1. Basu S, Ro EJ, Liu Z, Kim H, Bennett A, Kang S, Suh H. The Mef2c gene dose-dependently controls hippocampal neurogenesis and the expression of autism-like behaviors. J Neurosci;2023 (Dec 20)

Mutations in the activity-dependent transcription factor MEF2C have been associated with several neuropsychiatric disorders. Among these, autism spectrum disorder (ASD)-related behavioral deficits are manifested. Multiple animal models that harbor mutations in Mef2c have provided compelling evidence that Mef2c is indeed an ASD gene. However, studies in mice with germline or global brain knockout of Mef2c are limited in their ability to identify the precise neural substrates and cell types that are required for the expression of Mef2c-mediated ASD behaviors. Given the role of hippocampal neurogenesis in cognitive and social behaviors, in this study we aimed to investigate the role of Mef2c in the structure and function of newly-generated dentate granule cells (DGCs) in the postnatal hippocampus, and to determine whether disrupted Mef2c function is responsible for manifesting ASD behaviors. Overexpression of Mef2c (Mef2c(OE) ) arrested the transition of neurogenesis at progenitor stages, as indicated by sustained expression of Sox2(+) in Mef2c(OE) DGCs. Conditional knockout of Mef2c (Mef2c(cko) ) allowed neuronal commitment of Mef2c(cko) cells; however, Mef2c(cko) impaired not only dendritic arborization and spine formation, but also synaptic transmission onto Mef2c(cko) DGCs. Moreover, the abnormal structure and function of Mef2c(cko) DGCs led to deficits in social interaction and social novelty recognition, which are key characteristics of ASD behaviors. Thus, our study revealed a dose-dependent requirement of Mef2c in the control of distinct steps of neurogenesis, as well as a critical cell-autonomous function of Mef2c in newborn DGCs in the expression of proper social behavior in both sexes.Significance Statement Autism spectrum disorder (ASD) is a neurodevelopmental disorder causing significant social, communication and behavioral deficits in children worldwide. Genetic complexity and heterogeneity associated with ASD have hindered the filed from establishing any precise cellular substrate associated with ASD. Recent studies have implicated hippocampal neurogenesis as one of the key players in social behavior and ASD-like behaviors. Here, using conditional deletion of transcriptional factor Mef2c, in hippocampal newborn neurons or abDGCs, we have demonstrated how Mef2c impacts behavior by regulating the structural development, physiology, and function of abDGCs. Our results revealed the essential role of Mef2c in neurogenesis and identified hippocampal neurogenesis as a neural substrate necessary for social behaviors.

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2. Cho CH, Deyneko IV, Cordova-Martinez D, Vazquez J, Maguire AS, Diaz JR, Carbonell AU, Tindi JO, Cui MH, Fleysher R, Molholm S, Lipton ML, Branch CA, Hodgson L, Jordan BA. ANKS1B encoded AIDA-1 regulates social behaviors by controlling oligodendrocyte function. Nat Commun;2023 (Dec 21);14(1):8499.

Heterozygous deletions in the ANKS1B gene cause ANKS1B neurodevelopmental syndrome (ANDS), a rare genetic disease characterized by autism spectrum disorder (ASD), attention deficit/hyperactivity disorder, and speech and motor deficits. The ANKS1B gene encodes for AIDA-1, a protein that is enriched at neuronal synapses and regulates synaptic plasticity. Here we report an unexpected role for oligodendroglial deficits in ANDS pathophysiology. We show that Anks1b-deficient mouse models display deficits in oligodendrocyte maturation, myelination, and Rac1 function, and recapitulate white matter abnormalities observed in ANDS patients. Selective loss of Anks1b from the oligodendrocyte lineage, but not from neuronal populations, leads to deficits in social preference and sensory reactivity previously observed in a brain-wide Anks1b haploinsufficiency model. Furthermore, we find that clemastine, an antihistamine shown to increase oligodendrocyte precursor cell maturation and central nervous system myelination, rescues deficits in social preference in 7-month-old Anks1b-deficient mice. Our work shows that deficits in social behaviors present in ANDS may originate from abnormal Rac1 activity within oligodendrocytes.

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3. Donadio DMO, Simões-Zenari M, Santos THF, Sanchez MG, Molini-Avejonas DR, Cardilli-Dias D. Use of the Prompts for Reestructuring Oral Muscular Phonetic Targets (PROMPT) in Autism Spectrum Disorder: a case study. Codas;2023;36(2):e20220299.

Autism Spectrum Disorder (ASD) is classified by Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as a neurodevelopmental disorder, whose characteristics are mainly deficits in social communication and a restricted range of interests. There are several studies about autism, speech, and language in the literature, but few correlate speech and autism. This study aims to carry out a case study that will address autism, speech, and PROMPT (Restructuring Oral Muscular Phonetic Targets) and also to describe the speech improvement in the participant with autism using the method. The target words were defined for the entire intervention according to the System Analysis Observation (SAO) and Motor Speech Hierarchy (MSH), which are parts of the PROMPT evaluation. After the evaluation, the participant was attended for 16 sessions, once weekly, with the objective of improving their speech. After analyzing the data, it was possible to observe improvement in all aspects outlined according to the pre-treatment evaluation of the method such as phonatory control, mandibular control, lip-facial control and lingual control as well as in the sequenced movement although this was not the aim outlined in the evaluation. It was also possible to measure the improvement of an adequate number of words, an adequate number of phonemes, percentages of correct consonants – revised (PCC-R), and intelligibility.

