1. Arroyo HA. [Environmental factors influencing developmental disorders]. Medicina (B Aires);2022 (Aug 30);82 Suppl 3:35-39.

Neurodevelopmental disorders have been associated with multiple causes especially, genetic a nd environmental -nutritional, infectious, toxic, traumatic and psychosocial stress among others- that in general do not operate alone, but interact with each other. Of special interest is to identify the mechanism(s) that lead to these disorders. Inflammation and epigenetic changes may play a common end for many forms of environmental risk.

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2. Caldwell ALM, Sancho L, Deng J, Bosworth A, Miglietta A, Diedrich JK, Shokhirev MN, Allen NJ. Aberrant astrocyte protein secretion contributes to altered neuronal development in multiple models of neurodevelopmental disorders. Nat Neurosci;2022 (Sep);25(9):1163-1178.

Astrocytes negatively impact neuronal development in many models of neurodevelopmental disorders (NDs); however, how they do this, and if mechanisms are shared across disorders, is not known. In this study, we developed a cell culture system to ask how astrocyte protein secretion and gene expression change in three mouse models of genetic NDs (Rett, Fragile X and Down syndromes). ND astrocytes increase release of Igfbp2, a secreted inhibitor of insulin-like growth factor (IGF). IGF rescues neuronal deficits in many NDs, and we found that blocking Igfbp2 partially rescues inhibitory effects of Rett syndrome astrocytes, suggesting that increased astrocyte Igfbp2 contributes to decreased IGF signaling in NDs. We identified that increased BMP signaling is upstream of protein secretion changes, including Igfbp2, and blocking BMP signaling in Fragile X and Rett syndrome astrocytes reverses inhibitory effects on neurite outgrowth. This work provides a resource of astrocyte-secreted proteins in health and ND models and identifies novel targets for intervention in diverse NDs.

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3. Crippa A. Motor abilities as a possible specifier of autism: A response to Bhat (2021). Autism Res;2022 (Aug 29)

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4. Daniolou S, Pandis N, Znoj H. The Efficacy of Early Interventions for Children with Autism Spectrum Disorders: A Systematic Review and Meta-Analysis. J Clin Med;2022 (Aug 30);11(17)

The superiority of early interventions for children with autism spectrum disorders (ASDs) compared to treatment as usual (TAU) has recently been questioned. This study was aimed to investigate the efficacy of early interventions in improving the cognitive ability, language, and adaptive behavior of pre-school children with ASDs through a systematic review of randomized controlled trials (RCTs). In total, 33 RCTs were included in the meta-analysis using the random effects model. The total sample consisted of 2581 children (age range: 12-132 months). Early interventions led to positive outcomes for cognitive ability (g = 0.32; 95% CI: 0.05, 0.58; p = 0.02), daily living skills (g = 0.35; 95% CI: 0.08, 0.63; p = 0.01), and motor skills (g = 0.39; 95% CI: 0.16, 0.62; p = 0.001), while no positive outcomes were found for the remaining variables. However, when studies without the blinding of outcome assessment were excluded, positive outcomes of early interventions only remained for daily living skills (g = 0.28; 95% CI: 0.04, 0.52; p = 0.02) and motor skills (g = 0.40; 95% CI: 0.11, 0.69; p = 0.007). Although early intervention might not have positive impacts on children with ASDs for several outcomes compared to controls, these results should be interpreted with caution considering the great variability in participant and intervention characteristics.

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5. Deveau N, Washington P, Leblanc E, Husic A, Dunlap K, Penev Y, Kline A, Mutlu OC, Wall DP. Machine learning models using mobile game play accurately classify children with autism. Intell Based Med;2022 (Aug 24):100057.

Digitally-delivered healthcare is well suited to address current inequities in the delivery of care due to barriers of access to healthcare facilities. As the COVID-19 pandemic phases out, we have a unique opportunity to capitalize on the current familiarity with telemedicine approaches and continue to advocate for mainstream adoption of remote care delivery. In this paper, we specifically focus on the ability of GuessWhat? a smartphone-based charades-style gamified therapeutic intervention for autism spectrum disorder (ASD) to generate a signal that distinguishes children with ASD from neurotypical (NT) children. We demonstrate the feasibility of using « in-the-wild », naturalistic gameplay data to distinguish between ASD and NT by children by training a random forest classifier to discern the two classes (AU-ROC = 0.745, recall = 0.769). This performance demonstrates the potential for GuessWhat? to facilitate screening for ASD in historically difficult-to-reach communities. To further examine this potential, future work should expand the size of the training sample and interrogate differences in predictive ability by demographic.

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6. Fritz C, Engelhardt A, Grohmann J, Dähnert I, Hummel J, Tanase D, Ewert P, Eicken A. A multi-center trial on efficacy and safety of the LifeTech CeraFlex(TM) ASD occluder for transcatheter closure in patients with secundum atrial septal defects. Cardiovasc Diagn Ther;2022 (Aug);12(4):475-484.

BACKGROUND: The last decades have brought remarkable improvements in treatment strategy and occluder modification of secundum atrial septal defect (ASD) closure. Approval, efficacy and safety of ASD closure devices have previously been demonstrated. This study investigated the clinical efficacy and safety of the LifeTech CeraFlex(TM) ASD occluder for interventional closure of secundum ASD with a 6-month follow-up (FU). METHODS: Procedure specific data was collected on patients considered for ASD closure with the CeraFlex(TM) occluder between April 2016 and December 2019 in three German centers. Efficacy and safety were assessed after device closure, at discharge, and at 6-month FU. RESULTS: The primary endpoint (successful ASD closure without severe complications) was reached by 102/103 patients (99%). Device embolization occurred in two patients (one early and one late embolization). After early snare-retrieval of an embolized device, this ASD was closed surgically and in the other patient with late device embolization the defect was closed with a larger CeraFlex(TM) occluder. The secondary endpoint (clincal efficacy after 6 months) was reached by 94/98 patients since new onset of arrhythmia occurred in four patients. Three patients had withdrawn their study-participation and one patient had moderate residual shunt, but not related to the occluder. Incomplete right bundle branch block (iRBBB) was seen in 31 patients. At last FU only 17 patients had remaining iRBBB documenting effective volume unloading of the right ventricle. CONCLUSIONS: Catheter interventional closure of secundum ASDs with the CeraFlex(TM) ASD occluder was feasible, safe and effective in this study.

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7. Hou S, Liu N, Zou J, Yin X, Liu X, Zhang S, Chen J, Wei Z. Young children with autism show atypical prefrontal cortical responses to humanoid robots: An fNIRS study. Int J Psychophysiol;2022 (Aug 28);181:23-32.

