1. Bauminger-Zviely N, Shefer A. Naturalistic evaluation of preschoolers’ spontaneous interactions : The Autism Peer Interaction Observation Scale. Autism. 2021 : 1362361321989919.

Peer interaction can be challenging in autism spectrum disorder, but naturalistic peer-observation scales for preschoolers are limited. This study examined the newly developed Autism Peer Interaction Observation Scale, with 17 subcategories, which evaluate naturalistic peer interaction processes in preschoolers with autism spectrum disorder and typical development. We tested the Autism Peer Interaction Observation Scale to (a) characterize peer interactions of preschoolers with autism spectrum disorder who were cognitively able versus typical age-mates, (b) explore each group’s hierarchical pattern of peer interaction behaviors, and (c) identify Autism Peer Interaction Observation Scale’s links with standard reports for assessing social-communication functioning (Vineland Behavior Scales, 2nd ed.), social impairment (Social Responsiveness Scale, 2nd ed.), autism severity (Autism Diagnostic Observation Schedule, 2nd ed.), and intelligence quotient (Mullen) in the cognitively able preschoolers with autism spectrum disorder group. Participants comprised 85 preschoolers (50 cognitively able preschoolers with autism spectrum disorder, intelligence quotient > 75 ; 35 typical). Groups were matched according to age, intelligence quotient, and maternal education. Significant group differences emerged on all Autism Peer Interaction Observation Scale categories, with the typical group showing better social-communication functioning as compared to the cognitively able preschoolers with autism spectrum disorder group. Also, in cognitively able preschoolers with autism spectrum disorder that observed as demonstrating more typical peer relations on the Autism Peer Interaction Observation Scale showed better adaptive and socialization skills on the Vineland (Vineland Behavior Scales, 2nd ed.) and fewer social atypicalities on the Social Responsiveness Scale, 2nd ed. Higher intelligence quotient scores were linked with better observed social-communication functioning (on Autism Peer Interaction Observation Scale). Few Autism Peer Interaction Observation Scale social-communicative categories significantly correlated with the Autism Diagnostic Observation Schedule, 2nd ed. Findings highlight the Autism Peer Interaction Observation Scale as differentiating the two preschooler groups and providing additional knowledge about socially communicative peer interaction in natural settings. This new tool can help personalize social-communication programs and evaluations of early intervention outcomes, thereby leading to a fuller picture of these young children’s functioning.

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2. DeMayo MM, Harris AD, Song YJC, Pokorski I, Thapa R, Patel S, Ambarchi Z, Thomas EE, Hickie IB, Guastella AJ. Age-related parietal GABA alterations in children with autism spectrum disorder. Autism Res. 2021.

GABA is the primary inhibitory neurotransmitter in the brain, and is essential to the balance of cortical excitation and inhibition. Reductions in GABA are proposed to result in an overly excitatory cortex that may cause, or contribute to, symptoms of autism spectrum disorder (ASD). This study employed a cross-sectional design to explore GABA+ differences in ASD and the impact of age, comparing 4-12 year olds with ASD (N = 24) to typically developing children (N = 35). GABA+ concentration was measured using edited magnetic resonance spectroscopy in the left parietal lobe. This study used a mixed model to investigate group differences between children with ASD and typically developing children. There was a significant difference in GABA+ levels between the groups, a significant effect of age and interaction between age and diagnostic group. The ASD group showed an association between GABA+ and age, with GABA+ levels gradually increasing with age (r = 0.59, p = 0.003). Typically developing children did not show age-related change in GABA+ concentration (r = 0.09, p = 0.60). By the age of 9, children with ASD showed GABA+ levels that were comparable to their typically developing peers. This study suggests that children with ASD have initially lower levels of GABA+ in the left parietal lobe compared to typically developing children, and that these initially lower levels of GABA+ increase with age in ASD within this region. It is suggested that this developmental shift of GABA+ levels within the left parietal lobe provides a possible explanation for the previously found reductions in childhood that does not persist in adults. LAY SUMMARY : This study measured levels of GABA in the left parietal lobe using magnetic resonance spectroscopy in children with ASD and typically developing children. GABA levels were initially lower in the ASD group, and increased with age, while GABA did not change with age in the typically developing group. This suggests that alterations in GABA signaling may be associated with ASD in childhood.