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4. Godbole N, Tirupathi SP, Nair S, Afnan L, Nallapu A, Nallapu A. Effectiveness of picture-based interventions of toothbrush training on improvement of oral hygiene in children with autism spectrum disorders: A systematic review and meta-analysis. Spec Care Dentist;2023 (Dec 21)

BACKGROUND: Children with autism exhibit a higher risk of poor oral health due to difficulty in the performance of simple tasks such as toothbrushing. AIM: This current systematic review aims to evaluate the effectiveness of Picture based intervention of toothbrush training on improvement of oral hygiene in children with autism spectrum disorders (ASD) MATERIALS AND METHODS: Prospero registered (CRD42023450156). PubMed, Cochrane, Scopus databases are searched from years January 1, 1980 to August 1, 2023 using broad search terms (brush) AND (autism). RESULTS: The search queries have identified 853 titles, from three databases (PubMed, Scopus, Cochrane), after application of filters for exclusion of systematic reviews and meta-analysis, duplicate exclusion and removal of irrelevant titles led to the final inclusion of 24 articles for full text screening. From the 24 included studies, 10 studies (four RCTs and six non-randomized clinical studies) sustained the final rigorous PICO search. Quantitative pooling of data were performed for limited articles. CONCLUSION: Low quality evidence suggest that picture-based intervention of toothbrush training has significant improvement (p ≤ .05) in improving toothbrushing habit as well as performance as indicated by the Plaque Index score (PI), Gingival index (GI) and Oral hygiene index score (OHI-S).

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5. Gonçalves CL, Doifode T, Rezende VL, Costa MA, Rhoads JM, Soutullo CA. The many faces of microbiota-gut-brain axis in autism spectrum disorder. Life Sci;2024 (Jan 15);337:122357.

The gut-brain axis is gaining more attention in neurodevelopmental disorders, especially autism spectrum disorder (ASD). Many factors can influence microbiota in early life, including host genetics and perinatal events (infections, mode of birth/delivery, medications, nutritional supply, and environmental stressors). The gut microbiome can influence blood-brain barrier (BBB) permeability, drug bioavailability, and social behaviors. Developing microbiota-based interventions such as probiotics, gastrointestinal (GI) microbiota transplantation, or metabolite supplementation may offer an exciting approach to treating ASD. This review highlights that RNA sequencing, metabolomics, and transcriptomics data are needed to understand how microbial modulators can influence ASD pathophysiology. Due to the substantial clinical heterogeneity of ASD, medical caretakers may be unlikely to develop a broad and effective general gut microbiota modulator. However, dietary modulation followed by administration of microbiota modulators is a promising option for treating ASD-related behavioral and gastrointestinal symptoms. Future work should focus on the accuracy of biomarker tests and developing specific psychobiotic agents tailored towards the gut microbiota seen in ASD patients, which may include developing individualized treatment options.

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6. Hessl D, Mandujano Rojas K, Ferrer E, Espinal G, Famula J, Schneider A, Hagerman R, Tassone F, Rivera SM. FMR1 Carriers Report Executive Function Changes Prior to Fragile X-Associated Tremor/Ataxia Syndrome: A Longitudinal Study. Mov Disord;2023 (Dec 20)

BACKGROUND: Men with fragile X-associated tremor/ataxia syndrome (FXTAS) often develop executive dysfunction, characterized by disinhibition, frontal dyscontrol of movement, and working memory and attention changes. Although cross-sectional studies have suggested that earlier executive function changes may precede FXTAS, the lack of longitudinal studies has made it difficult to address this hypothesis. OBJECTIVE: To determine whether executive function deterioration experienced by premutation carriers (PC) in daily life precedes and predicts FXTAS. METHODS: This study included 66 FMR1 PC ranging from 40 to 78 years (mean, 59.5) and 31 well-matched healthy controls (HC) ages 40 to 75 (mean, 57.7) at baseline. Eighty-four participants returned for 2 to 5 follow up visits over a duration of 1 to 9 years (mean, 4.6); 28 of the PC developed FXTAS. The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) was completed by participants and their spouses/partners at each visit. RESULTS: Longitudinal mixed model regression analyses showed a greater decline with age in PC compared to HC on the Metacognition Index (MI; self-initiation, working memory, organization, task monitoring). Conversion to FXTAS was associated with worsening MI and Behavioral Regulation Index (BRI; inhibition, flexibility, emotion modulation). For spouse/partner report, FXTAS conversion was associated with worsening MI. Finally, increased self-report executive function problems at baseline significantly predicted later development of FXTAS. CONCLUSIONS: Executive function changes experienced by male PC represent a prodrome of the later movement disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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7. Imbiriba T, Demirkaya A, Singh A, Erdogmus D, Goodwin MS. Wearable Biosensing to Predict Imminent Aggressive Behavior in Psychiatric Inpatient Youths With Autism. JAMA Netw Open;2023 (Dec 1);6(12):e2348898.