BACKGROUND: Previous behavioral studies have found that children with autism spectrum disorder (ASD) show greater interest in humanoid robots than in humans. However, the neural mechanism underlying this is not clear. This study compared brain activation patterns between children with ASD and neurotypical children while they watched videos with robots and humans. METHOD: We recruited 45 children with ASD and 53 neurotypical children aged 4-6 years and recorded their neural activity in the dorsolateral prefrontal cortex (DLPFC) using a functional near-infrared spectroscopy (fNIRS) device when the two groups interacted with a robot or a human in a video. RESULTS: First, neural activity in the right DLPFC in children with ASD was significantly lower in the robot condition than in the human condition. Neural activity in the right DLPFC in children with ASD was also significantly lower than that of neurotypical children in the robot condition. Second, the neural activity in the left DLPFC between the human and robot conditions was negatively correlated in children with ASD, while it was positively correlated in neurotypical children. Moreover, neural activity in the left DLPFC in children with ASD was significantly correlated with the ADOS scores in both conditions. CONCLUSIONS: While neurotypical children showed comparable neural activity to humanoid robots and human beings, the children with ASD showed significantly different neural activity under those two conditions. Children with ASD may need more selective attention resources for human interaction than for robot interaction. It is also much more difficult for children with ASD to neglect the attraction of robots. Neural activity of the left DLPFC of children with ASD is correlated with their symptoms, which maybe a possible indicator for early diagnosis. Neural activity of the right DLPFC guided their atypical reactions and engagements with robots. Our study contributes to the current understanding of the neural mechanisms responsible for the different behavioral reactions in children with ASD toward robots and humans.

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8. Jaudon F, Thalhammer A, Zentilin L, Cingolani LA. CRISPR-mediated activation of autism gene Itgb3 restores cortical network excitability via mGluR5 signaling. Mol Ther Nucleic Acids;2022 (Sep 13);29:462-480.

Many mutations in autism spectrum disorder (ASD) affect a single allele, indicating a key role for gene dosage in ASD susceptibility. Recently, haplo-insufficiency of ITGB3, the gene encoding the extracellular matrix receptor β3 integrin, was associated with ASD. Accordingly, Itgb3 knockout (KO) mice exhibit autism-like phenotypes. The pathophysiological mechanisms of Itgb3 remain, however, unknown, and the potential of targeting this gene for developing ASD therapies uninvestigated. By combining molecular, biochemical, imaging, and pharmacological analyses, we establish that Itgb3 haplo-insufficiency impairs cortical network excitability by promoting extra-synaptic over synaptic signaling of the metabotropic glutamate receptor mGluR5, which is similarly dysregulated in fragile X syndrome, the most frequent monogenic form of ASD. To assess the therapeutic potential of regulating Itgb3 gene dosage, we implemented CRISPR activation and compared its efficacy with that of a pharmacological rescue strategy for fragile X syndrome. Correction of neuronal Itgb3 haplo-insufficiency by CRISPR activation rebalanced network excitability as effectively as blockade of mGluR5 with the selective antagonist MPEP. Our findings reveal an unexpected functional interaction between two ASD genes, thereby validating the pathogenicity of ITGB3 haplo-insufficiency. Further, they pave the way for exploiting CRISPR activation as gene therapy for normalizing gene dosage and network excitability in ASD.

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9. Karavasilis G, Statiri A. Relationship between sleep and measures of attention, executive functions, and processing speed in children with autism spectrum disorder: systematic review. Psychiatriki;2022 (Aug 30)

Sleep disorders represent a common comorbidity among children and adolescents with autism spectrum disorder with prevalence ranging from 50 to 80%. Poor quality sleep has negative impact on individuals’ cognitive functions such as self-regulation, attention, executive functions, memory, and speed of processing. The aim of this literature review was to examine the correlation between sleep and measures of attention, executive functions, and processing speed among children with autism. This review included research articles published between 2012 and May 2022 in PubMed and Scopus databases, using the keywords « sleep » AND « attention » OR « executive functions » OR « processing speed » AND « autism » AND « children ». These key-words were accompanied by synonym, close-related, or underlying terms using the Boolean connector OR. 1226 results yielded but the total number of original papers was reduced to 90 after checking for duplicate publications and title/abstract screening. 68 out of the 90 articles were excluded as irrelevant to the scope of the present study, after reading the full text. As a result, 22 studies were included in the present review, which was compiled by the PRISMA protocol. Exclusion criteria were papers published in any other language rather than English, non-research articles and studies in typically developing and/or adult population. Regarding the measurement of sleep quality, most studies used subjective measures, such as questionnaires with reports and parental observations of participants’ sleep habits and behaviours. In terms of measuring the under examination cognitive functions, most studies used subjective rather than objective instruments. In the case of attention, most studies tested it as a unitary construct by using questionnaires. Contrary, regarding Executive Functions, the majority of studies examined specific aspects, such inhibition, shifting and working memory, rather than executive functions as a unitary construct. Results showed a strong correlation between sleep and measures of attention, whereas results for executive functions and processing speed are less clear. Early and accurate diagnosis of sleep disorders could prove to be crucial in the regulation of these cognitive functions in children with autism, as it implies early and targeted intervention. Conclusively, further research on sleep quality improvement interventions is needed in autism individuals.

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10. Keeratitanont K, Theerakulpisut D, Auvichayapat N, Suphakunpinyo C, Patjanasoontorn N, Tiamkao S, Tepmongkol S, Khiewvan B, Raruenrom Y, Srisuruk P, Paholpak S, Auvichayapat P. Brain laterality evaluated by F-18 fluorodeoxyglucose positron emission computed tomography in autism spectrum disorders. Front Mol Neurosci;2022;15:901016.

BACKGROUND AND RATIONALE: Autism spectrum disorder (ASD) is a neuropsychiatric disorder that has no curative treatment. Little is known about the brain laterality in patients with ASD. F-18 fluorodeoxyglucose positron emission computed tomography (F-18 FDG PET/CT) is a neuroimaging technique that is suitable for ASD owing to its ability to detect whole brain functional abnormalities in a short time and is feasible in ASD patients. The purpose of this study was to evaluate brain laterality using F-18 FDG PET/CT in patients with high-functioning ASD. MATERIALS AND METHODS: This case-control study recruited eight ASD patients who met the DSM-5 criteria, the recorded data of eight controls matched for age, sex, and handedness were also enrolled. The resting state of brain glucose metabolism in the regions of interest (ROIs) was analyzed using the Q.Brain software. Brain glucose metabolism and laterality index in each ROI of ASD patients were compared with those of the controls. The pattern of brain metabolism was analyzed using visual analysis and is reported in the data description. RESULTS: The ASD group’s overall brain glucose metabolism was lower than that of the control group in both the left and right hemispheres, with mean differences of 1.54 and 1.21, respectively. We found statistically lower mean glucose metabolism for ASD patients than controls in the left prefrontal lateral (Z = 1.96, p = 0.049). The left laterality index was found in nine ROIs for ASD and 11 ROIs for the control. The left laterality index in the ASD group was significantly lower than that in the control group in the prefrontal lateral (Z = 2.52, p = 0.012), precuneus (Z = 2.10, p = 0.036), and parietal inferior (Z = 1.96, p = 0.049) regions. CONCLUSION: Individuals with ASD have lower brain glucose metabolism than control. In addition, the number of ROIs for left laterality index in the ASD group was lower than control. Left laterality defects may be one of the causes of ASD. This knowledge can be useful in the treatment of ASD by increasing the left-brain metabolism. This trial was registered in the Thai Clinical Trials Registry (TCTR20210705005).