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3. Derbis M, Kul E, Niewiadomska D, Sekrecki M, Piasecka A, Taylor K, Hukema RK, Stork O, Sobczak K. Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats. Nat Commun. 2021 ; 12(1) : 1265.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an incurable neurodegenerative disorder caused by expansion of CGG repeats in the FMR1 5’UTR. The RNA containing expanded CGG repeats (rCGG(exp)) causes cell damage by interaction with complementary DNA, forming R-loop structures, sequestration of nuclear proteins involved in RNA metabolism and initiation of translation of polyglycine-containing protein (FMRpolyG), which forms nuclear insoluble inclusions. Here we show the therapeutic potential of short antisense oligonucleotide steric blockers (ASOs) targeting directly the rCGG(exp). In nuclei of FXTAS cells ASOs affect R-loop formation and correct miRNA biogenesis and alternative splicing, indicating that nuclear proteins are released from toxic sequestration. In cytoplasm, ASOs significantly decrease the biosynthesis and accumulation of FMRpolyG. Delivery of ASO into a brain of FXTAS mouse model reduces formation of inclusions, improves motor behavior and corrects gene expression profile with marginal signs of toxicity after a few weeks from a treatment.

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4. Espinoza JC, Deavenport-Saman A, Solomon O, Chowdhuri S, Wee CP, Azen C, Orozco J, Kreutzer C, Yin L. Not just at school : Inclusion of children with autism spectrum disorder in a weight management program in a community pediatric setting. Autism. 2021 : 1362361321993710.

LAY ABSTRACT : Children diagnosed with autism are likely to be more overweight than children who do not have autism. There are many group programs that help children to be more physically active and improve their eating habits to achieve healthy weight, but most of these programs do not allow children with autism to participate. We studied a program that was specially adapted so children with autism could participate together with peers who do not have autism. The program lasted 8 weeks and was offered in the evening at a large healthcare center in a big city. The children participated with a parent or another adult who takes care of them. We analyzed data that were part of a previous project where we studied how physical activity trackers called Fitbit help overweight children to change their eating and exercise habits so they can achieve healthier weight. Out of 158 families in the study, 15 families had a child or children with autism. We measured changes in the weight of children with and without autism and compared how many of the children completed the program. Children who had autism had similar results in achieving healthy weight and finishing the program compared to their peers without autism. Our study found that when a group weight management program is slightly changed to meet the needs of children with autism, they can successfully participate and benefit similarly to their peers who do not have autism. REGISTRATION : This trial was registered with ClinicalTrials.gov (NCT03215641).

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5. Garbulowski M, Smolinska K, Diamanti K, Pan G, Maqbool K, Feuk L, Komorowski J. Interpretable Machine Learning Reveals Dissimilarities Between Subtypes of Autism Spectrum Disorder. Front Genet. 2021 ; 12 : 618277.

Autism spectrum disorder (ASD) is a heterogeneous neuropsychiatric disorder with a complex genetic background. Analysis of altered molecular processes in ASD patients requires linear and nonlinear methods that provide interpretable solutions. Interpretable machine learning provides legible models that allow explaining biological mechanisms and support analysis of clinical subgroups. In this work, we investigated several case-control studies of gene expression measurements of ASD individuals. We constructed a rule-based learning model from three independent datasets that we further visualized as a nonlinear gene-gene co-predictive network. To find dissimilarities between ASD subtypes, we scrutinized a topological structure of the network and estimated a centrality distance. Our analysis revealed that autism is the most severe subtype of ASD, while pervasive developmental disorder-not otherwise specified and Asperger syndrome are closely related and milder ASD subtypes. Furthermore, we analyzed the most important ASD-related features that were described in terms of gene co-predictors. Among others, we found a strong co-predictive mechanism between EMC4 and TMEM30A, which may suggest a co-regulation between these genes. The present study demonstrates the potential of applying interpretable machine learning in bioinformatics analyses. Although the proposed methodology was designed for transcriptomics data, it can be applied to other omics disciplines.

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6. Goldfarb Y, Zafrani O, Hedley D, Yaari M, Gal E. Autistic adults’ subjective experiences of hoarding and self-injurious behaviors. Autism. 2021 : 1362361321992640.

