collected. Scores derived from the autism behavior checklist (ABC), the childhood autism rating scale (CARS), the Bristol stool form scale (BSFS), and the gastrointestinal symptom rating scale (GSRS) were analyzed at baseline and at the 1st, 3rd, 6th, 12th, 24th, 36th, 48th and 60th month after FMT. Records of any adverse reactions were collected. Generalized estimating equations were used for analysis of data on time points before and after FMT. Results: A total of 328 patients met the inclusion criteria for this study. Their mean age was 6.1±3.4 years old. The cohort included 271 boys and 57 girls. The percentage of patients remaining in the study for post-treatment follow-up at the 1st, 3rd, 12th, 24th, 36th, 48th and 60th month were as follows: 303 (92.4%), 284 (86.7%), 213 (64.9%), 190 (57.9%), 143 (43.6%), 79 (24.1%), 46 (14.0%), 31 (9.5%). After FMT, the average ABC score was significantly improved in the first 36 months and remained improved at the 48th month. However, the average score was not significantly different from baseline by the 60th month (1st-36th month, P<0.001; 48th month, P=0.008; 60th month, P=0.108). The average CARS score improved significantly during the first 48 months and remained improved at the 60th month (1st-48th month, P<0.001; 60th month, P=0.010). The average BSFS score was also significantly improved in the first 36 months (with an accompanying stool morphology that resembled type 4). This improvement was maintained at the 48th month. However, the average score was similar to baseline at the 60th month (1st-36th month, P<0.001; 48th month, P=0.008; 60th month, P=0.109). The average GSRS score was significantly improved during the first 24 months, but not afterwards (1st-24th month, P<0.001; 36th month, P=0.209; 48th month, P=0.996; 60th month, P=0.668). The adverse events recorded during treatment included abdominal distension in 21 cases (6.4%), nausea in 14 cases (4.3%), vomiting in 9 cases (2.7%), abdominal pain in 15 cases (4.6%), diarrhea in 18 cases (5.5%), fever in 13 cases (4.0%), and excitement in 24 cases (7.3%). All adverse reactions were mild to moderate and improved immediately after suspension of FMT or on treatment of symptoms. No serious adverse reactions occurred. Conclusion: FMT has satisfactory long-term efficacy and safety for the treatment of ASD with gastrointestinal symptoms.

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23. Zhao J, Lu Y, Wu X, Zhou F, Fei F, Ding X, Wang M. Bibliometric analysis of research themes and trends in childhood autism spectrum disorders from 2012 to 2021. Front Public Health;2022;10:925475.

BACKGROUND: Autism spectrum disorders (ASD) are heterogeneous neurodevelopmental conditions that affect people worldwide. Early diagnosis and clinical support help achieve good outcomes. However, medical system structure and restricted resource availability create challenges that increase the risk of poor outcomes. Understanding the research progress of childhood ASD in recent years, based on clinical literature reports, can give relevant researchers and rehabilitation therapists more resonable research guides. OBJECTIVE: This bibliometric study aimed to summarize themes and trends in research on childhood ASD and to suggest directions for future enquiry. METHODS: Citations were downloaded from the Web of Science Core Collection database on childhood ASD published from 1 January 2012, to 31 December 2021. The retrieved information was analyzed using CiteSpace.5.8. R3, and VOS viewer. RESULTS: A total of 7,611 papers were published across 103 areas. The United States was the leading source of publications. The clusters that have continued into 2020 include coronavirus disease 2019, gut microbiota, and physical activity, which represent key research topics. Keywords with frequency spikes during 2018-2021 were « disabilities monitoring network, » « United States, » and « caregiver. » CONCLUSIONS: The Autism and Developmental Disabilities Monitoring Network in the United States can be used as a reference for relevant workers worldwide. An intelligent medical assistant system is being developed. Further studies are required to elucidate challenges associated with caring for a child with ASD.

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