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11. Lei HH, Liu LL, Wang XL, Tie XC, Tian N, Ji Y, Yang Y. [Smith-Kingsmore syndrome caused by MTOR gene variation: 2 cases and literature review]. Zhonghua Er Ke Za Zhi;2022 (Sep 2);60(9):935-939.

Objective: To investigate the clinical manifestations and genetic features of 2 children with Smith-Kingsmore syndrome caused by MTOR gene variation and review the literature. Methods: The clinical data of 2 children carrying MTOR gene variant, diagnosed at Xi’an Children’s Hospital from April 2018 to April 2021, were retrospectively summarized. »MTOR »and »Smith-Kingsmore syndrome »were used as key words to search at China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, PubMed and OMIM up to August 2021. The characteristics of MTOR gene variation and the clinical phenotype of children with Smith-Kingsmore syndrome were summarized. Results: Two children were both females, aged 1.5 years and 2 years respectively, the onset age were both in infancy. They both had developmental delay, megalencephaly and abnormal face. Both whole exome sequencing revealed a de novo heterozygous missense variant in MTOR gene. One case carried c.5395G>A (p.Glu1799Lys) and the other case carried c.7234G>C (p.Asp2412His). There was no literature of MTOR gene variation in Chinese. So far, a total of 45 cases were reported worldwide with detailed clinical information. Eleven variations in MTOR gene were involved, which were all heterozygous missense mutations. Among them, p.Glu1799Lys was the most common sites (28 cases,62%). Another case carried c.7234G>C (p.Asp2412His) was not reported before. Summarizing the 47 cases (including these 2 cases), 46 cases had developmental delay or intellectual disability, 9 cases had developmental regression,42 cases had megalencephaly, 30 cases had facial malformation,16 cases had hypotonia, 17 cases had autism spectrum disorders, 3 cases had hyperactivity, 3 cases had obsessive compulsive disorder, 13 cases had eye diseases, 11 cases had cutaneous vascular malformation, and 9 cases had hypoglycemia. Conclusions: The main clinical features of Smith-Kingsmore syndrome include megalencephaly, developmental delay or intellectual disability, and facial malformation, which can be combined with epilepsy, autism spectrum disorder, hypotonia, hypoglycemia and so on. The variation of MTOR gene is the cause of Smith-Kingsmore syndrome.

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12. Li LS, Zhang Q, Liu H, Wu QH, Yang T, Chen J, Li TY. Involvement of retinoic acid receptor α in the autistic-like behavior of rats with vitamin A deficiency by regulating neurexin 1 in the visual cortex: a mechanism study. Zhongguo Dang Dai Er Ke Za Zhi;2022 (Aug 15);24(8):928-935.

OBJECTIVES: To study the mechanism of retinoic acid receptor α (RARα) signal change to regulate neurexin 1 (NRXN1) in the visual cortex and participate in the autistic-like behavior in rats with vitamin A deficiency (VAD). METHODS: The models of vitamin A normal (VAN) and VAD pregnant rats were established, and some VAD maternal and offspring rats were given vitamin A supplement (VAS) in the early postnatal period. Behavioral tests were performed on 20 offspring rats in each group at the age of 6 weeks. The three-chamber test and the open-field test were used to observe social behavior and repetitive stereotyped behavior. High-performance liquid chromatography was used to measure the serum level of retinol in the offspring rats in each group. Electrophysiological experiments were used to measure the long-term potentiation (LTP) level of the visual cortex in the offspring rats. Quantitative real-time PCR and Western blot were used to measure the expression levels of RARα, NRXN1, and N-methyl-D-aspartate receptor 1 (NMDAR1). Chromatin co-immunoprecipitation was used to measure the enrichment of RARα transcription factor in the promoter region of the NRXN1 gene. RESULTS: The offspring rats in the VAD group had autistic-like behaviors such as impaired social interactions and repetitive stereotypical behaviors, and VAS started immediately after birth improved most of the behavioral deficits in offspring rats. The offspring rats in the VAD group had a significantly lower serum level of retinol than those in the VAN and VAS groups (P<0.05). Compared with the offspring rats in the VAN and VAS groups, the offspring rats in the VAD group had significant reductions in the mRNA and protein expression levels of NMDAR1, RARα, and NRXN1 and the LTP level of the visual cortex (P<0.05). The offspring rats in the VAD group had a significant reduction in the enrichment of RARα transcription factor in the promoter region of the NRXN1 gene in the visual cortex compared with those in the VAN and VAS groups (P<0.05). CONCLUSIONS: RARα affects the synaptic plasticity of the visual cortex in VAD rats by regulating NRXN1, thereby participating in the formation of autistic-like behaviors in VAD rats.

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13. Li Y, Fan T, Li X, Liu L, Mao F, Miao Z, Zeng C, Song W, Pan J, Zhou S, Wang H, Wang Y, Sun ZS. Npas3 deficiency impairs cortical astrogenesis and induces autistic-like behaviors. Cell Rep;2022 (Aug 30);40(9):111289.

Transcription factors with basic-helix-loop-helix (bHLH) motifs can control neural progenitor fate determination to neurons and oligodendrocytes. How bHLH transcription factors regulate astrogenesis remains largely unknown. Here, we report that NPAS3, a bHLH transcription factor, is a critical regulator of astrogenesis. Npas3 deficiency impairs cortical astrogenesis, correlating with abnormal brain development and autistic-like behaviors. Single-cell transcriptomes reveal that Npas3 knockout induces abnormal transition states in the differentiation trajectories from radial glia to astrocytes. Analysis of chromatin immunoprecipitation sequencing data in primary cortical astrocytes shows that NPAS3 binding targets are involved in functions of brain development and synapse organization. Co-culture assay further indicates that NPAS3-impaired astrogenesis induces synaptic deficits in wild-type neurons. Astrocyte-specific knockdown of NPAS3 in wild-type cortex causes synaptic and behavioral abnormalities associated with the core symptoms in autism. Together, our findings suggest that transcription factor NPAS3 regulates astrogenesis and its subsequent consequences for brain development and behavior.