Hoarding and self-injurious behaviors are relatively common in autism, but knowledge about their expressions in adulthood is scarce. Through interviews collecting subjective experiences of autistic adults, these behaviors were explored, and categorized to their underlying purposes. Findings portray the occurrence of these behaviors in the lives of autistic adults, their self-regulatory purposes, and their relationship to other behaviors in the domain of Restrictive and Repetitive Behaviors and Interests.

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7. Green HL, Dipiero M, Koppers S, Berman JI, Bloy L, Liu S, McBride E, Ku M, Blaskey L, Kuschner E, Airey M, Kim M, Konka K, Roberts TPL, Edgar JC. Peak Alpha Frequency and Thalamic Structure in Children with Typical Development and Autism Spectrum Disorder. J Autism Dev Disord. 2021.

Associations between age, resting-state (RS) peak-alpha-frequency (PAF = frequency showing largest amplitude alpha activity), and thalamic volume (thalamus thought to modulate alpha activity) were examined to understand differences in RS alpha activity between children with autism spectrum disorder (ASD) and typically-developing children (TDC) noted in prior studies. RS MEG and structural-MRI data were obtained from 51 ASD and 70 TDC 6- to 18-year-old males. PAF and thalamic volume maturation were observed in TDC but not ASD. Although PAF was associated with right thalamic volume in TDC (R(2) = 0.12, p = 0.01) but not ASD (R(2) = 0.01, p = 0.35), this group difference was not large enough to reach significance. Findings thus showed unusual maturation of brain function and structure in ASD as well as an across-group thalamic contribution to alpha rhythms.

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8. Holmes H, Sawer F, Clark M. Autism spectrum disorders and epilepsy in children : A commentary on the occurrence of autism in epilepsy ; how it can present differently and the challenges associated with diagnosis. Epilepsy Behav. 2021 : 107813.

Autism occurs more frequently in epilepsy, but is often not diagnosed. This could be due to a focus on medical issues, or because it presents differently from classic autism in its timing, phenotype, fluctuating profiles, and high level of comorbidity. Without a diagnosis, these children miss out on interventions that could modify outcome and their families and local teams will struggle to understand and support them. They also become a hidden group that does not participate in or benefit from research. This paper examined the issues and challenges of diagnosing autism in a population with a high-risk of epilepsy, drawing on more than 20 years’ experience of a specialist multi-disciplinary Developmental Epilepsy Clinic (DEC).

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9. Hurley S, Mohan C, Suetterlin P, Ellingford R, Riegman KLH, Ellegood J, Caruso A, Michetti C, Brock O, Evans R, Rudari F, Delogu A, Scattoni ML, Lerch JP, Fernandes C, Basson MA. Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development. Mol Autism. 2021 ; 12(1) : 16.

BACKGROUND : CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development. METHODS : To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate. RESULTS : Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice. CONCLUSIONS : Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work.

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10. Irwin J, Avery T, Kleinman D, Landi N. Audiovisual Speech Perception in Children with Autism Spectrum Disorders : Evidence from Visual Phonemic Restoration. J Autism Dev Disord. 2021.

Children with autism spectrum disorders have been reported to be less influenced by a speaker’s face during speech perception than those with typically development. To more closely examine these reported differences, a novel visual phonemic restoration paradigm was used to assess neural signatures (event-related potentials [ERPs]) of audiovisual processing in typically developing children and in children with autism spectrum disorder. Video of a speaker saying the syllable /ba/ was paired with (1) a synthesized /ba/ or (2) a synthesized syllable derived from /ba/ in which auditory cues for the consonant were substantially weakened, thereby sounding more like /a/. The auditory stimuli are easily discriminable ; however, in the context of a visual /ba/, the auditory /a/ is typically perceived as /ba/, producing a visual phonemic restoration. Only children with ASD showed a large /ba/-/a/ discrimination response in the presence of a speaker producing /ba/, suggesting reduced influence of visual speech.

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11. Koç B, Fucile G, Schmucki R, Giroud N, Bergauer T, Hall BJ. Identification of Natural Antisense Transcripts in Mouse Brain and Their Association With Autism Spectrum Disorder Risk Genes. Front Mol Neurosci. 2021 ; 14 : 624881.