IMPORTANCE: Aggressive behavior is a prevalent and challenging issue in individuals with autism. OBJECTIVE: To investigate whether changes in peripheral physiology recorded by a wearable biosensor and machine learning can be used to predict imminent aggressive behavior before it occurs in inpatient youths with autism. DESIGN, SETTING, AND PARTICIPANTS: This noninterventional prognostic study used data collected from March 2019 to March 2020 from 4 primary care psychiatric inpatient hospitals. Enrolled participants were 86 psychiatric inpatients with confirmed diagnoses of autism exhibiting operationally defined self-injurious behavior, emotion dysregulation, or aggression toward others; 16 individuals were not included (18.6%) because they would not wear the biosensor (8 individuals) or were discharged before an observation could be made (8 individuals). Data were analyzed from March 2020 through October 2023. MAIN OUTCOMES AND MEASURES: Research staff performed live behavioral coding of aggressive behavior while inpatient study participants wore a commercially available biosensor that recorded peripheral physiological signals (cardiovascular activity, electrodermal activity, and motion). Logistic regression, support vector machines, neural networks, and domain adaptation were used to analyze time-series features extracted from biosensor data. Area under the receiver operating characteristic curve (AUROC) values were used to evaluate the performance of population- and person-dependent models. RESULTS: There were 70 study participants (mean [range; SD] age, 11.9 [5-19; 3.5] years; 62 males [88.6%]; 1 Asian [1.4%], 5 Black [7.1%], 1 Native Hawaiian or Other Pacific Islander [1.4%], and 63 White [90.0%]; 5 Hispanic [7.5%] and 62 non-Hispanic [92.5%] among 67 individuals with ethnicity data). Nearly half of the population (32 individuals [45.7%]) was minimally verbal, and 30 individuals (42.8%) had an intellectual disability. Participant length of inpatient hospital stay ranged from 8 to 201 days, and the mean (SD) length was 37.28 (33.95) days. A total of 429 naturalistic observational coding sessions were recorded, totaling 497 hours, wherein 6665 aggressive behaviors were documented, including self-injury (3983 behaviors [59.8%]), emotion dysregulation (2063 behaviors [31.0%]), and aggression toward others (619 behaviors [9.3%]). Logistic regression was the best-performing overall classifier across all experiments; for example, it predicted aggressive behavior 3 minutes before onset with a mean AUROC of 0.80 (95% CI, 0.79-0.81). CONCLUSIONS AND RELEVANCE: This study replicated and extended previous findings suggesting that machine learning analyses of preceding changes in peripheral physiology may be used to predict imminent aggressive behaviors before they occur in inpatient youths with autism. Further research will explore clinical implications and the potential for personalized interventions.

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8. Ioannidis V, Pandey R, Bauer HF, Schön M, Bockmann J, Boeckers TM, Lutz AK. Disrupted extracellular matrix and cell cycle genes in autism-associated Shank3 deficiency are targeted by lithium. Mol Psychiatry;2023 (Dec 20)

The Shank3 gene encodes the major postsynaptic scaffolding protein SHANK3. Its mutation causes a syndromic form of autism spectrum disorder (ASD): Phelan-McDermid Syndrome (PMDS). It is characterized by global developmental delay, intellectual disorders (ID), ASD behavior, affective symptoms, as well as extra-cerebral symptoms. Although Shank3 deficiency causes a variety of molecular alterations, they do not suffice to explain all clinical aspects of this heterogenic syndrome. Since global gene expression alterations in Shank3 deficiency remain inadequately studied, we explored the transcriptome in vitro in primary hippocampal cells from Shank3∆11(-/-) mice, under control and lithium (Li) treatment conditions, and confirmed the findings in vivo. The Shank3∆11(-/-) genotype affected the overall transcriptome. Remarkably, extracellular matrix (ECM) and cell cycle transcriptional programs were disrupted. Accordingly, in the hippocampi of adolescent Shank3∆11(-/-) mice we found proteins of the collagen family and core cell cycle proteins downregulated. In vitro Li treatment of Shank3∆11(-/-) cells had a rescue-like effect on the ECM and cell cycle gene sets. Reversed ECM gene sets were part of a network, regulated by common transcription factors (TF) such as cAMP responsive element binding protein 1 (CREB1) and β-Catenin (CTNNB1), which are known downstream effectors of synaptic activity and targets of Li. These TFs were less abundant and/or hypo-phosphorylated in hippocampi of Shank3∆11(-/-) mice and could be rescued with Li in vitro and in vivo. Our investigations suggest the ECM compartment and cell cycle genes as new players in the pathophysiology of Shank3 deficiency, and imply involvement of transcriptional regulators, which can be modulated by Li. This work supports Li as potential drug in the management of PMDS symptoms, where a Phase III study is ongoing.

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9. Irie K, Zhao S, Aruga R, Matsumoto A, Ogawa A, Liang N. Lack of action-sentence compatibility effect in non-clinical individuals with high autistic traits. Front Psychol;2023;14:1293405.