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14. Lim JM, Letchumanan V, Tan LT, Hong KW, Wong SH, Ab Mutalib NS, Lee LH, Law JW. Ketogenic Diet: A Dietary Intervention via Gut Microbiome Modulation for the Treatment of Neurological and Nutritional Disorders (a Narrative Review). Nutrients;2022 (Aug 30);14(17)

The ketogenic diet (KD) has been important in treating epilepsy since the 1920s. The benefits of KD further expanded to other neurological diseases, including Alzheimer’s diseases, autism spectrum disorder, and nutritional disorder (obesity). Although the therapeutic efficacy of KD has been generally accepted, there is limited knowledge about its underlying mechanism of action, particularly its effect on our gut microbiome. Gut dysbiosis has been proposed to be involved in those diseases, and KD can promote gut microbiota remodeling that may assist in recovery. This review explores the therapeutic applications of KD, the roles of the gut microbiome in neurological diseases and obesity, as well as the effect of KD on the gut microbiome. The present information suggests that KD has significant roles in altering the gut microbiome to improve disease symptoms, mainly by incrementing Bacteroidetes to Firmicutes (B/F) ratio and reducing Proteobacteria in certain cases. However, current gaps call for continued research to understand better the gut microbiota profile altered by KD.

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15. Liu L, Lai Y, Zhan Z, Fu Q, Jiang Y. Identification of Ferroptosis-Related Molecular Clusters and Immune Characterization in Autism Spectrum Disorder. Front Genet;2022;13:911119.

Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with clinical presentation and prognostic heterogeneity. Ferroptosis is a regulated non-apoptotic cell death program implicated in the occurrence and progression of various diseases. Therefore, we aimed to explore ferroptosis-related molecular subtypes in ASD and further illustrate the potential mechanism. Methods: A total of 201 normal samples and 293 ASD samples were obtained from the Gene Expression Omnibus (GEO) database. We used the unsupervised clustering analysis to identify the molecular subtypes based on ferroptosis-related genes (FRGs) and evaluate the immune characteristics between ferroptosis subtypes. Ferroptosis signatures were identified using the least absolute shrinkage and selection operator regression (LASSO) and recursive feature elimination for support vector machines (SVM-RFE) machine learning algorithms. The ferroptosis scores based on seven selected genes were constructed to evaluate the ferroptosis characteristics of ASD. Results: We identified 16 differentially expressed FRGs in ASD children compared with controls. Two distinct molecular clusters associated with ferroptosis were identified in ASD. Analysis of immune infiltration revealed immune heterogeneity between the two clusters. Cluster2, characterized by a higher immune score and a larger number of infiltrated immune cells, exhibited a stronger immune response and was markedly enriched in immune response-related signaling pathways. Additionally, the ferroptosis scores model was capable of predicting ASD subtypes and immunity. Higher levels of ferroptosis scores were associated with immune activation, as seen in Cluster2. Lower ferroptosis scores were accompanied by relative immune downregulation, as seen in Cluster1. Conclusion: Our study systematically elucidated the intricate correlation between ferroptosis and ASD and provided a promising ferroptosis score model to predict the molecular clusters and immune infiltration cell profiles of children with ASD.

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16. Lord JS, Gay SM, Harper KM, Nikolova VD, Smith KM, Moy SS, Diering GH. Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice. Mol Autism;2022 (Aug 29);13(1):35.

BACKGROUND: Patients with autism spectrum disorder (ASD) experience high rates of sleep disruption beginning early in life; however, the developmental consequences of this disruption are not understood. We examined sleep behavior and the consequences of sleep disruption in developing mice bearing C-terminal truncation mutation in the high-confidence ASD risk gene SHANK3 (Shank3ΔC). We hypothesized that sleep disruption may be an early sign of developmental divergence, and that clinically relevant Shank3(WT/ΔC) mice may be at increased risk of lasting deleterious outcomes following early life sleep disruption. METHODS: We recorded sleep behavior in developing Shank3(ΔC/ΔC), Shank3(WT/ΔC), and wild-type siblings of both sexes using a noninvasive home-cage monitoring system. Separately, litters of Shank3(WT/ΔC) and wild-type littermates were exposed to automated mechanical sleep disruption for 7 days prior to weaning (early life sleep disruption: ELSD) or post-adolescence (PASD) or undisturbed control (CON) conditions. All groups underwent standard behavioral testing as adults. RESULTS: Male and female Shank3(ΔC/ΔC) mice slept significantly less than wild-type and Shank3(WT/ΔC) siblings shortly after weaning, with increasing sleep fragmentation in adolescence, indicating that sleep disruption has a developmental onset in this ASD model. ELSD treatment interacted with genetic vulnerability in Shank3(WT/ΔC) mice, resulting in lasting, sex-specific changes in behavior, whereas wild-type siblings were largely resilient to these effects. Male ELSD Shank3(WT/ΔC) subjects demonstrated significant changes in sociability, sensory processing, and locomotion, while female ELSD Shank3(WT/ΔC) subjects had a significant reduction in risk aversion. CON Shank3(WT/ΔC) mice, PASD mice, and all wild-type mice demonstrated typical behavioral responses in most tests. LIMITATIONS: This study tested the interaction between developmental sleep disruption and genetic vulnerability using a single ASD mouse model: Shank3ΔC (deletion of exon 21). The broader implications of this work should be supported by additional studies using ASD model mice with distinct genetic vulnerabilities. CONCLUSION: Our study shows that sleep disruption during sensitive periods of early life interacts with underlying genetic vulnerability to drive lasting and sex-specific changes in behavior. As individuals progress through maturation, they gain resilience to the lasting effects of sleep disruption. This work highlights developmental sleep disruption as an important vulnerability in ASD susceptibility.

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17. Maggio AG, Shu HT, Laufer BI, Bi C, Lai Y, LaSalle JM, Hu VW. Elevated exposures to persistent endocrine disrupting compounds impact the sperm methylome in regions associated with autism spectrum disorder. Front Genet;2022;13:929471.