Genome-wide sequencing technologies have greatly contributed to our understanding of the genetic basis of neurodevelopmental disorders such as autism spectrum disorder (ASD). Interestingly, a number of ASD-related genes express natural antisense transcripts (NATs). In some cases, these NATs have been shown to play a regulatory role in sense strand gene expression and thus contribute to brain function. However, a detailed study examining the transcriptional relationship between ASD-related genes and their NAT partners is lacking. We performed strand-specific, deep RNA sequencing to profile expression of sense and antisense reads with a focus on 100 ASD-related genes in medial prefrontal cortex (mPFC) and striatum across mouse post-natal development (P7, P14, and P56). Using de novo transcriptome assembly, we generated a comprehensive long non-coding RNA (lncRNA) transcriptome. We conducted BLAST analyses to compare the resultant transcripts with the human genome and identified transcripts with high sequence similarity and coverage. We assembled 32861 de novo antisense transcripts mapped to 12182 genes, of which 1018 are annotated by Ensembl as lncRNA. We validated the expression of a subset of selected ASD-related transcripts by PCR, including Syngap1 and Cntnap2. Our analyses revealed that more than 70% (72/100) of the examined ASD-related genes have one or more expressed antisense transcripts, suggesting more ASD-related genes than previously thought could be subject to NAT-mediated regulation in mice. We found that expression levels of antisense contigs were mostly positively correlated with their cognate coding sense strand RNA transcripts across developmental age. A small fraction of the examined transcripts showed brain region specific enrichment, indicating possible circuit-specific roles. Our BLAST analyses identified 110 of 271 ASD-related de novo transcripts with >90% identity to the human genome at >90% coverage. These findings, which include an assembled de novo antisense transcriptome, contribute to the understanding of NAT regulation of ASD-related genes in mice and can guide NAT-mediated gene regulation strategies in preclinical investigations toward the ultimate goal of developing novel therapeutic targets for ASD.

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12. Kong Q, Wang B, Tian P, Li X, Zhao J, Zhang H, Chen W, Wang G. Daily intake of Lactobacillus alleviates autistic-like behaviors by ameliorating the 5-hydroxytryptamine metabolic disorder in VPA-treated rats during weaning and sexual maturation. Food & function. 2021.

Probiotic therapy targeting gut-brain axis has been proven to be effective in treating autistic patients. The present study aimed to assess the ability of three Lactobacillus strains (L. helveticus CCFM1076, L. acidophilus La28, and L. acidophilus JCM 1132) to alleviate autistic-like behavioral symptoms in VPA-treated rats from weaning to sexual maturation. For the first time, we assessed the synthesis of 5-hydroxytryptamine (5HT) and the metabolic capacity of the 5HT system in the peripheral and central nervous systems (PNS and CNS, respectively) based on tryptophan metabolism based on VPA-induced autism model. We also assessed gut microbiota, and short-chain fatty acids (SCFAs) at the end of week 8. While improving autistic-like behavioral symptoms, we found L. helveticus CCFM1076 was more beneficial in regulating 5HT anabolism and catabolism, balancing excitatory and inhibitory neurotransmitter release in the PNS and CNS, and increasing oxytocin (OT) synthesis in the hypothalamus. A significant correlation was noted between 5HT levels and the release of GABA, glutamate (Glu), and OT, suggesting that 5HT plays a vital role in the neuroendocrine network. Analyses of the gut microbiota and SCFA levels revealed greater Turicibacter abundance and lower butyric acid levels in VPA-treated rats, which have been reported to be associated with 5HT levels. L. helveticus CCFM1076 helped reduce Turicibacter abundance and up-regulate butyric acid levels, while L. acidophilus La28 and L. acidophilus JCM 1132 did not. L. helveticus CCFM1076 restored neurotransmitter homeostasis by improving the balance of the 5HT system in the PNS and CNS, thereby ameliorating autistic-like behaviors. This finding will help in the development of bioproducts for treating autism and in the establishment of a treatment model mimicking the intestinal environment of autistic patients.

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13. Krämer J, Beer M, Bode H, Winter B. Two Novel Compound Heterozygous Mutations in the TRAPPC9 Gene Reveal a Connection of Non-syndromic Intellectual Disability and Autism Spectrum Disorder. Front Genet. 2020 ; 11 : 972.