INTRODUCTION: Patients with autism spectrum disorder (ASD) exhibit atypical responses to language use and comprehension. Recently, various degrees of primary autistic symptoms have been reported in the general population. We focused on autistic traits and examined the differences in mechanisms related to language comprehension using the action-sentence compatibility effect (ACE). ACE is a phenomenon in which response is facilitated when the action matches the behavior described in the statement. METHODS: In total, 70 non-clinical individuals were divided into low autistic and high autistic groups according to their autism spectrum quotient (AQ) scores. ACEs with adverbs and onomatopoeias were examined using a stimulus set of movement-related sentences. A choice-response task helped determine the correct sentence using antonym adverbs (slow and fast) and onomatopoeia (quick and satto) related to the speed of the movement. RESULTS: The low-AQ group showed ACEs that modulated the reaction time in antonym sentences. The high-AQ group showed less temporal modulation, and their overall reaction time was shorter. The low-AQ group showed faster reaction times for onomatopoeic words; however, the high-AQ group showed a tendency to reverse this trend. In individuals with intermediate autistic traits, the angle effect may be moderated by individual differences in motor skills and experience rather than autistic traits. The stimulus presentation involved a passive paradigm. DISCUSSION: This study provides insight into language comprehension processes in non-clinical individuals ranging from low to high autistic idiosyncrasy and elucidates language and behavior in individuals at different locations on the autistic trait continuum.

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10. Jalil-Abkenar SS. Triple-P: Interaction of mother-adolescent with intellectual and developmental disability. J Intellect Disabil;2023 (Dec 21):17446295231224125.

This study aimed to investigate the effect of a Positive Parenting Program (Triple-P) on the interaction of the mother-adolescent with intellectual disability. The pre-test and post-test randomized experimental design was used for this research. Thirty-four mothers of adolescents with intellectual disability took part in the present research and were assigned to experimental and control groups, each comprised of 17 people. The experimental group took part in an 8-session Triple-P and each session lasted 75 minutes, but the control group did not participate in this intervention. The data were analyzed using MANCOVA. The findings revealed that Triple-P intervention significantly influenced dependency, closeness, conflict, and positive interaction between the mother and the child with intellectual disability. The present study emphasized that Triple-P will improve the interaction of mother-adolescent with intellectual disability; therefore, Triple-P is a useful intervention.

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11. Jia Q, Wang X, Zhou R, Ma B, Fei F, Han H. Systematic bibliometric and visualized analysis of research hotspots and trends in artificial intelligence in autism spectrum disorder. Front Neuroinform;2023;17:1310400.

BACKGROUND: Artificial intelligence (AI) has been the subject of studies in autism spectrum disorder (ASD) and may affect its identification, diagnosis, intervention, and other medical practices in the future. Although previous studies have used bibliometric techniques to analyze and investigate AI, there has been little research on the adoption of AI in ASD. This study aimed to explore the broad applications and research frontiers of AI used in ASD. METHODS: Citation data were retrieved from the Web of Science Core Collection (WoSCC) database to assess the extent to which AI is used in ASD. CiteSpace.5.8. R3 and VOSviewer, two online tools for literature metrology analysis, were used to analyze the data. RESULTS: A total of 776 publications from 291 countries and regions were analyzed; of these, 256 publications were from the United States and 173 publications were from China, and England had the largest centrality of 0.33; Stanford University had the highest H-index of 17; and the largest cluster label of co-cited references was machine learning. In addition, keywords with a high number of occurrences in this field were autism spectrum disorder (295), children (255), classification (156) and diagnosis (77). The burst keywords from 2021 to 2023 were infants and feature selection, and from 2022 to 2023, the burst keyword was corpus callosum. CONCLUSION: This research provides a systematic analysis of the literature concerning AI used in ASD, presenting an overall demonstration in this field. In this area, the United States and China have the largest number of publications, England has the greatest influence, and Stanford University is the most influential. In addition, the research on AI used in ASD mostly focuses on classification and diagnosis, and « infants, feature selection, and corpus callosum are at the forefront, providing directions for future research. However, the use of AI technologies to identify ASD will require further research.

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12. Kose S, Turer F, Inal Kaleli I, Calik Senturk HN, Ozuysal Uyar DH, Bildik T. The Relationship Between Social Skills and Sensory Profile, Emotion Regulation, and Empathizing/Systemizing in Adolescents on the Autism Spectrum. J Autism Dev Disord;2023 (Dec 20)

This study aims to evaluate the relationship between social skills and sensory features, emotion regulation, and empathy in adolescents on the autism spectrum. One hundred and twenty-three adolescents were included in the study (50 autistic, 73 typically developing-TD adolescents). The participants filled out the Adolescent/Adult Sensory Profile (AASP) and Emotion Regulation Questionnaire. Parents of the participants completed the Child Empathy and Systemizing Quotient (EQ-C/SQ-C) and Autism-Social Skills Profile (ASSP) scales. Social reciprocity, social participation/avoidance, ASSP total scores, empathy and systemizing scores were lower, and detrimental social behaviors, low registration sensory profile scores were higher in the autism spectrum group. While a difference between genders was observed in sensory sensitivity, sensation avoiding, low registration quadrants and empathy scores, no gender and group interaction was found in any domain. Social skill total scores were correlated to sensation seeking and low registration sensory features, empathy, systemizing, and reappraisal emotion regulation scores. A hierarchical multiple linear regression analysis was conducted controlling for group and gender, sensation seeking (p = .032, β = 0.138), low registration (p = .012, β = – 0.215) of the AASP, and empathy (p < .001, β = 0.555) and systemizing (p = .033, β = 0.138) scores of the EQ/SQ-C was found to significantly predict social skill total scores. Although emotional regulation strategies may play a role, sensory processing features and empathy and systemizing skills seem to be the more significant contributors to social skills during adolescence. Interventions targeting sensory processing and especially improving empathy and systematization skills may positively affect social skills in adolescents on the autism spectrum.