Environmental exposures to endocrine disrupting compounds (EDCs) such as the organochlorines have been linked with various diseases including neurodevelopmental disorders. Autism spectrum disorder (ASD) is a highly complex neurodevelopmental disorder that is considered strongly genetic in origin due to its high heritability. However, the rapidly rising prevalence of ASD suggests that environmental factors may also influence risk for ASD. In the present study, whole genome bisulfite sequencing was used to identify genome-wide differentially methylated regions (DMRs) in a total of 52 sperm samples from a cohort of men from the Faroe Islands (Denmark) who were equally divided into high and low exposure groups based on their serum levels of the long-lived organochlorine 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), a primary breakdown product of the now banned insecticide dichlorodiphenyltrichloroethane (DDT). Aside from being considered a genetic isolate, inhabitants of the Faroe Islands have a native diet that potentially exposes them to a wide range of seafood neurotoxicants in the form of persistent organic pollutants (POPs). The DMRs were mapped to the human genome using Bismark, a 3-letter aligner used for methyl-seq analyses. Gene ontology, functional, and pathway analyses of the DMR-associated genes showed significant enrichment for genes involved in neurological functions and neurodevelopmental processes frequently impacted by ASD. Notably, these genes also significantly overlap with autism risk genes as well as those previously identified in sperm from fathers of children with ASD in comparison to that of fathers of neurotypical children. These results collectively suggest a possible mechanism involving altered methylation of a significant number of neurologically relevant ASD risk genes for introducing epigenetic changes associated with environmental exposures into the sperm methylome. Such changes may provide the potential for transgenerational inheritance of ASD as well as other disorders.

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18. Mirza M, Brown-Hollie JP, Suarez-Balcazar Y, Parra-Medina D, Camillone S, Zeng W, Garcia-Gomez E, Heydarian N, Magaña S. Interventions for Health Promotion and Obesity Prevention for Children and Adolescents with Developmental Disabilities: a Systematic Review. Rev J Autism Dev Disord;2022 (Aug 22):1-24.

This systematic review evaluated interventions and relevant outcomes for health promotion and obesity prevention among children and adolescents with developmental disabilities (DD). Twenty-one studies including randomized control trials (n= 9) and quasi-experimental studies (n=12) published between 2010 and 2021 met inclusion criteria related to participant characteristics, intervention type, and child obesity-related outcomes. Five types of intervention programs were identified: aerobic and strength training, sport-based physical activity, aquatic exercise, active video gaming, and diet and lifestyle. Whereas analysis of intervention outcomes, efficacy, and study rigor showed mixed results and weak evidence of effective interventions, this review identified gaps in the literature, promising strategies for addressing obesity in children with DD, and implications for practice and future research. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40489-022-00335-5.

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19. Nakamura M, Nakagami A, Nakagaki K, Yasue M, Kawai N, Ichinohe N. Prenatal valproic acid-induced autism marmoset model exhibits higher salivary cortisol levels. Front Behav Neurosci;2022;16:943759.

Individuals with autism spectrum disorder (ASD) are exposed to a variety of stressors owing to their behavioral traits. Cortisol is a hormone typically associated with stress, and its concentration and response to stress are higher in individuals with ASD than in controls. The mechanisms underlying cortisol dysregulation in ASD have been explored in rodents. Although rodent models have successfully replicated the major symptoms of autism (i.e., impaired vocal communication, social interaction deficits, and restricted/repetitive patterns of behavior), evidence suggests that the hypothalamic-pituitary-adrenal (HPA) axis system differs between rodents and primates. We developed an ASD model in the common marmoset (Callithrix jacchus), a New World monkey, utilizing prenatal exposure to valproic acid (VPA). In this study, we collected the salivary cortisol levels in VPA-exposed and unexposed marmosets in the morning and afternoon. Our results revealed that both VPA-exposed and unexposed marmosets showed similar diurnal changes in cortisol levels, which were lower in the afternoon than in the morning. However, heightened cortisol levels were observed throughout the day in VPA-exposed marmosets. These results are consistent with those of ASD in humans. Our results suggest that VPA-exposed marmosets show similarities not only in their behavioral patterns and brain pathologies, which we have reported previously, but also in hormonal regulation, validating the usefulness of VPA-exposed marmosets also as a tool for ASD stress research.

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20. Ogourtsova T, Boychuck Z, O’Donnell M, Ahmed S, Osman G, Majnemer A. Telerehabilitation for Children and Youth with Developmental Disabilities and Their Families: A Systematic Review. Phys Occup Ther Pediatr;2022 (Aug 30):1-47.

AIM: To determine the level of evidence for the effectiveness of telerehabilitation against comparison interventions in improving child- and parent-related outcomes in children and youth with developmental disabilities. METHOD: A systematic approach, comprised of a comprehensive search; transparent study selection, data extraction, quality assessment by independent reviewers; and synthesis of sufficiently similar data (per diagnostic group, health profession, and overall level of evidence for each outcome) was undertaken. RESULTS: Fifty-five studies (29 randomized trials) were included across six diagnostic groups and ten health professions. Common telerehabilitation targets varied across diagnostic groups and included motor function, behavior, language, and parental self-efficacy. Telerehabilitation was found to be either more effective or as effective versus comparison intervention in improving 46.9% or 53.1% of outcomes, respectively. It was never found to be detrimental or less effective. Strong to moderate, limited, and insufficient levels of evidence were found for 36.5%, 24.5%, and 38.6% of the outcomes, respectively. CONCLUSION: There is sufficient evidence suggesting that telerehabilitation is a promising alternative when face-to-face care is limited. It is comparable to usual care and is more effective than no treatment. Blending in-person and telerehabilitation approaches could be beneficial for the post-pandemic future of rehabilitation in pediatric care.

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21. Pan N, Lin LZ, Wang X, Guo CH, Jing J, Li XH. Association between paternal age at childbirth and autism spectrum disorder in offspring. Zhongguo Dang Dai Er Ke Za Zhi;2022 (Aug 15);24(8):863-868.

OBJECTIVES: To study the association between paternal age at childbirth and the risk of autism spectrum disorder (ASD) in offspring. METHODS: In this cross-sectional study, 71 children with ASD who were diagnosed in the Department of Child Healthcare in six hospitals in Guangzhou, Foshan, Beijing, Wuhan, Hangzhou, and Chongqing of China from August 2016 to March 2017 were enrolled as subjects, and 284 typically developing children matched for age, sex, and maternal age at childbirth with the ASD children served as controls. A self-design questionnaire was used to collect the data on social demography, maternal pregnancy, and delivery. The association between paternal age at childbirth and the development of ASD in offspring was evaluated by the logistic regression analysis. RESULTS: After control for demographic factors and pregnancy- and delivery-related factors, the logistic regression analysis showed that a relatively high paternal age at childbirth was significantly associated with the increased risk of ASD in offspring (OR=1.12, 95%CI: 1.02-1.23, P<0.05). After grouping based on the paternal age, the logistic regression analysis showed that paternal age at childbirth of ≥40 years was significantly associated with the risk of ASD in offspring (before adjustment: OR=7.08, 95%CI: 1.77-28.32, P<0.05; after adjustment: OR=8.50, 95%CI: 1.71-42.25, P<0.05). CONCLUSIONS: High paternal age at childbirth is significantly associated with the increased risk of ASD in offspring, and paternal age at childbirth ≥40 years may be the high-risk age group for ASD in offspring.

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22. Ruggieri V. [Autism. Neurobiological aspects]. Medicina (B Aires);2022 (Aug 30);82 Suppl 3:57-61.