INTRODUCTION : Autism spectrum disorder (ASD) is characterized by deficits in communication, social interaction, and repetitive behavior. Up to 70% of ASD cases are linked with intellectual disability (ID). The major genetic causes for ASD and ID are largely unknown, however, a shared genetic etiology between ASD and ID must be assumed. The trafficking protein particle complex subunit 9 (TRAPPC9) is highly expressed in postmitotic neurons of the cerebral cortex, playing a key role in development. Among 43 reported cases with mutations in TRAPPC9, all (100%) showed ID and developmental delay. Among the cases including information about ASD, 26% were affected (19 cases with information, among them 5 with ASD). Nevertheless, in some cases not classified as ASD, descriptions of autistic features like hand-flapping movements were present. CLINICAL FINDINGS : The affected individual presented with delay of speech development. Physical development was normal. Besides lateral slope of the eye-lid axis no facial abnormalities were evident. The individual was diagnosed with ID and ASD by structured testing. Cerebral MRI revealed associated abnormalities. GENETICAL FINDINGS : The chromosome set was 46,XY without structural changes. Array-CGH showed a normal molecular karyotype (arr(1-22)x2,(X,Y)x1). PCR for the FMR1 gene showed 41 ± 1 CGG repeats, and therefore no evidence of fragile X syndrome. A panel diagnostic for syndromal ID (CASK, EP300, HIVEP2, KIF1A, TRAPPC9) revealed two structural changes in TRAPPC9 in the compound heterozygosity. The mutations c.1678C > T (p.Arg560Cys) and c.3370C > T (p.Pro1124Ser) are classified as missense mutations and are both not described in the literature. CONCLUSION : We report two new missense mutations in the TRAPPC9 gene in one individual with ID and ASD. The TRAPPC9 gene should be part of the diagnostic assessment in ID. ASD must be considered as a feature of TRAPPC9-associated ID. It might have been neglected in the literature and should result in specific testing for ASD in affected individuals.

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14. Kutluk G, Kadem N, Bektas O, Eroglu HN. A Rare Cause of Autism Spectrum Disorder : Megaconial Muscular Dystrophy. Annals of Indian Academy of Neurology. 2020 ; 23(5) : 694-6.

Megaconial congenital muscular dystrophy (OMIM 602541) is defined by early-onset hypotonia, mildly elevated serum creatine kinase (CK) levels, muscle wasting, cardiomyopathy, psychomotor developmental delay and intellectual disability. The disease is caused by loss-of-function mutations in Choline kinase beta gene (CHKB) and has specific muscle biopsy findings. Here we investigate two patients with weakness of proximal muscles and generalized muscle atrophy, skin changes, agressiveness, social communication and empathy difficulties. Both patients had mildly elevated serum CK levels. Whole exome sequencing (WES) performed for both patients and homozygous c.818+1G>A and homozygous c.1031+1G>A variants were detected in patient 1 and patient 2, respectively. We would like to draw the attention of autism spectrum disorder in early diagnosis of congenital muscular dystrophies.

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15. Lugo-Marín J, Gisbert-Gustemps L, Setien-Ramos I, Español-Martín G, Ibañez-Jimenez P, Forner-Puntonet M, Arteaga-Henríquez G, Soriano-Día A, Duque-Yemail JD, Ramos-Quiroga JA. COVID-19 pandemic effects in people with Autism Spectrum Disorder and their caregivers : Evaluation of social distancing and lockdown impact on mental health and general status. Res Autism Spectr Disord. 2021 ; 83 : 101757.

Among the difficulties associated with Autism Spectrum Disorder (ASD) are those related to adaptation to changes and new situations, as well as anxious-depressive symptoms frequently related to excessive environmental requirements. The main objective of this research is to study the psychological impact of the lockdown due to the social emergency situation (COVID-19) in children/adolescents and adults diagnosed with ASD. Participants were 37 caregivers of children/adolescents with ASD, also 35 ASD adults and 32 informants. Evaluation was conducted through a web survey system and included standardized clinical questionnaires (CBCL and SCL-90-R), which were compared with results before lockdown start, and a brief self-reported survey addressing the subjective perception of changes in daily functioning areas. The results revealed a reduction of psychopathological symptoms in both age groups, but only reaching statistical significance in the adult group, except for Somatization, Anxiety, and Obsessive-Compulsive domains. ASD severity Level 2 showed greater improvement after lockdown onset in the children/adolescent group when compared to ASD Level 1 participants. Younger adults (18-25 yoa) reported greater improvement than older adults (=>25 yoa). Survey results indicate an improvement of feeding quality and a reduction in the number of social initiations during the lockdown. Adult ASD participants perceived a decrease in stress levels after the lockdown onset, whereas caregivers reported higher stress levels at the same point in both age groups. Limitations included the small number of participants and a heterogeneous evaluation window between measures. Pyschopathological status after two months of social distancing and lockdown seems to improve in ASD young adult population.

