1. Ali MT, Gebreil A, ElNakieb Y, Elnakib A, Shalaby A, Mahmoud A, Sleman A, Giridharan GA, Barnes G, Elbaz AS. A personalized classification of behavioral severity of autism spectrum disorder using a comprehensive machine learning framework. Scientific reports. 2023; 13(1): 17048.

Autism Spectrum Disorder (ASD) is characterized as a neurodevelopmental disorder with a heterogeneous nature, influenced by genetics and exhibiting diverse clinical presentations. In this study, we dissect Autism Spectrum Disorder (ASD) into its behavioral components, mirroring the diagnostic process used in clinical settings. Morphological features are extracted from magnetic resonance imaging (MRI) scans, found in the publicly available dataset ABIDE II, identifying the most discriminative features that differentiate ASD within various behavioral domains. Then, each subject is categorized as having severe, moderate, or mild ASD, or typical neurodevelopment (TD), based on the behavioral domains of the Social Responsiveness Scale (SRS). Through this study, multiple artificial intelligence (AI) models are utilized for feature selection and classifying each ASD severity and behavioural group. A multivariate feature selection algorithm, investigating four different classifiers with linear and non-linear hypotheses, is applied iteratively while shuffling the training-validation subjects to find the set of cortical regions with statistically significant association with ASD. A set of six classifiers are optimized and trained on the selected set of features using 5-fold cross-validation for the purpose of severity classification for each behavioural group. Our AI-based model achieved an average accuracy of 96%, computed as the mean accuracy across the top-performing AI models for feature selection and severity classification across the different behavioral groups. The proposed AI model has the ability to accurately differentiate between the functionalities of specific brain regions, such as the left and right caudal middle frontal regions. We propose an AI-based model that dissects ASD into behavioral components. For each behavioral component, the AI-based model is capable of identifying the brain regions which are associated with ASD as well as utilizing those regions for diagnosis. The proposed system can increase the speed and accuracy of the diagnostic process and result in improved outcomes for individuals with ASD, highlighting the potential of AI in this area.

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2. Chen Y, Chen G, Liu Y, Dong GH, Yang BY, Li S, Huang H, Jin Z, Guo Y. Exposure to greenness during pregnancy and the first three years after birth and autism spectrum disorder: A matched case-control study in shanghai, China. Environmental pollution (Barking, Essex : 1987). 2023: 122677.

Causes of autism spectrum disorder (ASD) have not been fully understood. Previous studies have linked environmental factors with ASD. However, evidence for the greenness-ASD association is limited, especially in China. To fill this gap, we conducted a matched case-control study to examine the association between greenness and ASD in China. Participants in this study were 84,934 children aged 3-12 years in Shanghai, China, selected using a multi-stage cluster sampling method. ASD cases were firstly screened by questionnaires completed by both children’s parents and teachers, and were then confirmed by clinical examinations. Further, 10 healthy controls were randomly selected to match each ASD case by age and sex. The final analyses included 146 ASD cases and 1460 healthy controls. Participants’ exposure to greenness before and after birth was assessed by normalized difference vegetation index (NDVI) and enhanced vegetation index (EVI) from NASA’s Earth Observing System according to their residential locations. We used conditional logistic regression to examine the ASD-greenness association. Per interquartile range (IQR) increase in EVI(500m) and NDVI(500m) during the year before birth were associated with lower risks of ASD with adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of 0.96 (95%CI: 0.946, 0.975, IQR = 0.074) and 0.937 (95%CI: 0.915, 0.959, IQR = 0.101). Exposure to greenness during the first 3 years after birth was also significantly associated with lower risk of ASD [IQR ORs for EVI(500m) and NDVI(500m) were 0.935 (95%CI: 0.91, 0.962, IQR = 0.06) and 0.897 (95%CI: 0.861, 0.935, IQR = 0.09), respectively]. Mediation analyses indicated that greenness has beneficial effects on ASD children by absorbing air pollutants. Greenness was observed to have stronger beneficial effects on children without historical diseases and term birth. More greenness exposure before and after birth were significantly associated with lower risks of ASD in children. Our results highlight the importance of greenness in urban planning.

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3. Gardner L, Gilchrest C, Campbell JM. Intellectual, Adaptive, and Behavioral Functioning Associated with Designated Levels of Support in a Sample of Autistic Children Referred for Tertiary Assessment. Journal of autism and developmental disorders. 2023.