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13. Laighneach A, Kelly JP, Desbonnet L, Holleran L, Kerr DM, McKernan D, Donohoe G, Morris DW. Social isolation-induced transcriptomic changes in mouse hippocampus impact the synapse and show convergence with human genetic risk for neurodevelopmental phenotypes. PLoS One;2023;18(12):e0295855.

Early life stress (ELS) can impact brain development and is a risk factor for neurodevelopmental disorders such as schizophrenia. Post-weaning social isolation (SI) is used to model ELS in animals, using isolation stress to disrupt a normal developmental trajectory. We aimed to investigate how SI affects the expression of genes in mouse hippocampus and to investigate how these changes related to the genetic basis of neurodevelopmental phenotypes. BL/6J mice were exposed to post-weaning SI (PD21-25) or treated as group-housed controls (n = 7-8 per group). RNA sequencing was performed on tissue samples from the hippocampus of adult male and female mice. Four hundred and 1,215 differentially-expressed genes (DEGs) at a false discovery rate of < 0.05 were detected between SI and control samples for males and females respectively. DEGS for both males and females were significantly overrepresented in gene ontologies related to synaptic structure and function, especially the post-synapse. DEGs were enriched for common variant (SNP) heritability in humans that contributes to risk of neuropsychiatric disorders (schizophrenia, bipolar disorder) and to cognitive function. DEGs were also enriched for genes harbouring rare de novo variants that contribute to autism spectrum disorder and other developmental disorders. Finally, cell type analysis revealed populations of hippocampal astrocytes that were enriched for DEGs, indicating effects in these cell types as well as neurons. Overall, these data suggest a convergence between genes dysregulated by the SI stressor in the mouse and genes associated with neurodevelopmental disorders and cognitive phenotypes in humans.

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14. Liu W, Shah N, Ma I, Rosenblau G. Strategic social decision making undergoes significant changes in typically developing and autistic early adolescents. Dev Sci;2023 (Dec 21):e13463.

Information sampling about others’ trustworthiness prior to cooperation allows humans to minimize the risk of exploitation. Here, we examined whether early adolescence or preadolescence, a stage defined as in between childhood and adolescence, is a significant developmental period for strategic social decisions. We also sought to characterize differences between autistic children and their typically developing (TD) peers. TD (N = 48) and autistic (N = 56) 8- to 12-year-olds played an online information sampling trust game. While both groups adapted their information sampling and cooperation to the various trustworthiness levels of the trustees, groups differed in how age and social skills modulated task behavior. In the TD group social skills were a stronger overall predictor of task behavior. In the autistic group, age was a stronger predictor and interacted with social skills. Computational modeling revealed that both groups used the same heuristic information sampling strategy-albeit older TD children were more efficient as reflected by decreasing decision noise with age. Autistic children had lower prior beliefs about the trustee’s trustworthiness compared to TD children. These lower priors indicate that children believed the trustees to be less trustworthy. Lower priors scaled with lower social skills across groups. Notably, groups did not differ in prior uncertainty, meaning that the priors of TD and autistic children were equally strong. Taken together, we found significant development in information sampling and cooperation in early adolescence and nuanced differences between TD and autistic children. Our study highlights the importance of deep phenotyping of children including clinical measures, behavioral experiments and computational modeling. RESEARCH HIGHLIGHTS: We specified how early adolescents with and without an autism diagnosis sampled information about their interaction partners and made cooperation decisions in a strategic game. Early adolescence is a significant developmental period for strategic decision making, marked by significant changes in information sampling efficiency and adaptivity to the partner’s behavior. Autistic and non-autistic groups differed in how age and social skills modulated task behavior; in non-autistic children behavior was more indicative of overall social skills. Computational modeling revealed differences between autistic and non-autistic groups in their initial beliefs about cooperation partners; autistic children expected their partners to be less trustworthy.

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15. Malachowski T, Chandradoss KR, Boya R, Zhou L, Cook AL, Su C, Pham K, Haws SA, Kim JH, Ryu HS, Ge C, Luppino JM, Nguyen SC, Titus KR, Gong W, Wallace O, Joyce EF, Wu H, Rojas LA, Phillips-Cremins JE. Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome. Cell;2023 (Dec 21);186(26):5840-5858.e5836.

Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a CGG STR represses FMR1 via local DNA methylation. Here, we find megabase-scale H3K9me3 domains on autosomes and encompassing FMR1 on the X chromosome in FXS patient-derived iPSCs, iPSC-derived neural progenitors, EBV-transformed lymphoblasts, and brain tissue with mutation-length CGG expansion. H3K9me3 domains connect via inter-chromosomal interactions and demarcate severe misfolding of TADs and loops. They harbor long synaptic genes replicating at the end of S phase, replication-stress-induced double-strand breaks, and STRs prone to stepwise somatic instability. CRISPR engineering of the mutation-length CGG to premutation length reverses H3K9me3 on the X chromosome and multiple autosomes, refolds TADs, and restores gene expression. H3K9me3 domains can also arise in normal-length iPSCs created with perturbations linked to genome instability, suggesting their relevance beyond FXS. Our results reveal Mb-scale heterochromatinization and trans interactions among loci susceptible to instability.

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16. Methods In Medicine CAM. Retracted: Brain Network for Exploring the Change of Brain Neurotransmitter 5-Hydroxytryptamine of Autism Children by Resting-State EEG. Comput Math Methods Med;2023;2023:9865892.

[This retracts the article DOI: 10.1155/2022/5451277.].

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17. Montenegro ACA, Silva AGS, Queiroga B, Lima RA, Xavier I. Method for Developing Communication Skills in Autism – DHACA: appearance and content validation. Codas;2023;36(3):e20230138.

PURPOSE: To validate the appearance and content of the DHACA method to develop communication skills in autism. METHODS: This qualitative and quantitative validation study included 10 speech-language-hearing judges with expertise in alternative communication. The judges received the communication book, the description of the principles, skills, and strategies in the DHACA method, and a form with items for them to appraise the appearance and content of the method. The validity was calculated with the content validity index. RESULTS: The response analysis made it possible to calculate the degree of agreement between judges and develop the new instrument version. The calculation of the content validity index revealed excellent content validity. The judges made suggestions regarding the content of the communication book, texts regarding the participation of communication partners and modeling, using cues, and communicative skills. CONCLUSION: The degree of agreement between judges ensured the validation of the appearance and content of the DHACA method, considering the items alone and the whole instrument. Hence, its use can be recommended for speech-language-hearing clinical practice.

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18. Morel C, Paoli J, Emond C, Debaugnies F, Hardy EM, Creta M, Montagne M, Borde P, Nieuwenhuyse AV, Duca RC, Schroeder H, Grova N. Pharmacokinetic characterisation of a valproate Autism Spectrum Disorder rat model in a context of co-exposure to α-Hexabromocyclododecane. Environ Toxicol Pharmacol;2023 (Dec 19);105:104343.

Assessing the role of α-hexabromocyclododecane α-HBCDD as a factor of susceptibility for Autism Spectrum disorders by using valproic acid-exposed rat model (VPA) required characterizing VPA pharmacokinetic in the context of α-HBCDD-co-exposure in non-pregnant and pregnant rats. The animals were exposed to α-HBCDD by gavage (100 ng/kg/day) for 12 days. This was followed by a single intraperitoneal dose of VPA (500 mg/kg) or a daily oral dose of VPA (500 mg/kg) for 3 days. Exposure to α-HBCDD did not affect the pharmacokinetics of VPA in pregnant or non-pregnant rats. Surprisingly, VPA administration altered the pharmacokinetics of α-HBCDD. VPA also triggered higher foetal toxicity and lethality with the PO than IP route. α-HBCDD did not aggravate the embryotoxicity observed with VPA, regardless of the route of exposure. Based on this evidence, a single administration of 500 mg/kg IP is the most suitable VPA model to investigate α-HBCDD co-exposure.

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19. Pan YD, Zhang Y, Zheng WY, Zhu MZ, Li HY, Ouyang WJ, Wen QQ, Zhu XH. Intermittent Hypobaric Hypoxia Ameliorates Autistic-Like Phenotypes in Mice. J Neurosci;2023 (Dec 19)

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and stereotyped behaviors. Although major advances in basic research on autism have been achieved in the past decade, and behavioral interventions can mitigate the difficulties that individuals with autism experience, little is known about the many fundamental issues of the interventions, and no specific medication has demonstrated efficiency for the core symptoms of ASD. Intermittent hypobaric hypoxia (IHH) is characterized by repeated exposure to lowered atmospheric pressure and oxygen levels, which triggers multiple physiological adaptations in the body. Here, using two mouse models of ASD, male Shank3B (-/-) and Fmr1 (-/y) mice, we found that IHH training at an altitude of 5000 m for 4 h per day, for 14 consecutive days, ameliorated autistic-like behaviors. Moreover, IHH training enhanced hypoxia inducible factor (HIF) 1α signaling in the dorsal raphe nucleus (DRN) and activated the DRN serotonergic neurons. Infusion of cobalt chloride into the DRN, to mimic IHH in increasing HIF1α expression or genetically knockdown PHD2 to upregulate HIF1α expression in the DRN serotonergic neurons, alleviated autistic-like behaviors in Shank3B (-/-) mice. In contrast, downregulation of HIF1α in DRN serotonergic neurons induced compulsive behaviors. Furthermore, upregulating HIF1α in DRN serotonergic neurons increased the firing rates of these neurons, whereas downregulation of HIF1α in DRN serotonergic neurons decreased their firing rates. These findings suggest that IHH activated DRN serotonergic neurons via upregulation of HIF1α signaling, and thus ameliorated autistic-like phenotypes, providing a novel therapeutic option for ASD.Significance Statement Autism spectrum disorder (ASD) affects more than 78 million individuals worldwide resulting in heavy social and economic burdens. However, no specific medication is effective for the core symptoms of ASD. Intermittent hypobaric hypoxia (IHH), a form of « living high-training low, » has been used to train pilots and mountaineers. Here, we found that IHH at an altitude of 5000 m for 4 h per day, for 14 consecutive days ameliorated autistic-like behavior in male Shank3B (-/-) and Fmr1 (-/y) mice. Moreover, IHH training increased the activation of serotonergic neurons in the dorsal raphe nucleus via upregulating HIF1α signaling, which contributes to the anti-autistic-like effect of IHH. These findings highlight the therapeutic potential of IHH in the treatment of ASD.