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16. Nguyen PM, Tran TT, Thach TNA, Van Nguyen T. An Unexpected Positive Effect of Social Distancing Measures on the Care of Children With Autism in Vietnam. Asia-Pacific journal of public health. 2021 : 1010539521997717.

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17. Ni HC, Chen YL, Chao YP, Wu CT, Wu YY, Liang SH, Chin WC, Chou TL, Gau SS, Huang YZ, Lin HY. Intermittent theta burst stimulation over the posterior superior temporal sulcus for children with autism spectrum disorder : A 4-week randomized blinded controlled trial followed by another 4-week open-label intervention. Autism. 2021 : 1362361321990534.

Intermittent theta burst stimulation is a varied form of repetitive transcranial magnetic non-invasive brain stimulation technique used to treat several neurological and psychiatric disorders. Its feasibility and therapeutic effects on the bilateral posterior superior temporal sulcus in children with autism are unknown. We conducted a single-blind, sham-controlled parallel randomized clinical trial in a hitherto largest sample of intellectually able children with autism (N = 78). Participants randomized to the active group received two-session/week intermittent theta burst stimulation for continuous 8 weeks. Those in the sham group received two-session/week sham stimulations in the first 4 weeks and then active intervention for the following 4 weeks after unblinding. First, we found that continuous 8-week intermittent theta burst stimulation on the bilateral posterior superior temporal sulcus in children with autism is safe and tolerable. Second, we found that 8-week intermittent theta burst stimulation produced greater therapeutic efficacy, although we did not find any significant effects of 4-week intermittent theta burst stimulation on core symptoms and social cognitive performances in autism. Further analysis revealed that participants with higher intelligence and better social cognitive performance, alongside less attention-deficit hyperactivity disorder severity at baseline, were more likely to be responders. This study identified that the factors contribute to responders and the results suggest that longer courses of non-invasive brain stimulation may be needed to produce therapeutic benefits in autism, with consideration of heterogeneous responses.

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18. Rashid A. Yonder : Autism, home visits, suicidal ideation, and young sudden cardiac death. The British journal of general practice : the journal of the Royal College of General Practitioners. 2021 ; 71(704) : 129.

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19. Sicherman N, Charite J, Eyal G, Janecka M, Loewenstein G, Law K, Lipkin PH, Marvin AR, Buxbaum JD. Clinical signs associated with earlier diagnosis of children with autism Spectrum disorder. BMC pediatrics. 2021 ; 21(1) : 96.

BACKGROUND : The objective of this study is to gain new insights into the relationship between clinical signs and age at diagnosis. METHOD : We utilize a new, large, online survey of 1743 parents of children diagnosed with ASD, and use multiple statistical approaches. These include regression analysis, factor analysis, and machine learning (regression tree). RESULTS : We find that clinical signs that most strongly predict early diagnosis are not necessarily specific to autism, but rather those that initiate the process that eventually leads to an ASD diagnosis. Given the high correlations between symptoms, only a few signs are found to be important in predicting early diagnosis. For several clinical signs we find that their presence and intensity are positively correlated with delayed diagnosis (e.g., tantrums and aggression). Even though our data are drawn from parents’ retrospective accounts, we provide evidence that parental recall bias and/or hindsight bias did not play a significant role in shaping our results. CONCLUSION : In the subset of children without early deficits in communication, diagnosis is delayed, and this might be improved if more attention will be given to clinical signs that are not necessarily considered as ASD symptoms. Our findings also suggest that careful attention should be paid to children showing excessive tantrums or aggression, as these behaviors may interfere with an early ASD diagnoses.

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20. Tiwari A, Khera R, Rahi S, Mehan S, Makeen HA, Khormi YH, Rehman MU, Khan A. Neuroprotective Effect of α-Mangostin in the Ameliorating Propionic Acid-Induced Experimental Model of Autism in Wistar Rats. Brain Sci. 2021 ; 11(3).