The diagnostic criteria for autism spectrum disorder in the DSM-5-TR features the option to designate levels of support for social communication (SC) and restricted, repetitive behaviors (RRB). These levels are conceptual in nature, but research indicates standardized assessment outcomes correspond with clinician-assigned levels of support. The purpose of the present study was to identify factors that influence designated levels of support for SC and RRBs when diagnosing autism. Standardized assessment scores across intellectual functioning, adaptive skills, and ASD symptomology were analyzed to determine corresponding levels of support in SC and RRBs assigned by clinicians for 136 autistic children following a comprehensive diagnostic evaluation. At diagnosis, approximately 46% of participants were described as needing substantial support (Level 2) for SC and 49% were described as needing substantial support (Level 2) for RRB. There was a consistent pattern of higher to lower intellectual and adaptive functioning needing Level 1-Level 3 support. Autism assessment results followed a gradient of fewer to greater autism symptoms from Level 1 to Level 3 support. Findings indicated clinician-assigned levels of support for SC and RRB were associated with intellectual functioning, adaptive functioning, autism symptomology, and age, but not sex.

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4. Guo X, Zhai G, Liu J, Zhang X, Zhang T, Cui D, Zhou R, Gao L. Heterogeneity of dynamic synergetic configurations of salience network in children with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research. 2023.

Atypical functional connectivity (FC) patterns have been identified in autism spectrum disorders (ASD), especially within salience network (SN) and between SN and default mode network (DMN) and central executive network (CEN). But whether the dynamic configuration of intra-SN and inter-SN (SN with DMN and CEN) FC in ASD is also heterogeneous remains unknown. Based on the resting-state functional magnetic resonance imaging data from 105 ASD and 102 typically-developing controls (TC), we calculated the time-varying FC of intra-SN and inter-SN (SN with DMN and CEN). Then, the joint recurrence features for the time-varying FC were calculated to assess how the SN dynamically recruits different configurations of network segregation and integration in ASD, that is, synergies, from the dynamical systems perspective. We analyzed the differences in synergetic patterns between ASD subtypes obtained by k-means clustering algorithm based on the synergy of SN and TC, and investigated the relationships between synergy of SN and severity of clinical symptoms of ASD for ASD subtypes. Two ASD subtypes were revealed, where the synergy of SN in ASD subtype 1 has lower stability and periodicity compared to the TC, and ASD subtype 2 exhibits the opposite alteration. Synergy of SN for ASD subtype 1 and 2 was found to predict the severity of communication impairments and restricted and repetitive behaviors in ASD, respectively. These results suggest the existence of subtypes with distinct patterns of the synergy of SN in ASD, and provide insight into the complex pathophysiological mechanism of clinical manifestations of ASD.

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5. Kars S, Akı E. Relationship between play skills and sensory processing in children with autism. Applied neuropsychology Child. 2023: 1-11.

Play skills in children with autism are limited due to autism symptoms. It is important to determine the effect of sensory processing skill, which is one of these symptoms, on play skills. Therefore, we aimed to investigate of the relationship between play skills and sensory processing of children with autism. A total of 58 children with autism (n = 29) and typically developing children (n = 29) participated. We used the Sensory Profile and the Revised Knox Preschool Play Scale. Spearman’s correlation coefficient was used. Children with autism demonstrated a significantly lower developmental play age and were rated lower on all dimensions of the RKPPS than typically developing children. Moreover, the results of this study showed that there are complex correlations between play skills and sensory processing in children with autism. Sensory processing and play skills have complex relationships in children with autism.