Autism is a neurodevelopmental disorder with a neurobiological basis, characterized by a qualitative disturbance in social interaction and communication, associated with restricted interests and stereotyped behaviors. The genesis of autism cannot be interpreted through a single theory, and we can’t compartmentalize brain areas as the only ones responsible for it. Among the neurobiological bases we can include: deficit in the social reward system, which generates poor social initiative; dysfunctions and disorders of the amygdala and the mirror neuron system, related to compromised empathy and social cognition; abnormalities in the minicolumns related to hyper-systematization; persistent inflammatory phenomena of the central nervous system related to microglia; alterations of neuropeptides such as oxytocin, vasopressin and cortisol, which compromise socialization, and neuronal inhibition disorders, expressed in GABAergic dysfunctions in interneurons, linked to autistic behaviors, epilepsy and sensory phenomena. Understanding the neurobiological bases of autism is complex and there is no single explanation or specific biological marker. However, identifying processes related to social cognition, molecular, inflammatory, neuromodulation mechanisms and bases linked to sensory disorders are fundamental elements.

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23. Ruggieri V. [Autism throughout life]. Medicina (B Aires);2022 (Aug 30);82 Suppl 3:2-6.

Autism is a neurodevelopmental disorder characterized by deficits in social cognition and communication, restricted interests, and stereotyped behaviors. It is often associated with sensory dysfunctions, other neurodevelopmental disorders, neuropsychiatric disorders, epilepsy and/or sleep disorders. This condition will accompany people throughout their lives, with variations in its evolution. In the last ten years, only 1% of all autism research focused on developing post-secondary education programs and training in adult health services. Taking into account this dichotomy of interests, we must think about the different stages of life, such as early intervention, school inclusion, bullying, associated mental and medical disorders, lack of group belonging, job opportunities and the aging. Only by becoming aware of each of them can we achieve a better quality of life for people with autism and their families.

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24. Sabag M, Geva R. Hyper and hypo attention networks activations affect social development in children with autism spectrum disorder. Front Hum Neurosci;2022;16:902041.

Children with autism spectrum disorder (ASD) experience a range of social and non-social attention deficits. To date, most studies assessed the neurological framework or discrete behavioral traits related to one attention network, leaving a gap in the understanding of the developmental cascade affecting the inter-relations among attention networks in ASD in a pervasive manner. We propose a theoretical framework that integrates the behavioral deficits and neurological manifestations through a cohesive developmental prism of attention networks’ activations while assessing their impact on social deficits in children with ASD. Insights arising from the model suggest hyper-and-hypoactivation of posterior attention networks leads to an altered prefrontal anterior attention network weight in ways that conjointly impact social performance in ASD. This perspective on how attention networks develop and interact in ASD may inform future research directions regarding ASD and attention development.

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25. Shen LP, Li W, Pei LZ, Yin J, Xie ST, Li HZ, Yan C, Wang JJ, Zhang Q, Zhang XY, Zhu JN. Oxytocin Receptor in Cerebellar Purkinje Cells Does Not Engage in Autism-Related Behaviors. Cerebellum;2022 (Aug 30)

The classical motor center cerebellum is one of the most consistent structures of abnormality in autism spectrum disorders (ASD), and neuropeptide oxytocin is increasingly explored as a potential pharmacotherapy for ASD. However, whether oxytocin targets the cerebellum for therapeutic effects remains unclear. Here, we report a localization of oxytocin receptor (OXTR) in Purkinje cells (PCs) of cerebellar lobule Crus I, which is functionally connected with ASD-implicated circuits. OXTR activation neither affects firing activities, intrinsic excitability, and synaptic transmission of normal PCs nor improves abnormal intrinsic excitability and synaptic transmission of PCs in maternal immune activation (MIA) mouse model of autism. Furthermore, blockage of OXTR in Crus I in wild-type mice does not induce autistic-like social, stereotypic, cognitive, and anxiety-like behaviors. These results suggest that oxytocin signaling in Crus I PCs seems to be uninvolved in ASD pathophysiology, and contribute to understanding of targets and mechanisms of oxytocin in ASD treatment.

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26. Singh J, Fiori F, Law ML, Ahmed R, Ameenpur S, Basheer S, Chishti S, Lawrence R, Mastroianni M, Mosaddegh A, Santosh P. Development and Psychometric Properties of the Multi-System Profile of Symptoms Scale in Patients with Rett Syndrome. J Clin Med;2022 (Aug 30);11(17)

Background: Rett Syndrome (RTT) is a rare, neurodevelopmental disorder characterised by a range of problematic symptoms. There is yet to be a robust instrument to adequately capture the range of disease severity across the lifespan. In this study, we aimed to develop and assess the validity of an RTT-specific electronic Observer Reported Outcome (eObsRO), the Multi-System Profile of Symptoms Scale (MPSS). Methods: The study was conducted in two phases. Phase 1 consisted of a systematic literature review, focus groups, expert feedback, and a pilot test of the new scale. Modifications were made based on preliminary analysis and feedback collected in the pilot phase. Phase 2 consisted of the validation of the questionnaire based on two samples (Sample 1, n = 18; Sample 2, n = 106). Participants were all parents or caregivers of individuals with RTT. Results: The MPSS consists of 12 validated sub-scales (mental health problems, autonomic problems, cardiac problems, communication problems, problems in social behaviour, problems in engagement, gastrointestinal problems, problems in motor skills, neurological problems, orofacial problems, respiratory problems, and sleep problems), which explore symptom frequency in the past month and a supplement to the scale consisting of five sub-scales (sensory problems, immune dysfunction and infection, endocrine problems, skeletal problems, and dermatological problems), which is designed to capture symptom changes over a longer time period. The frequency of symptoms was rated on a 10-point slider scale, which then was automatically transformed into a 0 to 5 Likert score. All 12 sub-scales showed strong internal consistency (α ≥ 0.700) and good stability, ranging from 0.707 to 0.913. Pearson’s correlation showed a statistically significant (r = 0.649) correlation between the MPSS and the Rett Syndrome Behaviour Questionnaire (RSBQ) total score and significant correlations between sub-scales with items that were presented in both the MPSS and RSBQ. Conclusions: The MPSS is a psychometrically validated eObsRO using the HealthTracker(TM) platform and has the potential to be used in clinical trials.

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27. Stark EA. Empowering autistic academics. Nat Hum Behav;2022 (Aug 29)

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28. Ursino M, Serra M, Tarasi L, Ricci G, Magosso E, Romei V. Bottom-up vs. top-down connectivity imbalance in individuals with high-autistic traits: An electroencephalographic study. Front Syst Neurosci;2022;16:932128.