Several studies have documented the role of hyper-activation of extracellular signal-regulated kinases (ERK) in Autism pathogenesis. Alpha-mangostin (AMG) is a phytoconstituents with anti-oxidants, anti-inflammatory, and ERK inhibition properties in many diseases. Our research aims to investigate the neuroprotective effect of AMG in the rat model of intracerebroventricular-propionic acid (ICV-PPA) induced autism with a confirmation of its effect on the ERK signaling. Autism was induced in Wistar rats (total 36 rats ; 18 male/18 female) by multiple doses of PPA through ICV injection for 11 days. Actophotometer and beam walking tasks were used to evaluate animals’ motor abilities, and the Morris water maze task was utilized to confirm the cognition and memory in animals. Long term administration of AMG 100 mg/kg and AMG 200mg/kg continued from day 12 to day 44 of the experiment. Before that, animals were sacrificed, brains isolated, morphological, gross pathological studies were performed, and neurochemical analysis was performed in the brain homogenates. Cellular and molecular markers, including ERK, myelin basic protein, apoptotic markers including caspase-3, Bax, Bcl-2, neuroinflammatory markers, neurotransmitters, and oxidative stress markers, have been tested throughout the brain. Thus, AMG reduces the overactivation of the ERK signaling and also restored autism-like behavioral and neurochemical alterations.

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21. Wang L, Li D, Pan S, Zhai J, Xia W, Sun C, Zou M. The relationship between 2019-nCoV and psychological distress among parents of children with autism spectrum disorder. Globalization and health. 2021 ; 17(1) : 23.

OBJECTIVES : The psychological distress caused by COVID-19 may be pronounced among the parents of children with autism spectrum disorder (ASD). This study aimed to investigate psychological distress among parents of children with ASD during the COVID-19 pandemic. METHODS : A total of 1764 parents of children with ASD and 4962 parents of typically developing (TD) children were recruited. The participants completed an online survey which contained demographic information, the impact due to COVID-19 crisis, resilience, coping styles, anxiety and depression. Hierarchical linear regression was used to assess the contributions of these variables to anxiety and depression. RESULTS : After adjusting for demographic variables, the following factors were associated with parents’ anxiety and depression symptoms : (i) Whether or not the participants had a child with ASD ; (ii) resilience ; (iii) coping strategies, and ; (iv) the impact due to COVID-19. Among these, the psychological stress caused by COVID-19 played the most important role in parental anxiety (β = 0.353) and depression (β = 0.242) symptoms. Parents of children with ASD had lower levels of resilience and positive coping, and used more negative coping strategies than parents of TD children. Among all participants, 8.0 and 24.2% of parents had symptoms of anxiety and depression, respectively. Compared to parents of TD children, more parents of children with ASD exhibited symptoms of anxiety and depression (12.2% vs. 6.6% ; 31.0% vs. 21.7%, respectively). CONCLUSIONS : During the COVID-19 pandemic, parents experienced varying levels of anxiety and depression, particularly, parents of children with ASD. More specific attention should be paid to parental mental health and long-term effective intervention programs, that are targeted towards parents of children with ASD, and such programs should be promoted around China in the wake of the COVID-19 crisis.

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22. Wilkinson CL, Nelson CA. Increased aperiodic gamma power in young boys with Fragile X Syndrome is associated with better language ability. Mol Autism. 2021 ; 12(1) : 17.