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20. Pitt AR, Osabuohien LW, Brady NC. Phonemic Feature Scoring as a Tool for Progress Monitoring During Language Interventions for Children With Autism and Minimal Verbal Skills. Am J Speech Lang Pathol;2023 (Dec 20):1-17.

PURPOSE: An increasing number of studies focus on verbal treatments for children with autism and minimal verbal skills. However, clinical tools for progress monitoring during interventions are lacking. The aim of this clinical focus article is to provide illustrations on the utility of a phonemic feature scoring system as a progress-monitoring tool, focusing on benefits and limitations as well as indications for use. METHOD: Current practices for progress monitoring during language interventions with children with autism and minimal verbal skills are reviewed. A phonemic feature scoring tool is provided to aid clinicians in assessing the accuracy and consistency of expressive word productions. The authors illustrate the use of phonemic feature scoring as a progress-monitoring tool for two children with autism and minimal verbal skills, contrasting the phonemic feature scoring system to correct/incorrect, phoneme-level, and whole-word scoring. RESULTS: Case 1 demonstrates a scenario where the child’s speech intelligibility is low and clinical use of the phonemic feature scoring system captures discrete changes in speech production progress not represented by correct/incorrect, phoneme-level, and whole-word scoring. However, Case 2 represents a situation where once a child’s speech intelligibility improves, the phonemic feature scoring system is no longer needed, and correct/incorrect scoring may be sufficient. CONCLUSION: The phonemic feature scoring system allows clinicians to track phonemic feature changes in word productions and provides detailed progress monitoring information, leading to adaptations of the intervention for each individual.

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21. Rudaks LI, Yeow D, Kumar KR. Expert commentary for fragile X premutation mimicking late onset hereditary spastic paraplegia. Parkinsonism Relat Disord;2023 (Dec 21):105969.

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22. Singh M, Saxena S, Mohan KN. DNMT1 downregulation as well as its overexpression distinctly affect mostly overlapping genes implicated in schizophrenia, autism spectrum, epilepsy, and bipolar disorders. Front Mol Neurosci;2023;16:1275697.

Data on schizophrenia (SZ), epilepsy (EPD) and bipolar disorders (BPD) suggested an association of DNMT1 overexpression whereas certain variants of the gene were predicted to result in its increased expression in autism spectrum disorder (ASD). In addition, loss of DNMT1 in frontal cortex resulted in behavioral abnormalities in mice. Here we investigated the effects of increased as well as lack of DNMT1 expression using Dnmt1(tet/tet) neurons as a model for abnormal neurogenesis and 10,861 genes showing transcript level dysregulation in datasets from the four disorders. In case of overexpression, 3,211 (∼ 30%) genes were dysregulated, affecting pathways involved in neurogenesis, semaphorin signaling, ephrin receptor activity, etc. A disproportionately higher proportion of dysregulated genes were associated with epilepsy. When transcriptome data of Dnmt1(tet/tet) neurons treated with doxycycline that downregulated DNMT1 was used, 3,356 genes (∼31%) were dysregulated with a significant proportion involved in pathways similar to those in untreated cells. Both conditions resulted in ∼68% of dysregulated genes wherein a majority showed similar patterns of transcript level changes. Among the genes with transcripts returning to normal levels, ribosome assembly/biogenesis was most significant whereas in absence of DNMT1, a new set of 903 genes became dysregulated and are involved in similar pathways as mentioned above. These findings provide support for overexpression of DNMT1 as well as its downregulation as risk factor for the four disorders and that its levels within a tight range are essential for normal neurodevelopment/mental health.

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23. Soueid J, Hamze Z, Bedran J, Chahrour M, Boustany RM. A novel autism-associated UBLCP1 mutation impacts proteasome regulation/activity. Transl Psychiatry;2023 (Dec 21);13(1):404.