Brain connectivity is often altered in autism spectrum disorder (ASD). However, there is little consensus on the nature of these alterations, with studies pointing to either increased or decreased connectivity strength across the broad autism spectrum. An important confound in the interpretation of these contradictory results is the lack of information about the directionality of the tested connections. Here, we aimed at disambiguating these confounds by measuring differences in directed connectivity using EEG resting-state recordings in individuals with low and high autistic traits. Brain connectivity was estimated using temporal Granger Causality applied to cortical signals reconstructed from EEG. Between-group differences were summarized using centrality indices taken from graph theory (in degree, out degree, authority, and hubness). Results demonstrate that individuals with higher autistic traits exhibited a significant increase in authority and in degree in frontal regions involved in high-level mechanisms (emotional regulation, decision-making, and social cognition), suggesting that anterior areas mostly receive information from more posterior areas. Moreover, the same individuals exhibited a significant increase in the hubness and out degree over occipital regions (especially the left and right pericalcarine regions, where the primary visual cortex is located), suggesting that these areas mostly send information to more anterior regions. Hubness and authority appeared to be more sensitive indices than the in degree and out degree. The observed brain connectivity differences suggest that, in individual with higher autistic traits, bottom-up signaling overcomes top-down channeled flow. This imbalance may contribute to some behavioral alterations observed in ASD.

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29. Vanes LD, Tye C, Tournier JD, Combes AJE, Shephard E, Liang H, Barker GJ, Nosarti C, Bolton P. White matter disruptions related to inattention and autism spectrum symptoms in tuberous sclerosis complex. Neuroimage Clin;2022 (Aug 25);36:103163.

Tuberous sclerosis complex is a rare genetic multisystem condition that is associated with a high prevalence of neurodevelopmental disorders such as autism and attention-deficit/hyperactivity disorder. The underlying neural mechanisms of the emergence of these symptom domains in tuberous sclerosis complex remain unclear. Here, we use fixel-based analysis of diffusion-weighted imaging, which allows for the differentiation between multiple fibre populations within a voxel, to compare white matter properties in 16 participants with tuberous sclerosis complex (aged 11-19) and 12 age and sex matched control participants. We further tested associations between white matter alterations and autism and inattention symptoms as well as cognitive ability in participants with tuberous sclerosis complex. Compared to controls, participants with tuberous sclerosis complex showed reduced fibre density cross-section (FDC) in the dorsal branch of right superior longitudinal fasciculus and bilateral inferior longitudinal fasciculus, reduced fibre density (FD) in bilateral tapetum, and reduced fibre cross-section (FC) in the ventral branch of right superior longitudinal fasciculus. In participants with tuberous sclerosis complex, the extent of FDC reductions in right superior longitudinal fasciculus was significantly associated with autism traits (social communication difficulties and restricted, repetitive behaviours), whereas FDC reductions in right inferior longitudinal fasciculus were associated with inattention. The observed white matter alterations were unrelated to cognitive ability. Our findings shed light on the fibre-specific biophysical properties of white matter alterations in tuberous sclerosis complex and suggest that these regional changes are selectively associated with the severity of neurodevelopmental symptoms.

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30. Velarde M, Cárdenas A. [Autism spectrum disorder and attention-deficit/hyperactivity disorder: challenge in diagnosis and treatment]. Medicina (B Aires);2022 (Aug 30);82 Suppl 3:67-70.

The coexistence of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) definitely poses new challenges, such as making an early diagnosis, considering that the former is usually diagnosed 2 years later in children with ADHD comorbid with autism compared to those with ASD alone; this is a problem at a personal, family and social level, since they must receive timely intervention. This coexistence raises questions about the efficacy of treatment in ADHD in people with autism, genetic, anatomical and functional concordances, among others; these are the challenges that are currently posed. In this review, we present some responses to the challenges posed by such coexistence, and we highlight some pending issues to be solved, being these of great importance for their better understanding and management. In all patients with ADHD or ASD, a coexistence between them should be sought. There are shared functional brain alterations in both disorders identified by functional brain magnetic resonance imaging; the treatment established for ADHD is also effective in this comorbidity.

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31. Voinsky I, Zoabi Y, Shomron N, Harel M, Cassuto H, Tam J, Rose S, Scheck AC, Karim MA, Frye RE, Aran A, Gurwitz D. Blood RNA Sequencing Indicates Upregulated BATF2 and LY6E and Downregulated ISG15 and MT2A Expression in Children with Autism Spectrum Disorder. Int J Mol Sci;2022 (Aug 30);23(17)

Mutations in over 100 genes are implicated in autism spectrum disorder (ASD). DNA SNPs, CNVs, and epigenomic modifications also contribute to ASD. Transcriptomics analysis of blood samples may offer clues for pathways dysregulated in ASD. To expand and validate published findings of RNA-sequencing (RNA-seq) studies, we performed RNA-seq of whole blood samples from an Israeli discovery cohort of eight children with ASD compared with nine age- and sex-matched neurotypical children. This revealed 10 genes with differential expression. Using quantitative real-time PCR, we compared RNAs from whole blood samples of 73 Israeli and American children with ASD and 26 matched neurotypical children for the 10 dysregulated genes detected by RNA-seq. This revealed higher expression levels of the pro-inflammatory transcripts BATF2 and LY6E and lower expression levels of the anti-inflammatory transcripts ISG15 and MT2A in the ASD compared to neurotypical children. BATF2 was recently reported as upregulated in blood samples of Japanese adults with ASD. Our findings support an involvement of these genes in ASD phenotypes, independent of age and ethnicity. Upregulation of BATF2 and downregulation of ISG15 and MT2A were reported to reduce cancer risk. Implications of the dysregulated genes for pro-inflammatory phenotypes, immunity, and cancer risk in ASD are discussed.

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32. Wang S, Chen D, Yoon I, Klich S, Chen A. Bibliometric analysis of research trends of physical activity intervention for autism spectrum disorders. Front Hum Neurosci;2022;16:926346.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social impairment, restricted interests, and repetitive stereotyped behaviors. At present, its pathogenesis has not been fully understood. Various methods are used for clinical treatment and intervention, among which physical activity (PA) intervention also has an obvious effect. This study has used bibliometric methods and visual analysis methods to analyze 885 studies of PA intervention in ASD from 2003 to 2022 in the Web of Science (WoS) database in order to provide theoretical support for the follow-up research on the effect of PA with ASD. The main findings of this study are as follows. First, the literature on PA interventions in ASD research showed a growing trend. The leading institution in this field is the University of Delaware, forming a core group of authors represented by authors such as Sean Healy and Carol Curtin et al. Second, the research focus of this research area mainly includes PA interventions for children and adolescents with ASD. PA can improve symptoms such as stereotyped behaviors and motor function in patients with ASD as well as can reduce childhood obesity rates and improve quality of life. Third, skill, youth, prevalence, and meta-analysis systematic reviews were found. It is the long-term concern and focus of researchers. In conclusion, the current research is only a short-term analysis, and it is not possible to verify the long-term effect; thus, future data analysis should evaluate and explore the long-term effects of PA interventions on ASD including cohort and longitudinal study types focused on the rehabilitation of patients with ASD. Moreover, testing the sustainability of benefits for children with ASD and constructing a multidimensional exercise integrated intervention model are the main directions for future research in this field.