BACKGROUND : The lack of robust and reliable clinical biomarkers in Fragile X Syndrome (FXS), the most common inherited form of intellectual disability, has limited the successful translation of bench-to-bedside therapeutics. While numerous drugs have shown promise in reversing synaptic and behavioral phenotypes in mouse models of FXS, none have demonstrated clinical efficacy in humans. Electroencephalographic (EEG) measures have been identified as candidate biomarkers as EEG recordings of both adults with FXS and mouse models of FXS consistently exhibit alterations in resting state and task-related activity. However, the developmental timing of these EEG differences is not known as thus far EEG studies have not focused on young children with FXS. Further, understanding how EEG differences are associated with core symptoms of FXS is crucial to successful use of EEG as a biomarker, and may improve our understanding of the disorder. METHODS : Resting-state EEG was collected from FXS boys with full mutation of Fmr1 (2.5-7 years old, n = 11) and compared with both age-matched (n = 12) and cognitive-matched (n = 12) typically developing boys. Power spectra (including aperiodic and periodic components) were compared using non-parametric cluster-based permutation testing. Associations between 30 and 50 Hz gamma power and cognitive, language, and behavioral measures were evaluated using Pearson correlation and linear regression with age as a covariate. RESULTS : FXS participants showed increased power in the beta/gamma range ( 25-50 Hz) across multiple brain regions. Both a reduction in the aperiodic (1/f) slope and increase in beta/gamma periodic activity contributed to the significant increase in high-frequency power. Increased gamma power, driven by the aperiodic component, was associated with better language ability in the FXS group. No association was observed between gamma power and parent report measures of behavioral challenges, sensory hypersensitivities, or adaptive behaviors. LIMITATIONS : The study sample size was small, although comparable to other human studies in rare-genetic disorders. Findings are also limited to males in the age range studied. CONCLUSIONS : Resting-state EEG measures from this study in young boys with FXS identified similar increases in gamma power previously reported in adults and mouse models. The observed positive association between resting state aperiodic gamma power and language development supports hypotheses that alterations in some EEG measures may reflect ongoing compensatory mechanisms.

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23. Yao F, Zhang K, Feng C, Gao Y, Shen L, Liu X, Ni J. Protein Biomarkers of Autism Spectrum Disorder Identified by Computational and Experimental Methods. Frontiers in psychiatry. 2021 ; 12 : 554621.

Background : Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that affects millions of people worldwide. However, there are currently no reliable biomarkers for ASD diagnosis. Materials and Methods : The strategy of computational prediction combined with experimental verification was used to identify blood protein biomarkers for ASD. First, brain tissue-based transcriptome data of ASD were collected from Gene Expression Omnibus database and analyzed to find ASD-related genes by bioinformatics method of significance analysis of microarrays. Then, a prediction program of blood-secretory proteins was applied on these genes to predict ASD-related proteins in blood. Furthermore, ELISA was used to verify these proteins in plasma samples of ASD patients. Results : A total of 364 genes were identified differentially expressed in brain tissue of ASD, among which 59 genes were predicted to encode ASD-related blood-secretory proteins. After functional analysis and literature survey, six proteins were chosen for experimental verification and five were successfully validated. Receiver operating characteristic curve analyses showed that the area under the curve of SLC25A12, LIMK1, and RARS was larger than 0.85, indicating that they are more powerful in discriminating ASD cases from controls. Conclusion : SLC25A12, LIMK1, and RARS might serve as new potential blood protein biomarkers for ASD. Our findings provide new insights into the pathogenesis and diagnosis of ASD.

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24. Zhang J, Ma X, Su Y, Wang L, Shang S, Yue W. Association Study of MTHFR C677T Polymorphism and Birth Body Mass With Risk of Autism in Chinese Han Population. Frontiers in psychiatry. 2021 ; 12 : 560948.

Objective : To explore the association of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with birth body mass and risk of autism in Chinese Han population. Methods : A total 1,505 Chinese Han autism patients were recruited, using the Diagnostic and Statistical Manual of Mental Disorders, 4th revised version (DSM-IV-R) diagnostic criteria for autism, and 1,308 sex-matched healthy controls were also enrolled for the study. All the participants’ birth body masses were counted according to the medical records. The MTHFR C677T genotypes were detected using the polymerase chain reaction-restrict fragment length polymorphism (PCR-RFLP) method. The association between C677T polymorphism, birth body mass, and risk of autism were analyzed using the chi-square tests. Results : The present study found that the MTHFR 677T was significantly associated with risk of autism [P = 0.004, odds ratio (OR) = 1.18, 95% CI = 1.02-1.29). The autism children more frequently showed low birth body mass (<2.5 kg) than healthy control subjects (8.6 vs. 5.3%, P = 0.001, OR = 1.67, 95% CI = 1.24-2.26). The interactive effects between MTHFR 677T and low birth body mass (P = 0.0001, OR = 2.18, 95% CI = 1.44-3.32) were also significantly associated with risk of autism. Conclusions : The MTHFR C677T polymorphism and low birth body mass may be associated with risk of autism in Chinese Han population.

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