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6. Khaledi F, Dehkordi HT, Zarean E, Shahrani M, Amini-Khoei H. Possible role of NO/NMDA pathway in the autistic-like behaviors induced by maternal separation stress in mice. PloS one. 2023; 18(10): e0292631.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Maternal separation (MS) stress is an established model of early-life stress associated with autistic-like behaviors. Altered glutamatergic and nitrergic neurotransmissions may contribute to the pathophysiology of ASD. However, the specific mechanisms underlying these alterations and their relationship to MS-induced autistic-like behaviors remain unclear. Addressing this knowledge gap, this study aims to elucidate the involvement of the nitric oxide (NO)/ N-methyl-D-aspartate (NMDA) pathway in MS-induced autistic-like behaviors in mice. This knowledge has the potential to guide future research, potentially leading to the development of targeted interventions or treatments aimed at modulating the NO/NMDA pathway to ameliorate ASD symptoms. Ninety male Naval Medical Research Institute (NMRI) mice were assigned to six groups (n = 15) comprising a control group (treated with saline) and five groups subjected to MS and treated with saline, ketamine, NMDA, L-NAME, and L-arginine. Behavioral tests were conducted, including the three-chamber test, shuttle box, elevated plus-maze, and marble burying test. Gene expression of iNOS, nNOS, and NMDA-R subunits (NR2A and NR2B), along with nitrite levels, was evaluated in the hippocampus. The findings demonstrated that MS induced autistic-like behaviors, accompanied by increased gene expression of iNOS, nNOS, NR2B, NR2A, and elevated nitrite levels in the hippocampus. Modulation of the NO/NMDA pathway with activators and inhibitors altered the effects of MS. These results suggest that the NO/NMDA pathway plays a role in mediating the negative effects of MS and potentially contributes to the development of autistic-like behaviors in maternally separated mice.

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7. Khan AJ, Afrose T, Nuha FA, Islam MA, Ahmad MSB. Bruxism management in individuals with autism spectrum disorder and down syndrome – A systematic review. Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry. 2023.

BACKGROUND: In dentistry, association between bruxism and individuals with autism spectrum disorders (ASD) and Down Syndrome (DS) is high. Bruxism is one of the most common oral and psychophysiological disorders, that is still an unsolved issue with limited data. OBJECTIVES: The purpose of this systematic review (SR) was to evaluate evidence about bruxism and its management in individuals with ASD and DS. MATERIALS AND METHODS: The researchers performed an electronic search using keywords on three databases, reference lists and complemented by manual searching from January 2000 to February 2023 to find out the relevant documents. An extensive literature review using the « Preferred Reporting Items for Systematic Review and Meta Analysis » method was carried out. PICO parameters were formulated, and studies risk of bias was evaluated using the JBI critical appraisal checklist tool for case reports. RESULTS: Out of 527 documents, 8 case studies and one review paper were identified as final articles for data synthesis. The findings showed, bruxism was reduced for all the participants with ASD and DS after implementation of functional analysis or dental treatment. CONCLUSION: The current SR found that despite the positive results of all the studies, there was a lack of evidence due to a limited number of studies and only case studies were conducted through functional analysis and dental treatment. NOVELTY: This SR is the first study on bruxism treatments in individuals with ASD and DS that included all the available studies (n = 9) since last 23 years and the first study that specifically addresses the incorporation of case reports in a systemic review.

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8. Kharrat M, Issa AB, Tlili A, Jallouli O, Alila-Fersi O, Maalej M, Chouchen J, Ghouylia Y, Kamoun F, Triki C, Fakhfakh F. A Novel Mutation in the MAP7D3 Gene in Two Siblings with Severe Intellectual Disability and Autistic Traits: Concurrent Assessment of BDNF Functional Polymorphism, X-Inactivation and Oxidative Stress to Explain Disease Severity. Journal of molecular neuroscience : MN. 2023.

Intellectual disabilities (ID) and autism spectrum disorders (ASD) are characterized by extreme genetic and phenotypic heterogeneity. However, understanding this heterogeneity is difficult due to the intricate interplay among multiple interconnected genes, epigenetic factors, oxidative stress, and environmental factors. Employing next-generation sequencing (NGS), we revealed the genetic cause of ID and autistic traits in two patients from a consanguineous family followed by segregation analysis. Furthermore, in silico prediction methods and 3D modeling were conducted to predict the effect of the variants. To establish genotype-phenotype correlation, X-chromosome inactivation using Methylation-specific PCR and oxidative stress markers were also investigated. By analyzing the NGS data of the two patients, we identified a novel frameshift mutation c.2174_2177del (p.Thr725MetfsTer2) in the MAP7D3 gene inherited from their mother along with the functional BDNF Val66Met polymorphism inherited from their father. The 3D modeling demonstrated that the p.Thr725MetfsTer2 variant led to the loss of the C-terminal tail of the MAP7D3 protein. This change could destabilize its structure and impact kinesin-1’s binding to microtubules via an allosteric effect. Moreover, the analysis of oxidative stress biomarkers revealed an elevated oxidative stress in the two patients compared to the controls. To the best of our knowledge, this is the first report describing severe ID and autistic traits in familial cases with novel frameshift mutation c.2174_2177del in the MAP7D3 gene co-occurring with the functional polymorphism Val66M in the BDNF gene. Besides, our study underlines the importance of investigating combined genetic variations, X-chromosome inactivation (XCI) patterns, and oxidative stress markers for a better understanding of ID and autism etiology.