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33. Wang T, Feng J, Xue Y, Shan L, Jia F, Yue X. Feeding problems, age of introduction of complementary food and autism symptom in children with autism spectrum disorder. Front Pediatr;2022;10:860947.

In this cross-sectional study, 84 children with autism spectrum disorder (ASD) and 77 healthy subjects showing typical development (TD) were reviewed. Parents reviewed the age of introduction of complementary foods (CFs), completed a demographic, diet behavior questionnaire and the Autism Behavior Checklist (ABC). The results showed that the age of introduction of CFs was later in children with ASD than their TD counterparts. The age of introduction of CFs in ASD group was positively correlated with feeding problem. While the correlation was not observed in TD group. Children in the ASD group had higher total scores of the diet behavior questionnaire and all four subdomains (poor eating ability, mealtime eating behavior, food selectivity, and parental feeding behavior). ASD symptoms were clearly associated with feeding problems. The sensory subdomain score in ABC was positively correlated with poor eating ability, mealtime behavior and total score of the diet behavior questionnaire. The social self-care subdomain score was positively correlated with food selectivity. The interaction subdomain score was negative correlated with parental feeding behavior and total score of the diet behavior questionnaire. Further studies are required to establish the utility of delayed CFs introduction and/or early feeding problems as potential indicators of ASD.

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34. Wilde M, Constantin L, Thorne PR, Montgomery JM, Scott EK, Cheyne JE. Auditory processing in rodent models of autism: a systematic review. J Neurodev Disord;2022 (Aug 30);14(1):48.

Autism is a complex condition with many traits, including differences in auditory sensitivity. Studies in human autism are plagued by the difficulty of controlling for aetiology, whereas studies in individual rodent models cannot represent the full spectrum of human autism. This systematic review compares results in auditory studies across a wide range of established rodent models of autism to mimic the wide range of aetiologies in the human population. A search was conducted in the PubMed and Web of Science databases to find primary research articles in mouse or rat models of autism which investigate central auditory processing. A total of 88 studies were included. These used non-invasive measures of auditory function, such as auditory brainstem response recordings, cortical event-related potentials, electroencephalography, and behavioural tests, which are translatable to human studies. They also included invasive measures, such as electrophysiology and histology, which shed insight on the origins of the phenotypes found in the non-invasive studies. The most consistent results across these studies were increased latency of the N1 peak of event-related potentials, decreased power and coherence of gamma activity in the auditory cortex, and increased auditory startle responses to high sound levels. Invasive studies indicated loss of subcortical inhibitory neurons, hyperactivity in the lateral superior olive and auditory thalamus, and reduced specificity of responses in the auditory cortex. This review compares the auditory phenotypes across rodent models and highlights those that mimic findings in human studies, providing a framework and avenues for future studies to inform understanding of the auditory system in autism.

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35. Woo P. Simultaneous Botox and Augmentation Injection Laryngoplasty in Patients With Adductor Spasmodic Dysphonia (ASD) and Tremor. J Voice;2022 (Aug 30)

OBJECTIVE: Although Botulinum Toxin (BOTOX) is effective for adductor spasmodic dysphonia (ASD) and essential vocal tremor (EVT), the side effects of breathy dysphonia may result in reluctance to pursue BOTOX treatment. We sought to improve results in selected elderly tremor patients with EVT and in professional voice users with ASD by simultaneous BOTOX injection and injection laryngoplasty using Hyaluronic acid (HA/Botox). MATERIAL AND METHODS: Between July 2018 and March 2022, 23 simultaneous HA/Botox using LEMG control were done in eight patients with ASD and EVT (23 of 406 Botox Injections). All eight patients have previously reported unwanted side effects with poor voice results with Botox. Three patients had tremor with presbyphonia. Injection of Botox is performed first using LEMG control, followed by bilateral LEMG guided injection of 0.1 cc of HA. RESULTS: All HA/Botox injections were tolerated well. All patients reported some improved voice. Two patients did not go on to further HA injections while the others six have requested ongoing simultaneous HA/Botox injections. Patients with EVT and presbyphonia noted greater stability of voice than Botox alone. It lasted through the injection cycle. The professional voice users reported less breathy voice that allowed them to work right after the BOTOX injection. CONCLUSION: Simultaneous BOTOX injection with injection laryngoplasty using HA may be helpful in patients with tremor and presbyphonia. It also may be considered in professional voice users with ASD to reduce side effects of BOTOX.

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36. Yasuda Y, Matsumoto J, Miura K, Hasegawa N, Hashimoto R. Genetics of autism spectrum disorders and future direction. J Hum Genet;2022 (Aug 30)

Autism spectrum disorders (ASDs) have been increasing in prevalence. ASD is a complex human genetic disorder with high heredity and involves interactions between genes and the environment. A significant inheritance pattern in ASD involves a rare genetic mutation; common copy number variants refer to duplication or deletion of stretches of chromosomal loci or protein-disrupting single-nucleotide variants. Haploinsufficiency is one of the more common single-gene causes of ASD, explaining at least 0.5% of cases. Epigenetic mechanisms, such as DNA methylation, act at an interface of genetic and environmental risk and protective factors. Advances in genome-wide sequencing have broadened the view of the human methylome and have revealed the organization of the human genome into large-scale methylation domains with a footprint over neurologically important genes involved in embryonic development. Psychiatric disorders, including ASD, are expected to be diagnosed based on their genetically regulated pathophysiology and to be linked to their treatment.

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37. Yu L, Huang D, Wang S, Zhang Y. Reduced Neural Specialization for Word-level Linguistic Prosody in Children with Autism. J Autism Dev Disord;2022 (Aug 29)

Children with autism often show atypical brain lateralization for speech and language processing, however, it is unclear what linguistic component contributes to this phenomenon. Here we measured event-related potential (ERP) responses in 21 school-age autistic children and 25 age-matched neurotypical (NT) peers during listening to word-level prosodic stimuli. We found that both groups displayed larger late negative response (LNR) amplitude to native prosody than to nonnative prosody; however, unlike the NT group exhibiting left-lateralized LNR distinction of prosodic phonology, the autism group showed no evidence of LNR lateralization. Moreover, in both groups, the LNR effects were only present for prosodic phonology but not for phoneme-free prosodic acoustics. These results extended the findings of inadequate neural specialization for language in autism to sub-lexical prosodic structures.

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