The landscape of autism spectrum disorder (ASD) in Lebanon is unique because of high rates of consanguinity, shared ancestry, and increased remote consanguinity. ASD prevalence in Lebanon is 1 in 68 with a male-to-female ratio of 2:1. This study aims to investigate the impact of an inherited deletion in UBLCP1 (Ubiquitin-Like Domain-Containing CTD Phosphatase 1) on the ubiquitin-proteasome system (UPS) and proteolysis. Whole exome sequencing in a Lebanese family with ASD without pathogenic copy number variations (CNVs) uncovered a deletion in UBLCP1. Functional evaluation of the identified variant is described in fibroblasts from the affected. The deletion in UBLCP1 exon 10 (g.158,710,261CAAAG > C) generates a premature stop codon interrupting the phosphatase domain and is predicted as pathogenic. It is absent from databases of normal variation worldwide and in Lebanon. Wild-type UBLCP1 is widely expressed in mouse brains. The mutation results in decreased UBLCP1 protein expression in patient-derived fibroblasts from the autistic patient compared to controls. The truncated UBLCP1 protein results in increased proteasome activity decreased ubiquitinated protein levels, and downregulation in expression of other proteasome subunits in samples from the affected compared to controls. Inhibition of the proteasome by using MG132 in proband cells reverses alterations in gene expression due to the restoration of protein levels of the common transcription factor, NRF1. Finally, treatment with gentamicin, which promotes premature termination codon read-through, restores UBLCP1 expression and function. Discovery of an ASD-linked mutation in UBLCP1 leading to overactivation of cell proteolysis is reported. This, in turn, leads to dysregulation of proteasome subunit transcript levels as a compensatory response.

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24. Tirkkonen SK, Vespermann D. Incels, autism, and hopelessness: affective incorporation of online interaction as a challenge for phenomenological psychopathology. Front Psychol;2023;14:1235929.

Recent research has drawn attention to the prevalence of self-reported autism within online communities of involuntary celibates (incels). These studies suggest that some individuals with autism may be particularly vulnerable to the impact of incel forums and the hopelessness they generate. However, a more precise description of the experiential connection between inceldom, self-reported autism, and hopelessness has remained unarticulated. Therefore, this article combines empirical studies on the incel community with phenomenological and embodiment approaches to autism, hopelessness, and online affectivity. We analyze three interrelated aspects of online interactions in incel communities – worldview, bodily self-relation, and mutual dismissals – and examine how these elements contribute to the consolidation of the loss of significant life possibilities. By investigating the potential negative influence of specific online environments on affective dispositions, our approach contributes to the debate on current challenges to « situate » phenomenological psychopathology.

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25. Whelan TP, Daly E, Puts NA, Malievskaia E, Murphy DGM, McAlonan GM. Editorial Perspective: Bridging the translational neuroscience gap in autism – development of the ‘shiftability’ paradigm. J Child Psychol Psychiatry;2023 (Dec 21)

Clinical trials of pharmacological candidates targeting the core features of autism have largely failed. This is despite evidence linking differences in multiple neurochemical systems to brain function in autism. While this has in part been explained by the heterogeneity of the autistic population, the field has largely relied upon association studies to link brain chemistry to function. The only way to directly establish that a neurotransmitter or neuromodulator is involved in a candidate brain function is to change it and observe a shift in that function. This experimental approach dominates preclinical neuroscience, but not human studies. There is little direct experimental evidence describing how neurochemical systems modulate information processing in the living human brain. Thus, our understanding of how neurochemical differences contribute to neurodiversity is limited, impeding our ability to translate findings from animal studies into humans. Here, we introduce our ‘shiftability’ paradigm, an approach to bridge the translational gap in autism research. We provide an overview of the guiding principles and methodologies we use to directly test the hypothesis that neurochemical systems function differently in autistic and non-autistic individuals.

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26. Wieting J, Jahn K, Bleich S, Frieling H, Deest M. A targeted long-read sequencing approach questions the association of OXTR methylation with high-functioning autism. Clin Epigenetics;2023 (Dec 20);15(1):195.

BACKGROUND: DNA sequence variation and altered epigenetic regulation of the oxytocin receptor gene (OXTR) have been implicated in autism and autistic-like behaviors. While previous studies have examined subsegments of OXTR, nanopore Cas9-targeted sequencing (nCATS) allows deep characterization of entire genes with simultaneous assessment of epigenetic 5-methylcytosine (5mC) modification and without the need for prior DNA amplification or bisulfite conversion. This pilot study uses an nCATS approach to sequence the entire OXTR gene and its regulatory construct and screen for 5mC modification to compare results between individuals with high-functioning autism (HFA) and neurotypical controls (NC). METHODS: Using DNA extracted from peripheral blood, OXTR (Hg38, chr3: 8750381-8770434, 20,054 base pairs) was analyzed by nCATS. 5mC modification probabilities were calculated and visualized across the gene and differential methylation analysis was performed. RESULTS: Twenty adults with HFA (10 males, 10 females) and 20 age- and sex-matched NC (± 5 years) were included. There were no apparent group differences in the entire OXTR gene sequence, except for the intron variant rs918316, which was clustered in the HFA group. However, differential methylation analysis did not reveal a single significant group-dependent differentially methylated site among the 412 CpG sites captured. LIMITATIONS: Limitations of this study include the small number of samples due to the pilot nature of the study, which particularly limits the relevance of the sequence variants found. It should also be noted that the use of peripheral blood material limits the ability to draw conclusions about central processes. CONCLUSIONS: Previous findings of autism-associated OXTR epigenetic alterations were not reproducible with our method. In our opinion, this may lead to a reconsideration of the relevance of altered methylation at individual OXTR CpG positions in autism research. However, given the pilot nature of the study, these results need to be replicated in independent cohorts and with larger sample sizes.

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