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9. Kim J, Jung MW, Lee D. Reward learning improves social signal processing in autism model mice. Cell reports. 2023; 42(10): 113228.

Social and reward signal processing and their association are critical elements of social motivation. Despite the use of reward learning to improve the social interactions of patients with autism spectrum disorder (ASD), the underlying neural mechanisms are unknown. Here, we found different yet conjunct neuronal representations of social and reward signals in the mouse medial prefrontal cortex (mPFC). We also found that social signal processing is selectively disrupted, whereas reward signal processing is intact in the mPFC of Shank2-knockout mice, a mouse model of ASD. Furthermore, reward learning not only allows Shank2-knockout mice to associate social stimuli with reward availability, but it also rescues the impaired social signal processing. These findings provide insights into the neural basis for the therapeutic use of reward learning in ASD.

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10. McKern N, Dargue N, Sweller N. Comparing gesture frequency between autistic and neurotypical individuals: A systematic review and meta-analysis. Psychological bulletin. 2023.

While diagnostic assessments for autism routinely screen for reduced frequency of gestures, evidence supporting reduced gesture production in autism is inconsistent. This systematic review and meta-analysis aimed to clarify differences in frequency of gestures between autistic and neurotypical individuals. Included studies compared frequency of gestures between autistic and neurotypical individuals. Database searches (APA PsycInfo, ERIC, MEDLINE, ProQuest Dissertations and Theses Global) and a call for unpublished data on the International Society for Gesture Studies listserv identified research from January 1994 to March 2023. Study quality was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Quasi-Experimental Designs. Quantitative synthesis involved a narrative review of all findings and meta-analysis of articles allowing effect size calculations, stratified by the type of gesture. Thirty-one articles comparing frequency of gestures between 701 autistic and 860 neurotypical individuals were included in the narrative review, 25 of which were also included in the meta-analysis. Compared to neurotypical individuals, meta-analyses found that autistic individuals produced significantly less total, deictic, and emblematic gestures. While the number of iconic gestures appeared comparable between groups, studies investigating iconic gestures exhibited an almost equal trend of both positive and negative effect sizes, which were mostly nonsignificant. The way gesture production was measured, age, observer familiarity, and task structure (but not overall study quality) moderated the effect size, albeit inconsistently across the types of gestures. Findings have implications relating to profiling gesture use in diagnostic assessments for autism and highlight gaps in our understanding of differences in gesture production in autism. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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11. Nies KJ, Baldwin J, Kaur M. Early Motor Delays During the First 2 Years of Life in Autism Spectrum Disorder: A Scoping Review. Pediatric physical therapy : the official publication of the Section on Pediatrics of the American Physical Therapy Association. 2023.

PURPOSE: To summarize and appraise the emerging evidence on early motor skills of infants later diagnosed with autism spectrum disorder (ASD), and the association of early motor delays to later ASD diagnosis/characteristics. METHODS: A literature search was conducted for studies published from 2000 to 2023 on the motor skills of infants later diagnosed with ASD, followed by screening and data extraction. RESULTS: Current evidence suggested presence of early motor deficits including poor anticipatory movements, postural control, and gross/fine motor skills during the first 2 years of ASD. However, there was variability among studies with regard to study sample and methodology. CONCLUSION: Although motor deficits are evident in infants, it is unclear whether these are specific to ASD or a consequence of general developmental disorder. Future research is needed on the investigation of specificity and severity of early motor delays, which can potentially assist in early identification of ASD.

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12. Rabaya S, Nairat S, Bader K, Herzallah MM, Darwish HM. Iron metabolism in autism spectrum disorder; inference through single nucleotide polymorphisms in key iron metabolism genes. Journal of the neurological sciences. 2023; 453: 120817.

Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental problems with various genetic and environmental components. The ASD diagnosis is based on symptom expression without reliance on any biomarkers. The genetic contributions in ASD remain elusive. Various studies have linked ASD with iron. Since iron plays a crucial role in brain development, neurotransmitter synthesis, neuronal myelination and mitochondrial function, we hypothesized that iron dysregulation in the brain could play a role and contribute to the pathogenesis of ASD. In this study, we investigated single nucleotide polymorphisms in ASD in various iron metabolism genes, including the Transferrin Receptor (TFRC) gene (rs11915082), the Solute Carrier Family 11 Member 2 (SLC11A2) gene (rs1048230 and rs224589), the Solute Carrier Family 40 Member 1 (SLC40A1) gene (rs1439816), and hepcidin antimicrobial peptide (HAMP) gene (rs10421768). We recruited 48 patients with ASD and 88 matched non-ASD controls. Our results revealed a significant difference between ASD and controls in the G allele of the TFRC gene rs11915082, and in the C allele of the SLC40A1 gene rs1439816. In silico analysis demonstrated potential positive role of the indicated genetic variations in ASD development and pathogenesis. These results suggest that specific genetic variations in iron metabolism genes may represent part of early genetic markers for early diagnosis of ASD. A significant effect of SNPs, groups (ASD/control) as well as interaction between SNPs and groups was revealed. Follow-up post hoc tests showed a significant difference between the ASD and control groups in rs11915082 (TFRC gene) and rs1439816 (SLC40A1 gene). Backward conditional logistic regression using both the genotype and allele data showed similar ability in detecting ASD using allel model (Nagelkerke R(2) = 0.350 p = 0.967; Variables: rs1439816, rs11915082) compared to genotype model (Nagelkerke R(2) = 0.347, p = 0.430; Variables: rs1439816 G, rs1439816 C, rs10421768 A). ROC curve showed 54% sensitivity in detecting ASD compared to 47% for the genotype model. Both models differentiated controls with high accuracy; the allele model had a specificity of 91% compared to 92% for the genotype model. In conclusion, our findings suggest that specific genetic variations in iron metabolism may represent early biomarkers for a diagnosis of ASD. Further research is needed to correlate these markers with specific blood iron indicators and their contribution to brain development and behavior.

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13. Stanislava B, Zuzana B, Jana O, Jan B. Mini review of molecules involved in altered postnatal neurogenesis in autism. The International journal of neuroscience. 2023: 1-15.

The neurobiology of autism is complex, but emerging research points to potential abnormalities and alterations in neurogenesis. The aim of the present review is to describe the advances in the understanding of the role of selected neurotrophins, neuropeptides, and other compounds secreted by neuronal cells in the processes of postnatal neurogenesis in conjunction with autism. We characterize the fundamental mechanisms of neuronal cell proliferation, generation of major neuronal cell types with special emphasis on neurogenic niches – the subventricular zone and hippocampal areas. We also discuss changes in intracellular calcium levels and calcium-dependent transcription factors in the context of the regulation of neurogenesis and cell fate determination. To sum up, this review provides specific insight into the known association between alterations in the function of the entire spectrum of molecules involved in neurogenesis and the etiology of autism pathogenesis.

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14. Wang X, Sun Z, Yang T, Lin F, Ye S, Yan J, Li T, Chen J. Erratum for Wang et al., « Sodium butyrate facilitates CRHR2 expression to alleviate HPA axis hyperactivity in autism-like rats induced by prenatal lipopolysaccharides through histone deacetylase inhibition ». mSystems. 2023: e0091523.

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15. Zeng J, Tian Y, Chen L, Cai J, Wang X, Liao Y, Shen H, Li X. [Genetic analysis of a child with developmental disorder and epilepsy due to a homozygous variant of PIGW gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2023; 40(10): 1288-91.

OBJECTIVE: To explore the genetic basis for a child featuring global developmental disorder with epilepsy. METHODS: A child who had presented at Guangzhou Women and Children’s Medical Center in July 2022 was selected as the study subject. Clinical data was collected. Potential variant was detected by whole exome sequencing (WES). Candidate variant was validated by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a three-year-old ethnic Zhuang Chinese girl, had presented with global developmental disorder and epilepsy, for which rehabilitation therapy was ineffective. Genetic testing revealed that she has harbored a homozygous c.821T>C (p.Leu274Pro) missense variant of the PIGW gene, for which both of her parents and sister were heterozygous carriers. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as variant of uncertain significance. CONCLUSION: The homozygous c.821T>C (p.Leu274Pro) variant of the PIGW gene probably underlay the onset of disease in this child. Above finding has enriched the mutational spectrum of the PIGW gene.

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